Naphthyridine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a naphthyridine compound as shown in a formula I as well as a preparation method, a pharmaceutical composition and application of the naphthyridine compound. The compound can highly selectively inhibit the activity of poly (adenosine diphosphate-ribose polymerase) 1, has low inhibitory activity on poly (adenosine diphosphate-ribose polymerase) 2, and also has good inhibitory activity on nicotinamide phosphoribose transferase; meanwhile, the compound has a remarkable treatment effect on BRAC1 / 2 mutation and BRAC1 / 2 non-mutation tumors, and is relatively small in toxic and side effects and relatively high in safety. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a naphthyridine compound and a preparation method, a pharmaceutical composition and an application thereof, and in particular to a naphthyridine poly(ADP-ribose) polymerase 1 inhibitor and a nicotinamide phosphoribosyltransferase dual inhibitor and a pharmaceutical composition and an application thereof. Background Art

[0002] Poly (ADP-ribose) polymerase can catalyze the transfer of ADP-ribose of nicotinamide adenine dinucleotide to receptor proteins, thereby catalyzing the poly (ADP-ribosylation) of proteins. Therefore, PARP plays a key role in single-strand DNA repair. The PARP protein family consists of 18 members, and their catalytic domains show a high degree of similarity. Broken single-stranded DNA can be repaired with the participation of PARP, and the cell can survive. When PARP is inhibited by its inhibitor, the unrepaired single-stranded DNA will form double-stranded DNA breaks. Under normal circumstances, the homologous recombination repair mechanism can repair the broken double-stranded DNA, and the cell can continue to survive. However, when there is a homologous recombination repair defect in the cell, that is, the lack of related enzymes involved in the HR repair pathway, such as BRAC1 / 2, the cell dies because the DNA damage cannot be repaired. This is the synthetic lethal mechanism of PARP inhibitors and HRD.

[0003] At present, there are PARP small molecule inhibitors for the treatment of ovarian cancer, breast cancer, pancreatic cancer and prostate cancer carrying BRAC mutations, including olaparib, rucaparib, niraparib, talazoparib, fluzoparib and pamiparib. Although PARP inhibitors have significantly improved the prognosis of a variety of HRD-positive malignant tumors, the development of PARP inhibitors currently faces many problems. First, the indication range of PARP inhibitors is narrow, the patient population that benefits is limited, and it is only effective for HRD-positive tumors that can induce synthetic lethality, which limits the clinical application of PARP inhibitors. Secondly, a large proportion of HRD-positive tumors also show innate resistance to PARP inhibitors, or develop acquired resistance after a period of medication. Furthermore, current PARP inhibitors have no selectivity for PARP1 and PARP2, and inhibiting PARP1 is sufficient to exert anti-tumor activity, while inhibiting PARP2 will produce toxic side effects.

[0004] NAD + It is a cofactor of many oxidoreductases in the body and participates in the energy metabolism process in the body. It is also a substrate for key enzymes in many signal transduction processes. The salvage synthesis pathway using nicotinamide as the starting material is to replenish NAD in the body. + The most important and direct source of NAD, and nicotinamide phosphoribosyltransferase is the key rate-limiting enzyme that catalyzes this process. Tumor cell proliferation and energy requirements are much greater than normal cells, so tumor cells have a high demand for NAD +NAMPT is more dependent on cancer cells and more sensitive to changes in NAMPT activity. A large number of studies have shown that in addition to participating in energy metabolism, NAMPT plays a key 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 research on FK866 and CHS828 has been terminated due to poor therapeutic effects and dose-dependent toxicity. Summary of the invention

[0005] Purpose of the invention: The first purpose of the present invention is to provide a naphthyridine compound having dual inhibitory activity of poly(ADP-ribose) polymerase 1) inhibitor and nicotinamide phosphoribosyltransferase, the second purpose is to provide a method for preparing the compound, the third purpose is to provide a pharmaceutical composition containing the compound, and the fourth purpose is to provide a pharmaceutical application of the compound and its pharmaceutical composition.

[0006] Technical solution: The naphthyridine compound of the present invention as shown in formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, hydrate,

[0007]

[0008] In Formula I:

[0009] X is N or C;

[0010] Y is C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, 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 is a single bond or C 6-10 Aryl;

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

[0014] R1 is a 9- to 10-membered bicyclic heteroaryl group containing 1 N and 1 to 2 N, O, and S heteroatoms.

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

[0016] n is 0, 1 or 2.

[0017] In some embodiments, Y is phenyl or

[0018] n is 0 or 1.

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

[0020] R1 is imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, thienopyridinyl, furopyridinyl, tetrahydropyrrolopyridinyl or tetrahydropyrrolophenyl.

[0021] In some embodiments, R1 is

[0022]

[0023] In some embodiments, the naphthyridine compound of the present invention or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated compound or hydrate thereof has a structure as shown in Formula IA, IB or IC.

[0024]

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

[0026] In some embodiments, the naphthyridine compound of Formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated substance, hydrate is selected from any one of the following compounds:

[0027]

[0028] NAMPT inhibitors inhibit NAD + The production of PARP inhibits the substrate supply of PARP and increases the competitive inhibition of PARP inhibitors on the PARP catalytic domain. Therefore, NAMPT inhibitors can increase DNA damage, thereby increasing the anti-tumor activity of PARP inhibitors. NAMPT activity can reduce the expression of BRAC1 / 2, reduce the expression of RAD51, and induce HRD. NAMPT inhibitors and PARP1 inhibitors exert synergistic anti-tumor effects in BRAC wild-type triple-negative breast cancer and Ewing sarcoma. However, combination therapy is prone to drug-drug interactions, unclear pharmacokinetic properties, and poor patient compliance; dual-target or multi-target drugs can reduce toxicity, increase efficacy, and avoid the defects of combination therapy. Therefore, the development of PARP and NAMPT dual-target inhibitors can improve the narrow indications of PARP inhibitors, improve the selectivity of PARP1, reduce the toxic and side effects of NAMPT inhibitors, and drug resistance.

[0029] In view of the limited use range and low selectivity of poly(ADP-ribose) polymerase inhibitors and the dose-dependence of nicotinamide phosphoribosyltransferase inhibitors, the present invention designs a naphthyridine poly(ADP-ribose) polymerase 1 and nicotinamide phosphoribosyltransferase dual inhibitor, which shows significant therapeutic effects on tumors carrying BRAC1 / 2 mutations and those not carrying BRAC1 / 2 mutations, and has less toxic side effects.

[0030] The compounds designed by the present invention may exist in specific stereoisomer forms. The term "isomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0031] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively non-toxic acids or bases. When the compounds of the present 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 amino or magnesium salts or similar salts. When the compounds of the present 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, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid and methanesulfonic acid and similar acids; organic acid salts also include amino acids (such as arginine, etc.), glucuronic acid and other organic acid salts. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and 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 solubility 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. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0033] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0034] Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (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 conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind 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. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled 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, whether radioactive or not, are included within the scope of the present invention.

[0035] In addition to the form of salts, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I) is a prodrug within the scope and spirit of the present invention. For example, a carboxyl-containing compound can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally, because hydrolysis occurs mainly under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.

[0036] The term "deuterated compound" means that any hydrogen atom in a molecule can be replaced by its isotope deuterium. Any hydrogen atom in the compound of the present invention 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, and when it is a bicyclic or tricyclic aromatic group, each ring satisfies the Huckel rule. 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 9-10 membered bicyclic heteroaryl containing one N and one or two other heteroatoms selected from N, O and S, including a bicyclic ring formed by condensing an unsaturated monocyclic ring containing heteroatoms with an aryl group, a bicyclic ring formed by condensing an unsaturated monocyclic ring containing heteroatoms with an unsaturated monocyclic ring containing heteroatoms, and a bicyclic ring formed by condensing a saturated monocyclic ring containing heteroatoms with a heteroaryl or aryl group. When the "heteroaryl" is a bicyclic ring formed by condensing a saturated monocyclic ring containing heteroatoms with a heteroaryl group, it is connected to other fragments and groups in the compound shown in Formula I through a saturated monocyclic ring containing a heterocyclic ring. The 9-10 membered bicyclic ring includes, but is not limited to, imidazopyridine, imidazopyrimidine, pyrazolopyridine, thienopyridine, furopyridine, tetrahydropyrrolopyridine or tetrahydropyrrolophenyl.

[0039] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group is connected to other fragments and groups in the compound shown in Formula I through this site.

[0040] The present invention provides a method for preparing a naphthyridine compound as shown in Formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated product, or hydrate thereof, which specifically comprises the following steps:

[0041] The compound of formula II and the compound of formula III undergo condensation reaction under the action of a base and a catalyst to obtain the compound of formula I:

[0042]

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

[0044] The solvent described in the above reaction includes but is not limited to N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane, N-methylpyrrolidone or a mixed solvent thereof;

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

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

[0047] The present invention provides a naphthyridine compound as shown in formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated product, hydrate thereof in the preparation of drugs for poly(ADP-ribose) polymerase 1 inhibitors and / or nicotinamide phosphoribosyltransferase inhibitors.

[0048] The present invention provides a naphthyridine compound as shown in formula I or its pharmaceutically acceptable salts, enantiomers, diastereomers, cis-trans isomers, tautomers, atropisomers, conformers, metabolites, prodrugs, solvates, hydrates for use in preparing drugs for treating and / or preventing cancer.

[0049] In some embodiments, the cancer is one or more of bone cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic 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, which contains a naphthyridine compound as shown in Formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, hydrate thereof and a pharmaceutically acceptable carrier or excipient.

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

[0052] The present invention provides an application of a pharmaceutical composition in preparing a drug of a poly(ADP-ribose) polymerase 1 inhibitor and / or a drug of a nicotinamide phosphoribosyltransferase inhibitor.

[0053] The present invention provides an application of a pharmaceutical composition in preparing a drug for treating and / or preventing cancer.

[0054] In some embodiments, the cancer is one or more of bone cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic 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 adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0056] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0057] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations 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 lozenges.

[0058] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the 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 the present invention can highly selectively inhibit the activity of poly(ADP-ribose) polymerase 1, but have lower inhibitory activity on poly(ADP-ribose) polymerase 2, and also have good inhibitory activity on nicotinamide phosphoribosyltransferase; at the same time, they have significant therapeutic effects on tumors with BRAC1 / 2 mutations and tumors without BRAC1 / 2 mutations, with less toxic and side effects and higher safety. DETAILED DESCRIPTION

[0061] The technical solution of the present invention is further described below in conjunction with 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 reaction was carried out at room temperature for 16 hours. After the reaction was complete, water was added and filtered to obtain 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, sodium borohydride (142 mg, 3.7246 mmol) was slowly added at 0°C, and the reaction was allowed to proceed for 12 hours at room temperature. After the reaction was complete, the mixture was filtered with diatomaceous earth, the filtrate was cooled to 0°C, 2M HCl aqueous solution was added to quench the sodium borohydride, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, 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), and imidazo[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 filtered to obtain 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), TFA (1 mL) was added to the reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the intermediate 5 (240 mg, 76%) was obtained by distillation under reduced pressure. 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), and thionyl chloride (214 μL, 2.9412 mmol) was slowly added to the reaction system at -15°C, and the reaction was carried out at room temperature for 6 hours. After the reaction was complete, the intermediate 7 (80 mg, 74%) was obtained by distillation under reduced pressure. 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, and the mixture was reacted at 80° C. for 2 hours. After the reaction was complete, the mixture was diluted with water and filtered. 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), 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 organic phases were combined, 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, and the reaction was allowed to react at room temperature for 16 hours. After the reaction was complete, saturated Na2S2O3 solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous Na2SO4, 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), K2CO3 (1.3 g, 9.4828 mmol) was added, and 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) The 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, sodium borohydride (408 mg, 10.7477 mmol) was slowly added at 0°C, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the filtrate was filtered with diatomaceous earth, the filtrate was cooled to 0°C, 2M HCl aqueous solution was added to quench the sodium borohydride, and the ethyl acetate was extracted three times. The organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography to obtain the 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), and 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 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), TFA (6 mL) was added to the reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the intermediate 14 (800 mg, 88%) was obtained by distillation under reduced pressure. 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 and filtered. 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 system, and the reaction was carried out at room temperature for 16 hours. After the reaction was complete, water was added and filtered to obtain 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, sodium borohydride (141 mg, 3.7221 mmol) was slowly added at 0°C, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the filtrate was filtered with diatomaceous earth, the filtrate was cooled to 0°C, 2M HCl aqueous solution was added to quench the sodium borohydride, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, 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 in anhydrous acetonitrile (6.5 mL), and 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine solution was added dropwise at 0°C. 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) in anhydrous acetonitrile / DMF (0.6 mL / 0.3 mL). The two solutions were mixed and transferred to room temperature for reaction for 12 hours. After the reaction was complete, water was added for dilution, and ethyl acetate was extracted three times. The organic phases were combined, 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), TFA (6 mL) was added to the reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the intermediate 19 (90 mg, 90%) was obtained by distillation under reduced pressure. 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 and filtered. 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 Example 2 and Example 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 in anhydrous acetonitrile (6.5 mL), and 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine solution was added dropwise at 0°C. 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) in anhydrous acetonitrile / DMF (1 mL / 0.5 mL). The two solutions were mixed and transferred to room temperature for reaction for 12 hours. After the reaction was complete, water was added for dilution, and ethyl acetate was extracted three times. The organic phases were combined, 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), TFA (2 mL) was added to the reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the intermediate 22 (85 mg, 85%) was obtained by distillation under reduced pressure. 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 and filtered. 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 activity

[0197] 1. Experimental methods

[0198] The PARP1 enzyme inhibition activity was measured using the PARP homogeneous test kit. The test system included 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, and then 500 nM NAD was added to start the PARylation reaction. The remaining unreacted NAD was incubated with the circulating test solution (1% ethanol, 25 μM resazurin, 0.30 U / mL alcohol dehydrogenase, and 0.25 U / mL diaphorase), and the concentration of NAD was proportional to the fluorescence signal of Ex 540 nm / Em 590 nm. The reduction rate of NAD under the action of different concentrations of compounds was used to evaluate the inhibitory activity IC of the compound on PARP1. 50 The numerical value of .

[0199] The NAMPT inhibitory activity test was performed according to the operating procedures provided by the manufacturer of the CycLex NAMPT colorimetric assay kit (MBL International Corp.). The basic principle is: NAM and PRPP generate NMN under the action of NAMPT, and NMN and ATP generate NAD under the action of NMNAT1, NAD generates NADH under the action of alcohol dehydrogenase (ADH), and NADH returns to NAD under the action of diaphorase. WST-1 forms orange-yellow formazan in the NAD / NADH enzyme catalytic cycle, and the effect of the compound on the NAMPT enzyme activity can be detected by detecting the change in absorbance at OD 450nM.

[0200] The specific experimental steps 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 required concentrations were prepared according to the test requirements. Starting from the starting concentration, 2-fold gradient dilution was performed to set 8 concentration gradients, and each concentration was repeated three times.

[0202] (2) ddH2O (10 μL) and NAM (5 μL) were added to a 96-well assay plate;

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

[0204] (4) Prepare mixture I, including: 20×NAMPT assay 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 a 96-well assay plate;

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

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

[0207] (7) Dynamically monitor the absorbance of each well at OD 450 nm on a microplate reader within 30 minutes, once every 5 minutes;

[0208] (8) The time period in which the absorbance and time showed a linear change was selected to calculate the reaction rate. The data were processed using GraphPad Prism5 software. In order 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 activity of NAMPT and PARP1 / 2 (IC 50 , nM)

[0211] Compound No. NAMPT PARP1 PARP2 Compound No. 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 the present invention have good inhibitory activity against NAMPT and PARP1, but low inhibitory activity against PARP2.

[0213] Example 30: Evaluation of anti-tumor activity

[0214] 1. Experimental methods

[0215] (1) Collect cells in the logarithmic growth phase, adjust the concentration of the cell suspension, and add 100 μL of the cell suspension to each well of a 96-well plate; the number of cells in each well is about 7,000, and incubate overnight at 5% CO2 and 37°C until the cells are completely attached to the wall;

[0216] (2) Setting a concentration gradient of the compound of the present invention, with 3 replicate wells for each concentration gradient, diluting the compound of the present invention into the corresponding culture medium to the desired final concentration, aspirating the original culture medium in the 96-well plate, adding 100 μL of the prepared culture medium containing the drug at the desired final concentration, and incubating at 5% CO2 and 37°C; and setting a blank group (containing only 100 μL of culture medium without cells, and subsequent treatment is the same as that of other wells) and a control group (containing cells and culture medium);

[0217] (3) After 68 hours of drug treatment, 10 μL MTT solution (5 mg / ml) was added to each well and cultured for another 4 hours (cells were treated with drugs for a total of 72 hours);

[0218] (4) Aspirate the culture medium in the wells (if the cells are suspended, centrifuge at 2500 rpm for 5 min before aspirating the culture medium). Add 150 μL of dimethyl sulfoxide to each well and shake until the crystals are fully dissolved. Detect the absorbance of each well at OD 490 nm on an ELISA 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 (IC 50 , μM)

[0223] Compound No. 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 Olaparib 0.32 0.12 3.89 10.21 7.95 ＞50

[0224] As shown in Table 2, the compounds designed in the present 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, MDA-MB-231); and have no cytotoxicity to normal cells MCF-10A, indicating that they have good safety.

Claims

1. A naphthyridine compound as shown in formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated product, hydrate 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; L1 is a single bond, 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; L2 is -(CH2) n -, n is 0, 1, 2 or 3; R1 is a 9- to 10-membered bicyclic heteroaryl group containing 1 N and 1 to 2 N, O, and S heteroatoms.

2. The naphthyridine compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, or hydrate thereof according to claim 1, characterized in that: In Formula I: Y is phenyl or pyridyl; n is 0, 1 or 2.

3. The naphthyridine compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, or hydrate thereof according to claim 1, characterized in that: In Formula I: Y is phenyl or n is 0 or 1.

4. The naphthyridine compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, or hydrate thereof according to claim 1, characterized in that: In Formula I: Z is a single bond or a phenyl group; R1 is imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, thienopyridinyl, furopyridinyl, tetrahydropyrrolopyridinyl or tetrahydropyrrolophenyl.

5. The naphthyridine compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, hydrate according to claim 1, characterized in that: In Formula I: R1 is 6. The naphthyridine compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, or hydrate thereof according to claim 1, characterized in that: Its structure is shown in formula IA, IB, and IC. Wherein, the definitions of X, Y and R1 are as described in claim 1.

7. The naphthyridine compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, or hydrate thereof according to claim 1, characterized in that: Any one of the following compounds:

8. A method for preparing the naphthyridine compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated substance or hydrate according to claim 1, characterized in that: The following steps are involved: The compound of formula II and the compound of formula III undergo condensation reaction under the action of a base and a condensing agent to obtain the compound of formula 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 in that Containing a therapeutically effective amount of the naphthyridine compound according to claim 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformational isomer, metabolite, prodrug, solvate, deuterated substance, hydrate thereof and a pharmaceutically acceptable carrier.

10. Use of the naphthyridine compound according to claim 1 or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated substance, hydrate or the pharmaceutical composition according to claim 9 in the preparation of a drug for a poly(ADP-ribose) polymerase 1 inhibitor and / or a drug for a nicotinamide phosphoribosyltransferase inhibitor.

11. Use of the naphthyridine compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, cis-trans isomer, tautomer, atropisomer, conformer, metabolite, prodrug, solvate, deuterated substance, hydrate according to claim 1 or the pharmaceutical composition according to claim 9 in the preparation of a drug for preventing and / or treating cancer.

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