Substituted tetrahydropyridine compound and application thereof

Abstract

The invention discloses a substituted tetrahydropyridine compound and application thereof, and belongs to the technical field of chemical medicines. The substituted tetrahydropyridine 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

Substituted tetrahydropyridine compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of chemical medicine and relates to a class of substituted tetrahydropyridine 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 object of the present invention is to provide a class of substituted tetrahydropyridine compounds and uses thereof, so as 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 II or a pharmaceutically acceptable form thereof, wherein the structure of Formula II is as follows:

[0008] The compound of formula I or a pharmaceutically acceptable form thereof is characterized in that: the structure of formula I is as follows:

[0009] in:

[0010] R1 is selected from halogen, C 1-4 Alkyl, C 1-4Fluorinated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl or C 2-4 alkenyl;

[0011] X1 is selected from N or CR 5a , X2 is selected from N or CR 5b , X3 is selected from N or CR 5c ;

[0012] R6 is selected from hydrogen or halogen;

[0013] 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;

[0014] R 9a Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered fluorinated cycloalkyl;

[0015] R 9c is selected from hydrogen or halogen;

[0016] R2 is selected from hydrogen or C 1-4 alkyl;

[0017] R 3a Selected from halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl or 3-6 membered cycloalkyl; R 3b Selected from hydrogen, halogen or C 1-4 alkyl;

[0018] R 3c Selected from hydrogen or C 1-4 alkyl;

[0019] 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;

[0020] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0021] In some preferred embodiments of the present invention, R1 is selected from chlorine, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or vinyl.

[0022] In some preferred embodiments of the present invention, R6 is selected from hydrogen or fluorine.

[0023] In some preferred embodiments of the present invention, R7 is selected from methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

[0024] In some preferred embodiments of the present invention, R 9a is selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

[0025] In some preferred embodiments of the present invention, R 9c is selected from hydrogen or fluorine.

[0026] In some preferred embodiments of the present invention, R2 is selected from hydrogen or methyl.

[0027] In some preferred embodiments of the present invention, R 3a is selected from fluorine, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R 3b is selected from hydrogen, fluorine or methyl.

[0028] In some preferred embodiments of the present invention, R 3c is selected from hydrogen or methyl.

[0029] In some preferred embodiments of the present invention, 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.

[0030] In some preferred embodiments of the present invention, the structural unit Selected from the following structures:

[0031] In some preferred embodiments of the present invention, the structural unit Selected from the following structures:

[0032] In some preferred embodiments of the present invention, the structural unit Selected from the following structures:

[0033] In some preferred embodiments of the present invention, the structural unit Selected from the following structures:

[0034] In some preferred embodiments of the present invention, the structural unit Selected from the following structures:

[0035] In some preferred embodiments of the present invention, the compound has a structure described by Formula II-1, Formula II-2 or Formula II-3:

[0036] In some preferred embodiments of the present invention, the compound has a structure described by Formula III-1, Formula III-2, Formula III-3 or Formula III-4:

[0037] The present invention also provides some specific compounds among the compounds shown, the structures of which are as follows:

[0038] The present invention also provides some specific compounds among the compounds shown, the structures of which are as follows:

[0039] The present invention also provides some specific compounds, the structures of which are as follows:

[0040] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites or prodrugs as active ingredients, supplemented with a pharmaceutically acceptable carrier.

[0041] 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 of the aforementioned compounds or pharmaceutically acceptable forms thereof, or mixtures thereof, with one or more pharmaceutically acceptable carriers.

[0042] 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).

[0043] 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.

[0044] 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.

[0045] The present invention also relates to a pharmaceutical preparation comprising any of the aforementioned compounds or pharmaceutically acceptable forms 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 semisolid preparation, a liquid preparation, or a gaseous preparation.

[0046] 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 a package. 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, the first therapeutic agent comprising: any of the compounds described above, 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.

[0047] 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.

[0048] 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.

[0049] 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).

[0050] In a third aspect, the present invention provides the use of the aforementioned compounds, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical compositions of the present invention in the preparation of drugs for preventing or treating PARP1 enzyme-related diseases.

[0051] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases, comprising administering the aforementioned compound or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.

[0052] The present invention provides the aforementioned compound or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention, for use in preventing or treating PARP1 enzyme-related diseases.

[0053] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases in combination with the aforementioned compound 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.

[0054] In some embodiments, the PARP1 enzyme-related disease is a disease that is sensitive or responsive to PARP1 enzyme inhibition.

[0055] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder.

[0056] In some preferred embodiments, the oncological disorder is deficient in a HR-dependent DNA DSB repair pathway.

[0057] 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.

[0058] In some preferred embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

[0059] 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 carcinoma) 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.

[0060] In some preferred embodiments, the PARP1 enzyme-related disease is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0061] 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.

[0062] Beneficial effects of the present invention:

[0063] 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.

[0064] Definition of terms:

[0065] 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."

[0066] 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.

[0067] 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.

[0068] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0069] In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. 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, the C1-4 in "C1-4 alkyl" refers to a group containing 1, 2, 3, or 4 carbon atoms in a linear or branched form.

[0070] 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.

[0071] 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.

[0072] 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 14C); 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).

[0073] 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.

[0074] 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%).

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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 GW H Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and

[0079] A. J. Boulton, Eds., Academic Press).

[0080] 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.

[0081] 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)).

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] FIG1 is a graph showing the changes in tumor volume in the MDA-MB-436 nude mouse model after administration of Compound 2.

[0089] Figure 2 is a ball-and-stick diagram of the molecular structure and atomic numbers of compound 2 in the crystal.

[0090] Figure 3 is a ball-and-stick diagram of the molecular structure and atomic number of compound 21 in the crystal. DETAILED DESCRIPTION

[0091] 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.

[0092] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0093] Table 1 Abbreviations and their meanings in the present invention

[0094] 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 -6 The units are given in ppm.

[0095] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0096] 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).

[0097] 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.

[0098] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0099] 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.

[0100] Intermediate preparation

[0101] Intermediate INT1: 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0102] 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.

[0103] 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.

[0104] 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; 1H 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).

[0105] 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.

[0106] 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).

[0107] 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.

[0108] Intermediate INT2: 7-(chloromethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0109] 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.

[0110] 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 stirred at room temperature for 10 min. Finally, a THF solution of INT1b (10.2 g, 45.4 mmol) was slowly added at -78°C. After addition, the mixture was stirred at -78°C for 1 h. After LC-MS confirmed the completion of the reaction, 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Example 1: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0115] Step 1: Weigh compound 1a (50 g, 235 mmol), add 300 ml of tetrahydrofuran, replace nitrogen, cool to -78 ° C, add lithium diisopropylamide (141 mL, 282 mmol) dropwise, stir for 30 minutes, add N-phenylbis(trifluoromethanesulfonyl)imide (92 g, 258 mmol) dissolved in 300 mL of tetrahydrofuran dropwise, warm to room temperature and react for 2 hours. After TLC detection, the reaction is complete, saturated ammonium chloride aqueous solution is added to quench, and the mixture is extracted three times with ethyl acetate. After the organic phases are combined, they are dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography gives compound 1b (78 g, colorless liquid).

[0116] Step 2: Compound 1b (78 g, 226 mmol), 2-methylpyridinium-5-boronate 1c (65 g, 249 mmol), Pd(dppf)Cl2 (8.2 g, 11 mmol) and potassium carbonate (62 g, 452 mmol) were added to a mixed solvent of 400 ml of dioxane and 40 ml of water. The nitrogen atmosphere was then replaced and the mixture was reacted at 80°C under nitrogen protection for 4 hours. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 300 ml of ethyl acetate and 200 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 1d (35 g, white solid); LC-MS: ESI [M+H] + =333.4.

[0117] Step 3: 1d (2 g, 6 mmol), methylamine aqueous solution (1.8 mL, 24 mmol), and anhydrous methanol (15 mL) were added to a 100 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 1e (1.76 g, white solid); LC-MS: ESI [M+H] + =332.4.

[0118] Step 4: Compound 1e (1.76 g, 5.3 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 14 ml of a 4 mol / L hydrochloric acid dioxane solution. The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to obtain compound 1f (2.1 g, white solid); LC-MS: ESI [M+H] + =232.3.

[0119] Step 5: Compound 1f (2.7 g, 9.0 mmol), INT1 (2.0 g, 9.0 mmol), N,N-diisopropylethylamine (6.2 mL, 36.0 mmol) and potassium iodide (0.15 g, 0.9 mmol) were added to 20 mL of anhydrous acetonitrile and stirred at 80°C for 2 hours. After the reaction was completed as monitored by TLC, 10 mL of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 1 (2.82 g, light yellow solid); LC-MS: ESI [M+H] + =418.5; 1H NMR (400MHz, CDCl3) δ11.83(s,1H),8.57(d,J=1.6Hz,1H),8.51(d,J=1.8Hz,1H),8.16(t,J=6.5Hz ,1H),7.98(d,J=5.1Hz,1H),7.87(s,1H),7.76(dd,J=8.0,2.1Hz,2H),6.01(t,J=3.2Hz,1H),3.77( dd,J=34.5,13.9Hz,2H),3.39–3.26(m,1H),3.14(d,J=17.1Hz,1H),3.05(t,J=5.7Hz,3H),2.90(s, 1H), 2.79–2.68 (m, 3H), 2.59 (dd, J=11.1, 4.0Hz, 1H), 1.31 (q, J=7.5Hz, 3H), 1.06 (t, J=6.6Hz, 3H).

[0120] Example 2: (S)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide and Example 3: (R)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0121] Compound 1 was chiral resolved to give Compound 2 and Compound 3. The resolution method was as follows: Instrument: Waters 150Prep-SFC, Column model: Chiralcel AD Column, Mobile phase A: carbon dioxide, Mobile phase B: 0.1% ammonia in isopropanol, Gradient: 70% mobile phase B, Pressure: 100 bar, Flow rate: 100 mL / min.

[0122] The absolute configuration of compound 2 was determined by X-ray diffractometer using a Bruker D8VENTURE double microfocus single crystal X-ray diffractometer at an ambient temperature of 193 K and an enhanced Cu light source with a wavelength of Through single crystal structure analysis, the following conclusions were drawn: the single crystal of the sample molecule belongs to the triclinic system, P1 space group; there is no characteristic symmetry element in the crystal; one unit cell contains 2 compounds and 2 molecules; the 2 compounds and 2 molecules in the unit cell include 2 chiral carbon atoms (black marks), and the absolute configuration of the chiral carbon atoms is C12 (S) and C39 (S).

[0123] Example 4: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3',3'-trimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0124] Step 1: Compound 4a (1.0 g, 3.0 mmol), 2-methylformate-5-bromopyridine 4b (0.65 g, 3.0 mmol), Pd(dppf)Cl2 (0.2 g, 0.3 mmol) and potassium carbonate (1.2 g, 9.0 mmol) were added to a mixed solvent of 30 ml of dioxane and 3 ml of water. The nitrogen atmosphere was then replaced and the mixture was reacted at 80°C for 3 hours under nitrogen protection. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 30 ml of ethyl acetate and 20 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 4c (0.4 g, white solid); LC-MS: ESI [M+H] + =347.3.

[0125] Step 3: 4c (0.4 g, 1.2 mmol), methylamine aqueous solution (0.4 mL, 4.8 mmol), and anhydrous methanol (15 mL) were added to a 50 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 4d (0.3 g, white solid); LC-MS: ESI [M+H] + =346.4.

[0126] Step 4: Compound 4d (0.3 g, 0.9 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 1 ml of a 4 mol / L hydrochloric acid dioxane solution. The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to obtain compound 4e (0.2 g, white solid); LC-MS: ESI [M+H] + =246.3.

[0127] Step 5: Compound 4e (0.1 g, 0.3 mmol), INT1 (67 mg, 0.3 mmol), N,N-diisopropylethylamine (160 mg, 1.2 mmol) and potassium iodide (5 mg, 0.03 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85 ° C for 2 hours. After the reaction was completed as monitored by TLC, 10 ml of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate the solid, which was filtered and dried to obtain compound 4 (42 mg, light yellow solid); LC-MS: ESI [M+H]+ =432.5; 1 H NMR (400MHz, DMSO) δ11.93(s,1H),8.74(d,J=4.9Hz,1H),8.44(d,J=1.6Hz,1H),8.39 (d,J=1.7Hz,1H),7.98(d,J=8.0Hz,1H),7.81(dd,J=8.1,2.1Hz,1H),7.76(s,1H),7. 70(s,1H),5.61(t,J=3.2Hz,1H),3.72(s,2H),3.12(d,J=3.1Hz,2H),2.82(d,J=4.8H z, 3H), 2.59–2.53 (m, 2H), 2.36 (s, 2H), 1.19 (t, J = 7.4Hz, 3H), 1.03 (d, J = 9.2Hz, 6H).

[0128] Example 5: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-fluoro-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0129] Step 1: Compound 5a (2.0 g, 9.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.2 g, 27.6 mmol) were weighed and added to 30 ml of tetrahydrofuran, the nitrogen was replaced, the temperature was lowered to -20°C, and perfluorobutylsulfonyl fluoride (8.3 g, 27.6 mmol) dissolved in 30 mL of tetrahydrofuran was added dropwise after stirring for 30 minutes. The reaction was allowed to proceed at -20°C for 30 minutes. After TLC detection, the reaction was completed, and saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography to obtain compound 5b (1.1 g, colorless liquid).

[0130] Step 2: Compound 5b (1.1 g, 2.1 mmol), 2-methylpyridinium-5-boronate 1c (0.1 g, 0.7 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol) and potassium phosphate (0.3 g, 1.4 mmol) were added to a mixed solvent of 30 ml of dioxane and 3 ml of water, and then the nitrogen atmosphere was replaced. The reaction was carried out at 80°C under nitrogen protection for 2 hours. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 30 ml of ethyl acetate and 20 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 5c (180 mg, white solid); LC-MS: ESI [M+H]+ =337.3.

[0131] Step 3: 5c (180 mg, 0.5 mmol), methylamine aqueous solution (0.2 mL, 2.7 mmol), and anhydrous methanol (5 mL) were added to a 25 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 5d (0.16 g, yellow solid); LC-MS: ESI [M+H] + =336.3.

[0132] Step 4: Compound 5d (0.16 g, 0.48 mmol) was added to 5 ml of anhydrous methanol, followed by the addition of 1 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to obtain compound 5e (0.15 g, white solid); LC-MS: ESI [M+H] + =236.2.

[0133] Step 5: Compound 5e (0.15 g, 0.5 mmol), INT1 (0.11 g, 0.5 mmol), N,N-diisopropylethylamine (0.32 g, 2.5 mmol) and potassium iodide (8 mg, 0.05 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 80 ° C for 2 hours. After the reaction was completed as monitored by TLC, 10 ml of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 5 (80 mg, white solid); LC-MS: ESI [M+H] + =422.5; 1 H NMR (400MHz, CDCl3) δ11.28 (s, 1H), 8.66 (d, J = 2.1Hz, 1H), 8.54 (d, J = 1.7Hz, 1H),8.19(d,J=8.2Hz,1H),7.98(d,J=5.0Hz,1H),7.94–7.90(m,1H),7.86(s, 1H),7.73(d,J=1.0Hz,1H),6.56–6.47(m,1H),5.38(d,J=48.9Hz,1H),3.93–3 .78(m,2H),3.54(ddd,J=17.9,7.7,4.7Hz,1H),3.34–3.22(m,1H),3.20–3.07 (m,1H),3.06(dd,J=9.0,5.1Hz,3H),2.84–2.68(m,3H),1.30(t,J=7.4Hz,3H).

[0134] Example 6: (S)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-fluoro-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide and Example 7: (R)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-fluoro-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0135] Compound 5 was subjected to chiral separation to give compounds 6 and 7. The separation method was as follows: Instrument: Waters 150Prep-SFC, Column model: Chiralcel AD Column, Mobile phase A: carbon dioxide, Mobile phase B: 0.1% ammonia in isopropanol, Gradient: 70% mobile phase B, Pressure: 100 bar, Flow rate: 100 mL / min.

[0136] Example 8: 3'-ethyl-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

[0137] Step 1: Weigh compound 8a (2.0 g, 8.8 mmol), add 30 ml of tetrahydrofuran, replace nitrogen, cool to -78 ° C, add lithium diisopropylamide (5.3 mL, 10.6 mmol) dropwise, stir for 30 minutes, add N-phenylbis(trifluoromethanesulfonyl)imide (3.5 g, 9.7 mmol) dissolved in 30 mL of tetrahydrofuran dropwise, warm to room temperature and react for 2 hours. After TLC detection, the reaction is complete, saturated ammonium chloride aqueous solution is added to quench, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography gives compound 8b (2.3 g, colorless liquid).

[0138] Step 2: Compound 8b (2.3 g, 6.4 mmol), 2-methylpyridinium-5-boronate 1c (1.8 g, 7 mmol), Pd(dppf)Cl2 (0.4 g, 0.6 mmol) and potassium carbonate (1.7 g, 12.4 mmol) were added to a mixed solvent of 40 ml of dioxane and 4 ml of water, and then the nitrogen atmosphere was replaced. The reaction was carried out at 80°C under nitrogen protection for 2 hours. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 30 ml of ethyl acetate and 20 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 8c (2.1 g, yellow solid); LC-MS: ESI [M+H] + =347.4.

[0139] Step 3: 8c (2 g, 5.7 mmol), methylamine aqueous solution (1.8 mL, 24 mmol), and anhydrous methanol (15 mL) were added to a 100 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 8d (1.9 g, yellow solid); LC-MS: ESI [M+H] + =346.4.

[0140] Step 4: Compound 8d (1.9 g, 5.5 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 14 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to obtain compound 8e (1.8 g, light yellow solid); LC-MS: ESI [M+H] + =246.3.

[0141] Step 5: Compound 8e (0.3 g, 0.9 mmol), INT1 (0.2 g, 0.9 mmol), N,N-diisopropylethylamine (0.6 mL, 3.6 mmol) and potassium iodide (15 mg, 0.09 mmol) were added to 10 mL of anhydrous acetonitrile and stirred at 80°C for 2 hours. After the reaction was completed as monitored by TLC, 10 mL of saturated sodium bicarbonate solution was added, and 20 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 8 (0.28 g, light yellow solid); LC-MS: ESI [M+H] + =432.5; 1H NMR (400MHz, CDCl3) δ12.09(s,1H),8.57(d,J=1.6Hz,1H),8.51(d,J=1.8Hz,1H),8.15(d,J=8.1Hz,1H) ,7.98(q,J=4.7Hz,1H),7.88(s,1H),7.75(dd,J=8.1,2.0Hz,2H),6.03(t,J=3.3Hz,1H),3.86–3.68(m, 2H),3.36(dd,J=17.3,3.9Hz,1H),3.14–3.06(m,1H),3.04(d,J=5.1Hz,3H),2.81(d,J=8.1Hz,1H),2.7 8–2.69(m,2H),2.66–2.55(m,2H),1.56(d,J=7.3Hz,2H),1.31(t,J=7.4Hz,3H),0.76(t,J=7.4Hz,3H).

[0142] Example 9: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3',3'-difluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0143] Step 1: Compound 9a (0.5 g, 2.1 mmol) was weighed, 15 ml of tetrahydrofuran was added, the nitrogen atmosphere was replaced, the temperature was lowered to -78°C, lithium diisopropylamide (1.25 mL, 2.5 mmol) was added dropwise, and N-phenylbis(trifluoromethanesulfonyl)imide (0.8 g, 2.3 mmol) dissolved in 20 mL of tetrahydrofuran was added dropwise after stirring for 30 minutes. The reaction was warmed to room temperature for 2 hours. After TLC detection, the reaction was completed, saturated ammonium chloride aqueous solution was added to quench, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography to obtain compound 9b (0.3 g, light yellow liquid).

[0144] Step 2: Compound 9b (0.3 g, 0.8 mmol), 2-methylpyridinium formate-5-boronate 1c (0.16 g, 0.9 mmol), Pd(dppf)Cl2 (95 mg, 0.08 mmol) and potassium carbonate (0.2 g, 1.6 mmol) were added to a mixed solvent of 18 ml of dioxane and 3 ml of water, and then the nitrogen atmosphere was replaced. The reaction was carried out at 80°C under nitrogen protection for 2 hours. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 30 ml of ethyl acetate and 200 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 9c (0.31 g, light yellow solid); LC-MS: ESI [M+H] + =355.3.

[0145] Step 3: 9c (0.3 g, 0.8 mmol), methylamine aqueous solution (0.24 mL, 3.2 mmol), and anhydrous methanol (8 mL) were added to a 25 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 9d (0.3 g, yellow solid); LC-MS: ESI [M+H] + =354.3.

[0146] Step 4: Compound 9d (0.3 g, 0.8 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 2 ml of a 4 mol / L hydrochloric acid dioxane solution. The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to obtain compound 9e (0.3 g, yellow solid); LC-MS: ESI [M+H] + =254.3.

[0147] Step 5: Compound 9e (0.3 g, 0.9 mmol), INT1 (0.2 g, 0.9 mmol), N,N-diisopropylethylamine (0.6 g, 4.6 mmol) and potassium iodide (15 mg, 0.09 mmol) were added to 20 ml of anhydrous acetonitrile and stirred at 80°C for 2 hours. After the reaction was completed as monitored by TLC, 10 ml of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 9 (0.2 g, yellow solid); LC-MS: ESI [M+H] + =440.4; 1H NMR (400MHz, DMSO) δ11.89(s,1H),8.77(t,J=4.8Hz,1H),8.71(s,1H),8.43(d,J=1.6Hz,1H),8.11–7.99(m,2H),7.95(s,2H),7.77(s,1H ),7.66(s,1H),6.86(s,1H),3.87(s,2H),3.09(dd,J=20.2,8.3Hz,2H),2.82(d,J=4.8Hz,3H),2.55(dd,J=14.3,6.9Hz,2H),1.19(s,3H).

[0148] Example 10: N-(2,2-difluoroethyl)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0149] Step 1: 1d (1.5 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. 3 x 25 mL of EA was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent to afford product 10a (660 mg, light yellow solid).

[0150] Step 2: Compound 10a (0.2 g, 0.6 mmol), 2,2-difluoroethylamine (97 mg, 1.2 mmol), N-methylmorpholine (0.24 g, 2.4 mmol), 1-hydroxybenzotriazole (0.16 g, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol) were weighed into a reaction flask, 5 mL of N,N-dimethylformamide was added, and the mixture was reacted at room temperature overnight. After the reaction was completed as monitored by TLC, water and ethyl acetate were added for extraction. The organic phases were combined, dried, rotary evaporated, and purified by column chromatography to obtain compound 10b (0.16 g, yellow solid); LC-MS: ESI [M+H] + =382.4.

[0151] Step 3: Compound 10b (0.16 g, 0.4 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 0.4 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to give compound 10c (0.1 g, yellow solid); LC-MS: ESI [M+H]+ =282.3.

[0152] Step 4: Compound 10c (0.1 g, 0.4 mmol), INT1 (86 mg, 0.4 mmol), N,N-diisopropylethylamine (0.2 g, 1.6 mmol) and potassium iodide (5 mg, 0.04 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. 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 10 (65 mg, white solid); LC-MS: ESI [M+H] + =468.5; 1 H NMR (400MHz, CDCl3) δ11.26(s,1H),8.55(dd,J=6.7,1.7Hz,2H),8.25(t,J=6.5Hz,1H),8.14(d ,J=8.1Hz,1H),7.87(s,1H),7.78(dd,J=8.2,2.2Hz,1H),7.69(s,1H),6.12-5.78(m,1H),6.03( t,J=3.3Hz,1H),3.93-3.68(m,4H),3.34(d,J=14.7Hz,1H),3.14(d,J=17.2Hz,1H),2.91(s,1H) ,2.79-2.68(m,3H),2.59(dd,J=11.1,4.1Hz,1H),1.31(t,J=7.4Hz,3H),1.06(d,J=6.9Hz,3H).

[0153] Example 11: N-cyclopropyl-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0154] Step 1: Compound 10a (0.55 g, 1.7 mmol), cyclopropylamine (0.2 g, 3.5 mmol), N-methylmorpholine (0.7 g, 6.9 mmol), 1-hydroxybenzotriazole (0.47 g, 3.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.66 g, 3.5 mmol) were weighed into a reaction flask, 5 mL of N,N-dimethylformamide was added, and the mixture was reacted at room temperature overnight. After the reaction was completed as monitored by TLC, water was added and extracted with ethyl acetate. The organic phases were combined and dried, rotary evaporated, and purified by column chromatography to obtain compound 11a (0.23 g, white solid); LC-MS: ESI [M+H] + =358.4.

[0155] Step 2: Compound 11a (0.23 g, 0.6 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 0.6 ml of a 4 mol / L hydrochloric acid and dioxane solution. The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 11b (0.2 g, white solid); LC-MS: ESI [M+H] + =258.3.

[0156] Step 3: Compound 11b (0.2 g, 0.6 mmol), INT1 (0.13 g, 0.6 mmol), N,N-diisopropylethylamine (0.3 g, 2.4 mmol) and potassium iodide (7 mg, 0.06 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. 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 11 (270 mg, light yellow solid); LC-MS: ESI [M+H] + =444.5; 1 H NMR (400MHz, CDCl3) δ11.28(s,1H),8.56(d,J=1.7Hz,1H),8.48(d,J=1.6Hz,1H),8.15(dd,J=8.1,0.5Hz,1H),7.99 (d,J=3.6Hz,1H),7.86(s,1H),7.75(dd,J=8.2,2.2Hz,1H),7.69(d,J=1.0Hz,1H),6.01(t,J=3.3Hz,1H),3.77(dd, J=34.1,13.8Hz,2H),3.30(d,J=2.2Hz,1H),3.19–3.08(m,1H),2.99–2.85(m,2H),2.78–2.68(m,3H),2.58(dd,J=1 1.1, 4.1Hz, 1H), 1.30 (dd, J = 9.8, 5.1Hz, 3H), 1.04 (d, J = 6.9Hz, 3H), 0.88 (td, J = 7.1, 5.5Hz, 2H), 0.69–0.62 (m, 2H).

[0157] Example 12: 1'-((7-ethyl-4-fluoro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0158] Step 1: To a solution of MeONa (618.0 g, 11.4 mol, 15.0 eq) in methanol (2 L) was slowly added compound 12a (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 12b was obtained as a white solid (150 g, 84.5% yield). 1 HNMR (400M Hz, DMSO-d6) δ (ppm) 9.06 (d, J = 2.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 4.07 (s, 3H).

[0159] Step 2: To a solution of compound 12b (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). The product 12c (81.5 g, 70% yield) was obtained as a yellow solid. 1 HNMR(400M Hz,DMSO-d6)δ(ppm)8.96(d,J=2.7Hz,1H),8.57(d,J=2.8Hz,1H),6.82(dd,J=17.8,1 1.3Hz, 1H), 6.15 (dd, J=17.7, 1.0Hz, 1H), 5.56 (dd, J=11.3, 1.0Hz, 1H), 4.05 (s, 3H).

[0160] Step 3: Pd / C (10% wt, 5.0 g) was added to a solution of 12c (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 12d as a dark purple solid (38.8 g, 92% yield). 1H 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).

[0161] The fourth step: to 12d (16g, 0.105mol) in EtOH (300mL) solution, 2-(ethoxymethylene) diethyl malonate (27.3g, 0.126mol, 25.5mL, 1.2eq) was added once, 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 by silica gel column chromatography (0-10% ethyl acetate / petroleum ether) to give compound 12e (32.0g, 94% yield, white solid). 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).

[0162] Step 5: Compound 12e (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 12f (21.3 g, 77% yield) was obtained as an off-white solid. LC-MS: ESI[M+H] + =277.1.

[0163] Step 6: DAST (37.3 g, 0.23 mol, 30.5 mL, 3.0 eq) was slowly added to a suspension of compound 12f (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 was 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 12 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).

[0164] Step 7: Compound 12g (13.0g, 0.047mol) was added to anhydrous THF (300mL). The reaction solution was cooled to -20°C. DIBAL-H (78.0mL, 0.117mol, 1.5M solution in toluene, 2.5eq.) was added under a -20°C N2 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 (300mL*3). The combined organic phases were washed with water (300mL) and brine (300ml), 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 12h was obtained as a yellow solid (8.0 g, 72% yield). 1H 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).

[0165] Step 8: A suspension of compound 12h (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 12i. 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).

[0166] 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 12i (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 12j (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 = 4.0Hz), 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) + .

[0167] Step 10: Compound 12j (40 mg, 0.17 mmol), 1f (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 12 (42 mg, white solid); LC-MS: ESI [M+H] + =436.5; 1 H NMR (400MHz, CDCl3) δ9.58(s,1H),8.58(d,J=8.7Hz,1H),8.49(d,J=1.8Hz,1H),8.14(d,J=8.1Hz ,1H),7.96(d,J=5.0Hz,1H),7.82(d,J=1.2Hz,1H),7.74(dd,J=8.2,2.2Hz,1H),6.00(t,J=3.3Hz, 1H),3.84(s,2H),3.33(d,J=15.0Hz,1H),3.16(d,J=17.0Hz,1H),3.03(d,J=5.1Hz,3H),2.90(s,1 H),2.83–2.67(m,3H),2.58(dd,J=11.1,4.2Hz,1H),1.31(t,J=7.4Hz,3H),1.02(d,J=6.9Hz,3H).

[0168] Example 13: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-N-(2,2,2-trifluoroethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0169] Step 1: Compound 10a (0.2 g, 0.6 mmol), 2,2,2-trifluoroethylamine (120 mg, 1.2 mmol), N-methylmorpholine (0.24 g, 2.4 mmol), 1-hydroxybenzotriazole (0.16 g, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol) were weighed into a reaction flask, 5 mL of N,N-dimethylformamide was added, and the mixture was reacted at room temperature overnight. After the reaction was complete as monitored by TLC, water and ethyl acetate were added for extraction. The organic phases were combined and dried, rotary evaporated, and purified by column chromatography to obtain compound 13a (0.15 g, yellow solid); LC-MS: ESI [M+H] + =400.4.

[0170] Step 2: Compound 13a (0.16 g, 0.4 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 0.4 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to give compound 13b (0.11 g, yellow solid); LC-MS: ESI [M+H] + =300.3.

[0171] Step 3: Compound 13b (0.11 g, 0.4 mmol), INT1 (86 mg, 0.4 mmol), N,N-diisopropylethylamine (0.2 g, 1.6 mmol) and potassium iodide (5 mg, 0.04 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. 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 13 (8 mg, white solid); LC-MS: ESI [M+H] + =486.5; 1H NMR (400MHz, CDCl3) δ11.50(s,1H),8.57(d,J=1.7Hz,1H),8.55(d,J=1.7Hz,1H),8.32(t,J=6.7Hz ,1H),8.16(d,J=8.1Hz,1H),7.87(s,1H),7.79(dd,J=8.2,2.2Hz,1H),7.70(s,1H),6.04(t,J=3.3 Hz,1H),4.24–4.03(m,2H),3.78(dd,J=33.9,13.8Hz,2H),3.42–3.26(m,1H),3.14(d,J=17.2Hz,1H),2.91(s,1H ), 2.74(ddd,J=11.1,7.3,5.5Hz,3H), 2.59(dd,J=11.1,4.1Hz,1H), 1.31(t,J=7.4Hz,3H), 1.06(d,J=6.9Hz,3H).

[0172] Example 14: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-fluoro-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0173] Step 1: Compound 14b (392.5 mg, 2.0 mmol), 14a (514.8 mg, 2.2 mmol), Cs2CO3 (1.3 g, 4 mmol), and Pd(dppf)Cl2 (146.3 mg, 0.2 mmol) were weighed into a reaction flask. The nitrogen atmosphere was purged three times, and 11 mL of a dioxane / H2O (10:1) solvent mixture was added. The nitrogen atmosphere was purged three more times, and the mixture was reacted at 90°C for 3 h under nitrogen. After completion of the reaction, the solvent was mostly removed by concentration under reduced pressure. The mixture was then extracted with water and EA (30 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and purified by column chromatography to afford 14c (513 mg, 73%) as a white solid. LC-MS: ESI [M+H] + =351.2.

[0174] Step 2: Compound 14c (500 mg, 1.4 mmol) was weighed into a reaction tube, 5 mL of methanol was added as solvent, and then a MeNH2 (40%, 2 mL) aqueous solution was added and stirred at room temperature overnight. After LC-MS confirmed the completion of the reaction, the solvent was removed by vacuum concentration to obtain a light yellow solid compound 14d (489 mg, 98%), which was used directly in the next step without any purification. LC-MS: ESI [M+H] + =350.2.

[0175] Step 3: Compound 14d (485 mg, 1.4 mmol) was weighed into a reaction tube, 5 mL of methanol was added as solvent, and then HCl (4 M in dioxane, 3.5 mL) was added and stirred at room temperature overnight. After LC-MS confirmed the completion of the reaction, the solvent was concentrated in vacuo and then slurried with ether and n-hexane (1:1) to obtain compound 14e (435 mg, 97%) as a white solid. LC-MS: ESI [M+H] + =250.1.

[0176] Step 4: Compound 14e (100 mg, 0.3 mmol), INT1 (62.8 mg, 0.28 mmol), DIEPA (182.3 mg, 1.4 mmol), and KI (4.7 mg, 0.028 mmol) were weighed into a reaction tube and added with 10 mL of acetonitrile, which was reacted at 80°C for 3 h. The reaction was cooled to room temperature, and saturated aqueous NaHCO₃ was added and stirred for 2 h. The solvent was concentrated in vacuo, and then extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography with MeOH (0-8%) and DCM to afford Compound 14 (87 mg, 71% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =436.2; 1 H NMR(400MHz,DMSO)δ11.87(s,1H),8.64(s,1H),8.43(s,1H),8.04(s,1H),7 .95(s,1H),7.76(s,1H),7.68(s,1H),6.02(s,1H),3.71(d,J=19.1Hz,2H), 3.48(s,2H),3.14(s,2H),2.80(d,J=4.8Hz,3H),2.56(s,2H),2.34(d,J=16.9Hz,1H),1.19(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H).

[0177] Example 15: 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0178] Compounds INT2 (161.6 mg, 0.69 mmol), 1f (220 mg, 0.72 mmol), DIEPA (445.1 mg, 3.4 mmol), and KI (11.4 mg, 0.07 mmol) were weighed into a reaction tube and added with 30 mL of acetonitrile. The mixture was reacted at 80°C for 3 h. The reaction mixture was cooled to room temperature, the solvent was concentrated, and the mixture was extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and then column purified with MeOH (0-8%) and DCM to afford Compound 15 (245 mg, 83% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =430.2; 1 H NMR(400MHz,DMSO)δ11.91(s,1H),8.71(d,J=4.9Hz,1H),8.64(s,1H),8.41(s,1H),8 .01–7.93(m,2H),7.65(s,1H),7.43(s,1H),6.20(s,1H),3.76(d,J=13.8Hz,1H),3.65 (d,J=13.4Hz,1H),3.14(dt,J=11.6,5.8Hz,1H),3.07–2.93(m,2H),2.82(d,J=4.8Hz ,3H),2.64–2.53(m,2H),2.20–2.10(m,1H),1.02–0.93(m,5H),0.83(q,J=6.0Hz,2H).

[0179] Example 16: 5-(5-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-5-azaspiro[2.5]octan-7-en-8-yl)-N-methylpicolinamide

[0180] Step 1: Compound 16a (430 mg, 2.0 mmol), 16b (437.4 mg, 2.1 mmol), Cs2CO3 (1.3 g, 4.0 mmol), and Pd(dppf)Cl2 (146.3 mg, 0.2 mmol) were weighed into a reaction flask. The nitrogen atmosphere was purged three times, dioxane / H2O (10:1) was added, and the nitrogen atmosphere was purged three more times. The mixture was then reacted at 90°C under nitrogen for 3 h. After completion of the reaction, the solvent was mostly removed by vacuum concentration, and the mixture was then extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and purified by column chromatography to obtain 16c (261.1 mg, 76%) as a white solid. LC-MS: ESI [M+H] + =344.2.

[0181] Step 3: Compound 16c (255 mg, 0.74 mmol) was weighed into a reaction tube, 3 mL of methanol was added as solvent, and then HCl (4 M in dioxane, 1.1 mL) was added and stirred at room temperature overnight. After LC-MS confirmed the completion of the reaction, the solvent was concentrated in vacuo and then slurried with ether and n-hexane (1:1) to obtain compound 16d (230 mg, 98%) as a white solid. LC-MS: ESI [M+H] + =244.1.

[0182] Step 4: Compound 16d (100 mg, 0.32 mmol), INT1 (67.1 mg, 0.3 mmol), DIEPA (194.6 mg, 1.5 mmol), and KI (5.0 mg, 0.03 mmol) were weighed into a reaction tube and added with 8 mL of acetonitrile, reacting at 80°C for 3 h. The reaction was cooled to room temperature, and saturated aqueous NaHCO₃ was added and stirred for 2 h. The solvent was concentrated in vacuo, and then extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography to afford Compound 16 (65 mg, 50% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =430.2; 1 H NMR (400MHz, DMSO) δ11.88(s,1H),8.75(q,J=4.6Hz,1H),8.42(d,J=1.8Hz,1H),8.33(d,J=1.5 Hz,1H),7.96(d,J=8.0Hz,1H),7.76(s,1H),7.70(dd,J=8.0,2.2Hz,1H),7.67(d,J=1.2Hz,1H) ,5.66(t,J=3.3Hz,1H),3.74(s,2H),3.24(d,J=3.3Hz,2H),2.81(d,J=4.9Hz,3H),2.58–2.52( m,2H),2.50(d,J=1.3Hz,2H),1.20–1.14(m,3H),0.55(t,J=5.5Hz,2H),0.45(t,J=5.4Hz,2H).

[0183] Example 17: 1'-((7-chloro-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0184] Step 1: Compound 17a (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 3-5 times, and 550 mL of dioxane / H2O (10:1) was added. The nitrogen atmosphere was purged again 3-5 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 × 3). The mother liquor was concentrated and extracted with EA (200 mL × 5) and H2O. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and purified by column chromatography to obtain 17b (44.5 g, 87%) as a yellow oil. LC-MS: ESI [M+H] + =223.1.

[0185] Step 2: Compound 17b (44.5 g, 0.20 mol) was weighed into a reaction flask, 400 mL of glacial acetic acid was added, and iron powder (35.4 g, 0.60 mol) was slowly added. The mixture was reacted 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 compound 17c (32.3 g, 84%) as a pale yellow solid. LC-MS: ESI [M+H] + =193.1.

[0186] Step 3: Compound 17c (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 complete addition, the mixture was stirred at 60°C for 5 h. After completion of the reaction, 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 diethyl ether. The solid residue was purified by column chromatography to afford 17d (3.2 g, 28%) as a white solid. LC-MS: ESI [M+H] + =219.1.

[0187] Step 4: Compound 17d (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 product was washed with saturated aqueous NaHCO₃ and extracted 3-5 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 17e (3.1 g, 84%). LC-MS: ESI [M+H] + =253.0.

[0188] Step 5: Compound 17e (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 protection. 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 a pale yellow solid crude product 17f (810 mg, 29%). LC-MS: ESI [M+H] + =225.0.

[0189] Step 6: Compound 17f (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, the solvent was concentrated in vacuo and purified by column chromatography to obtain 17 g (172 mg, 20%) of a light yellow solid. LC-MS: ESI [M+H] + =243.0.

[0190] Step 7: Compound 17g (40 mg, 0.16 mmol), 52f (55.1 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 and added with 5 mL of acetonitrile. The mixture was reacted at 80°C for 3 h. The reaction mixture 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 (0-8%) and DCM to afford Compound 17 (35 mg, 49% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =438.2; 1H NMR (400MHz, CDCl3) δ12.40(s,1H),8.59(d,J=1.6Hz,1H),8.43(d,J=1.7Hz,1H),8.08(d,J=8.1 Hz,1H),7.91(dd,J=10.1,5.0Hz,1H),7.79(d,J=1.4Hz,1H),7.68(dd,J=8.2,2.2Hz,1H),5.93(t ,J=3.2Hz,1H),3.29–3.21(m,1H),3.06(d,J=17.1Hz,1H),2.97(d,J=5.1Hz,3H),2.89(s,1H),2 .82(s,2H),2.72(s,3H),2.69–2.63(m,1H),2.51(dd,J=11.1,4.0Hz,1H),0.98(d,J=6.9Hz,3H).

[0191] Example 18: 1'-((7-chloro-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-fluoro-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0192] Compound 17g (40.0 mg, 0.16 mmol), 5e (55.8 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 and added with 5 mL of acetonitrile. The mixture was reacted at 80°C for 3 h. The reaction mixture 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 to afford Compound 18 (20 mg, 28% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =442.1; 1H NMR (400MHz, DMSO) δ12.32(s,1H),8.77(d,J=2.0Hz,1H),8.74(d,J=4.9Hz,1H),8.54(d, J=1.8Hz,1H),8.10(dd,J=8.2,2.1Hz,1H),8.02(d,J=8.2Hz,1H),7.72(d,J=1.7Hz,1H), 6.80–6.73(m,1H),5.67(d,J=48.6Hz,1H),3.87–3.77(m,2H),3.45(dd,J=18.2,12.6Hz, 2H), 3.18 (d, J = 28.8Hz, 1H), 3.02 (d, J = 30.5Hz, 1H), 2.82 (d, J = 4.9Hz, 3H), 2.65 (s, 3H).

[0193] Example 19: 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3',3'-trimethyl-1',2',3",6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0194] Compound INT2 (0.1 g, 0.3 mmol), 4e (70 mg, 0.3 mmol), N,N-diisopropylethylamine (160 mg, 1.2 mmol) and potassium iodide (5 mg, 0.03 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. After the reaction was completed as monitored by TLC, 10 ml of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 19 (46 mg, light yellow solid); LC-MS: ESI [M+H] + =444.5; 1 H NMR (400MHz, DMSO) δ11.96 (s, 1H), 8.74 (d, J = 4.8Hz, 1H), 8.41 (dd, J = 11.5, 1. 4Hz,2H),7.97(s,1H),7.81(dd,J=8.0,2.0Hz,1H),7.69(s,1H),7.42(s,1H),5 .61(s,1H),3.70(s,2H),3.12(d,J=2.9Hz,2H),2.82(d,J=4.8Hz,3H),2.36(s, 2H), 2.20–2.08 (m, 1H), 1.02 (s, 6H), 1.00–0.92 (m, 2H), 0.82 (d, J = 3.4Hz, 2H).

[0195] Example 20: N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0196] Step 1: Compound INT2 (200 mg, 0.6 mmol), 11b (140 mg, 0.6 mmol), N,N-diisopropylethylamine (310 mg, 2.4 mmol) and potassium iodide (10 mg, 0.06 mmol) were added to 20 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 20 (170 mg, white solid); LC-MS: ESI [M+H] + =404.5; 1 H NMR (400MHz, CDCl3) δ11.61(s,1H),8.54(d,J=1.7Hz,1H),8.48(d,J=1.7Hz,1H),8.15(d,J=8. 0Hz,1H),8.00(d,J=3.6Hz,1H),7.74(dd,J=8.2,2.2Hz,1H),7.72(s,1H),7.51(s,1H),6.00(t, J=3.3Hz,1H),3.75(dd,J=33.5,13.8Hz,2H),3.29(s,1H),3.12(d,J=17.1Hz,1H),2.93(ddd,J=17.6,10.6,6.6Hz,2H),2.73(dd,J=11.1,4 .3Hz,1H),2.57(dd,J=11.1,4.1Hz,1H),2.37–2.28(m,1H),1.12–1.06(m,2H),1.03(d,J=6.9Hz,3H),0.92–0.79(m,4H),0.70–0.61(m,2H).

[0197] Example 21: (S)-N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide and Example 22: (R)-N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0198] Compound 20 was chiral resolved to give compounds 21 and 22. The resolution was performed using a Waters 150 Prep-SFC column, Chiralcel AD column, mobile phase A: carbon dioxide, mobile phase B: 0.1% ammonia in isopropanol, gradient: 70% mobile phase B, pressure: 100 bar, flow rate: 100 mL / min.

[0199] The absolute configuration of compound 21 was determined by X-ray diffractometer using a Bruker D8VENTURE double microfocus single crystal X-ray diffractometer at an ambient temperature of 193 K and an enhanced Cu light source with a wavelength of Through single crystal structure analysis, the following conclusions were drawn: the single crystal of the sample molecule belongs to the monoclinic system, C2 space group; the characteristic element in the crystal is the secondary axis; one unit cell contains 4 compound 21 molecules; each compound 21 molecule in the unit cell includes 1 chiral carbon atom (black mark), and the absolute configuration of the chiral carbon atom is C16 (S).

[0200] Example 23: 1-(2-ethyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)-N,3-dimethyl-1,2,3,6-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0201] Step 1: Compound 23a (10.5 g, 47.7 mmol), methyl 2-aminobutyrate (7.3 g, 47.7 mmol), and DIEA (18.6 g, 143.1 mmol) were added to 40 ml of DMF and reacted at room temperature for 24 h. After completion of the reaction (as determined by LC-MS), 120 ml of ethyl acetate and 120 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 water and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to yield compound 23b (14.5 g, an orange-red solid).

[0202] Step 2: Compound 23b (14.5 g, 45.7 mmol), ammonium chloride (19.6 g, 365.7 mmol), and water (14.5 ml) were added to 220 ml of methanol. The mixture was stirred and cooled to 0°C. Zinc powder (23.7 g, 365.7 mmol) was added and stirred at room temperature for 2 h. After the reaction was complete, the mixture was filtered and the filter cake was washed with methanol:dichloromethane (2:8). The combined filtrates were then spin-dried. 100 ml of ethyl acetate and 100 ml of water were added and the layers were separated in a separatory funnel. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. 14.5 ml of ethyl acetate and 14.5 ml of methanol were added. 0.6 ml of a 4M hydrochloric acid / 1,4-dioxane solution was added with stirring and stirred at room temperature for 1 h. After the reaction was complete, the mixture was spin-dried to give compound 23c (11.6 g, gray solid).

[0203] Step 3: Compound 23c (5.0 g, 19.5 mmol) was added to 100 ml of anhydrous methanol, followed by dropwise addition of 16% sodium hydroxide solution (10.4 ml) and 30% hydrogen peroxide (31.2 ml). After the addition, the temperature was raised to 60°C and the reaction was allowed to proceed for 16 h. After the reaction was complete as detected by LC-MS, 20 ml of saturated sodium thiosulfate was added dropwise, followed by addition of 100 ml of water and 50 ml of dichloromethane. The mixture was stirred, filtered, and dried to obtain compound 23d (3.4 g, yellow solid).

[0204] Step 4: Compound 23d (3.0 g, 11.8 mmol), tributylmethanol (3.8 g, 11.8 mmol), and Xphos-G2-Pd (0.47 g, 0.59 mmol) were added to 30 ml of dioxane, replaced with nitrogen three times, heated to 80°C and stirred for 8 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 23e (1.8 g, yellow solid).

[0205] Step 5: Weigh 23e (0.5 g, 2.4 mmol), add 10 ml of HBr / H2O, and heat to 80°C for 6 h. After the reaction is complete by LC-MS, cool to room temperature and add dropwise to 30 ml of ice water to precipitate a yellow solid. Filter and wash the filter cake with water. The filter cake is then spin-dried to obtain compound 23f (460 mg, yellow solid).

[0206] Step 6: 23f (0.2 g, 0.74 mmol), 1f (271 mg, 0.89 mmol), DIEA (483 mg, 3.74 mmol), and KI (25 mg, 0.15 mmol) were added to 4 ml of acetonitrile and the reaction was heated to 80°C for 2 h. After the reaction was complete as determined by LC-MS, the mixture was cooled to room temperature and dried. The crude product was purified by column chromatography to obtain compound 23 (25 mg, white solid); LC-MS: ESI [M+H] + =418.5; 1 H NMR (400MHz, DMSO) δ12.29(s,1H),8.68(dd,J=27.1,3.0Hz,2H),7.97(dd,J=4.1,1.4Hz,2H),7.70(d,J=8.2Hz,1H),7.35-7.22(m,2H),6.21( s,1H),3.79-3.58(m,2H),3.31-3.21(m,1H),2.99(s,2H),2.86-2.75( m, 5H), 2.67-2.53 (m, 2H), 1.22 (t, J = 7.4Hz, 3H), 1.00 (d, J = 6.8Hz, 3H).

[0207] Example 24: 1,3-Dihydro-1,6-naphthyridine-7-methyl-N,3-dimethyl-1,2,3,6-tetrahydrobipyridine-6-carboxamide

[0208] Step 1: Compound 24a (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. n-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 afford compound 24b (0.8 g, pink solid).

[0209] Step 2: Compound 24b (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 completed as monitored by TLC, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 24c (0.1 g, yellow solid).

[0210] Step 3: Compound 24c (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 completed 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 24d (80 mg, yellow solid).

[0211] Step 4: Add 1f (131.6 mg, 0.44 mmol) and triethylamine (88 mg, 0.88 mmol) to 10 ml of dichloromethane and stir to dissolve. Add 74d (80 mg, 0.40 mmol) to 10 ml of dichloromethane and stir to dissolve. Add the DCM solution of 1f to the DCM solution of 24d and stir at room temperature for 1 h. Add sodium triacetoxyborohydride (501 mg, 2.4 mmol) and stir at room temperature for 2 h. After the reaction is complete as determined by LC-MS, add 20 ml of saturated ammonium chloride and stir to separate the layers. The organic layer is washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 24 (20 mg, yellow solid); LC-MS: ESI [M+H] + =418.5; 1H NMR (400MHz, CDCl3) δ10.74(s,1H),8.67(s,1H),8.37(d,J=2.1Hz,1H),8.11(d, J=8.1Hz,1H),7.89(d,J=5.2Hz,1H),7.74-7.56(m,2H),7.50(s,1H),5.81(s,1H) ,4.42(q,J=13.1Hz,2H),3.95(q,J=16.9Hz,2H),3.69(d,J=6.9Hz,1H),2.97(d,J =5.0Hz, 5H), 2.57 (q, J = 7.4Hz, 4H), 1.19 (d, J = 3.6Hz, 4H), 0.94 (d, J = 6.8Hz, 3H).

[0212] Example 25: 1-(6-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)-N,3-dimethyl-1,2,3,6-tetrahydrobipyridine-6-carboxamide

[0213] Step 1: Compound 25a (10.0 g, 53.0 mmol) was added to 200 ml of dichloromethane, cooled to -78°C, and DIBAL-H (107.0 ml, 106.0 mmol) was added dropwise. After the addition, a sample was taken. After the reaction was complete, LC-MS detection was performed, 300 ml of 6 M aqueous hydrochloric acid solution was added, stirred, and the layers were separated. The aqueous layer was adjusted to pH 8-9 with 20% sodium hydroxide, and then extracted twice with ethyl acetate. The organic phases were combined and dried by spin drying to obtain compound 25b (7.6 g, yellow solid).

[0214] Step 2: Compound 25b (7.6 g, 48.0 mmol) was added to 76 ml of dichloromethane, and the temperature was lowered to 0°C. Dess-Martin reagent (24.5 g, 57.7 mmol) was slowly added dropwise. After the addition, the reaction was returned to room temperature and stirred for 1 h. After the reaction was complete as detected by LC-MS, saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with ethyl acetate and dried to give compound 25c (5.0 g, oil).

[0215] Step 3: Weigh 25c (5.0 g, 32.0 mmol), potassium tert-butoxide (10.0 g, 96.1 mmol), and 100 ml of ethyl butyrate, heat to 120°C and stir for 1 h. After the reaction is complete as detected by LC-MS, cool to room temperature, add 200 ml of water, separate the layers, and extract the aqueous layer three times with 200 ml of ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified by column chromatography to obtain compound 25d (1.5 g, yellow solid).

[0216] Step 4: Compound 25d (1.5 g, 7.2 mmol), potassium vinyl trifluoroborate (1.93 g, 1.44 mmol), Pd(dppf)Cl2 (523.2 mg, 0.72 mmol), and potassium phosphate (4.58 g, 21.6 mmol) were added to 15 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 completed as monitored by LC-MS, 20 ml of water was added, the layers were separated, and the aqueous layer was extracted three times with 30 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 25e (1.2 g, yellow solid).

[0217] Step 5: Compound 25e (1.2 g, 6.0 mmol) was added to 60 ml of dioxane and 15 ml of water, followed by sodium periodate (2.56 g, 24.0 mmol) and potassium osmate (120 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete as detected by LC-MS, 200 ml of ethyl acetate and 200 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 and filtered. The crude product was purified by column chromatography to obtain compound 25f (770 mg, yellow solid).

[0218] Step 6: Add 1f (371 mg, 1.08 mmol) and triethylamine (400 mg, 3.96 mmol) to 10 ml of dichloromethane and stir to dissolve. Add 25f (400 mg, 0.99 mmol) to 10 ml of dichloromethane and stir to dissolve. Add the DCM solution of 1f to the DCM solution of 25f and stir at room temperature for 1 h. Add sodium triacetoxyborohydride (1.26 g, 5.94 mmol) and stir at room temperature for 2 h. After the reaction is complete as determined by LC-MS, add 20 ml of saturated ammonium chloride and stir to separate the layers. The organic layer is washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and purified by spin column chromatography to obtain compound 25 (70 mg, yellow solid); LC-MS: ESI [M+H] + =418.5;1H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.72(q,J=4.8Hz,1H),8.65(dd,J=2.2,1.0Hz,1H),8.16(s,1H),8.05(d,J=7.9Hz,1H),8.01-7.94(m,2 H),7.73(d,J=1.2Hz,1H),7.37(d,J=7.9Hz,1H),6.20(t,J=3.5Hz,1H),3.86-3.65(m,3H),3.31(dd,J=17.8,3.9Hz,3H),3.08(dt,J=17.4,2.8 Hz,1H),3.00(s,1H),2.82(d,J=4.8Hz,3H),2.67(dd,J=11.2,4.3Hz,1H),2.57(dd,J=11.2,3.9Hz,1H),1.17(t,J=7.4Hz,3H),0.99(d,J=6.8Hz,3H).

[0219] Example 26: 1-(7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-fluoro-N-methyl-1,2,3,6-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0220] Step 1: To 2 ml of acetonitrile were added INT2 (100 mg, 0.42 mmol), 5e (156 mg, 0.50 mmol), DIEA (271 mg, 2.1 mmol), and KI (14 mg, 0.084 mmol), and the mixture was heated to 80°C for 2 h. After the reaction was complete as determined by LC-MS, the mixture was cooled to room temperature, saturated sodium bicarbonate solution (4 ml) was added, and 20 ml of ethyl acetate was added and extracted three times. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 26 (30 mg, yellow solid); LC-MS: ESI [M+H] + =434.5;1H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.82-8.72(m,2H),8.53(d,J=1.9Hz,1H),8.13(dd,J=8.2,2.3Hz,1H),8.06(d,J=8.2Hz,1H),7.80(s,1H),7 .47(s,1H),6.79(t,J=2.1Hz,1H),3.80(s,3H),2.83(d,J=4.8Hz,3H),2. 19(tt,J=8.4,5.3Hz,1H),1.04-0.94(m,2H),0.86(dt,J=6.6,3.3Hz,2H).

[0221] Example 27: 1-(7-ethyl-4-fluoro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-fluoro-N-methyl-1,2,3,6-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0222] Step 1: Compound 27a (50 g, 314 mmol) and N-bromosuccinimide (67 g, 377 mmol) were weighed into a reaction flask, 300 mL of sulfuric acid was added, and the temperature was raised to 80°C for overnight reaction. After TLC detection of the reaction was complete, the reaction mixture was cooled to room temperature and slowly diluted with ice water. The reaction mixture was extracted three times with ethyl acetate. The organic phases were combined and then washed with water, saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 27b (65 g, light yellow solid); LC-MS: ESI [M+H] + =238.9.

[0223] Step 2: Compound 27b (43 g, 181 mmol), methyl 2-aminobutyrate (21 g, 181 mmol), N,N-diisopropylethylamine (70 g, 543 mmol), and N,N-dimethylformamide (100 ml) were added to a 500 ml reaction flask and stirred overnight at room temperature. After TLC monitoring of the reaction completion, the reaction solution was concentrated under reduced pressure, extracted three times with ethyl acetate and water, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to obtain compound 27c (37 g, orange-red solid); LC-MS: ESI [M+H] + =336.1.

[0224] Step 3: Compound 27c (26 g, 78 mmol) was added to 200 ml of anhydrous methanol and 5 ml of water, followed by the addition of ammonium chloride (35 g, 621 mmol). The temperature was lowered to 0°C, and zinc powder (43 g, 621 mmol) was slowly added. The temperature was raised to room temperature and the reaction was allowed to react for 1 hour. After TLC monitoring, the reaction was completed, and the mixture was filtered. The filtrate was concentrated under reduced pressure and 30 ml of a 4 mol / L hydrochloric acid solution in dioxane was added. The mixture was allowed to react at room temperature for 1 hour. After TLC monitoring, the reaction was completed, and petroleum ether was added to precipitate a solid, which was filtered and dried to obtain compound 27d (16 g, off-white solid). LC-MS: ESI [M+H] + =274.1.

[0225] Step 4: Compound 27d (16 g, 57 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (16 g, 69 mmol) were added to 500 ml of dichloromethane and reacted overnight at room temperature. After TLC monitoring, the reaction solution was concentrated under reduced pressure and quenched by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 27e (7.9 g, brown solid); LC-MS: ESI [M+H] + =272.1.

[0226] Step 5: Compound 27e (0.5 g, 1.8 mmol), tributyltin methanol (0.65 g, 2.0 mmol), and Xphos-Pd-G2 (73 mg, 0.09 mmol) were weighed, 15 ml of dioxane was added, the nitrogen atmosphere was replaced, and the temperature was raised to 80°C for overnight reaction. After TLC monitoring, the reaction was complete, and water and ethyl acetate were added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 27f (0.4 g, light yellow solid); LC-MS: ESI [M+H] + =223.2.

[0227] Step 6: Compound 27f (0.4 g, 0.8 mmol) was added to 10 ml of aqueous hydrobromic acid solution and heated to 80°C for 3 hours. After completion of the reaction as monitored by TLC, saturated aqueous sodium bicarbonate solution was added for quenching. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound 27g (0.24 g, light yellow solid); LC-MS: ESI [M+H] + =286.1.

[0228] Step 7: To 2 ml of acetonitrile were added 27 g (100 mg, 0.41 mmol), 5e (153 mg, 0.49 mmol), DIEA (268 mg, 2.05 mmol), and KI (14 mg, 0.082 mmol). The temperature was raised to 80°C and the reaction was allowed to react for 2 h. After completion of the reaction as determined by LC-MS, the mixture was cooled to room temperature, saturated sodium bicarbonate solution (4 ml) was added, and 20 ml of ethyl acetate was added and extracted three times. The organic layer was washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 27 (52 mg, white solid). LC-MS: ESI [M+H] + =440.5;1H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H), 8.80-8.68 (m, 2H), 8.48 (d, J = 8.5Hz, 1H), 8.09(dd,J=8.1,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.80(s,1H),6.78-6.72(m,1H ),5.67(d,J=48.7Hz,1H),3.87(s,2H),3.53-3.40(m,1H),3.20(t,J=14.6Hz,1H) ,3.12-2.98(m,1H),2.80-2.64(m,1H),2.63-2.53(m,2H),1.20(t,J=7.4Hz,3H).

[0229] Example 28: 1-(3-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-3-fluoro-N-methyl-1,2,3,6-tetrahydrobipyridine-6-carboxamide

[0230] To 10 ml of dichloromethane were added 5e (167 mg, 0.54 mmol) and triethylamine (198 mg, 1.96 mmol), and the mixture was stirred to dissolve. To 10 ml of dichloromethane was added 24d (100 mg, 0.49 mmol), and the mixture was stirred to dissolve. The DCM solution of 24d was added to the DCM solution of 5e, and the mixture was 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, and the layers were stirred and separated. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and purified by spin column chromatography to give compound 28 (43 mg, white solid); LC-MS: ESI [M+H] + =422.5;1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),8.85-8.56(m,3H),8.19-7.94(m,2H),7.82(d,J=1.6Hz,1H),7.35(s,1H),6.79(dt,J=4.6,2.1Hz,1H),5.68( d,J=48.6Hz,1H),3.83(s,2H),3.56-3.42(m,1H),3.21(d,J=13.9Hz,1H), 3.15-2.97(m,3H),2.83(d,J=4.8Hz,3H),2.81-2.64(m,1H),1.18(s,3H).

[0231] Example 29: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0232] Step 1: Compound 10a (150 mg, 0.47 mmol), compound 29a (80 mg, 0.47 mmol), N-methylmorpholine (190 mg, 1.88 mmol), 1-hydroxybenzotriazole (127 mg, 0.94 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) were weighed into a reaction flask, 5 mL of N,N-dimethylformamide was added, and the mixture was reacted at room temperature overnight. After the reaction was complete as monitored by TLC, water was added and extracted with ethyl acetate. The organic phases were combined and dried, rotary evaporated, and purified by column chromatography to obtain compound 29b (130 mg, light yellow solid); LC-MS: ESI [M+H] + =398.5.

[0233] Step 2: Compound 29b (130 mg, 0.33 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 0.4 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 29c (130 mg, light yellow solid); LC-MS: ESI [M+H] + =298.4.

[0234] Step 3: Compound 29c (130 mg, 0.3 mmol), INT1 (67 mg, 0.3 mmol), N,N-diisopropylethylamine (155 mg, 1.2 mmol) and potassium iodide (5 mg, 0.03 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. 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 29 (90 mg, white solid); LC-MS: ESI [M+H] + =484.6; 1 H NMR (400MHz, CDCl3) δ11.49(s,1H),9.75(s,1H),8.57(s,2H),8.20(d,J=8.1Hz,1H),8.09(s,1H),7. 87(s,1H),7.81(dd,J=8.2,2.1Hz,1H),7.71(s,1H),7.58(s,1H),6.05(t,J=3.2Hz,1H),3.92(s,3H), 3.78(dd,J=33.4,13.9Hz,2H),3.35(d,J=15.1Hz,1H),3.15(d,J=17.2Hz,1H),2.92(s,1H),2 .80–2.69(m,3H),2.60(dd,J=11.1,3.9Hz,1H),1.31(t,J=7.4Hz,3H),1.07(d,J=6.9Hz,3H).

[0235] Example 30: 1'-((2-cyclopropyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0236] Step 1: The hydrochloride of 30a (3.0 g, 18.1 mmol) and DIEA (9.4 g, 72.5 mmol) were weighed into a reaction flask and dissolved in 30 mL of DMF. 27b (4.5 g, 19.0 mmol) was added while stirring at room temperature. The mixture was stirred at room temperature for 5 h under nitrogen protection. After the reaction, 90 mL of pure water was added and the mixture was extracted with EA (150 mL × 2). The organic phases were combined and washed with saturated brine. The organic phase was separated and concentrated in vacuo to dryness. The organic phase was purified by column chromatography with PE and DCM (0-20%) to obtain 30b (4.4 g, 70%) as a yellow oily liquid. LC-MS: ESI [M+H] + =347.0.

[0237] Step 2: 30b (4.3 g, 12.4 mmol) was dissolved in 80 mL of glacial acetic acid. Reduced Fe powder was slowly added to the system with stirring at room temperature. After the addition, the mixture was stirred at 70°C for 1 h. The mixture was filtered while hot, and the filter cake was washed with a mixed solvent of DCM and MeOH. The filtrate was concentrated in vacuo and purified by column chromatography with PE and EA (0-25%) to give an off-white solid 30c (3.4 g, 96%). LC-MS: ESI [M+H] + =285.0.

[0238] Step 3: 30c (3.0 g, 10.5 mmol) was weighed into a reaction flask and stirred with 50 mL of DCM. Then, DDQ powder (3.6 g, 15.8 mmol) was slowly added and stirred at room temperature overnight. After the reaction, saturated aqueous NaHCO₃ was added to the system. The layers were separated, and the aqueous phase was extracted twice with a mixture of DCM and MeOH (5:1) (30 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography with DCM and MeOH (0-3%) to obtain an off-white solid 30d (2.6 g, 87%). LC-MS: ESI [M+H] + =283.0.

[0239] Step 4: 30d (1.5 g, 5.3 mmol), (tributyltin)methanol (3.4 g, 10.6 mmol) and XPhos-Pd-G2 (416.4 mg, 0.5 mmol) were weighed into a reaction flask, and 30 mL of dioxane was added to replace the nitrogen atmosphere 3-5 times. Then, the mixture was stirred at 90°C under nitrogen protection for 4 h. After the reaction, the solvent was concentrated in vacuo and purified by column chromatography with DCM and MeOH (0-5%) to obtain 30e (946.0 mg, 76%) as a white solid. LC-MS: ESI [M+H] + =235.1.

[0240] Step 5: 30e (400 mg, 1.7 mmol) and DMF (25.0 mg, 0.34 mmol) were weighed into a reaction flask and dissolved in 40 mL of toluene. SOCl2 (284.5 mg, 2.4 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 light yellow solid 30f (297.0 mg, 69%). LC-MS: ESI [M+H] + =253.0.

[0241] Step 6: Compound 30f (50 mg, 0.20 mmol), compound 11b (71.9 mg, 0.22 mmol), DIEPA (127.9 mg, 1.0 mmol), and KI (6.6 mg, 0.04 mmol) were weighed into a reaction tube and added with 5 mL of acetonitrile. The mixture was reacted at 85°C for 3 h. The reaction was cooled to room temperature, saturated aqueous NaHCO₃ was added, and stirred for 0.5 h. The mixture was then extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography with MeOH (0-6%) and DCM to yield 30 (53.0 mg, 57%) as a pale yellow solid. LC-MS: ESI [M+H] + =474.2; 1 H NMR(400MHz,DMSO)δ12.20(s,1H),8.66(d,J=4.9Hz,1H),8.59(s,1H),8.03–7.89( m,2H),7.43(d,J=8.3Hz,1H),7.29(t,J=7.7Hz,1H),6.16(s,1H),3.74(s,2H),3.2 4(d,J=14.8Hz,1H),3.03(d,J=17.3Hz,1H),2.99–2.85(m,2H),2.75–2.61(m,2H), 2.58–2.53(m,1H),1.09(t,J=7.1Hz,4H),0.93(d,J=6.8Hz,3H),0.74–0.62(m,4H).

[0242] Example 31: N-cyclopropyl-1'-((2-cyclopropyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3'-fluoro-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0243] Preparation of N-cyclopropyl-1'-((2-cyclopropyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3'-fluoro-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 5. LC-MS: ESI [M+H] + =478.2; 1 H NMR (400MHz, DMSO) δ8.78–8.66(m,2H),8.13–8.05(m,1H),8.00(d,J=8.2Hz ,1H),7.44(d,J=8.3Hz,1H),7.29(t,J=7.7Hz,1H),6.74(s,1H),5.65(d,J= 48.8Hz,1H),3.81(s,2H),3.22–3.11(m,2H),3.06–2.96(m,1H),2.90(td,J =11.4,4.5Hz,1H),2.76–2.62(m,2H),1.14–1.03(m,4H),0.73–0.64(m,4H).

[0244] Example 32: 1'-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0245] Step 1: Add 32a (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, wash with saturated brine, separate the layers, and concentrate the organic layer under reduced pressure at 40°C to obtain 32b (480 g) as a white solid.

[0246] Step 2: Compound 32b (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 afford 32c (612 g, 95.3% yield), a red solid.

[0247] Step 3: Compound 32c (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 the layers separated. The aqueous layer was extracted twice with ethyl acetate (2.0 L). The organic layers were combined and washed sequentially with saturated sodium thiosulfate solution and saturated brine. The organic layer was concentrated under reduced pressure at 40-45°C until no fractions remained, yielding 500 g of oily product 32d, which was used directly in the next step.

[0248] Step 4: Compounds 32d (512 g, 1.69 mol) and 32e (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 stratification. The organic layer was concentrated under reduced pressure at 40-45°C until no fractions were obtained. The mixture was purified by column chromatography to afford 32f (230 g, 36.5% yield) as a flocculent solid.

[0249] Step 5: Compound 32f (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 32g (800 mg, 77.78%) as a white solid. LC-MS: ESI [M+H] + =267.0.

[0250] Step 6: Under nitrogen protection, compound 32g (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 32h (740 mg, 97.64%) as a white solid. LC-MS: ESI [M + H] + =252.9.

[0251] Step 7: Compound 32h (0.74 g, 2.92 mmol) was added to anhydrous THF (300 mL), the reaction solution was cooled to -20°C, and DIBAL-H (4.9 mL, 7.3 mmol, 1.5 M toluene solution) was added under a -20°C N2 atmosphere. 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, maintaining the internal temperature above 0°C. Volatile substances were removed under reduced pressure at 25°C, and the resultant was extracted with ethyl acetate (30 mL*3). The combined organic phases were 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 32i (0.42 g) was obtained as a yellow solid. LC-MS: ESI [M+H] + =211.2.

[0252] Step 8: Under a nitrogen atmosphere at 0-5°C, SOCl2 (357 mg, 3.0 mmol) was slowly added to a solution of compound 32i (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, followed by the addition of water (10 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 obtain compound 32j (250 mg). LC-MS: ESI [M+H] + =229.0.

[0253] Step 9: 32j (30.0 mg, 0.13 mmol), compound 1f (43.8 mg, 0.14 mmol), DIEPA (84.6 mg, 0.65 mmol), and KI (4.3 mg, 0.03 mmol) were weighed into a reaction tube and added with 5 mL of acetonitrile. The mixture was reacted at 85°C for 2 h. The reaction was cooled to room temperature, saturated aqueous NaHCO₃ was added, and stirred for 0.5 h. The mixture was extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography with MeOH (0-5%) and DCM to yield 32 (28.0 mg, 50%) as a pale yellow solid. LC-MS: ESI [M+H] + =424.2; 1 H NMR (400MHz, DMSO) δ8.77–8.69(m,1H),8.65(s,1H),8.49(d,J=1.4Hz,1H),8.26(s,1H),7.97(p,J=8.3Hz,2H),7.74(s,1H),6.21(s,1H),3. 74(dd,J=43.1,14.0Hz,2H),3.27(s,2H),3.01(d,J=16.5Hz,2H),2.83(t,J=5.2Hz,3H),2.59(dd,J=21.4,3.8Hz,1H),0.99(d,J=6.8Hz,3H).

[0254] Example 33: 1-(7-ethyl-4-fluoro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-fluoro-N-methyl-1,2,3,6-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0255] Compound 12j (100 mg, 0.41 mmol), compound 5e (153 mg, 0.49 mmol), DIEA (268 mg, 2.05 mmol), and KI (14 mg, 0.082 mmol) were added to 2 ml of acetonitrile and the mixture was heated to 80°C for 2 h. After completion of the reaction by LC-MS, the mixture was cooled to room temperature, saturated sodium bicarbonate solution (4 ml) was added, and extraction was performed three times with 20 ml of ethyl acetate. The organic layer was washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound 33 (52 mg, white solid). LC-MS: ESI [M+H] + =440.5; 1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.80-8.68(m,2H),8.48(d,J=8.5Hz,1H), 8.09(dd,J=8.1,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.80(s,1H),6.78-6.72(m,1H ),5.67(d,J=48.7Hz,1H),3.87(s,2H),3.53-3.40(m,1H),3.20(t,J=14.6Hz,1H) ,3.12-2.98(m,1H),2.80-2.64(m,1H),2.63-2.53(m,2H),1.20(t,J=7.4Hz,3H).

[0256] Example 34: 3-ethyl-7-((5-fluoro-3'-methyl-3'-, 6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0257] Step 1: Compound 1b (7.8 g, 22.6 mmol), compound 34a (2.4 g, 24.9 mmol), Pd(dppf)Cl2 (8.2 g, 11 mmol), and potassium carbonate (62 g, 452 mmol) were added to a mixed solvent of 40 ml of dioxane and 4 ml of water. The nitrogen atmosphere was then replaced and the mixture was reacted at 80°C under nitrogen for 4 hours. After TLC detection, the reaction mixture was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 300 ml of ethyl acetate and 200 ml of water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 34b (12 g, white solid).

[0258] Step 2: Compound 34b (1 g, 3.4 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 34c (0.9 g, white solid).

[0259] Step 3: Compound 34c (0.05 g, 0.26 mmol), INT1 (0.069 g, 0.31 mmol), N,N-diisopropylethylamine (0.16 g, 2.3 mmol) and potassium iodide (0.20 g, 1.3 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 34 (0.022 g, white solid); LC-MS: ESI [M+H] + =365.2; 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.52(d,J=2.6Hz,1H),8.41(d,J=19.1Hz,2H),7.75(s,1H),7.69(s,1H),7.62(dd,J=8.8,4.5Hz ,1H),6.43(d,J=3.8Hz,1H),3.80(d,J=12.9Hz,1H),3.63(dd,J=10.0,6.2Hz,4H),3.16(dd,J=7.1,4.1Hz,4H),1.19(t,J=7.4Hz,3H).

[0260] Example 35: N-cyclopropyl-1'-((2-ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3'-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0261] Compound 11b (51 mg, 0.15 mmol), compound 27g (40 mg, 0.14 mmol), DIEPA (90.7 mg, 0.7 mmol), and KI (4.7 mg, 0.03 mmol) were weighed into a reaction tube and added with 10 mL of acetonitrile. The temperature was raised to 80°C and the reaction mixture was allowed to react for 3 h. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO₃ was added and stirred for 2 h. The solvent was concentrated in vacuo, and the mixture was then extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and then purified by column chromatography using MeOH (0-8%) and DCM to obtain 35 (22 mg, 34% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =462.2; 1H NMR (400MHz, CDCl3) δ9.43(s,1H),8.40(d,J=1.9Hz,1H),8.07(d,J=8.1Hz,1H),7.91(d,J=3.4Hz ,1H),7.67(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.4Hz,1H),7.35(t,J=7.5Hz,1H),5.92(t,J=3.1Hz, 1H),3.71(d,J=31.7Hz,2H),3.16(dd,J=59.0,16.3Hz,2H),2.95–2.83(m,4H),2.70(s,1H),2.53 –2.44(m,1H),1.28(t,J=7.4Hz,3H),0.93(d,J=6.9Hz,3H),0.83–0.77(m,2H),0.62–0.55(m,2H).

[0262] Example 36: N-cyclopropyl-1'-((2-ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3'-fluoro-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0263] Compound 31c (61.1 mg, 0.18 mmol), compound 27g (40.0 mg, 0.17 mmol), DIEPA (107.4 mg, 0.83 mmol), and KI (5.5 mg, 0.03 mmol) were weighed into a reaction tube and added with 5 mL of acetonitrile, which was reacted at 85°C for 2 h. The reaction was cooled to room temperature, and saturated aqueous NaHCO₃ was added and stirred for 2 h. The solvent was concentrated in vacuo, and then extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography with MeOH (0-7%) and DCM to afford Compound 36 (16 mg, 21% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =466.2; 1H NMR (400MHz, CDCl3) δ9.27(s,1H),8.62(d,J=1.8Hz,1H),8.17(d,J=8.2Hz,1H),7.99(d,J=3.2Hz,1H),7.91(dd, J=8.2,2.1Hz,1H),7.63(d,J=8.4Hz,1H),7.41(t,J=7.9Hz,1H),6.55–6.45(m,1H),5.34(dd,J=33.0,18.3Hz,1H ),3.91(s,2H),3.54(ddd,J=18.0,7.8,4.6Hz,1H),3.37–3.22(m,1H),3.12(dd,J=17.9,10.9Hz,1H),3.02–2.90 (m,3H),2.78(dd,J=29.9,10.2Hz,1H),1.35(t,J=7.4Hz,3H),1.25(s,3H),0.89–0.86(m,2H),0.69–0.62(m,2H).

[0264] Example 37: N-cyclopropyl-1'-((7-ethyl-4-fluoro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-fluoro-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0265] Compound 31c (76.4 mg, 0.23 mmol), compound 12j (50 mg, 0.21 mmol), DIEPA (113.3 mg, 1.0 mmol), and KI (6.9 mg, 0.04 mmol) were weighed into a reaction tube and added with 5 mL of acetonitrile, reacting at 85°C for 2 h. The reaction was cooled to room temperature, and saturated aqueous NaHCO₃ was added and stirred for 2 h. The solvent was concentrated in vacuo, and then extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography with MeOH (0-5%) and DCM to afford Compound 37 (58 mg, 60% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =466.2; 1H NMR (400MHz, DMSO) δ12.18(s,1H),8.76(dd,J=11.3,3.2Hz,2H),8.52(d,J=8.5Hz,1H),8.13(dd ,J=8.2,2.0Hz,1H),8.05(d,J=8.3Hz,1H),7.84(s,1H),6.85–6.72(m,1H),5.70(d,J=48.7Hz,1H ),3.92(s,2H),3.56–3.45(m,1H),3.29–3.18(m,1H),3.09(dd,J=17.3,12.4Hz,1H),3.00–2.90( m,1H),2.83–2.69(m,1H),2.62(q,J=7.4Hz,2H),1.24(dd,J=9.3,5.5Hz,3H),0.76–0.70(m,4H).

[0266] Example 38: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-(hydroxymethyl)-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0267] Step 1: Weigh compound 38a (0.25 g, 0.83 mmol), add 20 ml of tetrahydrofuran, replace nitrogen, cool to -78°C, add lithium diisopropylamide (0.46 mL, 0.91 mmol) dropwise, stir for 30 minutes, add N-phenylbis(trifluoromethanesulfonyl)imide (0.36 g, 1.0 mmol) dissolved in 10 mL of tetrahydrofuran dropwise, warm to room temperature and react for 2 hours. After TLC detection, the reaction is complete, saturated ammonium chloride aqueous solution is added to quench, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography gives compound 38b (0.25 g, colorless liquid).

[0268] Step 2: Compound 38b (0.25 g, 0.6 mmol), 2-methylpyridinium-5-boronate 1c (0.14 g, 0.66 mmol), Pd(dppf)Cl2 (0.04 g, 0.06 mmol) and potassium carbonate (0.16 g, 1.2 mmol) were added to a mixed solvent of 20 ml of dioxane and 2 ml of water, and then the nitrogen atmosphere was replaced. The reaction was carried out at 80°C under nitrogen protection for 3 hours. After TLC detection, the reaction was cooled to room temperature, concentrated by rotary evaporation, and extracted three times with 30 ml of ethyl acetate and 20 ml of water. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography, solidified by beating with petroleum ether, filtered, and dried to obtain compound 38c (180 mg, light yellow liquid); LC-MS: ESI [M+H] + =421.6.

[0269] Step 3: 38c (180 mg, 0.4 mmol), methylamine aqueous solution (0.12 mL, 1.6 mmol), and anhydrous methanol (15 mL) were added to a 25 mL reaction flask and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether, and filtered and dried to obtain compound 38d (160 mg, light yellow solid); LC-MS: ESI [M+H] + =420.6.

[0270] Step 4: Compound 38d (160 mg, 0.38 mmol) was added to 10 ml of anhydrous methanol, followed by the addition of 0.4 ml of a 4 mol / L hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, dioxane was added to precipitate a solid, which was filtered and dried to give compound 38e (80 mg, yellow solid); LC-MS: ESI [M+H] + =248.3.

[0271] Step 5: Compound 38e (80 mg, 0.25 mmol), INT1 (56 mg, 0.25 mmol), N,N-diisopropylethylamine (130 mg, 1.0 mmol) and potassium iodide (5 mg, 0.03 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85 ° C for 2 hours. After the reaction was completed as monitored by TLC, 10 ml of saturated sodium bicarbonate solution was added, and 30 mL of water was added to precipitate a solid, which was filtered and dried to obtain compound 38 (20 mg, white solid); LC-MS: ESI [M+H] + =434.5; 1H NMR (400MHz, CDCl3) δ8.51 (s, 1H), 8.48 (s, 1H), 8.15 (d, J = 8.1Hz, 1H), 8.10 (s, 1H) ,7.78(d,J=7.4Hz,2H),6.09(s,1H),4.62(d,J=13.4Hz,1H),4.33(d,J=13.2Hz,1H ),4.13(d,J=15.7Hz,1H),3.82–3.67(m,2H),3.67–3.50(m,2H),3.36(s,1H),3.23 (s, 1H), 3.04 (d, J = 3.9Hz, 3H), 2.67 (q, J = 7.3Hz, 2H), 1.28 (dd, J = 13.1, 5.7Hz, 6H).

[0272] Example 39: Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-methoxy-N-methyl-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0273] Step 1: Add tetrahydrofuran (7 ml) to tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate 39a (350 mg, 1.528 mmol), replace nitrogen, cool to -78 ° C, add lithium diisopropylamide (1.8 mL, 1.833 mmol) dropwise, stir for 30 min, add N-phenylbis(trifluoromethanesulfonyl)imide (655 mg, 1.833 mmol) dissolved in (2 ml) tetrahydrofuran dropwise, warm to room temperature and react for 2 h. After TLC detection, the reaction is complete, saturated aqueous ammonium chloride is added to quench, and the mixture is extracted three times with ethyl acetate. The organic phases are combined and dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give 400 mg of a crude compound 39b.

[0274] Step 2: Compound 39b (400 mg, 1.107 mmol), 2-methylpyridinium-5-boronate 1c (291 mg, 1.107 mmol), Pd(dppf)Cl2 (162 mg, 0.221 mmol), and potassium carbonate (458 mg, 3.321 mmol) were added to dioxane (5 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 90°C under nitrogen protection for 2 h. After the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound 39c (300 mg, yield: 77.65%). LC-MS: ESI [M+H] + =349.1.

[0275] Step 3: Compound 39c (300 mg, 0.861 mmol) and methylamine aqueous solution (2 mL) were added to anhydrous methanol (5 mL) and reacted at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 39d (300 mg, yield: 99.9%). LC-MS: ESI [M+H] + =348.1.

[0276] Step 4: Compound 39d (300 mg, 0.861 mmol) was added to dichloromethane (6 mL), and 4 mol / L dioxane hydrochloride solution (6 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 39e (300 mg). LC-MS: ESI [M+H] + =248.2.

[0277] Step 5: Compound 39e (200 mg, 0.890 mmol), INT1 (252 mg, 0.890 mmol), N,N-diisopropylethylamine (345 mg, 2.670 mmol) and potassium iodide (15 mg, 0.09 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 80 ° C for 2 h. After the reaction, the reaction solution was added to 20 mL of water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and sent to the preparation. The product was collected and lyophilized to obtain compound 39 (90 mg); LC-MS: ESI [M+H] + =434.2; 1 H NMR (400MHz, CDCl3) δ10.96 (s, 1H), 8.61 (s, 1H), 8.57 (d, J = 4.0Hz, 1H), 8.17-8 .13(m,1H),7.98-7.95(m,1H),7.89-7.86(m,2H),7.72(s,1H),6.36(t,J=4.0Hz ,1H),3.77–3.71(m,1H),3.54-3.48(m,2H),3.33(s,3H),3.15-3.09(m,2H),3.0 4(d,J=4.0Hz,3H),2.76-2.71(m,3H),2.60-2.54(m,1H),1.31(t,J=8.0Hz,3H).

[0278] Example 40: Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-hydroxy-N-methyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0279] Step 1: Compound 40a (5.0 g, 0.019 mol) was added to dichloromethane (25 mL), and trifluoroacetic acid (25 mL) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 5.0 g of a crude product of compound 40b.

[0280] Step 2: Compound 40b (5.0 g, 23.5 mmol), triethylamine (7.145 g, 70.7 mmol) and di-tert-butyl dicarbonate (7.71 g, 35.3 mmol) were added to ethanol (50 mL). After the addition, the mixture was reacted at room temperature for 4 h. After the reaction, water (30 mL) was added to quench the reaction. Ethyl acetate (30 mL × 3 times) was added for extraction. The organic phase was washed with water (10 mL × 3 times). The organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography to obtain compound 40c (2.0 g, yield: 39.56%).

[0281] Step 3: Compound 40c (2.0 g, 9.29 mmol) and imidazole (1.264 g, 18.58 mmol) were added to dichloromethane, the reaction system was cooled to 0°C, and tert-butyldimethylsilyl chloride (1.68 g, 11.1 mmol) was added. After the addition was complete, the reaction was allowed to react at room temperature for 1 h. After the reaction was complete, water (30 mL) was added to quench the reaction, and dichloromethane (30 mL × 3 times) was added for extraction. The organic phase was washed with water (10 mL × 3 times), and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain compound 40d (2.0 g, yield: 48.1%).

[0282] Step 4: Compound 40d (1.6 g, 4.860 mmol) was added to tetrahydrofuran (20 mL), the nitrogen atmosphere was replaced, the temperature was lowered to -78°C, potassium bistrimethylsilylamide (7.29 mL, 7.29 mmol) was added dropwise, and N-phenylbis(trifluoromethanesulfonyl)imide (2.251 g, 6.318 mmol) dissolved in (10 mL) tetrahydrofuran was added dropwise after stirring for 30 minutes. The mixture was heated to room temperature and reacted for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3 times). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 2.5 g of a crude product of compound 40e.

[0283] Step 5: Compound 40e (2.5 g, 5.421 mmol), 2-methylpyridinium-5-boronate 1c (1.426 g, 5.421 mmol), Pd(dppf)Cl2 (396 mg, 0.541 mmol), and potassium carbonate (2.244 g, 16.264 mmol) were added to dioxane (25 mL) and water (2.5 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C under nitrogen for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound 40f (400 mg, yield: 16.47%). LC-MS:ESI [M+H] + =449.2.

[0284] Step 6: Compound 40f (400 mg, 0.8923 mmol) and methylamine alcohol solution (3 mL) were added to anhydrous methanol (4 mL) and reacted at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 40g (380 mg, yield: 95.0%). LC-MS: ESI [M+H] + =448.2.

[0285] Step 7: Compound 40g (380 mg, 0.849 mmol) was added to dichloromethane (4 mL), and 4 mol / L dioxane hydrochloride solution (4 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 40h (380 mg). LC-MS: ESI [M+H] + =234.2.

[0286] Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3'-hydroxy-N-methyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 1. LC-MS: ESI [M+H] + =420.2; 1H NMR (400MHz, CDCl3) δ11.86 (s, 1H), 8.72-8.69 (m, 2H), 8.48 (d, J = 4.0Hz, 1H), 8.05- 8.03(m,1H),7.98-7.96(m,1H),7.77(s,1H),7.65(d,J=4.0Hz,1H),6.39(t,J=4.0Hz ,1H),4.98(d,J=8.0Hz,1H),4.61(s,1H),3.76(d,J=12.0Hz,2H),3.26–3.14(m,2H) ,3.12-3.07(m,1H),2.82(d,J=8.0Hz,3H),2.73-2.54(m,3H),1.31(t,J=8.0Hz,3H).

[0287] Example 41: 1'-((2-chloro-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0288] Step 1: 2-Hydroxy-6-methylnicotinic acid 41a (350 g, 2.287 mol) was added to concentrated sulfuric acid (1400 mL). Potassium nitrate (462.5 g, 4.575 mol) was slowly added in portions. After the addition was complete, the temperature was raised to 90°C and the reaction was allowed to proceed for 4 h. After the reaction was completed, the reaction solution was added to ice water (3000 mL), stirred for 1 h, filtered, and the product was collected and dried under reduced pressure to obtain compound 41b (red solid, 215 g, yield 47.48%). LC-MS: ESI [M+H] + =199.1.

[0289] Step 2: Compound 41b (215 g, 1.086 mol) was added to methanol (1000 mL). After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure until about 200 mL remained. The filter cake was collected by filtration and dried to obtain compound 41c (yellow solid, 226 g, yield 98.1%). LC-MS: ESI [M+H] + =213.4.

[0290] Step 3: Compound 41c (212 g, 1.04 mol) was added to phosphorus oxychloride (300 mL). The reaction system was heated to 110°C. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction solution was added to ice water (500 mL) to quench the reaction. Ethyl acetate (1000 mL × 3 times) was added for extraction. The organic phase was washed with water (500 mL × 3 times). The organic phase was concentrated under reduced pressure. Petroleum ether (500 mL) was added to the concentrate and the mixture was slurried. The mixture was filtered and the filter cake was collected to obtain compound 41d (yellow solid, 175 g, yield 73.32%). LC-MS: ESI [M+H] + =231.0.

[0291] Step 4: Compound 41d (126 g, 0.55 mol) and DMF-DMA (130.38 g, 1.1 mol) were added to DMF (800 mL). The reaction system was heated to 100°C for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure and quenched by adding ice water (2000 mL). The mixture was extracted with ethyl acetate (1000 mL × 3 times). The organic phase was washed with water (500 mL × 3 times), concentrated under reduced pressure, and the concentrate was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to collect the product, compound 41e (yellow solid, 60 g, yield 38.43%). LC-MS: ESI [M+H] + =286.1.

[0292] Step 5: Compound 41e (70 g, 0.2456 mol) was added to THF (700 mL), the reaction system was cooled to 0°C, and an aqueous solution of sodium periodate (158 g, 0.736 mol) was added. After the addition was complete, the reaction was allowed to react at room temperature for 12 h. After the reaction was completed, the reaction solution was quenched by adding water (1000 mL), and extracted with ethyl acetate (1000 mL × 3 times). The organic phase was washed with water (500 mL × 3 times), and the organic phase was concentrated under reduced pressure. The concentrate was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to collect the product to obtain compound 41f (red solid, 26 g, yield 43.38%). LC-MS: ESI [M+H] + =245.1.

[0293] Step 6: Sodium hydroxide (8.52 g, 0.213 mol) was added to THF (300 mL). The reaction system was cooled to 0°C and ethyl 2-(diethoxyphosphoryl)butyrate (53.76 g, 0.213 mol) was added. After complete addition, the mixture was allowed to return to room temperature and react for 2 h. The reaction solution was cooled to -70°C and compound 41f (26 g, 0.1065 mol) was added dropwise. The mixture was reacted at -70°C for 2 h. After completion of the reaction, water (200 mL) was added to quench the reaction. Ethyl acetate (300 mL x 2) was added, and the organic phase was washed with water (100 mL x 3). The organic phase was concentrated under reduced pressure and the concentrate was subjected to column chromatography (petroleum ether:ethyl acetate = 100:0 to 10:1) to obtain compound 41g (yellow oil, 15 g, yield 41.17%). LC-MS: ESI [M+H] + =343.2.

[0294] Step 7: Compound 41g (15.0g, 43.85mmol) and iron powder (14.73g, 263.1mmol) were added to glacial acetic acid (150mL), and the reaction system was heated to 80°C for 2h. After the reaction, dichloromethane (200mL) was added and filtered. The filtrate was collected and the pH of the filtrate was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The organic phase was washed with water (50mL×3 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain compound 41h (yellow solid, 5g, yield 42.76%). LC-MS: ESI [M+H] + =367.1.

[0295] Step 8: Compound 41h (4.8 g, 18.0 mmol) was added to tetrahydrofuran (50 mL), the reaction system was cooled to 0°C, diisobutylaluminum hydride (27 mL, 54.0 mmol) was added, and the temperature was naturally raised to room temperature after the addition. After the reaction was completed, the reaction solution was quenched by adding water (10 mL), and extracted with dichloromethane and methanol = 5:1 (300 mL × 2 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain compound 41i (yellow solid, 2 g, yield 46.8%), LC-MS: ESI [M+H] + =239.1.

[0296] Step 9: Compound 41i (100 mg, 0.420 mmol) was added to dichloromethane (2 mL), the reaction system was cooled to 0°C, and Dess-Martin periodinane (214 mg, 0.504 mmol) was added. After the addition was complete, the reaction was allowed to react at room temperature for 1 h. After the reaction was completed, water (2 mL) was added to quench the reaction, and dichloromethane was added for extraction. The organic phase was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (dichloromethane: methanol = 30:1 to 10:1) to collect the product to obtain compound 41j (90 mg, yield: 90.78%), LC-MS: ESI [M+H] + =452.2.

[0297] Step 10: Compound 1f (45 mg, 0.169 mmol) was added to dichloromethane (2 mL), triethylamine (17 mg, 0.169 mmol) was added and stirred for 10 min, then compound 41j (45 mg, 0.169 mmol) was added and stirred for 2 h, and finally sodium triacetoxyborohydride (36 mg, 0.169 mmol) was added and reacted at room temperature for 2 h. After the reaction, the reaction solution was added to water (2 mL), the liquid was separated, the organic phase was concentrated under reduced pressure, and the concentrate was sent to the preparation, and the product was collected to obtain compound 41 (white solid, 20 mg, yield: 26.2%), LC-MS: ESI [M+H] + =452.2, HNMR(400M-d-DMSO):11.11(s,1H),8.54(s,1H),8.17(d,J=8.0Hz,1H),7.99-7.96(m,1H),7.79-7.76(m,2H),6.05-6.03(m,1H),3.81(m 2H),3.24-3.18(m,1H),3.06(d,J=4.0Hz,3H),2.96(s,1H),2.86-2.82(m ,1H),2.70-2.65(m,3H),1.31-1.26(m,4H),1.31-1.26(d,J=8.0Hz,3H).

[0298] Example 42: (S)-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide and Example 43: (R)-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,3'-dimethyl-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0299] Compound 15 was chiral resolved to give compounds 42 and 43. The resolution was performed using a Waters 150 Prep-SFC column, Chiralcel AD column, mobile phase A: carbon dioxide, mobile phase B: 0.1% ammonia in isopropanol, gradient: 70% mobile phase B, pressure: 100 bar, flow rate: 100 mL / min.

[0300] Example 44: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,2,3'-trimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0301] Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,2,3'-trimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 14. LC-MS: ESI [M+H] + =432.2.

[0302] Example 45: 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

[0303] Step 1: Compound 4b (1 g, 4.6 mmol), 45a (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 45b (1 g, white solid).

[0304] Step 2: To a 100 mL reaction flask, add 45b (1 g, 3 mmol), aqueous methylamine (5 g, 161.3 mmol), and anhydrous methanol (20 mL). 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 afford compound 45c (0.8 g, white solid).

[0305] Step 3: Compound 45c (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 completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 45d (0.5 g, white solid).

[0306] Step 4: Compound 45d (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 45 (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).

[0307] Biological activity test:

[0308] 1. PARP-1 enzyme assay

[0309] 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).

[0310] 1.1 PARP1 enzyme assay

[0311] 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.

[0312] 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.

[0313] 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.

[0314] 1.1.4 Blocking: Transfer 50 μL of blocking solution to a 384-well reaction plate and let it stand for 1 hour.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 1.1.15 Reading: Use Envision to read the chemiluminescence value RLU.

[0327] The test results are shown in Table 2 below:

[0328] Table 2 PARP-1 enzyme test results

[0329] Conclusion: The compounds of the present invention have a significant inhibitory effect on PARP1.

[0330] 2. Cell anti-proliferation activity test:

[0331] 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%.

[0332] 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:

[0333] 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%.

[0334] The test results are shown in Table 3 below:

[0335] Table 3 Cell antiproliferative activity test results

[0336] Conclusion: Compounds 1, 2, 5, 6, 8, 21, 23, 29 and 38 of the present invention have significant inhibitory effects on BRCA mutant MDA-MB-436 cells, but have no obvious inhibitory effect on BRCA wild-type DLD-1 cells, indicating that compounds 1, 2, 5, 6, 8, 21, 23, 29 and 38 of the present invention specifically inhibit homologous recombination-deficient tumor cells.

[0337] 3. Inhibition experiment of compounds on hERG potassium channels

[0338] Cell Culture and Treatment: CHO cells stably expressing hERG were cultured in a cell culture flask at 37°C in a 5% CO2 incubator. When the cell density reached 60-80%, the cell culture medium was aspirated, the cells were washed once with PBS, and then digested with Detachin. After complete digestion, the cells were neutralized with culture medium, centrifuged, and the supernatant aspirated. The cells were then resuspended in culture medium to adjust the cell density to 2-5 × 106 / mL.

[0339] Compound Preparation: Dilute the compound stock solution with 100% DMSO by adding 10 μL of compound stock solution to 20 μL of DMSO and serially diluting the solution 3-fold to six concentrations. Add 4 μL of each of the six concentrations to 396 μL of extracellular fluid, achieving a 100-fold dilution to obtain six intermediate concentrations. Then, add 80 μL of each of the six intermediate concentrations to 320 μL of extracellular fluid, achieving a 5-fold dilution to the desired final concentration. The highest concentration tested was 40 μM, followed by six concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration has no effect on hERG potassium channels. Compound preparation was performed using the Bravo instrument throughout the entire dilution process.

[0340] Electrophysiological recordings: Single-cell high-impedance sealing and whole-cell pattern formation were automated by the Qpatch instrument. After acquiring whole-cell recording mode, cells were clamped at -80 mV. A 50-millisecond pre-depolarization of -50 mV was applied before a 5-second depolarization of +40 mV. The cells then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage was applied every 15 seconds. After recording for 2 minutes, extracellular solution was added for 5 minutes. Drug administration then began. Compound concentrations were administered for 2.5 minutes at each test concentration, starting with the lowest tested concentration. After all concentrations were administered, the positive control compound, 3 μM Cisapride, was administered. At least three cells were tested for each concentration (n ≥ 3).

[0341] Data processing: Data analysis and processing were performed using GraphPad Prism 5.0 and Excel software. Compound IC50 was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0342] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0343] The experimental results are shown in Table 4 below:

[0344] Table 4 Inhibition results of compounds on hERG potassium channels

[0345] Conclusion: Compounds 5 and 6 of the present invention have weak inhibitory effects on hERG potassium channels.

[0346] 4. Pharmacokinetic evaluation of the compound in Balb / c mice

[0347] Experimental purpose: To understand the pharmacokinetics of the compound.

[0348] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0349] 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.

[0350] 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.

[0351] 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. Reference compound AZD5305 was purchased from MedChemExpress (MCE)

[0352] The results of the pharmacokinetic evaluation are shown in Table 5 below:

[0353] Table 5 Pharmacokinetic test results of the compounds in Balb / c mice

[0354] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance. 1 mg / kg oral gavage, compounds 2, 6, 24 and 42 and other compound C max It is superior to reference compounds AZD5305 and compound 45, etc.

[0355] 5. Pharmacokinetic evaluation of the compound in SD rats

[0356] Experimental purpose: To understand the pharmacokinetics of the compound.

[0357] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0358] Experimental plan: The pharmacokinetics of the compound were investigated by oral and intravenous administration in SD rats.

[0359] 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.

[0360] The results of the pharmacokinetic evaluation are shown in Table 6 below:

[0361] Table 6 Pharmacokinetic test results of the compounds in SD rats

[0362] Conclusion: The compound of the present invention has good pharmacokinetic properties in SD rats, including good oral bioavailability, exposure, half-life and clearance.

[0363] 6. Evaluation of PARP enzymatic selectivity

[0364] Table 7 Reagents

[0365] Experimental process:

[0366] (1) Coating histone substrate: 5x histone was diluted to 1x with PARP buffer solution, 25uL per well was coated at 4℃ overnight.

[0367] (2) Add 100uL of PBST to the 384 reaction plate and wash the plate three times, 5 minutes each time.

[0368] (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.

[0369] (4) Compound preparation: Add 100 nL of compound to a 384-well reaction plate and centrifuge for 1 minute.

[0370] (5) Add 5uL PARP protein to the 384 reaction plate and centrifuge at 1000rpm for 1 minute.

[0371] (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.

[0372] (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.

[0373] (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.

[0374] (9) Read the luminescence signal of the compound using a BMG microplate reader.

[0375] The results of the enzyme selectivity experiment are shown in Table 8 below:

[0376] Table 8 Results of the test on the selectivity of compounds for PARP family enzymes

[0377] Conclusion: The compounds of this invention have high inhibitory activity against PARP-1 enzyme, but weaker inhibitory activity against PARP-2, PARP-5A, and PARP-11 of the same family. Compounds 2 and 42 have better selectivity against PARP-2, PARP-5A, and PARP-11 than the reference compound AZD5305.

[0378] 7. In vivo pharmacodynamic study of compound 2 on MDA-MB-436 nude mouse subcutaneous transplant tumor model

[0379] Experimental Procedure: Fifteen female NOD / SCID mice were randomly divided into three groups, each containing five mice: a blank control group, a Compound 2 (0.1 mg / kg) group, and a Compound 2 (0.3 mg / kg) group. All mice were orally administered once daily. Body weights were measured every two days, and tumor length and width were measured using a vernier caliper.

[0380] Conclusion: The experimental results are shown in Figure 1. Compound 2 of the present invention has a significant inhibitory effect on the MDA-MB-436 mouse model, especially when compound 2 is orally administered once a day at a dose of 0.3 mg / kg, the tumor is completely suppressed after 34 days.

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, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl or C 2-4 alkenyl; 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, cyano, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered fluorinated cycloalkyl; R 9c is selected from hydrogen or halogen; R2 is selected from hydrogen or C 1-4 alkyl; R 3a Selected from halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl or 3-6 membered cycloalkyl; R 3b Selected from hydrogen, halogen or C 1-4 alkyl; R 3c 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; 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 chlorine, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or vinyl.

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, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

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 3a is selected from fluorine, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R 3b is selected from hydrogen, fluorine or methyl.

9. The compound according to claim 1, characterized in that: R 3c is selected from hydrogen or methyl.

10. 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.

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

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

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

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

15. The compound according to any one of claims 1 to 14, characterized in that: Structural unit Selected from the following structures:

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable form thereof, characterized in that: It has the structure described in Formula II-1, Formula II-2 or Formula II-3:

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable form thereof, characterized in that: It has the structure described in Formula III-1, Formula III-2, Formula III-3 or Formula III-4:

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable form thereof, characterized in that: The compound is selected from:

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable form thereof, characterized in that: The compound is selected from:

20. A compound or a pharmaceutically acceptable form thereof, characterized in that: The compound is selected from:

21. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

22. The compound according to any one of claims 1 to 20, 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 21, are used in the preparation of a medicament for preventing and / or treating PARP1 enzyme-related diseases.

23. The use according to claim 22, characterized in that: The PARP1 enzyme-related disease is a tumor-related disease.

24. The use according to claim 23, characterized in that: The tumor-like disorders are deficient in the HR-dependent DNA DSB repair pathway.

25. The use according to claim 23 or 24, 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.

26. The use according to claim 25, characterized in that: The cancer cells have a BRCA1 or BRCA2 deficient phenotype.

27. The use according to any one of claims 23 to 26, 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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