Naphthyridine compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application discloses a naphthyridine compound as shown in formula I and a preparation method, a pharmaceutical composition and an application thereof. The compound can selectively inhibit the activity of poly (ADP-ribose) polymerase 1, has low inhibitory activity on poly (ADP-ribose) polymerase 2, and has good inhibitory activity on nicotinamide phosphoribosyltransferase. Meanwhile, the compound has significant therapeutic effect on tumors with BRAC1 / 2 mutation and tumors without BRAC1 / 2 mutation, has small toxic and side effects, and has high safety.

Description

Technical Field

[0001] This invention relates to a naphthidine compound, its preparation method, pharmaceutical composition and application, and more particularly to a naphthidine poly(ADP-ribose) polymerase 1 inhibitor and a nicotinamide phosphoribosyltransferase dual inhibitor, its pharmaceutical composition and application. Background Technology

[0002] Poly(ADP-ribose) polymerase catalyzes the ADP-ribose transfer of nicotinamide adenine dinucleotide to its receptor protein, thereby catalyzing poly(ADP-ribosylation) of the protein. Therefore, PARP plays a crucial role in single-stranded DNA repair. The PARP protein family consists of 18 members, whose catalytic domains exhibit high similarity. With the participation of PARP, broken single-stranded DNA can be repaired, allowing cells to survive. When PARP is inhibited by its inhibitors, the unrepaired single-stranded DNA leads to double-stranded DNA breaks. Under normal circumstances, homologous recombination repair mechanisms can repair broken double-stranded DNA, allowing cells to continue to survive. However, when homologous recombination repair is deficient in cells, i.e., when enzymes involved in the HR repair pathway, such as BRAC1 / 2, are lacking, cells die due to the inability to repair DNA damage. This is the synthetic lethal mechanism of PARP inhibitors and HRD.

[0003] Currently, there are small molecule PARP inhibitors available for treating BRAC-mutated ovarian, breast, pancreatic, and prostate cancer, including olaparib, rucaparib, niraparib, tapolazoparib, fluzoparib, and pamiparib. Although PARP inhibitors have significantly improved the prognosis of various HRD-positive malignancies, their development faces many challenges. First, the indications for PARP inhibitors are narrow, benefiting a limited patient population. They are only effective against HRD-positive tumors that can induce synthetic lethality, limiting their clinical application. Second, a significant proportion of HRD-positive tumors exhibit innate resistance to PARP inhibitors or develop acquired resistance after a period of use. Furthermore, current PARP inhibitors lack selectivity for both PARP1 and PARP2; inhibiting PARP1 is sufficient to exert antitumor activity, while inhibiting PARP2 can produce toxic side effects.

[0004] NAD + Nicotinamide is a cofactor for many redox enzymes in the body, participating in energy metabolism processes, and is also a substrate for key enzymes in many signal transduction processes. The salvage synthesis pathway using nicotinamide as a starting material involves the body's replenishment of NAD. + The most important and direct source is NAD+, and nicotinamide phosphoribosyltransferase is the key rate-limiting enzyme catalyzing this process. Tumor cells have a much higher proliferation and energy demand than normal cells; therefore, tumor cells have a high reliance on NAD+. +It exhibits a higher dependence on NAMPT and is more sensitive to changes in NAMPT activity. Numerous studies have shown that, in addition to participating in energy metabolism, NAMPT plays a crucial role in cancer stem cells, epithelial-mesenchymal transition and metastasis, DNA repair, signal transduction, and tumor immune escape. Currently, there are no NAMPT inhibitor drugs on the market, and further clinical trials of FK866 and CHS828 were terminated due to poor therapeutic effects and dose-dependent toxicity. Summary of the Invention

[0005] Objectives of the Invention: The first objective of this invention is to provide a naphthidine compound with dual inhibitory activities of poly(ADP-ribose) polymerase 1 inhibitor and nicotinamide phosphoribosyltransferase; the second objective is to provide a method for preparing the compound; the third objective is to provide a pharmaceutical composition containing the compound; and the fourth objective is to provide a pharmaceutical application of the compound and the pharmaceutical composition thereof.

[0006] Technical solution: This invention relates to naphthidine compounds as shown in Formula I, or their pharmaceutically acceptable salts, enantiomers, diastereomers, cis-trans isomers, tautomers, trans-blocking isomers, conformational isomers, metabolites, prodrugs, solvates, deuterated derivatives, and hydrates.

[0007]

[0008] In Formula I:

[0009] X is N or C;

[0010] Y is C 6-10 Aryl or 5- to 10-membered heteroaryl containing 1 to 3 N, O, or S heteroatoms;

[0011] L1 is a single bond. The left side is connected to Y, and the right side is connected to Z;

[0012] Z represents a single bond or C. 6-10 Aryl;

[0013] L2 is -(CH2) n -, where n is 0, 1, 2, or 3;

[0014] R1 is a 9- to 10-membered bicyclic heteroaryl group containing one N atom and one to two N, O, and S heteroatoms.

[0015] In some embodiments, Y is phenyl or pyridyl;

[0016] n is 0, 1, or 2.

[0017] In some implementations, Y is phenyl or

[0018] n is 0 or 1.

[0019] In some implementations, Z is a single bond or a phenyl group;

[0020] R1 is imidazopyridyl, imidazopyrimidyl, pyrazolopyridyl, thienopyridyl, furanopyridyl, tetrahydropyrrolopyridyl, or tetrahydropyrrolophenyl.

[0021] In some implementations, R1 is

[0022]

[0023] In some embodiments, the naphthidine compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, cis-trans isomers, tautomers, trans-blocking isomers, conformational isomers, metabolites, prodrugs, solvates, deuterates, or hydrates, have structures as shown in formulas IA, IB, and IC.

[0024]

[0025] The definitions of X, Y, and R1 are as described above.

[0026] In some embodiments, the naphthidine compound represented by Formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, trans-block isomer, conformational isomer, metabolite, prodrug, solvate, deuterated product, or hydrate is selected from any one of the following compounds:

[0027]

[0028] NAMPT inhibitors inhibit NAD + The generation of NAMPT inhibitors inhibits the substrate supply of PARP and enhances the competitive inhibition of the PARP catalytic domain by PARP inhibitors. Therefore, NAMPT inhibitors can increase DNA damage, thereby increasing the antitumor activity of PARP inhibitors. NAMPT activity can reduce BRAC1 / 2 expression, reduce RAD51 expression, and induce HRD. NAMPT inhibitors and PARP1 inhibitors exhibit synergistic antitumor effects in BRAC wild-type triple-negative breast cancer and Ewing sarcoma. However, combination therapy has drawbacks such as potential drug-drug interactions, unclear pharmacokinetic properties, and poor patient compliance. Dual-target or multi-target drugs can reduce toxicity, increase efficacy, and avoid the drawbacks of combination therapy. Therefore, developing dual-target inhibitors of PARP and NAMPT can improve the narrow indications of PARP inhibitors, increase the selectivity of PARP1, reduce the significant toxicity and drug resistance of NAMPT inhibitors.

[0029] To address the limitations of poly(ADP-ribose) polymerase inhibitors in terms of their limited application range and low selectivity, as well as the dose-dependent nature of nicotinamide phosphoribosyltransferase inhibitors, this invention designs a dual inhibitor of naphthidine-based poly(ADP-ribose) polymerase 1 and nicotinamide phosphoribosyltransferase. This inhibitor demonstrates significant therapeutic effects on both tumors carrying and not carrying BRAC1 / 2 mutations, with minimal toxic side effects.

[0030] The compounds designed in this invention can exist in specific stereoisomer forms. The term "isomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, transisomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0031] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acids such as citric acid, tartaric acid, and methanesulfonic acid; organic acid salts also include salts of organic acids such as amino acids (e.g., arginine), glucuronic acid, etc. Certain specific compounds of the present invention contain basic and acidic functional groups, thus allowing them to be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0032] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0033] The term "metabolite" refers to a pharmaceutically active product produced in vivo by the metabolism of a compound of Formula I or a salt thereof. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds produced by methods that expose the compounds of this invention to mammals for a sufficient period of time to obtain their metabolites.

[0034] The identification of metabolites is typically performed by preparing a radiolabeled isotope of the compound of the invention, administering it parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the metabolites from urine, blood, or other biological samples. These products are readily isolated because they are labeled (others are isolated using antibodies capable of binding to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS, or NMR analysis. Typically, the analysis of metabolites is performed using methods known to those skilled in the art for routine drug metabolism studies. The metabolite products can be used for assays of therapeutic doses of the compound of the invention, provided they are not otherwise undetectable in vivo. The compounds of the invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be radiolabeled with radioisotopes, such as tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0035] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of this invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., the compound shown in Formula I) is a prodrug within the scope and spirit of this invention. For example, compounds containing a carboxyl group can form physiologically hydrolyzable esters, which act as prodrugs by hydrolysis in vivo to yield the compound shown in Formula I itself. The prodrugs are preferably administered orally because hydrolysis in many cases occurs primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or when hydrolysis occurs in the bloodstream.

[0036] The term "deuterated compound" refers to a molecule in which any hydrogen atom can be replaced by its isotope deuterium. In the compounds involved in this invention, any hydrogen atom can be replaced by a deuterium atom.

[0037] The term "aryl" refers to an aromatic group having a specified number of carbon atoms, preferably a monocyclic, bicyclic, or tricyclic aromatic group. When it is bicyclic or tricyclic, each ring satisfies Hückel's rule. The present invention's C... 6-10 The aryl group refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl.

[0038] The term "heteroaryl" refers to a 9- to 10-membered bicyclic heteroaryl group containing one nitrogen atom and one or two other heteroatoms selected from nitrogen, oxygen, and sulfur. This includes bicyclic groups formed by the fusion of an unsaturated monocyclic ring containing a heteroatom and an aryl group, bicyclic groups formed by the fusion of two unsaturated monocyclic rings containing heteroatoms, and bicyclic groups formed by the fusion of a saturated monocyclic ring containing a heteroatom and a heteroaryl group or aryl group. When the "heteroaryl" is a bicyclic group formed by the fusion of a saturated monocyclic ring containing a heteroatom and a heteroaryl group, it is linked to other segments or groups in the compound shown in Formula I through the saturated monocyclic ring containing the heterocycle. The 9- to 10-membered bicyclic groups include, but are not limited to, imidazopyridine, imidazopyrimidine, pyrazolopyridine, thienopyridine, furanopyridine, tetrahydropyrrolopyridine, or tetrahydropyrrolophenyl.

[0039] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... This refers to the connection of the corresponding group to other segments or groups in the compound shown in Formula I through this site.

[0040] This invention provides a method for preparing naphthidine compounds as shown in Formula I, or their pharmaceutically acceptable salts, enantiomers, diastereomers, cis-trans isomers, tautomers, trans-blocking isomers, conformational isomers, metabolites, prodrugs, solvates, deuterated derivatives, or hydrates, specifically comprising the following steps:

[0041] Compound II and compound III undergo a condensation reaction in the presence of a base and a catalyst to yield compound I:

[0042]

[0043] Where X, Y, Z, L1, L2, and R1 are as described above; M is chlorine, bromine, or iodine.

[0044] The solvents mentioned in the above reactions include, but are not limited to, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane, N-methylpyrrolidone, or mixtures thereof;

[0045] The base mentioned in the above reaction is an organic base, including but not limited to triethylamine, pyridine, and N,N-diisopropylethylamine (DIPEA); preferably triethylamine or N,N-diisopropylethylamine.

[0046] The catalyst mentioned in the above reaction is sodium iodide or potassium iodide.

[0047] This invention provides the use of naphthidine compounds of Formula I or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, cis-trans isomers, tautomers, transisomers, conformational isomers, metabolites, prodrugs, solvates, deuterated products, and hydrates in the preparation of medicaments for poly(ADP-ribose) polymerase 1 inhibitors and / or nicotinamide phosphoribosyltransferase inhibitors.

[0048] This invention provides the use of naphthidine compounds as shown in Formula I, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, cis-trans isomers, tautomers, transisomers, conformational isomers, metabolites, prodrugs, solvates, and hydrates thereof, in the preparation of medicaments for the treatment and / or prevention of cancer.

[0049] In some implementations, the cancer is one or more of the following: bone cancer, lung cancer, stomach cancer, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, glioma, prostate cancer, pancreatic cancer, liver cancer, brain cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0050] The present invention provides a pharmaceutical composition comprising a naphthidine compound as shown in Formula I or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a cis-trans isomer, a tautomer, a transisomer, a conformational isomer, a metabolite, a prodrug, a solvate, a deuterated compound, a hydrate, and a pharmaceutically acceptable carrier or excipient.

[0051] In some embodiments, the amount of the naphthidine compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, transisomer, conformational isomer, metabolite, solvate, deuterated product, or hydrate in the pharmaceutical composition is a therapeutically effective amount.

[0052] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for a poly(adenosine diphosphate ribose) polymerase 1 inhibitor and / or a medicament for a nicotinamide phosphoribosyltransferase inhibitor.

[0053] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer.

[0054] In some implementations, the cancer is one or more of the following: bone cancer, lung cancer, stomach cancer, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, glioma, prostate cancer, pancreatic cancer, liver cancer, brain cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0055] The pharmaceutically acceptable carrier can be an excipient widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to allow the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient can be an inert filler, or it may provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0056] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0057] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0058] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0059] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0060] The compounds designed in this invention can selectively inhibit the activity of poly(ADP-ribose) polymerase 1 (PPB1), while exhibiting low inhibitory activity against PPB2, and also show good inhibitory activity against nicotinamide phosphoribosyltransferase (NPT). Furthermore, they demonstrate significant therapeutic effects on both BRAC1 / 2-mutated and non-BRAC1 / 2-mutated tumors, with minimal toxicity and high safety. Detailed Implementation

[0061] The technical solution of the present invention will be further described below with reference to the embodiments.

[0062] Example 1: Synthesis of compound S1

[0063]

[0064] Step 1: Synthesis of Intermediate 5

[0065]

[0066] a) Compound 1 (1.4 g, 4.9603 mmol) was dissolved in pyridine (10 mL). 4-Cyanobenzenesulfonyl chloride (1 g, 4.9603 mmol) was added to the reaction system, and the mixture was reacted at room temperature for 16 hours. After complete reaction, water was added and the mixture was filtered to give intermediate 2 (1.1 g, 50%). MS (ESI, m / z): 444.2 (M + +1).

[0067] b) Intermediate 2 (1.1 g, 2.4831 mmol) was dissolved in MeOH / DMF (15 mL / 15 mL). Nickel chloride hexahydrate (886 mg, 3.7246 mmol) was added to the reaction system, and sodium borohydride (142 mg, 3.7246 mmol) was slowly added at 0 °C. The reaction was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was cooled to 0 °C, and sodium borohydride was quenched with 2 M HCl aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 3 (350 mg, 32%). MS (ESI, m / z): 448.2 (M + +1).

[0068] c) Intermediate 3 (350 mg, 0.7830 mmol) was dissolved in DMF (4 mL). Imidazolo[1,2-A]pyridine-7-carboxylic acid (127 mg, 0.7830 mmol), HATU (389 mg, 1.0179 mmol), and DIPEA (303 mg, 2.3489 mmol) were added to the reaction system. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, water was added and the mixture was filtered to give intermediate 4 (380 mg, 83%). MS (ESI, m / z): 592.2 (M + +1).

[0069] d) Intermediate 4 (380 mg, 0.28 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added to the reaction system. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, intermediate 5 (240 mg, 76%) was obtained by vacuum distillation. MS (ESI, m / z): 492.2 (M + +1).

[0070] Step 2: Synthesis of compound S1

[0071]

[0072] a) Compound 6 (100 mg, 0.4902 mmol) was dissolved in DCM (6 mL) and DMF (0.2 mL). Thionyl chloride (214 μL, 2.9412 mmol) was slowly added to the reaction system at -15 °C. The reaction was carried out at room temperature for 6 hours. After complete reaction, the mixture was distilled under reduced pressure to give intermediate 7 (80 mg, 74%). MS (ESI, m / z): 223.1 (M + +1).

[0073] b) Intermediate 7 (80 mg, 0.3604 mmol) was dissolved in MeCN (1.5 mL) and DMF (3 mL), and compound 5 (177 mg, 0.3604 mmol), KI (90 mg, 0.5406 mmol) and DIPEA (377 μL, 2.1624 mmol) were added. The mixture was reacted at 80 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, filtered, and the filter cake was purified by column chromatography to obtain compound S1 (65 mg, 27%).

[0074] S1: 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.32(t,J=6.0Hz,1H),8.62(d,J=7.1Hz,1H),8. 38(d,J=1.8Hz,1H),8.17(s,1H),8.07(s,1H),7.83-7.70(m,5H),7.61(d,J=1.8Hz,1H) ,7.47(d,J=8.2Hz,2H),7.42-7.29(m,2H),7.04(d,J=9.0Hz,1H),4.53(d,J=5.8Hz,2H ),3.64(s,2H),3.06(s,4H),2.56(s,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):678.3(M + +1).

[0075] Example 2: Synthesis of compound S2

[0076]

[0077] a) Compound 8 (1.65 g, 7.3991 mmol), 4-mercaptobenzonitrile (1 g, 7.3991 mmol), CuI (281 mg, 1.4789 mmol), K3PO4 (4.7 g, 22.1698 mmol), and 1,10-phenanthroline (532 mg, 2.9556 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 90 °C for 5 hours. After the reaction was complete, the reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated sodium chloride solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 9 (1.5 g, 88%). MS (ESI, m / z): 230.0 (M + +1).

[0078] b) Intermediate 9 (1.5 g, 6.5502 mmol) was dissolved in anhydrous DCM (40 mL), and mCPBA (2.8 g, 16.3755 mmol) was slowly added at 0 °C. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, saturated Na₂S₂O₃ solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The mixture was washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. After drying with anhydrous Na₂SO₄, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain intermediate 10 (1.65 g, 97%). MS (ESI, m / z): 263.0 (M + +1).

[0079] c) Intermediate 10 (1.65 g, 6.3218 mmol) and N-methylpiperazine (1.3 g, 6.9540 mmol) were dissolved in dimethyl sulfoxide (15 mL), and K₂CO₃ (1.3 g, 9.4828 mmol) was added. The mixture was reacted at 110 °C for 3 hours. After the reaction was complete, the mixture was diluted with water, filtered, and the filter cake was purified by column chromatography to obtain intermediate 11 (2.3 g, 85%). MS (ESI, m / z): 429.2 (M + +1).

[0080] d) Intermediate 11 (2.3 g, 5.3738 mmol) was dissolved in MeOH / DMF (20 mL / 20 mL). Nickel chloride hexahydrate (2.6 g, 10.7477 mmol) was added to the reaction system, and sodium borohydride (408 mg, 10.7477 mmol) was slowly added at 0 °C. The reaction was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was cooled to 0 °C, and sodium borohydride was quenched with 2 M HCl aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 12 (1 g, 43%). MS (ESI, m / z): 433.2 (M + +1).

[0081] e) Intermediate 12 (1 g, 2.3148 mmol) was dissolved in DMF (20 mL). Imidazo[1,2-A]pyridine-7-carboxylic acid (375 mg, 2.3148 mmol), HATU (1.2 g, 3.009 mmol), and DIPEA (1.3 mL, 6.9444 mmol) were added to the reaction system. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, water was added and the mixture was filtered to obtain intermediate 13 (1.1 g, 82%). MS (ESI, m / z): 577.2 (M + +1).

[0082] f) Intermediate 13 (1.1 g, 1.910 mmol) was dissolved in DCM (6 mL), and TFA (6 mL) was added to the reaction system. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, intermediate 14 (800 mg, 88%) was obtained by vacuum distillation. MS (ESI, m / z): 477.2 (M + +1).

[0083] g) Intermediate 14 (100 mg, 0.2101 mmol) and intermediate 7 (177 mg, 0.2101 mmol) were dissolved in MeCN (1.5 mL) and DMF (3 mL), KI (53 mg, 0.3151 mmol) and DIPEA (227 μL, 1.2605 mmol), and reacted at 80 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, filtered, and the filter cake was purified by column chromatography to obtain compound S2 (20 mg, 35%).

[0084] S2: 1 H NMR (300MHz, DMSO-d6) δ11.84(s,1H),9.31(t,J=5.8Hz,1H),8.60(dd,J=7.2,0.9Hz,1H),8.37(d,J=1.8Hz,1 H),8.31(d,J=2.8Hz,1H),8.15(s,1H),8.06(d,J=0.9Hz,1H),7.91(d,J=9.0Hz,1H),7.88-7.81(m,2H),7.77- 7.68(m,2H),7.59(s,1H),7.53(d,J=8.2Hz,2H),7.40(dd,J=9.0,2.9Hz,1H),7.30(dd,J=7.2,1.8Hz,1H),4. 53(d,J=5.9Hz,2H),3.61(s,2H),3.3(s,4H),2.57-2.50(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):663.2(M + +1).

[0085] Example 3: Synthesis of compound S3

[0086]

[0087] a) Compound 15 (1.2 g, 4.3321 mmol) was dissolved in pyridine (10 mL). 4-Cyanobenzenesulfonyl chloride (920 mg, 4.3321 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 16 hours. After complete reaction, water was added and the mixture was filtered to give intermediate 16 (1.1 g, 57%). MS (ESI, m / z): 443.2 (M + +1).

[0088] b) Intermediate 16 (1.1 g, 2.4819 mmol) was dissolved in MeOH / DMF (15 mL / 15 mL). Nickel chloride hexahydrate (886 mg, 3.7228 mmol) was added to the reaction system, and sodium borohydride (141 mg, 3.7221 mmol) was slowly added at 0 °C. The reaction was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was cooled to 0 °C, and sodium borohydride was quenched with 2 M HCl aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 17 (360 mg, 32%). MS (ESI, m / z): 447.2 (M + +1).

[0089] c) Compound 17 (360 mg, 0.8068 mmol), N,N'-disuccinimidyl carbonate (227 mg, 0.8875 mmol), and pyridine (130 μL, 1.6136 mmol) were dissolved together in anhydrous acetonitrile (6.5 mL), and a solution of 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine was added dropwise at 0 °C. The 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine solution was prepared by dissolving 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine (115 mg, 0.9681 mmol) and DIPEA (0.3 mL, 1.6136 mmol) together in anhydrous acetonitrile / DMF (0.6 mL / 0.3 mL). The two solutions were mixed and reacted at room temperature for 12 hours. After complete reaction, the mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered to remove salt, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 18 (120 mg, 25%). MS (ESI, m / z): 593.2 (M + +1).

[0090] d) Intermediate 18 (120 mg, 0.2026 mmol) was dissolved in DCM (6 mL), and TFA (6 mL) was added to the reaction system. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, intermediate 19 (90 mg, 90%) was obtained by vacuum distillation. MS (ESI, m / z): 493.2 (M + +1).

[0091] e) Intermediate 19 (90 mg, 0.1829 mmol) and intermediate 7 (41 mg, 0.1829 mmol) were dissolved in MeCN (1.5 mL) and DMF (3 mL), KI (46 mg, 0.2744 mmol) and DIPEA (197 μL, 1.0974 mmol), and reacted at 80 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, filtered, and the filter cake was purified by column chromatography to obtain compound S3 (34 mg, 27%).

[0092] S3: 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.62(d,J=7.1Hz,1H),8.60(s,1H),8.49(d,J=5.0Hz,1H),8.38(d,J=1 .8Hz,1H),8.31(s,1H),8.17(s,1H),8.06(d,J=0.9Hz,1H),7.91(d,J=9.0Hz,1H),7.88-7.81(m,2H),7.77-7. 68(m,2H),7.59(s,1H),7.42(d,J=5.2Hz,1H),6.95(s,1H),4.81-4.73(m,4H),4.53(m,3H),3.61(s,2H),3.3 2(s,4H),2.59-2.52(q,J=7.4Hz,2H),1.93(m,2H),1.84(m,2H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):679.3(M + +1).

[0093] Example 4: Synthesis of compound S4

[0094]

[0095] Refer to Examples 2 and 3.

[0096] S4: 1H NMR (400MHz, DMSO-d6) δ11.84(s,1H),8.60(s,1H),8.47(d,J=5.0Hz,1H),8.36(d,J=1.8Hz,1H),8.32 (s,1H),8.23(s,1H),8.05(d,J=0.9Hz,1H),7.89(d,J=9.0Hz,1H),7.87-7.83(m,2H),7.72-7.68(m,2H ),7.57(s,1H),7.42(d,J=5.1Hz,1H),6.94(s,1H),4.81-4.71(m,4H),4.54(m,3H),3.62(s,2H),3.29 (s,4H),2.55(q,J=7.4Hz,2H),1.93(m,2H),1.82(m,2H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):664.3(M + +1).

[0097] Example 5: Synthesis of compound S5

[0098]

[0099] Refer to Example 1.

[0100] S5: 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.25(d,J=1.4Hz,1H),8.61(d,J=7.1Hz,1H),8.44(m, 2H),8.32(s,1H),8.21(d,J=1.4Hz,1H),8.16(s,1H),8.05(d,J=0.9Hz,1H),7.93(d,J=9.0H z,1H),7.85-7.81(m,2H),7.75-7.63(m,2H),7.52(s,1H),6.91(s,1H),4.52(d,J=5.8Hz,2H ),3.63(s,2H),3.31(s,4H),2.57-2.51(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):664.2(M + +1).

[0101] Example 6: Synthesis of compound S6

[0102]

[0103] Refer to Example 2.

[0104] S6: 1H NMR (400MHz, DMSO-d6) δ11.84 (s, 1H), 9.23 (d, J = 1.3Hz, 1H), 8.60 (s, 1H), 8.44 (m, 2H), 8. 31(s,1H),8.23(d,J=1.4Hz,1H),8.14(s,1H),8.06(d,J=0.9Hz,1H),7.92(d,J=9.0Hz,1H ),7.86-7.83(m,2H),7.75-7.65(m,2H),7.52(s,1H),6.91(s,1H),4.51(d,J=5.8Hz,2H), 3.62(s,2H),3.33(s,4H),2.58-2.56(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):664.2(M + +1).

[0105] Example 7: Synthesis of compound S7

[0106]

[0107] Refer to Example 1.

[0108] S7: 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.21(t,J=6.0Hz,1H),9.11(t,J=1.3Hz,1H),8.3 5(d,J=1.8Hz,1H),8.31(s,1H),8.25(s,1H),8.04(d,J=0.9Hz,1H),7.84-7.77(m,6H),7 .78-7.66(m,2H),7.72-7.68(m,2H),7.57(s,1H),6.96(s,1H),4.54(d,J=5.8Hz,2H),3. 61(s,2H),3.32(s,4H),2.58-2.50(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):677.3(M + +1).

[0109] Example 8: Synthesis of compound S8

[0110]

[0111] Refer to Example 2.

[0112] S8: 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.21(t,J=6.0Hz,1H),9.11(t,J=1.3Hz,1H) ,8.33(d,J=1.8Hz,1H),8.31(s,1H),8.25(s,1H),8.06(s,1H),7.88-7.77(m,6H), 7.78-7.66(m,2H),7.72-7.68(m,2H),7.57(s,1H),4.54(d,J=5.8Hz,2H),3.61(s, 2H),3.35(s,4H),2.59-2.52(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):662.3(M + +1).

[0113] Example 9: Synthesis of compound S9

[0114]

[0115] Refer to Example 1.

[0116] S9: 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.25(d,J=1.4Hz,1H),9.10(t,J=1.3Hz,1H),8.61(d ,J=7.1Hz,1H),8.44(m,2H),8.21(d,J=1.4Hz,1H),8.16(s,1H),8.05(d,J=0.9Hz,1H),7.83 -7.69(m,2H),7.47(d,J=8.2Hz,2H),7.42-7.29(m,4H),6.91(s,1H),4.54(d,J=5.8Hz,2H) ,3.62(s,2H),3.34(s,4H),2.57-2.55(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):678.3(M + +1).

[0117] Example 10: Synthesis of compound S10

[0118]

[0119] Refer to Example 2.

[0120] S10: 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.24(d,J=1.4Hz,1H),9.11(t,J=1.3Hz,1H), 8.61(d,J=7.1Hz,1H),8.45(m,2H),8.25(d,J=1.4Hz,1H),8.14(s,1H),8.05(d,J=0. 9Hz,1H),7.78(s,1H),7.75-7.57(m,6H),6.93(s,1H),4.52(d,J=5.8Hz,2H),3.62( s,2H),3.33(s,4H),2.57-2.55(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):663.2(M + +1).

[0121] Example 11: Synthesis of compound S11

[0122]

[0123] Refer to Example 3.

[0124] S11: 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.63(d,J=7.1Hz,1H),8.60(s,1H),8.48(d,J=5. 0Hz,1H),8.34(d,J=1.8Hz,1H),8.27(s,1H),7.84-7.79(m,6H),7.73-7.63(m,2H),7.58 (s,1H),7.41(d,J=5.2Hz,1H),6.94(s,1H),4.81-4.73(m,4H),4.51(d,J=5.8Hz,2H),3. 63(s,2H),3.35(s,4H),2.58-2.54(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):679.3(M + +1).

[0125] Example 12: Synthesis of compound S12

[0126]

[0127] Refer to Example 4.

[0128] S12: 1 H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 8.61 (s, 1H), 8.46 (d, J = 5.0Hz, 1H),

[0129] 8.33(d,J=1.8Hz,1H),8.26(s,1H),7.85-7.79(m,6H),7.73-7.62(m,2H),7.56(s,1H),7.42(d,J=5.2Hz,1H),6.93(s,1H),4.80 -4.73(m,4H),4.55(d,J=5.8Hz,2H),3.62(s,2H),3.34(s,4H),2.59-2.54(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):664.3(M + +1).

[0130] Example 13: Synthesis of compound S13

[0131]

[0132] Refer to Example 1.

[0133] S13: 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.31(t,J=6.0Hz,1H),8.63(d,J=7.1Hz,1H),8.35(d,J= 1.8Hz,1H),8.16(s,1H),8.05(s,1H),7.81-7.72(m,5H),7.63(d,J=1.8Hz,1H),7.46(d,J=8.2 Hz,2H),7.43-7.28(m,2H),7.03(d,J=9.0Hz,1H),4.52(m,3H),3.59(s,2H),3.31(s,4H),2.59 -2.55(q,J=7.4Hz,2H),1.93(m,2H),1.82(m,2H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):677.3(M + +1).

[0134] Example 14: Synthesis of compound S14

[0135]

[0136] Refer to Example 2.

[0137] S14: 1H NMR (400MHz, DMSO-d6) δ11.85(s,1H),9.32(t,J=5.8Hz,1H),8.64(dd,J=7.2,0.9Hz,1H),8.35(d,J=1.8Hz,1H),8. 33(d,J=2.8Hz,1H),8.14(s,1H),8.05(d,J=0.9Hz,1H),7.93(d,J=9.0Hz,1H),7.87-7.82(m,2H),7.75-7.66(m,2H ),7.59(s,1H),7.53(d,J=8.2Hz,2H),7.42(dd,J=9.0,2.9Hz,1H),7.31(dd,J=7.2,1.8Hz,1H),4.57(m,3H),3.62( s,2H),3.29(s,4H),2.55(q,J=7.4Hz,2H),1.92(m,2H),1.81(m,2H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):662.2(M + +1).

[0138] Example 15: Synthesis of compound S15

[0139]

[0140] Refer to Example 3.

[0141] S15: 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.64(d,J=7.1Hz,1H),8.60(s,1H),8.49(d,J=5.0Hz,1H ),8.35(d,J=1.8Hz,1H),8.29(s,1H),7.82-7.76(m,6H),7.71-7.64(m,2H),7.59(s,1H),7.43 (d,J=5.2Hz,1H),6.92(s,1H),4.85-4.74(m,4H),4.52(m,3H),3.62(s,2H),3.31(s,4H),2.58 -2.51(q,J=7.4Hz,2H),1.92(m,2H),1.85(m,2H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):678.3(M + +1).

[0142] Example 16: Synthesis of compound S16

[0143]

[0144] Refer to Example 4.

[0145] S16: 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.63(s,1H),8.45(d,J=5.0Hz,1H),8.31(d,J=1. 8Hz,1H),8.25(s,1H),7.84-7.79(m,6H),7.72-7.61(m,2H),7.55(s,1H),7.41(d,J=5. 2Hz,1H),6.91(s,1H),4.82-4.73(m,4H),4.53(m,3H),3.64(s,2H),3.27(s,4H),2.56( q,J=7.4Hz,2H),1.92(m,2H),1.83(m,2H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):663.3(M + +1).

[0146] Example 17: Synthesis of compound S17

[0147]

[0148] Refer to Example 1.

[0149] S17: 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.25(d,J=1.4Hz,1H),9.10(t,J=1.3Hz,1H),8.61(d,J=7.1Hz ,1H),8.35(d,J=1.8Hz,1H),8.31(s,1H),8.21(d,J=1.4Hz,1H),8.16(s,1H),8.05(d,J=0.9Hz,1H), 7.83-7.69(m,2H),7.57(s,1H),7.47(d,J=8.2Hz,2H),7.42-7.29(m,4H),6.91(s,1H),4.58(d,J=5. 8Hz,2H),3.62(s,2H),3.34(s,4H),2.62-2.58(m,6H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):677.3(M + +1).

[0150] Example 18: Synthesis of compound S18

[0151]

[0152] Refer to Example 2.

[0153] S18: 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.23(d,J=1.4Hz,1H),9.14(t,J=1.3Hz,1H),8.63(d ,J=7.1Hz,1H),8.36(d,J=1.8Hz,1H),8.31(s,1H),8.24(d,J=1.4Hz,1H),8.13(s,1H),8.07 (d,J=0.9Hz,1H),7.78-7.74(m,2H),7.71-7.58(m,6H),6.92(s,1H),4.53(d,J=5.8Hz,2H) ,3.65(s,2H),3.31(s,4H),2.58-2.55(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):662.2(M + +1).

[0154] Example 19: Synthesis of compound S19

[0155]

[0156] Refer to Example 1.

[0157] S19: 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.20(d,J=1.4Hz,1H),9.15(t,J=1.3Hz,1H),8.62(d,J=7 .1Hz,1H),8.38(d,J=1.8Hz,1H),8.30(s,1H),8.24(d,J=1.4Hz,1H),8.13(s,1H),8.06(d,J=0. 9Hz,1H),7.83(m,2H),7.48(d,J=8.2Hz,2H),7.43-7.31(m,4H),6.93(s,1H),4.58(d,J=5.8Hz, 2H),3.62(s,2H),3.34(s,4H),2.62-2.59(m,6H),1.17(t,J=7.3Hz,3H).MS(ESI,m / z):694.2(M + +1).

[0158] Example 20: Synthesis of compound S20

[0159]

[0160] Refer to Example 2.

[0161] S20:1 H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 9.25 (d, J = 1.4Hz, 1H), 9.14 (t, J = 1.3Hz, 1H), 8.6 3(d,J=7.1Hz,1H),8.38(d,J=1.8Hz,1H),8.24(d,J=1.4Hz,1H),8.14(s,1H),8.08(d,J= 0.9Hz,1H),7.78-7.75(m,2H),7.68-7.57(m,6H),6.98(s,1H),4.55(d,J=5.8Hz,2H),3. 67(s,2H),3.30(s,4H),2.59-2.55(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):679.2(M + +1).

[0162] Example 21: Synthesis of compound S21

[0163]

[0164] Refer to Example 1.

[0165] S21: 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.25(d,J=1.4Hz,1H),9.15(t,J=1.3Hz,1H),8.62( d,J=7.1Hz,1H),8.44(m,2H),8.24(d,J=1.4Hz,1H),8.13(s,1H),8.06(d,J=0.9Hz,1H),7 .81(m,2H),7.45(d,J=8.2Hz,2H),7.43-7.35(m,4H),6.92(s,1H),4.57(d,J=5.8Hz,2H), 3.61(s,2H),3.32(s,4H),2.63-2.59(m,6H),1.18(t,J=7.3Hz,3H).MS(ESI,m / z):678.2(M + +1).

[0166] Example 22: Synthesis of compound S22

[0167]

[0168] Refer to Example 2.

[0169] S22: 1H NMR (400MHz, DMSO-d6) δ11.87 (s, 1H), 9.25 (d, J = 1.4Hz, 1H), 9.15 (t, J = 1.3Hz, 1H), 8.62(d,J=7.1Hz,1H),8.44(m,2H),8.24(d,J=1.4Hz,1H),8.13(s,1H),8.06(d,J=0. 9Hz,1H),7.81(s,1H),7.45-7.35(m,6H),6.92(s,1H),4.59(d,J=5.7Hz,2H),3.63( s,2H),3.36(s,4H),2.63-2.59(m,6H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):663.2(M + +1).

[0170] Example 23: Synthesis of compound S23

[0171]

[0172] a) Compound 20 (360 mg, 1.2950 mmol), N,N'-disuccinimidyl carbonate (398 mg, 1.554 mmol), and pyridine (105 μL, 1.2950 mmol) were dissolved together in anhydrous acetonitrile (6.5 mL), and a solution of 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine was added dropwise at 0 °C. The 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine solution was prepared by dissolving 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine (250 mg, 1.2950 mmol) and DIPEA (0.5 mL, 2.5900 mmol) together in anhydrous acetonitrile / DMF (1 mL / 0.5 mL). The two solutions were mixed and reacted at room temperature for 12 hours. After complete reaction, the mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered to remove salt, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 21 (130 mg, 23%). MS (ESI, m / z): 425.2 (M + +1).

[0173] b) Intermediate 21 (130 mg, 0.3059 mmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added to the reaction system. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, intermediate 22 (85 mg, 85%) was obtained by vacuum distillation. MS (ESI, m / z): 325.2 (M + +1).

[0174] c) Intermediate 22 (85 mg, 0.2623 mmol) and intermediate 7 (59 mg, 0.2623 mmol) were dissolved in MeCN (1.5 mL) and DMF (3 mL), KI (65 mg, 0.3935 mmol) and DIPEA (275 μL, 1.5740 mmol), and reacted at 80 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, filtered, and the filter cake was purified by column chromatography to obtain compound S23 (19 mg, 41%).

[0175] S23: 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.61(s,1H),8.45(d,J=5.0Hz,1H),8.39(s,1H),8.25(s,1H),7.75(s,1H),7.67(s,1H),7.41(d,J=5.1H z,1H),7.38(s,H),6.83(m,2H),4.81-4.73(m,4H),3.62(s,2H),3.05(s,4H),2.61-2.51(m,6H),1.16(t,J=7.4Hz,3H).MS(ESI,m / z):511.3(M + +1).

[0176] Example 24: Synthesis of compound S24

[0177]

[0178] Refer to Example 23.

[0179] S24: 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.60(s,1H),8.49(d,J=5.0Hz,1H),8 .41(s,1H),8.23(s,1H),7.76(s,1H),7.65(s,1H),7.42(d,J=5.2Hz,1H),7 .39-7.34(m,2H),6.86(d,J=8.7Hz,2H),4.82-4.71(m,4H),3.64(s,2H),3. 07(s,4H),2.60-2.52(m,6H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):510.3(M + +1).

[0180] Example 25: Synthesis of compound S25

[0181]

[0182] Refer to Example 23.

[0183] S25: 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.60-8.59(m,2H),8.47(d,J=5.0Hz,1H),8.43(m,2H),7.74(s,1H),7.66(s,1H),7.41(d,J=5.1Hz,1H),7 .39(s,1H),6.89(d,J=8.7Hz,2H),4.83-4.69(m,4H),3.63(s,2H),3.08 (s,4H),2.60-2.53(m,6H),1.17(t,J=7.4Hz,3H).MS(ESI,m / z):510.3(M + +1).

[0184] Example 26: Synthesis of compound S26

[0185]

[0186] Refer to Example 23.

[0187] S26: 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.61-8.58(m,2H),8.47(d,J=5.0Hz,1H),8.42(m,2H),7.73(s,1H),7.65(s,1H),7.39(d,J=5.1Hz,1H),7.34 -7.32(m,2H),6.83(d,J=8.7Hz,2H),4.82-4.70(m,4H),3.61(s,2H),3.0 5(s,4H),2.60-2.52(m,6H),1.18(t,J=7.4Hz,3H).MS(ESI,m / z):509.3(M + +1).

[0188] Example 27: Synthesis of compound S27

[0189]

[0190] Refer to Example 23.

[0191] S27: 1H NMR (400MHz, DMSO-d6) δ11.87 (s, 1H), 8.60-8.59 (m, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.4 5(m,2H),7.72(s,1H),7.65(s,1H),7.41(d,J=5.1Hz,1H),7.37(s,1H),6.88(d,J=8. 7Hz,2H),4.83-4.71(m,4H),3.66(m,1H),3.59(s,2H),3.31(m,4H),2.60-2.55(q,J =7.4Hz,2H),1.92(m,2H),1.82(m,2H),1.18(t,J=7.3Hz,3H).MS(ESI,m / z):510.3(M + +1).

[0192] Example 28: Synthesis of compound S28

[0193]

[0194] Refer to Example 23.

[0195] S28: 1 H NMR (400MHz, DMSO-d6) δ11.88 (s, 1H), 8.60-8.59 (m, 1H), 8.46 (d, J = 5.0Hz, 1H), 8. 48(m,2H),7.75(s,1H),7.62(m,2H),7.41(d,J=5.1Hz,1H),7.37(s,1H),6.88(d,J =8.7Hz,2H),4.75(m,4H),3.64(m,1H),3.42(s,2H),3.30(m,4H),2.66-2.56(q,J= 7.4Hz,2H),1.99(m,2H),1.85(m,2H),1.18(t,J=7.3Hz,3H).MS(ESI,m / z):509.3(M + +1).

[0196] Example 29: Evaluation of PARP1 / 2 and NAMPT enzyme inhibitory activities

[0197] 1. Experimental Methods

[0198] PARP1 inhibitory activity was assessed using a homogeneous PARP assay kit. The assay consisted of 1 ng / μL PARP-1, 20 ng / μL activated DNA (Sigma), and 500 nM NAD dissolved in the following reaction buffer: 100 mM Tris-HCl (pH 8.0), 100 mM NaCl, and 20 mM MgCl2. At room temperature, PARP-1 protein (1 ng / μL) was pre-incubated with different concentrations of the test compound for 30 min, followed by the addition of 500 nM NAD to initiate the parylation reaction. Remaining unreacted NAD was incubated with a circulating assay solution (1% ethanol, 25 μM resazurin, 0.30 U / mL alcohol dehydrogenase, and 0.25 U / mL myocardial flavin). The NAD concentration was proportional to the fluorescence signal at Ex 540 nm / Em 590 nm. The IC50 of the compounds was assessed by evaluating the rate of NAD reduction under different concentrations of the compounds. 50 The value.

[0199] The NAMPT inhibitory activity assay was performed according to the operating procedures provided by CycLex NAMPT colorimetric assay kit (MBL International Corp.). The basic principle is as follows: NAM and PRPP react with NAMPT to generate NMN, while NMN and ATP react with NMNAT1 to generate NAD. NAD then reacts with alcohol dehydrogenase (ADH) to generate NADH, which is subsequently converted back to NAD by myocardial flavin enzyme. WST-1 forms an orange-yellow formazan in the NAD / NADH enzymatic cycle. The effect of the compound on NAMPT enzyme activity can be detected by measuring the change in absorbance at OD 450 nM.

[0200] The specific experimental procedures are as follows:

[0201] (1) Preparation of test compound solutions: All compounds were dissolved in DMSO with a stock solution concentration of 10 mM. The solutions were prepared to the required concentrations according to the test requirements. Starting from the initial concentration, the solutions were diluted 2 times in a gradient, and 8 concentration gradients were set. Each concentration was repeated three times.

[0202] (2) Add ddH2O (10 μL) and NAM (5 μL) to the 96-well detection plate;

[0203] (3) Add 5 μL of the test compound or DMSO to the 96-well detection plate;

[0204] (4) Prepare mixture I, comprising: 20×NAMPT test buffer (5 μL), PRPP (5 μL), ATP (5 μL), recombinant NMNAT1 (5 μL), ddH2O (35 μL), and NAMPT (5 μL), totaling 60 μL. Add mixture I to the 96-well detection plate;

[0205] (5) Place the 96-well plate in a 30°C incubator and incubate for 60 min;

[0206] (6) Prepare mixture I, including: WST-1 (5 μL), ADH (5 μL), myocardial flavin (5 μL), ethanol (5 μL), totaling 20 μL. After incubation, remove the 96-well plate and add mixture II to the 96-well plate;

[0207] (7) Monitor the absorbance of each well at OD 450nm dynamically within 30 min using an ELISA reader, and perform the test every 5 min.

[0208] (8) Select a time period in which absorbance and time change linearly, and calculate the reaction rate. Process using GraphPad Prism5 software. To compensate for the NAMPT inhibitory activity of DMSO, the values ​​were corrected using DMSO as a solvent control.

[0209] 2. Experimental Results

[0210] Table 1. Inhibitory activities of NAMPT and PARP1 / 2 (IC50) 50 (nM)

[0211] Compound numbering NAMPT PARP1 PARP2 Compound numbering NAMPT PARP1 PARP2 S1 100 0.8 ＞100 S15 22 1.7 ＞100 S2 222 1.2 ＞100 S16 29 1.5 ＞100 S3 59 1.5 ＞100 S17 53 1.8 ＞100 S4 32 1.3 ＞100 S18 49 2.1 ＞100 S5 100 0.8 ＞100 S19 88 1.8 ＞100 S6 89 1.1 ＞100 S20 92 1.6 ＞100 S7 22 0.75 ＞100 S21 59 1.3 ＞100 S8 36 0.9 ＞100 S22 39 1.2 ＞100 S9 44 0.8 ＞100 S23 28 0.9 ＞100 S10 39 0.7 ＞100 S24 13 1.2 ＞100 S11 42 1.0 ＞100 S25 23 1.0 ＞100 S12 38 1.3 ＞100 S26 322 1.0 ＞100 S13 59 2.0 ＞100 S27 42 0.8 ＞100 S14 47 1.5 ＞100 S28 36 1.2 ＞100

[0212] As shown in Table 1, the compounds designed in this invention exhibit good inhibitory activity against NAMPT and PARP1, but low inhibitory activity against PARP2.

[0213] Example 30: Evaluation of antitumor activity

[0214] 1. Experimental Methods

[0215] (1) Collect cells in the logarithmic growth phase, adjust the cell suspension concentration, and add 100 μL of cell suspension to each well of a 96-well plate; the number of cells per well is about 7000, and incubate overnight at 37°C with 5% CO2 until the cells are completely attached.

[0216] (2) Set up a concentration gradient of the compound of the present invention, with 3 replicates for each concentration gradient. Dilute the compound of the present invention to the corresponding culture medium to the required final concentration. Remove the original culture medium from the 96-well plate and add 100 μL of the prepared culture medium containing the required final concentration of the drug. Incubate at 37°C with 5% CO2. At the same time, set up a blank group (containing only 100 μL of culture medium, without cells, and subsequent treatment is the same as other wells) and a control group (containing cells and culture medium).

[0217] (3) Add 10 μL MTT solution (5 mg / ml) to each well after 68 hours of drug treatment and continue culturing for 4 hours (total drug treatment of cells for 72 hours);

[0218] (4) Remove the culture medium from the wells (if the cells are suspended, centrifuge at 2500 rpm for 5 min before removing the culture medium). Add 150 μL of dimethyl sulfoxide to each well and shake until the crystals are fully dissolved. Measure the absorbance of each well at OD 490 nm using a microplate reader;

[0219] (5) Calculate the inhibition rate: Inhibition rate = 1 - (OD value of the drug-treated group - OD value of the blank group) / (OD value of the control group - OD value of the blank group) = (OD value of the control group - OD value of the drug-treated group) / (OD value of the control group - OD value of the blank group);

[0220] (6) IC was calculated using GraphPad Prism fitting. 50 value.

[0221] 2. Experimental Results

[0222] Table 2 Anti-cell proliferation activity (IC50) 50 (μM)

[0223] Compound numbering MDA-MB-436 HCC1937 MDA-MB-468 MCF-7 MDA-MB-231 MCF-10A S24 0.12 0.22 0.053 0.024 0.039 ＞50 FK866 19.2 20.3 40.3 9.8 34.5 ＞50 Olapani 0.32 0.12 3.89 10.21 7.95 ＞50

[0224] As shown in Table 2, the compounds designed in this invention have good anti-proliferative activity against BRAC-mutant triple-negative breast cancer cells (MDA-MB-436 and HCC1937) and BRAC wild-type triple-negative breast cancer cells (MDA-MB-468, MCF-7, and MDA-MB-231); and have no cytotoxicity to normal cells MCF-10A, indicating that they have good safety.

Claims

1. A naphthidine compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, ， In Formula I: X is N or C; Y is C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O, S heteroatoms; L1is a single bond, or , the left side is connected to Y and the right side is connected to Z; Z is a single bond or C 6-10 aryl; L2is -(CH2) n n is 0, 1, 2 or 3; R1 is imidazopyridyl, pyrazolopyridyl, thienopyridyl, furanopyridyl, tetrahydropyrrolopyridyl, or tetrahydropyrrolophenyl.

2. The naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized by In Formula I: Y is phenyl or pyridyl; n is 0, 1, or 2.

3. The naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein In Formula I: Y is phenyl or ; n is 0 or 1.

4. The naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein In Formula I: Z represents a single bond or a phenyl group.

5. The naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein In Formula I: R1is .

6. The naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Its structure is shown in equations IA, IB, and IC. ， The definitions of X, Y, and R1 are as described in claim 1.

7. The naphthyridine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Selected from any one of the following compounds: 。 8. A method of preparing the naphthyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized by, Includes the following steps: Compound II and compound III undergo a condensation reaction under the action of a base and a condensing agent to produce compound I: ， Wherein, X, Y, Z, L1, L2, and R1 are as described in claim 1, and M is chlorine or bromine.

9. A pharmaceutical composition, characterized by, The compound contains a therapeutically effective amount of the naphthidine compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. The use of a naphthidine compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the preparation of a medicament for a poly(adenosine diphosphate ribose) polymerase 1 inhibitor and / or a medicament for a nicotinamide phosphoribosyltransferase inhibitor.

11. The use of a naphthidine compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating triple-negative breast cancer.

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