2-Formyltetrahydronaphthyridine compounds and pharmaceutical compositions and applications thereof

Abstract

The present invention provides a 2-formyltetrahydronaphthyridine compound of the structure shown in formula (Ⅰ) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, and a pharmaceutical composition and application thereof. The compound and the pharmaceutically acceptable salt thereof related to the present invention can inhibit FGFR4 protease with high activity and high selectivity, can effectively inhibit the growth of various tumor cells, especially have a highly selective inhibitory effect on liver cancer cells and breast cancer cells, and have good pharmacokinetic properties, can be used to prepare anti-tumor drugs, and can be used to treat transitional proliferative diseases such as tumors in humans and other mammals.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a class of 2-formyltetrahydronaphthyridine compounds and a pharmaceutical composition and application thereof. Background Art

[0002] Hepatocellular carcinoma (HCC) is the most common primary liver malignancy (80%-90%), has become the sixth most common cancer in the world, and is the third leading cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and C, alcohol addiction, metabolic liver disease (especially non-alcoholic fatty liver disease), and exposure to dietary toxins such as aflatoxin and maltonergic acid. Currently approved HCC treatments include multi-target kinase inhibitors sorafenib, lenvatinib, regorafenib, cabozantinib, and immune checkpoint inhibitor nivolumab. These treatments partially meet the needs of patients, but the median overall survival of these HCC patients is still less than 1 year. In addition, surgical resection for HCC has a high recurrence rate and poor prognosis, and there is an urgent need to develop new HCC treatments. There is increasing evidence that the FGF19 / FGFR4 pathway plays a role in the development of liver cancer, and abnormalities in this pathway are significantly correlated with the recurrence and poor prognosis of hepatocellular carcinoma.

[0003] FGF19 / FGFR4-mediated signaling pathways play an important role in the progression and metastasis of various cancers, including hepatocellular carcinoma (HCC), making FGFR4 a promising target for the treatment of related cancers. FGFR4 small molecule inhibitors have gone through three research stages, from multi-target inhibitors to Pan-FGFR inhibitors to highly selective FGFR4 inhibitors, and have made some progress. However, the large toxic side effects of multi-target inhibitors and Pan-FGFR inhibitors limit their clinical application. Encouragingly, subtype-selective FGFR4 inhibitors targeting the poorly conserved cysteine ​​(Cys552) near the ATP binding site in the intracellular kinase domain of FGFR4 have recently been developed and reported. Among them, the irreversible covalent inhibitors BLU554 and H3B-6527 are in clinical trials for hepatocellular carcinoma. However, the rapid resynthesis rate of FGFR4 in liver cancer cells requires inhibitors to allow frequent administration to achieve complete and sustained targeted inhibition to achieve maximum anti-tumor effects, which inevitably produces toxic side effects.Covalent reversible FGFR4 inhibitors show great advantages. The recently disclosed Roblitinib has shown significant anti-tumor activity in preclinical studies and has now entered the Phase II clinical study stage. However, the oral bioavailability of Roblitinib is low, with an oral bioavailability of only 20% in rats [Fairhurst, RA; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N.; Luu, VH; Madoerin, M.; W irth,J.;Graus-Porta,D.;Weiss,A.;Kiffe,M.;Wartmann,M.;Kinyamu-Akunda,J.;Sterker,D.;Stamm,C.;Adler,F.;Buhles,A.;Schadt,H.; Couttet, P.; Blank, J.; Galuba, I.; Trappe, J.; Voshol, J.; Ostermann, N.; Zou, C.; Berghau-sen, J.; Del, REA; Jahnke, W.; Furet, P. Discovery of Roblitinib(FGF401) as a Reversible-Covalent Inhibitor of theKinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542-12573.].

[0004] Irreversible or reversible covalent inhibitors have been reported to selectively inhibit FGFR4, but they are still in the early clinical trial stage. In order to fully verify the use of FGFR4 selective inhibitors to treat HCC with abnormal FGF19 / FGFR4 signaling, more compound types need to be evaluated in more comprehensive clinical studies. Therefore, it is of great significance to develop new types of highly selective and efficient FGFR4 inhibitors, especially to develop new types of FGFR4 inhibitors with higher oral bioavailability and better drugability. Summary of the invention

[0005] In view of the above problems, the present invention provides a new class of 2-formyltetrahydronaphthyridine compounds, which can inhibit the activity of FGFR4 protein kinase with high selectivity and high activity, thereby inhibiting the proliferation of various tumor cells.

[0006] The specific technical solutions are as follows:

[0007] A 2-formyltetrahydronaphthyridine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:

[0008]

[0009] Wherein, G is selected from: ethynyl or -(CH2) n -; n is selected from: 0, 1 or 2;

[0010] R 1 Select from: one or more R 4 Substituted or unsubstituted C6-C 10 Aryl, one or more R 4 a substituted or unsubstituted 5-10 membered heteroaryl group;

[0011] R 2 Selected from: Halogen or -WR 5 ; W is selected from NR 6 , O or S;

[0012] R 3 Selected from: H, one or more R 7 Substituted or unsubstituted C1-C6 alkyl;

[0013] R 4 Selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, halogen-substituted C1-C6 alkyl;

[0014] R 5 Selected from: C1-C6 alkyl, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by C1-C6 alkylamino, C3-C8 cycloalkyl;

[0015] R 6 Selected from: H or C1-C6 alkyl;

[0016] R 7 Select from: one or more R 8 a substituted or unsubstituted 5-8 membered heterocyclic group;

[0017] R 8 Selected from: H or C1-C6 alkyl.

[0018] In some embodiments, the 2-formyltetrahydronaphthyridine compound has a structure shown in formula (II):

[0019]

[0020] In some embodiments, the 2-formyltetrahydronaphthyridine compound has a structure shown in formula (III):

[0021] And, R 1 Selected from:

[0022] In some embodiments, the 2-formyltetrahydronaphthyridine compound has a structure shown in formula (IV):

[0023]

[0024] And, R 1 Selected from:

[0025] In some embodiments, R 1 Select from: one or more R 4 Substituted or unsubstituted phenyl, one or more R 4 substituted or unsubstituted benzofuranyl, one or more R 4 Substituted or unsubstituted benzothienyl, one or more R 4 A substituted or unsubstituted 5-6 membered nitrogen-containing heteroaryl group.

[0026] In some embodiments, R 1 Select from: one or more R 4 Substituted or unsubstituted phenyl, one or more R 4 substituted or unsubstituted benzofuranyl, one or more R 4 Substituted or unsubstituted benzothienyl, one or more R 4 Substituted or unsubstituted pyridyl, one or more R 4 Substituted or unsubstituted pyrimidinyl, one or more R 4 Substituted or unsubstituted pyrazinyl, one or more R 4 Substituted or unsubstituted imidazolyl, one or more R 4 a substituted or unsubstituted pyrazolyl group.

[0027] In some embodiments, R 4 Selected from: H, methoxy, ethoxy, propoxy, chlorine, fluorine, methyl, ethyl, propyl, isopropyl, cyano, trifluoromethyl.

[0028] In some embodiments, R 1 Selected from the following groups:

[0029]

[0030] In some embodiments, R 2 Selected from: Halogen or -WR5 ; W is selected from NH, O;

[0031] R 5 Selected from: C1-C4 alkyl, C1-C3 alkyl substituted by C1-C3 alkoxy, C1-C3 alkyl substituted by C1-C3 alkylamino, and C3-C6 cycloalkyl.

[0032] In some embodiments, R 2 Selected from: halogen, C1-C4 alkoxy, C1-C3 alkoxy substituted with C1-C3 alkoxy, or -NH-R 5 ; R 5 Selected from: C1~C3 alkyl substituted by C1~C3 alkoxy.

[0033] In some embodiments, R 2 Selected from: fluorine,

[0034] In some embodiments, R 3 Selected from: H, C1-C3 alkyl, R 7 Substituted C1-C3 alkyl; R 7 Selected from: 5-6 membered nitrogen-containing heterocyclic group substituted by C1-C3 alkyl.

[0035] In some embodiments, R 3 Select from: H or

[0036] The present invention also provides the use of the above-mentioned 2-formyltetrahydronaphthyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

[0037] The specific technical solutions are as follows:

[0038] Use of the above-mentioned 2-formyltetrahydronaphthyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of FGFR4 inhibitors.

[0039] Use of the above-mentioned 2-formyltetrahydronaphthyridine compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof in the preparation of drugs for preventing and / or treating tumors.

[0040] In some embodiments, the tumor is: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyosarcoma.

[0041] The present invention also provides a pharmaceutical composition for preventing and / or treating tumors.

[0042] The specific technical solutions are as follows:

[0043] A pharmaceutical composition for preventing and / or treating tumors is prepared from active ingredients and pharmaceutically acceptable excipients. The active ingredients include the above-mentioned 2-formyltetrahydronaphthyridine compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof.

[0044] The 2-formyltetrahydronaphthyridine compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof of the present invention can inhibit FGFR4 protease with high activity and high selectivity, can effectively inhibit the growth of various tumor cells, especially have a highly selective inhibitory effect on liver cancer cells and breast cancer cells, and have good pharmacokinetic properties, high oral bioavailability, good drugability, can be used to prepare anti-tumor drugs, and can be used to treat transitional proliferative diseases such as tumors in humans and other mammals. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The test results of the compound's effect on the phosphorylation of FGFR4 kinase and its downstream signaling pathway proteins;

[0046] Figure 2 The test results of the effect of the compound on the cell clone formation ability;

[0047] Figure 3 These are the test results of the compound's inhibition of mouse transplanted tumors and its effect on mouse body weight. DETAILED DESCRIPTION

[0048] In the compounds described in the present invention, when any variable (such as R 4 , R 7 , R 8 If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in stable compounds. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0049] As used herein, the term "alkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0050] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

[0051] The term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0052] The term "alkylamino" refers to a group having an -N-(alkyl)2 or -NH-alkyl structure, such as -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH2CH(CH3)2, -NHCH2CH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH)2, -N(CH2CH3)2, and the like.

[0053] The term "heterocycloalkyl" or "heterocyclyl" is a saturated or partially unsaturated monocyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon or C=O, for example: 2-oxopiperazinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, etc., and N-oxides thereof. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0054] The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. The heteroaryl groups within the scope of the present invention include, but are not limited to, quinolyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, and benzothienyl; "heteroaryl" is also understood to include any N-oxide derivative of heteroaryl containing nitrogen.

[0055] As will be appreciated by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0056] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic radicals such as morpholinyl, piperidinyl, etc.

[0057] The present invention includes free forms of compounds of formula I-IV, as well as pharmaceutically acceptable salts and stereoisomers thereof. The term "free form" refers to amine compounds in non-salt form. The pharmaceutically acceptable salts included include not only the exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formula I-IV. The free form of the specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with an appropriate dilute aqueous base solution, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form is somewhat different from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purpose of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0058] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with an appropriate inorganic or organic base.

[0059] Therefore, the pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting the alkaline compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0060] If the compound of the present invention is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0061] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0062] Since deprotonated acidic moieties such as carboxyl groups in the compounds may be anionic under physiological conditions, and this charge may then be balanced by the internal protonated or alkylated basic moieties such as quaternary nitrogen atoms carrying cations, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0063] Synthetic methods: In addition to standard methods known in the literature or exemplified in the experimental procedures, the following synthetic routes (Synthetic Routes 1-2) can be used to prepare the compounds of the present invention. In conjunction with the following synthetic schemes, the compounds and synthetic methods described in the present invention can be better understood. The synthetic schemes described describe methods that can be used to prepare the compounds described in the present invention. The described methods are merely illustrative scheme descriptions for illustrative purposes and do not constitute a limitation on the scope of the present invention.

[0064]

[0065]

[0066] In some embodiments, the present invention provides a method for treating hyperproliferative diseases or symptoms such as tumors in humans or other mammals using compounds having formula I-IV and pharmaceutically acceptable salts thereof.

[0067] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts can be used to treat or control transitional proliferative diseases such as liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyosarcoma, etc.

[0068] Drug metabolites and prodrugs

[0069] The metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention.

[0070] Combination medication

[0071] The compounds of formula I-IV can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug remain unchanged, and the compounds of formula I-IV are taken simultaneously or subsequently. When the compounds of formula I-IV are taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compounds of formula I-IV. Drug combination also includes taking the compounds of formula I-IV and one or more other known drugs in overlapping time periods. When the compounds of formula I-IV are used in combination with one or more other drugs, the dosage of the compounds of formula I-IV or the known drugs may be lower than when they are used alone.

[0072] Drugs or active ingredients that can be used in combination with the compounds of formula I-IV include but are not limited to:

[0073] Estrogen receptor modulators, androgen receptor modulators, retinal receptor modulators, cytotoxins / cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, etc.

[0074] In some embodiments, the drugs or active ingredients that can be used in combination with the compounds of formula I-IV include but are not limited to: aldesleukin, alendronic acid, interferon, atrenoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arnosin, 5-azacytidine, azathioprine, bacillus Calmette-Guérin or tice bacillus Calmette-Guérin, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezosumab injection, capecitabine, carboplatin, casodex, cefes one, cisplatin, cladribine, cladribine, clodrophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin 2, depomet, deslorelin, delazosen, diethylstilbestrol, diflucan, docetaxel, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, epoetin, levamisole tablets, estradiol preparations, 17-β-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphoric acid, vanbifu, etoposide, fadrozole, Tamoxifen preparations, filgrastim, finasteride, firaprestin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, granisiron hydrochloride, histrelin, and mexin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentan isobetamin, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, interferon α-n3, interferon β, interferon gamma-la, interleukin-2, intron A, Iressa, irinotecan, Kateri, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levomizole, levofolinic acid calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, doxorubicin citrate liposome, nedaplatin, pegfilgrastim, oprelleukin, neupogen, nilutamide, tamoxifen,NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, dehydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, pegaspargase, PEGASYS, pentostatin, lysin, pilocarpine hydrochloride, pilocarpine, plicamycin, porfimer sodium, prednimustine, stiprenisolone, prednisone, premarin, procarbazine, recombinant human erythropoietin, raltitrexed, libi, etidronate rhenium-186, rituximab, doxycycline-A, romotide, pilocarpine hydrochloride tablets, octreotide, sarmustine, semustine, sizoran, sobuzosine, sodium methylprednisolone, pafosic acid, stem cell therapy, streptozocin, strontium-89 chloride, levothyroxine sodium, tamoxifen Fen, tamsulosin, tasofenamin, tastolactone, taxotere, tesifazines, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, retinoic acid, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufodine, uridine, valrubicin, vesirinone, vinblastine, vincristine, vinamide, vinorelbine, virulizine, dextromethorphan, statins ester, zofran, paclitaxel protein stabilized preparation, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, a soprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, clenatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exitecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, miproxifene, minocycline, MS- 209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, nevastatin, noratript, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium bromoglutamate, PN-401, QS-21, quasi-sea, R-154, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin αl, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100 and zoledronic acid or a combination thereof.

[0075] The reagents used in the following examples are all commercially available.

[0076] The present invention is further described in the following examples, but the examples are not intended to limit the scope of protection of the present invention.

[0077] Example 1

[0078] N-(5-((3,5-dimethoxyphenyl)ethynyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2121) (Synthesis method refers to Synthesis Route 1)

[0079]

[0080] Step 1: 4-Fluoro-5-iodopyridin-2-amine (Compound 2)

[0081]

[0082] 2-Amino-4-fluoropyridine (Compound 1, 12 g, 116.6 mmol), N-iodosuccinimide (26.4 g, 117.3 mmol) and triethylamine (3.2 mL, 42.6 mmol) were dissolved in 400 mL of acetonitrile. Stir at room temperature for 5 hours. After the reaction was completed, it was diluted with ethyl acetate, washed twice with saturated sodium sulfite solution, and washed twice with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude compound 2 (22 g, 86%). MS (ESI) m / z 239.0 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.12(dd,J=13.7,8.6Hz,1H),6.45(s,2H),6.31(d,J=10.9Hz,1H).

[0083] Step 2: 5-iodo-4-isopropoxypyridin-2-amine (3)

[0084]

[0085] Compound 2 (1.44 g, 6.05 mmol) was added to an isopropanol solution of potassium tert-butoxide (1.36 g, 12.1 mmol), and the reaction solution was stirred at 60°C for 3 hours. After the reaction solution was cooled, it was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (SiO2, PE / EA2:1 to 1:1 gradient elution) to obtain the target product compound 3 as a white solid (1.47 g, 88%). 1HNMR (400MHz, CDCl3) δ8.19 (s, 1H), 5.97 (d, J = 6.2Hz, 1H), 4.60 (dt, J = 12.1, 6.1Hz, 1H), 4.41 (s, 2H), 1.42 (d, J = 6.1Hz, 6H).

[0086] Step 3: 2-(Dimethoxymethyl)-1,8-naphthyridine (Compound 7)

[0087]

[0088] 2-Aminonicotinaldehyde (20 g, 164 mmol), 1,1-dimethoxyacetone (25.7 mL, 214 mmol) and 3N NaOH (71 mL, 213 mmol) were dissolved in a mixed solvent of ethanol and water (400 mL: 40 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated to remove excess solvent and then separated between ethyl acetate and saturated brine. The combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain intermediate compound 7 (29.8 g, 86%). MS (ESI) m / z 227 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ9.15 (dd, J=4.2, 2.0Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.23 ​​(dd, J=8.1, 2.0Hz,1H),7.81(d,J=8.4Hz,1H),7.53(dd,J=8.1,4.2Hz,1H),5.50(s,1H),3.54(s,6H).

[0089] Step 4: 7-(Dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (Compound 8)

[0090]

[0091] Compound 7 (15 g, 73.45 mmol) and platinum dioxide (500 mg, 2.2 mmol) were dissolved in ethanol and stirred at room temperature for 36 hours under hydrogen protection. After the reaction, the insoluble matter was filtered out using diatomaceous earth and concentrated under reduced pressure to obtain intermediate compound 8 as a white solid (12.2 g, 80%). 1 H NMR (400MHz, CDCl3) δ7.18 (dd, J=7.4, 0.5Hz, 1H), 6.72 (d, J=7.4Hz, 1H), 5.16 (s, 1H), 4.94(s,1H),3.44–3.41(m,2H),3.39(s,6H),2.74(t,J=6.3Hz,2H),1.96–1.89(m,2H).

[0092] Step 5: 7-(Dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylic acid phenyl ester (Compound 9)

[0093]

[0094] Compound 8 (5.0 g, 24 mmol) and diphenyl carbonate (6, 1 g, 28.8 mmol) were dissolved in tetrahydrofuran, the reaction solution was cooled to -78 °C, and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 26.4 mL, 26.4 mmol) was slowly added. The reaction solution was then heated to room temperature for 1 hour, quenched with saturated ammonium chloride solution, then extracted with dichloromethane, washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA2:1 to 1:1 gradient elution) to obtain the target product compound 9 as a white solid (5.3 g, 67%). 1 HNMR(400MHz, CDCl3)δ7.55–7.51(m,1H),7.38(tt,J=4.1,2.0Hz,2H),7.34–7.31(m,1H),7.27–7.17(m,4H),6.79(dd ,J=8.5,0.9Hz,1H),5.32(s,1H),3.99–3.95(m,2H),3.41(s,6H),2.86(t,J=6.6Hz,2H),2.06(dt,J=16.6,6.5Hz,2H).

[0095] Step 6: 7-(Dimethoxymethyl)-N-(5-iodo-4-isopropoxypyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Compound 10)

[0096]

[0097] Compound 9 (0.5 g, 1.5 mmol) and compound 3 (0.466 g, 1.67 mmol) were dissolved in tetrahydrofuran, cooled to -15 °C, and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 2.3 mL, 2.3 mmol) was slowly added. The reaction solution was then heated to room temperature for 1 hour, quenched with a saturated ammonium chloride solution, then extracted with dichloromethane, washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 8:1 to 3:1 gradient elution) to obtain the target product, compound 10, as a white solid (620 mg, 72.2%). 1HNMR (600MHz, CDCl3) δ8.29(s,1H),7.91(s,1H),7.54(d,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),5.52(s,1H),4.82(dp,J=12 .1,6.0Hz,1H),4.09–4.03(m,2H),3.51(d,J=5.6Hz,6H),2.87(t,J=6.3Hz,2H),2.04–2.00(m,2H),1.46(d,J=6.1Hz,6H).

[0098] Step 7: Compound 10 (300 mg, 0.5 mmol), 3,5-dimethoxyphenylacetylene (72 mg, 0.07 mmol), bis(triphenylphosphine)palladium dichloride (41 mg, 0.058 mmol), cuprous iodide (11 mg, 0.058 mmol), and triethylamine (0.23 ml, 1.76 mmol) were dissolved in N,N-dimethylformamide. The reaction mixture was heated to 80 ° C under argon protection. After 3 hours, the system was cooled to room temperature. The reaction system was separated with dichloromethane and water. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 8:1 to 3:1 gradient elution), and the obtained solid was dissolved in a mixed solvent of 6 ml tetrahydrofuran and 3 ml water, and 1 ml hydrochloric acid was added. After stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, and the pH of the reaction solution was adjusted to neutral, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain the target product ZZ2121 as a white solid (450 mg, 66.8%). HRMS (ESI) m / z [M+H] + calcd:501.2132;found:501.2115;purity:95.5%; 1 H NMR (400MHz, CDCl3) δ13.57(s,1H),10.18(d,J=0.6Hz,1H),8.32(s,1H),7.90(s,1H),7.69(dd,J=7.6,0.7Hz,1H),7.64(d,J=7.5Hz,1H),6.72(d,J=2 .3Hz,2H),6.48(t,J=2.3Hz,1H),4.90–4.80(m,1H),4.18–4.10(m,2H),3. 84(s,6H),2.98(t,J=6.3Hz,2H),2.12–2.04(m,2H),1.48(t,J=5.6Hz,6H). 13C NMR (101MHz, CDCl3) δ191.49,165.71,160.48(2C),153.78,152.92,152.30,152.17,147.64,139.22,128.17,124. 96,115.66,109.29(2C),106.01,101.55,97.48,94.25,83.19,71.20,55.44(2C),43.79,28.69,21.86(2C),20.99.

[0099] Example 2

[0100] N-(5-(3,5-dimethoxyphenyl)ethyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2122)

[0101]

[0102] Compound ZZ2121 (50 mg, 0.106 mmol) was dissolved in ethanol, 10% palladium carbon (12 mg, 0.01 mmol) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 8 hours, and then the palladium carbon was filtered out using diatomaceous earth, and then the reaction solution was concentrated and separated by silica gel column chromatography (SiO2, PE / EA 3:1 to 1:1 gradient elution) to obtain the target compound ZZ2122 (360 mg, 52.3%). HRMS (ESI) m / z [M+H] + calcd:505.2445;found:505.2426;purity:98.6%; 1 H NMR (400MHz, CDCl3) δ13.57(s,1H),10.18(d,J=0.6Hz,1H),8.32(s,1H),7.90(s,1H),7.69(dd,J=7.6,0.7Hz,1H),7.64(d,J=7.5Hz,1H),6.72(d,J=2 .3Hz,2H),6.48(t,J=2.3Hz,1H),4.90–4.80(m,1H),4.18–4.10(m,2H),3. 84(s,6H),2.98(t,J=6.3Hz,2H),2.12–2.04(m,2H),1.48(t,J=5.6Hz,6H). 13C NMR (101MHz, CDCl3) δ191.61,163.38,160.70(2C),153.12,152.81,152.37,148.35,147.67,144.56,139.05,128. 07,121.75,115.44,106.54(2C),97.84,97.58,69.85,55.25(2C),43.70,36.33,29.82,28.74,21.95(2C),21.03.

[0103] Example 3

[0104] 7-Formyl-N-(4-isopropoxy-5-((3-methoxyphenyl)ethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2123)

[0105]

[0106] The synthesis method was referred to Example 1 (140 mg, 50.8%). HRMS (ESI) m / z [M+H] + calcd:471.2027;found:471.2014;purity:99.3%; 1 H NMR (600MHz, CDCl3) δ13.61(s,1H),10.21(s,1H),8.33(s,1H),7.92(s,1H),7.69(d ,J=7.5Hz,1H),7.65(d,J=7.5Hz,1H),7.28(t,J=7.9Hz,1H),7.16(d,J=7.6Hz,1H), 7.09(dd,J=2.4,1.3Hz,1H),6.93–6.89(m,1H),4.89–4.82(m,1H),4.19–4.09(m,2H ),3.86(s,3H),2.98(t,J=6.3Hz,2H),2.16–2.06(m,2H),1.50(s,3H),1.49(s,3H). 13 C NMR (151MHz, CDCl3) δ191.61,165.66,159.24,153.71,152.95,152.27,152.15,147.57,139.26,129.37,128.23,12 4.62,124.12,116.18,115.72,114.68,106.04,97.42,94.18,83.38,71.17,55.32,43.76,28.71,21.87(2C),20.97.

[0107] Example 4

[0108] 7-Formyl-N-(4-isopropoxy-5-(3-methoxyphenethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2124)

[0109]

[0110] The synthesis method was referred to Example 2 (34 mg, 67.42%). HRMS (ESI) m / z [M+H] + calcd:475.2340; found:475.2326; purity:97.95%; 1 H NMR (400MHz, CDCl3) δ13.31(s,1H),10.16(s,1H),7.90(s,1H),7.81(s,1H),7.70–7.57(m,2H),7.21(t,J=7.6Hz,1H),6.87–6.71(m,3H),4 .81(hept,J=5.9Hz,1H),4.17–4.07(m,2H),3.81(s,3H),2.96(t,J=6.2Hz,2H),2.84(s,4H),2.09–2.00(m,2H),1.44(s,3H),1.42(s,3H). 13 C NMR (151MHz, CDCl3) δ191.67,163.40,159.53,153.13,152.76,152.33,148.30,147.59,143.78,139.09,129.29,12 8.13,121.77,120.93,115.50,114.20,111.10,97.55,69.85,55.15,43.70,36.06,29.97,28.75,21.96(2C),21.01.

[0111] Example 5

[0112] 7-Formyl-N-(4-isopropoxy-5-(phenylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2125)

[0113]

[0114] The synthesis method was referred to Example 1 (140 mg, 50.8%). HRMS (ESI) m / z [M+H] +calcd:441.1921;found:441.1908;purity:99.3%; 1 H NMR (400MHz, CDCl3) δ13.55(s,1H),10.32–10.07(m,1H),8.32(s,1H),7.90(s,1H),7.71–7.61(m,2H),7.55(dt,J=8.3,2.2Hz,2H), 7.42–7.30(m,3H),4.85(hept,J=6.1Hz,1H),4.17–4.11(m,2H),2.97(t,J=6.3Hz,2H),2.11–2.04(m,2H),1.49(s,3H),1.48(s,3H). 13 C NMR (151MHz, CDCl3) δ191.61,165.62,153.66,152.95,152.21,152.13,147.56,139.25,131.51(2C),128.31 (2C),128.24,128.07,123.61,115.73,106.13,97.44,94.27,83.51,71.16,43.75,28.70,21.87(2C),20.95.

[0115] Example 6

[0116] N-(5-((2,6-dichloro-3,5-dimethoxyphenyl)ethynyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2126)

[0117]

[0118] The synthesis method was referred to Example 1 (70 mg, 53.5%). HRMS (ESI) m / z [M+H] + calcd:569.1353;found:569.1327;purity:98.9%; 1H NMR (400MHz, CDCl3) δ13.62–13.59(m,1H),10.19–10.17(m,1H),8.44–8.40(m,1H),7.95–7.90(m,1H),7.70–7.63(m,2H),6.60–6.55 (m,1H),5.32(s,2H),4.91–4.84(m,1H),4.16–4.12(m,2H),3.96(s,6H),3.01–2.95(m,2H),2.12–2.05(m,3H),1.48(d,J=6.0Hz,6H).

[0119] Example 7

[0120] N-(3,5-dimethoxyphenyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2127)

[0121]

[0122] Compound 10 (300 mg, 0.585 mmol), 3,5-dimethoxyphenylboronic acid pinacol ester (114 mg, 0.7 mmol), tetrakistriphenylphosphine palladium (67.6 mg, 0.058 mmol), and sodium carbonate (124 mg, 0.117 mmol) were dissolved in a mixed solvent of dioxane and water in a volume ratio of 4:1. The reaction was protected by argon and heated to 100°C. After three hours, the reaction was completed and the mixture was cooled to room temperature. The excess solvent was evaporated and then separated by dichloromethane and water. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 3:1 to 2:1 gradient elution), and the obtained solid was dissolved in a mixed solvent of 6 ml tetrahydrofuran and 3 ml water, and 1 ml hydrochloric acid was added. After stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, and the pH of the reaction solution was adjusted to neutral, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain the target product ZZ2127 as a white solid (210 mg, 78.6%). HRMS (ESI) m / z [M+H] + calcd:477.2132; found:477.2070; purity:95.1%; 1H NMR (400MHz, CDCl3) δ13.48(s,1H),10.20(s,1H),8.22(s,1H),7.95(s,1H),7.66(dd,J=19.5,7.6Hz,2H),6.75(d,J=2.3Hz,2H),6.48 (t,J=2.3Hz,1H),4.91–4.82(m,1H),4.19–4.13(m,2H),3.85(s,6H),2.98(t,J=6.3Hz,2H),2.13–2.04(m,2H),1.43(d,J=6.1Hz,6H). 13 CNMR(151MHz, CDCl3)δ191.50,162.45,160.35(2C),153.53,153.12,152.29,148.98,147.68,139.15,137. 34,128.13,122.51,115.62,107.38(2C),99.58,97.94,70.52,55.34(2C),43.76,28.73,21.85(2C),21.02.

[0123] Example 8

[0124] 7-Formyl-N-(4-isopropoxy-5-(6-methoxybenzofuran-2-yl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2128)

[0125]

[0126] The synthesis method was referred to Example 7 (120 mg, 63.18%). HRMS (ESI) m / z [M+H] + calcd:487.1976; found:487.1961; purity:98.4%; 1 H NMR (600MHz, CDCl3) δ13.57(s,1H),10.21(s,1H),8.83(s,1H),7.98(s,1H), 7.64(q,J=7.5Hz,2H),7.45(d,J=8.5Hz,1H),7.20(s,1H),7.09(s,1H),6.87 (dd,J=8.4,2.0Hz,1H),4.97(hept,J=5.9Hz,1H),4.17–4.09(m,2H),3.90(s ,3H),2.95(t,J=6.2Hz,2H),2.07(p,J=6.2Hz,2H),1.57(s,3H),1.56(s,3H). 13C NMR (151MHz, CDCl3) δ191.64,161.43,157.94,154.79,153.20,153.07,152.21,149.82,147.62,146.23,139.22,128 .20,122.77,120.92,115.65,112.69,111.79,105.58,97.44,95.52,71.06,55.79,43.77,28.73,22.13(2C),20.99.

[0127] Example 9

[0128] 7-Formyl-N-(4-isopropoxy-5-(5-methoxybenzofuran-2-yl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ2129)

[0129]

[0130] The synthesis method was referred to Example 7 (80 mg, 55.6%). HRMS (ESI) m / z [M+H] + calcd:487.1976; found:487.1970; purity:98.9%; 1 H NMR (600MHz, CDCl3) δ13.65(s,1H),10.27(s,1H),8.88(s,1H),8.03(s,1H),7.68( dd,J=17.9,7.5Hz,2H),7.42(d,J=8.8Hz,1H),7.24(s,1H),7.08(d,J=2.5Hz,1H), 6.91(dd,J=8.8,2.4Hz,1H),5.00(dt,J=11.8,5.9Hz,1H),4.17–4.13(m,2H),3.88 (s,3H),2.98(t,J=6.3Hz,2H),2.09(dt,J=15.1,4.7Hz,2H),1.58(d,J=6.0Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.65,155.86,153.03,152.10,148.78,147.65,139.27,129.95,128.20,124.49,124.01, 119.05,115.77,112.82,112.58,111.34,106.02,103.20,97.51,55.91,43.80,29.75,28.70,22.05(2C),20.99.

[0131] Example 10

[0132] 7-Formyl-N-(4-isopropoxy-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21210)

[0133]

[0134] The synthesis method was referred to Example 7 (150 mg, 53.5%). HRMS (ESI) m / z [M+H] + calcd:517.1904;found:517.1898;purity:96.4%; 1 H NMR (600MHz, CDCl3) δ13.62(s,1H),10.23(s,1H),8.58(s,1H),8.00(s,1H),7.70(s,1H),7.65(d,J=7.2Hz,2H),7.25(s,1H),6.61(s,1H ),4.99–4.94(m,1H),4.17–4.13(m,2H),4.02(s,3H),2.98(t,J=6.2Hz,2H),2.50(s,3H),2.09(d,J=11.4Hz,2H),1.55(d,J=6.1Hz,6H). 13 C NMR(151MHz, CDCl3)δ191.55,153.78(2C),152.98,152.08,147.64,141.63,139.27(2C),135.55,128.21(2C),1 25.56,121.80,116.56,116.02(2C),115.89,105.90(2C),97.76,71.67,55.61,43.82,28.69,21.94(2C),20.98.

[0135] Embodiment 11

[0136] N-(5-((4-cyanophenyl)ethynyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21211)

[0137]

[0138] The synthesis method was referred to Example 1 (80 mg, 76.9%). HRMS (ESI) m / z [M+H] +calcd:466.1874; found:466.1868; purity:99.3%; 1 H NMR (600MHz, CDCl3) δ13.67(s,1H),10.18(s,1H),8.33(s,1H),7.92(s,1H),7.78–7.51(m,5H),4.86(hept,J= 6.0Hz,1H),4.24–4.09(m,2H),2.98(t,J=6.3Hz,2H),2.08(dt,J=11.0,5.6Hz,2H),1.49(s,3H),1.48(s,3H). 13 C NMR (151MHz, CDCl3) δ191.60,163.33,153.16,153.08,152.30,148.44,147.65,147.57,139.14,132.17(2C),129 .38(2C),128.17,120.62,119.23,115.65,109.67,97.53,69.93,43.72,36.09,29.49,28.75,21.94(2C),21.00.

[0139] Example 12

[0140] N-(5-((3-cyanophenyl)ethynyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21212)

[0141]

[0142] The synthesis method was referred to Example 1 (90 mg, 83.2%). HRMS (ESI) m / z [M+H] + calcd:466.1874; found:466.1839; purity:96.5%; 1 H NMR (400MHz, CDCl3) δ13.63(s,1H),10.18(s,1H),8.32(s,1H),7.93(s,1H),7.82(s,1H),7.76(d,J=7.8Hz,1H),7.69(d,J=7.6Hz,1H),7.63(dd, J=14.2,7.7Hz,2H),7.48(t,J=7.8Hz,1H),4.91–4.82(m,1H),4.18–4.10 (m,2H),2.98(t,J=6.2Hz,2H),2.14–2.04(m,2H),1.49(d,J=6.0Hz,6H). 13C NMR (151MHz, CDCl3) δ191.60,163.33,153.16,153.08,152.30,148.44,147.65,147.57,139.14,132.17(2C),129 .38(2C),128.17,120.62,119.23,115.65,109.67,97.53,69.93,43.72,36.09,29.49,28.75,21.94(2C),21.00.

[0143] Embodiment 13

[0144] 7-Formyl-N-(4-isopropoxy-5-(pyridin-2-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21213)

[0145]

[0146] The synthesis method was referred to Example 1 (110 mg, 76.5%). HRMS (ESI) m / z [M+H] + calcd:442.1874; found:442.1862; purity:97.3%; 1 H NMR (600MHz, CDCl3) δ13.65 (s, 1H), 10.20 (s, 1H), 8.65 (d, J = 4.4Hz, 1H), 8.40 ( s,1H),7.93(s,1H),7.74–7.68(m,2H),7.65(d,J=7.5Hz,1H),7.56(d,J=7.8Hz ,1H),7.27(dd,J=7.1,4.7Hz,1H),4.87(dt,J=12.1,6.1Hz,1H),4.16–4.11(m, 2H), 2.98 (t, J = 6.3Hz, 2H), 2.08 (dt, J = 12.0, 6.2Hz, 2H), 1.49 (d, J = 6.1Hz, 6H). 13 C NMR (151MHz, CDCl3) δ191.58,166.02,154.23,153.04,152.97,152.12,150.01,147.59,143.78,139.31,136 .15,128.25,127.29,122.56,115.77,105.13,97.28,93.44,83.89,71.28,43.77,28.70,21.83(2C),20.96.

[0147] Embodiment 14

[0148] 7-Formyl-N-(4-isopropoxy-5-(2-(pyridin-2-yl)ethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21214)

[0149]

[0150] The synthesis method was referred to Example 2 (54 mg, 68.3%). HRMS (ESI) m / z [M+H] + calcd:446.2186;found:446.2184;purity:98.8%; 1 H NMR (400MHz, CDCl3) δ13.28 (s, 1H), 10.15 (s, 1H), 8.57 (d, J = 5.6Hz, 1H), 7.88 (s, 1H), 7.80 (s,1H),7.66(d,J=7.7Hz,1H),7.61(d,J=7.5Hz,1H),7.59–7.54(m,1H),7.12(dd,J=7.4,5 .0Hz,1H),7.07(d,J=7.8Hz,1H),4.81(dt,J=12.1,6.0Hz,1H),4.15–4.10(m,2H),3.08(dd ,J=8.5,6.0Hz,2H),2.97(dd,J=13.4,7.1Hz,4H),2.09–2.04(m,2H),1.42(d,J=6.0Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.70,163.45,161.46,153.15,152.77,152.32,149.25,148.47,147.59,139.09,136 .34,128.13,123.07,121.45,121.15,115.52,97.56,69.87,43.71,38.04,28.75,28.00,21.95(2C),21.01.

[0151] Embodiment 15

[0152] 7-Formyl-N-(4-isopropoxy-5-(pyridin-3-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21215)

[0153]

[0154] The synthesis method was referred to Example 1 (105 mg, 74.6%). HRMS (ESI) m / z [M+H] +calcd:442.1874; found:442.1858; purity:96.9%; 1 H NMR (600MHz, CDCl3) δ13.66(s,1H),10.19(s,1H),8.79(s,1H),8.56(d,J=4.1H z,1H),8.34(s,1H),7.92(s,1H),7.85(d,J=7.9Hz,1H),7.70(d,J=7.5Hz,1H), 7.65(d,J=7.5Hz,1H),7.35–7.30(m,1H),4.86(dt,J=12.1,6.1Hz,1H),4.17–4 .10(m,2H),2.98(t,J=6.3Hz,2H),2.08(d,J=5.8Hz,2H),1.49(d,J=6.1Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.54,165.84,154.00,152.93,152.16,152.08,151.97,148.12,147.56,139.32,138 .48,128.28,123.14,120.94,115.89,105.40,97.37,90.81,87.04,71.38,43.79,28.68,21.84(2C),20.95.

[0155] Example 16

[0156] 7-Formyl-N-(4-isopropoxy-5-(2-(pyridin-3-yl)ethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21216)

[0157]

[0158] The synthesis method was referred to Example 2 (67 mg, 69.9%). HRMS (ESI) m / z [M+H] + calcd:446.2187; found:446.2180; purity:97.8%; 1H NMR (600MHz, CDCl3) δ13.36 (s, 1H), 10.17 (s, 1H), 8.46 (d, J = 3.4Hz, 2H), 7.88 (s, 1H) ),7.82(s,1H),7.67(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.49(d,J=7.8Hz,1H), 7.24–7.21(m,1H),4.83–4.78(m,1H),4.15–4.11(m,2H),2.97(t,J=6.3Hz,2H),2.8 9(d,J=5.9Hz,2H),2.85(d,J=7.7Hz,2H),2.09–2.05(m,2H),1.42(d,J=6.1Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.66,163.59,153.10,152.82,152.24,149.74,147.99,147.59,147.15,139.15,137 .25,136.29,128.17,123.39,120.89,115.68,97.62,70.09,43.73,33.06,29.64,28.72,21.91(2C),21.00.

[0159] Embodiment 17

[0160] 7-Formyl-N-(4-isopropoxy-5-(pyridin-4-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21217)

[0161]

[0162] The synthesis method was referred to Example 1 (24 mg, 37.0%). HRMS (ESI) m / z [M+H] + calcd:442.1874; found:442.1861; purity:98.5%; 1 H NMR (400MHz, CDCl3) δ13.63(s,1H),10.17(s,1H),8.61(d,J=5.9Hz,2H),8.33(s,1H),7.92(s,1H),7.77–7.63(m,2H),7.49–7.38(m, 2H), 4.98–4.62 (m, J=6.0Hz, 1H), 4.13 (dd, J=6.7, 4.8Hz, 2H), 2.98 (t, J=6.3Hz, 2H), 2.08 (p, J=6.2Hz, 2H), 1.50 (s, 3H), 1.48 (s, 3H).13 C NMR (151MHz, CDCl3) δ191.51,165.94,154.44,152.94,152.71,152.08,149.66(2C),147.54,139.33,131 .88,128.29,125.42(2C),115.88,104.94,97.28,91.67,88.68,71.34,43.78,28.69,21.83(2C),20.94.

[0163] Embodiment 18

[0164] 7-Formyl-N-(4-isopropoxy-5-(2-(pyridin-4-yl)ethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21218)

[0165]

[0166] The synthesis method was referred to Example 2 (38 mg, 83.2%). HRMS (ESI) m / z [M+H] + calcd:446.2187; found:446.2180; purity:95.4%; 1 H NMR (400MHz, CDCl3) δ13.35(s,1H),10.16(s,1H),8.49(d,J=5.9Hz,2H),7.87(s,1H),7.82(s,1H),7.70–7.59(m,2H),7.11(d,J=5.8Hz,2H),4.81( hept,J=5.9Hz,1H),4.17–4.10(m,2H),2.97(t,J=6.3Hz,2H),2.93–2.76 (m,J=4.0Hz,4H),2.07(dt,J=12.2,6.2Hz,2H),1.42(s,3H),1.41(s,3H). 13 C NMR (151MHz, CDCl3) δ191.62,163.34,153.15,153.06,152.30,150.89,149.64(2C),148.41,147.57,139 .13,128.17,124.05(2C),120.73,115.62,97.53,69.94,43.72,35.28,28.86,28.74,21.92(2C),21.00.

[0167] Embodiment 19

[0168] 7-Formyl-N-(4-isopropoxy-5-(pyrimidin-5-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21219)

[0169]

[0170] The synthesis method was referred to Example 1 (70 mg, 58.3%). HRMS (ESI) m / z [M+H] + calcd:443.1826; found:443.1798; purity:96.7%; 1 H NMR (400MHz, CDCl3) δ13.65(s,1H),10.17(s,1H),9.15(s,1H),8.87(s,2H),8.33(s,1H),7.93(s,1H),7.69(d,J=7.6Hz,1H),7.64(d ,J=7.5Hz,1H),4.86(dt,J=12.2,6.1Hz,1H),4.16–4.12(m,2H),2.98(t,J=6.3Hz,2H),2.11–2.07(m,2H),1.48(d,J=6.1Hz,6H).13C NMR (151MHz, CDCl3) δ191.45,184.04,165.86,158.46,156.40,154.54,152.94,152.54,152.07,147.53 ,139.34,128.30,120.37,115.91,104.66,97.25,90.98,87.17,71.41,43.79,28.68,21.82(2C),20.93.

[0171] Embodiment 20

[0172] 7-Formyl-N-(4-isopropoxy-5-(pyrazin-2-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21220)

[0173]

[0174] The synthesis method was referred to Example 1 (120 mg, 46.3%). HRMS (ESI) m / z [M+H] + calcd:443.1826; found:443.1808; purity:98.2%; 1H NMR (400MHz, CDCl3) δ13.64(s,1H),10.17(s,1H),8.77(s,1H),8.59(s,1H),8.48(d,J=2.3Hz,1H),8.39(s,1H),7.93(s,1H), 7.70–7.61(m,2H),4.92–4.82(m,1H),4.16–4.11(m,2H),2.97(t,J=6.3Hz,2H),2.10–2.04(m,2H),1.49(s,3H),1.48(s,3H). 13 C NMR (151MHz, CDCl3) δ191.45,166.16,154.70,153.16,152.92,152.05,147.85,147.53,144.40,142.45 ,140.77,139.33,128.28,115.86,104.36,97.19,90.72,88.29,71.44,43.78,28.67,21.81(2C),20.92.

[0175] Embodiment 21

[0176] 7-Formyl-N-(4-isopropoxy-5-((3-methylpyridin-2-yl)ethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21221)

[0177]

[0178] The synthesis method was referred to Example 1 (55 mg, 55.3%). HRMS (ESI) m / z [M+H] + calcd:456.2030;found:456.1967;purity:95.2%; 1 H NMR (400MHz, CDCl3) δ13.61(s,1H),10.19(s,1H),8.45(d,J=18.2Hz,2H),7.93(s,1H),7.66(dd,J=18.5,7.6Hz,2H),7.57(d,J=7.7Hz,1H) ,7.19–7.13(m,1H),4.89(t,J=9.0Hz,1H),4.20–4.07(m,2H),2.98(t,J=6.2Hz,2H),2.58(s,3H),2.14–2.04(m,2H),1.48(d,J=6.0Hz,6H). 13C NMR (151MHz, CDCl3) δ191.44,166.00,154.17,152.93,152.76,152.12,147.66,147.22,143.50,139.25,136.88 ,136.03,128.15,122.41,115.69,105.43,97.14,92.68,87.84,71.11,43.76,28.67,21.89(2C),20.98,19.52.

[0179] Embodiment 22

[0180] 7-Formyl-N-(4-isopropoxy-5-((4-methylpyridin-3-yl)ethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21222)

[0181]

[0182] The synthesis method was referred to Example 1 (85 mg, 64.2%). HRMS (ESI) m / z [M+H] + calcd:456.2030;found:456.1971;purity:95.3%; 1 H NMR (400MHz, CDCl3) δ13.61(s,1H),10.18(s,1H),8.70(s,1H),8.41(d,J=5.0Hz,1H),8.34(s,1H),7.93(s,1H),7.67(dd,J=19.3,7.5Hz,2H ),7.19(d,J=5.0Hz,1H),4.93–4.80(m,1H),4.17–4.10(m,2H),2.98(t,J=6.2Hz,2H),2.56(s,3H),2.13–2.04(m,2H),1.48(d,J=6.0Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.45,165.71,154.04,152.93,152.14,152.04,151.72,148.74,147.98,147.64,139.26 ,128.19,124.23,121.13,115.74,105.73,97.28,90.72,89.98,71.15,43.76,28.68,21.89(2C),20.98,20.26.

[0183] Embodiment 23

[0184] 7-Formyl-N-(4-isopropoxy-5-((1-methyl-1H-imidazol-5-yl)ethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21223)

[0185]

[0186] The synthesis method was referred to Example 1 (35 mg, 34.3%). HRMS (ESI) m / z [M+H] + calcd:445.1983;found:445.1925;purity:96.5%; 1 H NMR (400MHz, CDCl3) δ13.61(s,1H),10.18(s,1H),8.29(s,1H),7.92(s,1H),7.69(d,J=7.6Hz,1H),7.64(d,J=7.6Hz,1H),7.54(s,1H), 7.42–7.31(m,1H),4.90–4.81(m,1H),4.16–4.10(m,2H),3.78(s,3H),2.98(t,J=6.3Hz,2H),2.12–2.04(m,2H),1.46(d,J=6.0Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.42,165.38,153.94,152.93,152.14,151.71,147.63,139 .26,128.20,115.77,105.49,97.28,90.64,71.12,43.76,28.68,21.88(2C),20.98.

[0187] Embodiment 24

[0188] N-(5-(((1H-imidazol-5-yl)ethynyl)-4-isopropoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21224)

[0189]

[0190] The synthesis method was referred to Example 1 (80 mg, 44.2%). HRMS (ESI) m / z [M+H] + calcd:431.1826;found:431.1807;purity:96.5%; 13C NMR(151MHz,DMSO-d6)δ191.30,170.85,165.00,153.73,152.66,152.20,152.10,147.11,141.56,140.33,13 1.99,129.65,117.39,106.02,101.82,97.38,86.83,83.77,71.30,60.25,28.23,21.92,21.26,20.77,14.56.

[0191] Embodiment 25

[0192] N-(4-fluoro-5-(pyridin-2-ylethynyl)pyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21525) (Synthesis method refers to Synthesis Route 1)

[0193]

[0194] Step 1: 4-Fluoro-5-(pyridin-2-ethylideneynyl)pyridin-2-amine (Compound 4a)

[0195]

[0196] Compound 2 (2.38 g, 1 mmol), 2-pyridine acetylene (1.03 g, 1 mmol), bis(triphenylphosphine) palladium dichloride (702 mg, 0.1 mmol), cuprous iodide (190 mg, 0.1 mmol), triethylamine (3 ml, 3 mmol) were dissolved in N, N-dimethylformamide, and the reaction was heated to 80 ° C under argon protection. After 3 hours, the system was cooled to room temperature, and the reaction system was separated with dichloromethane and water. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 8:1 to 3:1 gradient elution) to obtain compound 4a as a white solid (1.75 g, 82.1%). 1 H NMR (400MHz, CDCl3) δ8.64(d,J=4.6Hz,1H),8.33(d,J=9.9Hz,1H),7.70(td,J=7.7,1.7Hz,1 H),7.54(d,J=7.8Hz,1H),7.26(dd,J=7.1,5.5Hz,1H),6.25(d,J=10.7Hz,1H),4.83(s,2H).

[0197] Step 2: 7-(Dimethoxymethyl)-N-(4-fluoro-5-(pyridin-2-ethylideneynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Compound 13a)

[0198]

[0199] The synthesis method was based on compound 10 (780 mg, 77.6%). 1 HNMR (400MHz, CDCl3) δ13.92(s,1H),8.65(d,J=4.2Hz,1H),8.53(d,J=9.9H z,1H),8.09(d,J=12.0Hz,1H),7.72(td,J=7.7,1.8Hz,1H),7.59–7.53(m,2H ),7.30–7.26(m,2H),7.20(t,J=6.4Hz,1H),5.47(s,1H),4.08(dd,J=6.7,4 .7Hz,2H),3.53(s,7H),2.88(t,J=6.3Hz,2H),2.02(dd,J=11.9,6.1Hz,2H).

[0200] Step 3: Compound 13a was dissolved in a mixed solvent of 6 mL tetrahydrofuran and 3 mL water, 1 mL hydrochloric acid was added, and after stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, the reaction solution was adjusted to neutral, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain the target product ZZ21525 as a white solid (110 mg, 88.6%). HRMS (ESI) m / z [M+H] + calcd:402.1361; found:402.1355; 1 HNMR (600MHz, CDCl3) δ13.87(s,1H),10.16(s,1H),8.66(d,J=4.5Hz,1H),8.52(d,J=9.7Hz,1H),8.09(d,J=11.7Hz,1H),7.75–7.69( m,2H),7.65(d,J=7.5Hz,1H),7.59(d,J=7.7Hz,1H),7.32–7.29(m,1H),4.16–4.12(m,2H),2.99(t,J=6.2Hz,2H),2.11–2.07(m,2H). 13C NMR (151MHz, CDCl3) δ191.32,168.48,154.75,153.44,152.67,151.98,150.18,147.49,142.89,13 9.44,136.31,128.39,127.34,123.18,116.05,103.84,100.87,94.66,79.94,43.83,28.67,20.85.

[0201] Embodiment 26

[0202] 7-Formyl-N-(4-(2-methoxyethoxy)-5-(pyridin-2-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21526)

[0203]

[0204] Compound 13a (220 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) were dissolved in N, N-dimethylformamide, and ethylene glycol methyl ether (0.1 mL, 1 mmol) was added to heat the reaction to 60 ° C and stir for 6 hours. After the reaction, dichloromethane and water were used to separate, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 3:1 to 1:1 gradient elution), and the product was dissolved in a mixed solvent of 6 ml tetrahydrofuran and 3 ml water, 1 ml hydrochloric acid was added, and after stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, the reaction solution was adjusted to neutral, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain the target product as a white solid (150 mg, 66.9%). HRMS (ESI) m / z [M+H] + calcd:458.1823;found:458.1807;purity:96.3%; 1 H NMR (600MHz, CDCl3) δ13.68(s,1H),10.16(s,1H),8.63(s,1H),8.39(s,1 H),7.91(s,1H),7.71–7.65(m,2H),7.62(d,J=7.5Hz,1H),7.52(d,J=7.8H z,1H),7.25(dd,J=7.5,4.9Hz,1H),4.39–4.33(m,2H),4.14–4.09(m,2H), 3.91–3.87(m,2H),3.53(s,3H),2.96(t,J=6.3Hz,2H),2.10–2.04(m,2H). 13C NMR (151MHz, CDCl3) δ191.48,166.59,154.35,152.88,152.76,152.03,150.00,147.52,143.60,139.31,136. 16,128.27,127.12,122.64,115.82,104.60,96.44,93.77,83.42,70.38,68.26,59.59,43.76,28.67,20.90.

[0205] Embodiment 27

[0206] 7-Formyl-N-(4-((2-methoxyethyl)amino)-5-(pyridin-2-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21527)

[0207]

[0208] The synthesis method was referred to Example 26 (120 mg, 56.3%). HRMS (ESI) m / z [M+H] + calcd:457.1983;found:457.1970;purity:98.2%; 1 H NMR (600MHz, CDCl3) δ13.42 (s, 1H), 10.17 (s, 1H), 8.62 (d, J = 4.5Hz, 1H), 8.21 (s, 1H), 7. 71(td,J=7.7,1.6Hz,1H),7.66(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.55–7.51(m,2H) ,7.26(dd,J=7.1,5.3Hz,1H),5.72(t,J=5.2Hz,1H),4.15–4.09(m,2H),3.69(t,J=5.2Hz, 2H), 3.54 (dd, J=10.6, 5.3Hz, 2H), 3.44 (s, 3H), 2.96 (t, J=6.3Hz, 2H), 2.09–2.04 (m, 2H). 13 C NMR (151MHz, CDCl3) δ191.70,155.15,153.56,152.89,152.18,151.69,149.94,147.58,143.37,139.17,136 .32,128.16,126.87,122.63,115.55,99.82,95.70,92.94,84.07,70.42,58.95,43.72,42.16,28.72,20.97.

[0209] Embodiment 28

[0210] 7-Formyl-N-(4-(isobutylamino)-5-(pyridin-2-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21528)

[0211]

[0212] The synthesis method was referred to Example 26 (60 mg, 56.9%). HRMS (ESI) m / z [M+H] + calcd:455.2190; found:455.2174; purity:94.3%; 1 H NMR(600MHz, CDCl3)δ13.41(s,1H),10.18(s,1H),8.63(s,1H),8.21(s,1H) ,7.72(s,1H),7.66(s,1H),7.63(s,1H),7.53(d,J=9.1Hz,2H),7.26(t,J=8 .4Hz,1H),5.39(s,1H),4.16–4.12(m,2H),3.17(t,J=6.2Hz,2H),2.97(t,J =6.2Hz,2H),2.08(s,2H),2.03(s,1H),1.90(s,2H),1.06(d,J=6.6Hz,6H). 13 C NMR (151MHz, CDCl3) δ191.78,155.39,153.54,152.90,152.23,151.64,150.04,147.60,143.42,139.16,136.3 1,128.15,126.84,122.64,115.50,99.44,95.74,92.96,84.07,50.21,43.73,28.73,28.12,20.99,20.46(2C).

[0213] Embodiment 29

[0214] N-(4-(Cyclopropylamino)-5-(pyridin-2-ylethynyl)pyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21529)

[0215]

[0216] The synthesis method was referred to Example 26 (35 mg, 45.5%). HRMS (ESI) m / z [M+H] +calcd:439.1877; found:439.1864; purity:90.6%; 1 H NMR (600MHz, CDCl3) δ13.45(s,1H),10.18(s,1H),8.62(d,J=4.8Hz,1H),8.21(s,1H),7.90(s ,1H),7.72(td,J=7.7,1.7Hz,1H),7.67(d,J=7.5Hz,1H),7.63(d,J=7.5Hz,1H),7.54(d,J=7. 8Hz,1H),7.27(ddd,J=7.5,4.9,1.0Hz,1H),5.64(s,1H),4.19–4.12(m,2H),2.97(t,J=6.2Hz ,2H),2.67–2.60(m,1H),2.11–2.03(m,2H),0.94(tt,J=16.0,8.1Hz,2H),0.73–0.67(m,2H). 13 C NMR (151MHz, CDCl3) δ191.74,156.20,153.40,152.87,152.26,151.66,149.95,147.59,143.35,139.16,13 6.34,128.16,126.99,122.70,115.51,99.45,95.44,94.50,83.96,43.74,28.75,24.28,21.00,7.59(2C).

[0217] Embodiment 30

[0218] N-(4-(Cyclopentylamino)-5-(pyridin-2-ylethynyl)pyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21530)

[0219]

[0220] The synthesis method was referred to Example 26 (55 mg, 67.9%). HRMS (ESI) m / z [M+H] + calcd:467.2190; found:467.2177; purity:95.2%; 1H NMR (600MHz, CDCl3) δ13.42 (s, 1H), 10.17 (s, 1H), 8.62 (d, J = 4.5Hz, 1H), 8.21 (s, 1H), 7. 71(td,J=7.7,1.6Hz,1H),7.66(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.55–7.51(m,2H) ,7.26(dd,J=7.1,5.3Hz,1H),5.72(t,J=5.2Hz,1H),4.15–4.09(m,2H),3.69(t,J=5.2Hz, 2H), 3.54 (dd, J=10.6, 5.3Hz, 2H), 3.44 (s, 3H), 2.96 (t, J=6.3Hz, 2H), 2.09–2.04 (m, 2H). 13 C NMR (151MHz, CDCl3) δ191.75,154.76,153.41,152.91,152.24,151.69,150.05,147.61,143.44,139.15,136 .28,128.14,126.93,122.65,115.50,99.47,95.60,93.71,84.12,53.87,43.74,33.38,28.74,24.17,21.01.

[0221] Embodiment 31

[0222] N-(4-Fluoro-5-(pyridin-3-ylethynyl)pyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21531)

[0223]

[0224] The synthesis method was referred to Example 25 (160 mg, 89.1%). HRMS (ESI) m / z [M+H] + calcd:402.1361;found:402.1350;purity:95.2%; 1H NMR (400MHz, CDCl3) δ13.84(s,1H),10.17(s,1H),8.82(s,1H),8.60(d,J=3.7Hz,1H),8.47(d,J=9.8Hz,1H),8.10(d,J=11.8Hz,1H),7.87(d,J =7.9Hz,1H),7.71(d,J=7.6Hz,1H),7.65(d,J=7.5Hz,1H),7.36–7.30(m,1H),4.31–4.12(m,2H),2.99(t,J=6.3Hz,2H),2.09(p,J=6.2Hz,2H).

[0225] Embodiment 32

[0226] 7-Formyl-N-(4-(2-methoxyethoxy)-5-(pyridin-3-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21532)

[0227]

[0228] The synthesis method was referred to Example 26 (85 mg, 68.5%). HRMS (ESI) m / z [M+H] + calcd:458.1823;found:458.1807;purity:97.2%; 1 H NMR (400MHz, CDCl3) δ13.67(s,1H),10.18(s,1H),8.78(s,1H),8.56(d,J=4.0Hz ,1H),8.35(s,1H),7.94(s,1H),7.83(d,J=6.3Hz,1H),7.70(d,J=7.6Hz,1H),7. 66(s,1H),7.31(dd,J=7.8,4.9Hz,1H),4.43–4.34(m,2H),4.14(dd,J=6.7,4.7H z,2H),3.94–3.82(m,2H),3.54(s,3H),2.98(t,J=6.3Hz,2H),2.16–2.00(m,2H). 13C NMR (151MHz, CDCl3) δ191.40 (d, J = 6.6Hz), 166.40, 154.26, 152.90, 152.19, 152.12, 152.10, 148.34, 147.64, 139.3 1,138.28,128.24,123.07,120.83,115.82,104.96,96.54,91.13,86.66,70.47,68.36,59.59,43.77,28.67,20.96.

[0229] Embodiment 33

[0230] 7-Formyl-N-(4-((2-methoxyethyl)amino)-5-(pyridin-3-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21533)

[0231]

[0232] The synthesis method was referred to Example 26 (110 mg, 53.9%). HRMS (ESI) m / z [M+H] + calcd:457.1983;found:457.1915;purity:97.9%; 1 H NMR(400MHz, CDCl3)δ13.41(s,1H),10.18(s,1H),8.80–8.74(m,1H),8.59–8.53(m,1H), 8.18(s,1H),7.82(d,J=7.9Hz,1H),7.67(d,J=7.6Hz,1H),7.63(d,J=7.6Hz,1H),7.56(s ,1H),7.31(dt,J=8.3,4.1Hz,1H),5.48(t,J=4.9Hz,1H),4.24–4.07(m,2H),3.71(t,J=5 .1Hz,2H),3.53(q,J=5.4Hz,2H),3.46(s,3H),2.97(t,J=6.3Hz,2H),2.11–2.03(m,2H).

[0233] Embodiment 34

[0234] (S)-7-Formyl-N-(4-(((1-methoxypropan-2-yl)amino)-5-(pyridin-3-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21534)

[0235]

[0236] The synthesis method was referred to Example 26 (64 mg, 30.4%). HRMS (ESI) m / z [M+H] + calcd:471.2139;found:471.2075;purity:95.1%; 1 H NMR (400MHz, CDCl3) δ13.39(s,1H),10.18(s,1H),8.81–8.73(m,1H),8.57(d,J=3.8Hz,1 H),8.17(s,1H),7.82(dt,J=7.9,1.7Hz,1H),7.66(t,J=8.8Hz,2H),7.58(s,1H),7.32(dd ,J=7.8,4.9Hz,1H),5.42(d,J=7.9Hz,1H),4.19–4.09(m,2H),4.02–3.90(m,1H),3.61–3 .50(m,2H),3.46(s,3H),2.97(t,J=6.3Hz,2H),2.11–1.98(m,2H),1.37(d,J=6.5Hz,3H). 13 C NMR (151MHz, CDCl3) δ191.76 (d, J = 6.6Hz), 154.09, 153.31, 152.92, 152.22, 151.86, 150.96, 148.45, 147.61, 139.21, 1 38.09,128.19,123.18,120.52,115.65,100.28,93.28,93.12,87.03,75.43,59.36,47.40,43.75,28.72,20.99,17.51.

[0237] Embodiment 35

[0238] (R)-7-Formyl-N-(4-((1-methoxypropane-2-yl)amino)-5-(pyridin-3-ylethynyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ21535)

[0239]

[0240] The synthesis method was referred to Example 26 (50 mg, 23.7%). HRMS (ESI) m / z [M+H] + calcd:471.2139;found:471.2071;purity:96.1%; 1H NMR (400MHz, CDCl3) δ13.37(s,1H),10.18(s,1H),8.77(s,1H),8.59–8.53(m,1H),8.17(s,1H) ,7.81(d,J=7.8Hz,1H),7.67(d,J=7.7Hz,1H),7.62(d,J=7.5Hz,1H),7.58(s,1H),7.32(dd,J= 7.9,4.9Hz,2H),5.41(d,J=8.0Hz,1H),4.15(s,2H),3.95(tt,J=7.3,3.9Hz,1H),3.61–3.48(m ,2H),3.46(s,3H),2.97(t,J=6.3Hz,2H),2.08(dd,J=10.6,4.7Hz,2H),1.36(d,J=6.5Hz,3H). 13 C NMR (151MHz, CDCl3) δ191.77 (d, J = 6.4Hz), 154.06, 153.43, 153.03, 152.93, 152.24, 152.21, 151.87, 151.13, 148.43, 14 7.62,139.19,138.08,128.19,123.18,120.55,115.60,100.26,93.28,75.44,59.36,47.38,43.74,28.73,21.00,17.52.

[0241] Embodiment 36

[0242] N-(((3,5-dimethoxyphenyl)ethynyl)-4-isopropoxypyridin-2-yl-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ22536) (Synthesis method refers to Synthesis Route 2)

[0243]

[0244] Step 1: 6-Bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (Compound 19)

[0245]

[0246] At room temperature, compound 8 (9 g, 43.3 mmol) was dissolved in acetonitrile, and N-bromosuccinimide (8.1 g, 45.4 mmol) was added in batches. The mixture was stirred for 1 hour. After the reaction, the reaction solution was concentrated, dissolved in dichloromethane, washed with 1 M NaOH aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 19 (9.5 g, 76.55%). 1 HNMR (400MHz, CDCl3) δ7.28(s,1H),5.57(s,1H),3.47(s,6H),3.42–3.38(m,2H),2.72(t,J=6.3Hz,2H),1.88(dd,J=11.6,6.2Hz,2H).

[0247] Step 2: 2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxaldehyde (Compound 20)

[0248]

[0249] At -78°C, methyl lithium (1.6M ether solution, 13mL, 20.9mmol) was added dropwise to a tetrahydrofuran solution of compound 19 (5g, 17.4mmol), and n-butyl lithium solution (1.6M tetrahydrofuran solution, 22mL, 34.8mmol) was added dropwise after stirring for 5 minutes. After stirring for 15 minutes, dry N,N-dimethylformamide was added dropwise, and the reaction solution was slowly warmed to room temperature and stirred for another half an hour. Saturated ammonium chloride solution was added to the reaction to quench, and after stirring for 5 minutes, it was extracted with dichloromethane, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, PE / EA 3:1 to 1:1 gradient elution) to obtain the target compound 19 (2.2g. 53.48%). 1 H NMR (400MHz, CDCl3) δ10.31(s,1H),7.74(s,1H),5.77(s,1H),5.42(s,1H),3.45(d,J=2.7Hz,8H),2.75(t,J=6.3Hz,2H),1.90(dd,J=11.6,6.1Hz,2H).

[0250] Step 3: N-(2-aminoethyl)-N-methylglycine ethyl ester (Compound 18)

[0251]

[0252] At 0°C, ethyl bromoacetate (3.81 mL, 34.4 mmol) was added to a tetrahydrofuran solution of tert-butyl 2-(methylamino)ethylcarbamate (6 g, 34.4 mmol) and triethylamine (14.43 mL). After stirring at room temperature for 24 hours, the mixture was separated with dichloromethane and saturated sodium bicarbonate solution. The organic phases were combined and dried to obtain a crude product, which was dissolved in a mixed solvent of tetrahydrofuran and ethanol (60 mL: 300 mL). 30 mL of concentrated hydrochloric acid was added at room temperature. After stirring for one hour, the reaction solution was evaporated to dryness, 60 mL of ethanol was added, and the reaction mixture was evaporated to dryness. The reaction mixture was repeated twice to obtain the target compound 18 (3.2 g, 58%). 1 H NMR (400MHz, DMSO) δ8.60(s,3H),4.31(s,2H),4.25–4.21(m,2H),3.50(s,2H),3.28(d,J=5.6Hz,2H),2.92(s,3H),1.25(t,J=7.1Hz,3H).

[0253] Step 4: 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (Compound 21)

[0254]

[0255] Compound 20 (230 mg, 0.973 mmol), compound 18 (260 mg, 1.62 mmol) and 0.7 mL of triethylamine were dissolved in 1,2-dichloroethane at room temperature, sodium triacetyl borohydride (900 mg, 3 mmol) was added in batches, and stirred at room temperature for 36 hours. After the reaction was completed, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, DCM / MeOH 100:0 to 10:1 gradient elution) to obtain the target compound 21 (180 mg, 55.3%). 1 H NMR(400MHz, CDCl3)δ7.15(s,1H),5.24(s,1H),4.71(s,2H),3.44(s,6H),3.41(s,2H),3.25–3.2 1(m,2H),3.20(s,2H),2.71(t,J=6.3Hz,2H),2.62–2.57(m,2H),2.35(s,3H),1.93–1.88(m,2H).

[0256] Step 5: 5-((3,5-dimethoxyphenyl)ethynyl)-4-isopropoxypyridin-2-amine (Compound 22a)

[0257]

[0258] The synthesis method refers to compound 3 and compound 4a (120 mg, 21.37%). 1 H NMR (400MHz, CDCl3) δ8.14 (s, 1H), 6.68 (d, J = 2.3Hz, 2H), 6.45 (t, J = 2.3Hz, 1H),5.96(s,1H),4.66–4.54(m,3H),3.82(s,6H),1.44(s,3H),1.42(s,3H).

[0259] Step 6: 7-(Dimethoxymethyl)-N-(5-((3,5-dimethoxyphenyl)ethynyl)-4-isopropoxypyridin-2-yl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Compound 24a)

[0260]

[0261] Triphosgene (18.6 mg, 0.062 mmol) was dissolved in dichloromethane, and 22a (56 mg, 0.18 mmol), triethylamine (0.07 mL, 0.54 mmol), and compound 21 (72 mg, 0.22 mmol) were added to the reaction solution in sequence and stirred at room temperature. After the reaction was completed, a saturated aqueous solution of NaHCO3 was added for washing, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (SiO2, DCM / MeOH 100:0 to 10:1 gradient elution) to obtain the target compound 24a (82 mg, 67.9%). 1 HNMR(400MHz, CDCl3)δ13.71(s,1H),8.32(s,1H),7.88(s,1H),7.47(s,1H),6.7 0(d,J=1.8Hz,2H),6.47(s,1H),5.49(s,1H),4.95–4.76(m,3H),4.08–4.00(m,2 H),3.82(s,6H),3.52(s,6H),3.32–3.26(m,2H),3.23(s,2H),2.83(t,J=5.8Hz, 2H),2.64(d,J=4.7Hz,2H),2.36(s,3H),2.00(s,2H),1.47(s,3H),1.46(s,3H).

[0262] Step 7: Compound 24a was dissolved in a mixed solvent of 6 mL tetrahydrofuran and 3 mL water, 1 mL hydrochloric acid was added, and after stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, the reaction solution was adjusted to neutral, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain the target product ZZ22536 as a white solid (42 mg, 90.2%). HRMS (ESI) m / z [M+H] + calcd:627.2926; found:627.2905; purity:95.1%; 1 HNMR (400MHz, CDCl3) δ13.55 (s, 1H), 10.29 (s, 1H), 8.30 (s, 1H), 7.89 (d, J = 3.2Hz, 1H), 7. 64(s,1H),6.72(t,J=2.6Hz,2H),6.47(t,1H),5.12(s,2H),4.87–4.81(m,1H),4.14–4.06( m,2H),3.83(d,J=2.0Hz,6H),3.42–3.32(m,2H),3.22(d,J=4.6Hz,2H),2.94(t,J=6.2Hz, 2H),2.71–2.63(m,2H),2.37(s,3H),2.06(q,J=6.4,5.8Hz,2H),1.49(s,3H),1.47(s,3H). 13 C NMR(151MHz, CDCl3)δ193.89,165.71,160.44(3C),153.68,152.84,152.26,151.09,143.94,140.09,128.21,124.89,109.23(2C),1 05.94,101.52,97.30,94.26,83.15,71.20,59.26,55.46(2C),51.75,47.08,45.18,43.89,43.75,29.74,28.52,21.86(2C),20.89.

[0263] Embodiment 37

[0264] N-(5-(3,5-dimethoxyphenethyl)-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ22537)

[0265]

[0266] Compound 24a (50 mg, 0.074 mmol) was dissolved in methanol solution, palladium carbon (8 mg, 0.0074 mmol) was added, and the insoluble matter was filtered out after reacting for 8 hours under hydrogen atmosphere, and the mixture was concentrated under reduced pressure. The compound was then dissolved in a mixed solvent of 3 ml tetrahydrofuran and 1 ml water, and 0.5 ml hydrochloric acid was added. After stirring at room temperature for half an hour, the reaction was quenched with a saturated sodium bicarbonate solution, and the reaction solution was adjusted to neutral, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target product ZZ22537 was then recrystallized from ethyl acetate to obtain a white solid (33 mg, 70.8%). HRMS (ESI) m / z [M+H] + calcd:631.3239;found:631.3222;purity:97.7%; 1 H NMR (400MHz, CDCl3) δ13.30(s,1H),10.28(s,1H),7.89(s,1H),7.80(s,1H),7.62(s,1H), 6.38(d,J=2.2Hz,2H),6.33(t,J=2.2Hz,1H),5.11(s,2H),4.82(tp,J=11.6,6.0,5.5Hz,1H ),4.13–4.07(m,2H),3.79(s,6H),3.39–3.33(m,2H),3.21(s,2H),2.93(t,J=6.2Hz,2H), 2.82(s,3H),2.71–2.62(m,2H),2.37(s,3H),2.06–1.97(m,2H),1.44(s,3H),1.42(s,3H). 13 C NMR(151MHz, CDCl3)δ193.95,167.52,163.41,160.65(2C),153.02,152.73,151.28,148.24,144.55,143.98,139.96,128.10,128.03,1 21.75,106.48(2C),97.76,97.44,69.88,59.29,55.27(2C),51.76,47.05,45.19,43.80,43.70,36.30,29.87,28.57,21.95(2C),20.94.

[0267] Embodiment 38

[0268] 7-Formyl-N-(4-isopropoxy-5-(pyridin-2-ylethynyl)pyridin-2-yl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ22538)

[0269]

[0270] The synthesis method was referred to Example 36 (60 mg, 41.3%). HRMS (ESI) m / z [M+H] + calcd:568.2667; found:568.2647; 1 H NMR (600MHz, CDCl3) δ13.61 (s, 1H), 10.28 (s, 1H), 8.63 (d, J = 4.6Hz, 1H), 8.36 (s, 1H), 7.90 (s, 1H), 7 .70(td,J=7.7,1.5Hz,1H),7.62(s,1H),7.55(d,J=7.8Hz,1H),7.25(dd,J=7.1,5.2Hz,1H),5.11(s, 2H),4.84(dq,J=11.8,5.9Hz,1H),4.15–4.08(m,2H),3.36(t,J=5.4Hz,2H),3.22(s,2H),2.94(t,J= 6.2Hz, 2H), 2.67 (t, J = 5.4Hz, 2H), 2.37 (s, 3H), 2.04 (dd, J = 11.7, 6.0Hz, 2H), 1.48 (d, J = 6.1Hz, 6H). 13 C NMR (151MHz, CDCl3) δ193.83,167.55,166.00,154.16,153.00,152.83,151.04,149.98,143.94,143.73,140.12,136.14,128.29, 128.21,127.27,122.57,105.11,97.16,93.45,83.86,71.30,59.26,51.75,47.10,45.18,43.87,43.76,28.51,21.81(2C),20.88.

[0271] Embodiment 39

[0272] 7-Formyl-N-(4-isopropoxy-5-(pyridin-3-ylethynyl)pyridin-2-yl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (ZZ22539)

[0273]

[0274] The synthesis method was referred to Example 36 (120 mg, 22.3%). HRMS (ESI) m / z [M+H] +calcd:568.2666;found:568.2637;purity:95.08%; 1 H NMR (400MHz, CDCl3) δ13.59(s,1H),10.29(s,1H),8.81–8.76(m,1H),8.55(dd,J=4.8,1.5Hz,1H) ,8.31(s,1H),7.91(s,1H),7.83(dt,J=7.9,1.8Hz,1H),7.64(s,1H),7.34–7.28(m,1H),5.12(s,2 H),4.85(dq,J=12.0,6.0Hz,1H),4.11(d,J=5.5Hz,2H),3.37(t,J=5.4Hz,2H),3.22(s,2H),2.94( t,J=6.2Hz,2H),2.67(t,J=5.4Hz,2H),2.37(s,3H),2.07–2.03(m,2H),1.49(s,3H),1.48(s,3H). 13 C NMR (151MHz, CDCl3) δ193.83,167.53,165.76,154.05,152.84,152.36,152.17,151.06,148.32,143.93,140.11,138.29,128.32, 128.23,123.05,120.87,105.40,97.22,90.84,86.99,71.30,59.27,51.76,47.12,45.19,43.91,43.76,28.52,21.84(2C),20.89.

[0275] Embodiment 40

[0276] Kinase inhibitory activity test of 2-formyltetrahydronaphthyridine compounds

[0277] FGFR1-4 kinase inhibition assay: The inhibitory activity of compounds against FGFR1-4 was determined using the FRET-based Z'-Lyte assay system according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA). The reactions were performed in 384-well plates in 5 μL reaction volumes in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35 with the appropriate amount of kinase. The reactions were incubated at room temperature for 1.5 hours in the presence of 2 μM substrate and each kinase (corresponding to ATP concentrations: FGFR1: 25 μM, FGFR2: 5 μM, FGFR3: 75 μM, FGFR4: 150 μM) and in the presence of various concentrations of compounds, followed by the addition of 2.5 μL of developer, followed by another incubation at room temperature for 1 hour, followed by the addition of 2.5 μL of stop solution. The fluorescence signal ratio of 445 nm (coumarin) / 520 nm (fluorescein) was detected using EnVision Multilabel Reader (Perkin Elmer, Inc.). Data were analyzed using Graphpad Prism 5 (Graphpad Software, Inc). The inhibition rate of the compound was calculated using the following formula:

[0278]

[0279] The IC50 value was calculated by four-parameter fitting of the inhibition curve. The kinase inhibitory activity results of the 2-formyltetrahydronaphthyridine compounds of the present invention are shown in Table 1. The compound numbers listed in Table 1 correspond to the compound numbers in Examples 1-39.

[0280] Table 1 Kinase inhibitory activity of compounds

[0281]

[0282]

[0283] From the results of kinase activity detection, it can be seen that the 2-formyltetrahydronaphthyridine compounds of the present invention showed no inhibitory activity against FGFR1-3 subtype kinases, but showed higher inhibitory activity against FGFR4, and most compounds showed potent kinase inhibitory activity.

[0284] Embodiment 41

[0285] Test of the inhibitory activity of 2-formyltetrahydronaphthyridine compounds on the proliferation of various cancer cells

[0286] In vitro cell proliferation inhibition was detected by CCK8 assay. MDA-MB-453, Huh 7, Hep3b2.1-7, SNU16, NCI-H1581 and other cells (all from Shanghai Cell Bank) were stored in the corresponding growth medium and passed at least two generations before recovery. The experimental steps are as follows: Take an appropriate amount of cells in the logarithmic growth phase and inoculate them in a 96-well plate with a volume of 100 μL per well, and then culture them at 37 ° C in an incubator containing 5% CO2 overnight. The compound to be tested was dissolved in DMSO to prepare a 10 μM / L mother solution, and then diluted 10 gradients, and 2 μL of the compound solution of different concentrations was mixed with 998 μL of culture medium. Take 100 μL of the mixed culture medium and add it to the corresponding 96-well plate. 2 μL DMSO solution was used as the corresponding blank control. After 72 hours of co-culture incubation, CCK8 (CK04, Dojindo Laboratories, Kumamoto, Japan) was added. Dilute CCK8 and culture medium 1:2, for example, add 1ml CCK8 to 2ml culture medium, mix well, add 30μl diluted CCK8 to each well of the 96-well plate, tap to mix well, and leave for about 1-4h. Use a super microplate reader to measure the OD value; first, according to the OD 450 and OD 650 The actual absorbance value A (A = OD 450 -OD 650 ), and then according to the actual absorbance value A of each well, the cell survival rate of each treatment well is obtained:

[0287] Cell survival rate (%) = [(As-Ac) / (Ab-Ac)] × 100%]

[0288] As: absorbance value of experimental wells (wells containing cells and different concentrations of drugs)

[0289] Ab: absorbance value of vehicle control well (vehicle-treated well containing cells and drug concentration of 0)

[0290] Ac: absorbance value of blank well (well without cells and drugs)

[0291] Then the cell survival rate data and the corresponding concentrations of the test compounds and control compounds were input into GraphPadPrism 5Demo software, and the IC 50 The results are shown in Table 2.

[0292] Table 2 Inhibitory activity of compounds on cell proliferation

[0293]

[0294]

[0295] From the results of the cell proliferation inhibition activity test, it can be seen that the 2-formyltetrahydronaphthyridine compounds of the present invention have strong proliferation inhibition activity on FGFR4-dependent hepatocellular carcinoma cells Huh7, Hep3B2.1-7, and triple-negative breast cancer cells MDA-MB-453 that highly express FGFR4, and the 2-formyltetrahydronaphthyridine compounds of the present invention have no obvious inhibitory effect on FGFR4-independent FGFR2 amplified human gastric cancer cells SNU16 and non-small cell lung cancer cells NCI-H1581.

[0296] Embodiment 42

[0297] Effects of 2-formyltetrahydronaphthyridine compounds on FGFR4 kinase phosphorylation and downstream signaling pathway activation in Baf3 cells and Hep3b cells (both from Shanghai Cell Bank)

[0298] Changes in cell signaling pathways in vitro were detected by immunoblotting. Cells were seeded in 6-well plates at appropriate density and co-cultured with gradient concentrations of compounds or control DMSO. The cells were collected at the predetermined time points, the culture medium was discarded, and the cells were rinsed twice with 4°C pre-cooled PBS buffer to remove residual liquid. The cells were lysed using 1×SDS sample lysis buffer (CST) containing protease and phosphatase inhibitors. After ultrasonic shearing and boiling, the lysate was loaded on a 10-12% SDS-PAGE gel, and the separated proteins were transferred to a PVDF membrane after electrophoresis. After blocking with 5% BSA solution (in TBST, 0.5% Tween-20) at room temperature for 4 hours, the membrane was incubated with the corresponding primary antibody (1:3000-1:500) at 4°C overnight. After rinsing the membrane with TBST solution 3-5 times, it was incubated with the corresponding horseradish peroxidase (HRP)-labeled secondary antibody at room temperature for 2 hours. Antibodies FGFR4 (8562), PLCγ1 (5690), Erk1 / 2 (4695), p-FGFR (3471), p-Erk1 / 2 (4370), p-FRS2α (3861), p-PLCγ1 (14008), GAPDH (5174) and HRP-linked secondary antibodies were purchased from Cell Signaling Technology (Boston, MA, USA). Antibody FRS2α (sc-17841) was purchased from Santa Cruz Biotechnologies (Dallas, TX, USA). Protein signals were visualized by ECL Western Blot Detection Kit (Thermo Scientific, Waltham, MA, USA) and detected with Amersham Imager 600 system (GE, Boston, MA, USA).

[0299] The results are as follows Figure 1As shown, the results show that the compound ZZ22539 of the present invention can inhibit the activation of FGFR4 and downstream signal proteins in a dose-dependent manner, but will not cause changes in the total amount of target proteins and downstream effector proteins. In BA / F3-FGFR4 cells, the compound ZZ22539 at a concentration of 11.1nM has a significant inhibitory effect on the phosphorylation of FGFR4, PLCγ1, FRS2, and ERK, and its phosphorylation is almost completely inhibited.

[0300] Embodiment 43

[0301] Effects of 2-formyltetrahydronaphthyridine compounds on cell clone formation ability

[0302] Hep3b2.1-7 and NCI-H1581 cell lines were seeded in 6-well plates at a density of 4000 cells / mL and 1000 cells / mL, respectively, and different concentrations of test compounds or control DMSO were added for co-culture. The complete medium with corresponding treatment was replaced every 3 days. After 10 days, the supernatant was discarded, the cells were carefully washed twice with PBS buffer, fixed with cold methanol at 4°C for 30 minutes, and then stained with crystal violet dye (0.1% w / v) at room temperature for 1 hour. After washing away the residual crystal violet dye with distilled water, dry, scan and count. The results are shown in Figure 2 As shown, the results showed that compound ZZ22539 could reduce the cloning ability of Hep3B2.1-7 cells in a dose-dependent manner, with a significant effect at a concentration of 33.3 nM, while it had no significant effect on non-FGFR4-dependent non-small cell lung cancer cells NCI-H1581.

[0303] Embodiment 44

[0304] In vivo pharmacokinetic properties of 2-formyltetrahydronaphthyridine compounds

[0305] Drug administration and sample collection

[0306] 1. Intravenous administration in rats: 3 SD rats, weighing 180-220 g. Fast for 12 h before administration, eat a small amount during the test, and drink water freely. The compound was administered by intravenous injection at a dose of 5 mg / kg. About 0.3 mL of blood was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after administration, placed in a heparinized test tube, centrifuged at 6000 rpm for 10 min, and plasma was separated and stored at 4°C for testing.

[0307] 2. Oral administration in rats: 3 SD rats, weighing 180-220g. Fast for 12h before administration, eat a small amount during the test, and drink water freely. The compound was orally administered at a dose of 25mg / kg. About 0.3mL of blood was collected from the eye socket at 0.25, 0.5, 1, 2, 4, 6, 8, and 24h after administration, placed in a heparinized test tube, centrifuged at 6000rpm for 10min, and plasma was separated and stored at 4℃ for testing.

[0308] Plasma sample assay

[0309] 1. Plasma Sample Processing

[0310] Add 150 μL of internal standard solution (5 μg / mL, acetonitrile solution) to 50 μL of rat plasma sample and mix well; vortex mix for 2 min, centrifuge for 30 min (13000 rpm, 4°C), take the supernatant into another centrifuge tube, and take 20 μL for LC / MS / MS analysis.

[0311] 2. Preparation of standard curve

[0312] Take 50 μL of blank rat plasma, add 10 μL of compound standard series solution in sequence, prepare compound plasma samples with plasma concentrations of 20, 50, 100, 500, 1000, 2000, 4000, 6000, 12000, 40000 ng / mL, and establish a standard curve according to the operation under "Plasma Sample Processing". Take the concentration of the test compound (x) as the horizontal axis, the peak area ratio of the test compound to the internal standard (y) as the vertical axis, and use weighting (W = 1 / x 2 ) The least squares method is used for regression calculation to obtain the linear regression equation, which is the standard curve.

[0313] 3. Data Processing and Analysis

[0314] The pharmacokinetic parameters of rats after administration were calculated using DAS 2.0 software. The test results of compound ZZ22539 are shown in Table 3.

[0315] Table 3 Pharmacokinetic parameters of compound ZZ22539 in SD rats

[0316]

[0317] The results show that the compound ZZ22539 of the present invention has excellent pharmacokinetic properties and high oral bioavailability, which is much higher than that of the compound Roblitinib (the oral bioavailability in rats is 20%). [Fairhurst, RA; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N.; Luu, VH; Madoerin, M.; Wirth, J.; Graus-Porta, D.; Weiss, A.; Kiffe, M.; Wartmann, M.; K inyamu-Akunda,J.;Sterker,D.;Stamm,C.;Adler,F.;Buhles,A.;Schadt,H.;Couttet,P.;Blank,J.;Galuba, I.; Trappe, J.; Voshol, J.; Ostermann, N.; Zou, C.; Berghau-sen, J.; Del, REA; Jahnke, W.; Furet, P. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542-12573.].

[0318] Embodiment 45

[0319] Effects of 2-formyltetrahydronaphthyridine derivatives on the growth inhibition of transplanted tumors in mice

[0320] Female CB17-SCID mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., animal qualification certificate number: SCXK (Beijing) 2016-0006. After the animals were admitted to the room, they were quarantined for one week. Hep3b2.1-7 cells were cultured in vitro and then collected after being expanded to 40 plates. The cells were adjusted to an appropriate cell concentration (3.5×10 7 The tumor volume reached 200-300mm after about 15 days. 3The tumor-bearing mice were randomly divided into two groups: solvent control group (0.1 ml / 10 kg, qd) and test drug group (30 mg / kg, q2d), with 6 animals in each group. For oral administration, the test drug was suspended in 0.5% CMC-Na aqueous solution, twice a day for 14 days. The weight and tumor volume of mice in each group were measured every other day, and the tumor volume was determined by the following formula: V = 0.5a × b 2 , where a and b are the long diameter and short diameter of the tumor, respectively. After the last administration, the animal tumors were collected for pathological and histochemical analysis.

[0321] The tumor inhibition (TGI) calculation formula is: TGI = [1-(T-T0) / (C-C0)] × 100, where T and T0 are the tumor volumes of the test drug group on the measurement day and the first day, respectively, and C and C0 are the tumor volumes of the blank control group on the measurement day and the first day, respectively.

[0322] The experimental results are as follows Figure 3 As shown, compound ZZ22539 can effectively inhibit the growth of Hep3b2.1-7 tumors in mice, and does not significantly affect the changes in the weight of mice. The tumor growth inhibition calculation results show that when compound ZZ22539 is used to treat mice at 30 mg / kg, its TGI (tumor growth inhibition) value is 95.19%.

[0323] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0324] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A 2-formyltetrahydronaphthyridine compound having a structure represented by formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: in, R 1 Selected from: R 2 Selected from: C1-C4 alkoxy, C1-C3 alkoxy substituted with C1-C3 alkoxy, or -NH-R 5 ; R 5 Selected from: C1-C3 alkyl substituted with C1-C3 alkoxy; R 3 Select from: H or 2. The 2-formyltetrahydronaphthyridine compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R 2 Selected from:

3. The 2-formyltetrahydronaphthyridine compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: The 2-formyltetrahydronaphthyridine compound is selected from the following compounds:

4. Use of the 2-formyltetrahydronaphthyridine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a FGFR4 inhibitor.

5. Use of the 2-formyltetrahydronaphthyridine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating a tumor, wherein the tumor is a tumor that highly expresses FGFR4.

6. The use according to claim 5, characterized in that: The tumors are: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, and rhabdomyosarcoma.

7. The use according to claim 6, characterized in that: The tumor cells of the tumor are Huh7 liver cancer cells that highly express FGFR4.

8. The use according to claim 6, characterized in that: The tumor cells of the tumor are Hep3B2.1-7 liver cancer cells that highly express FGFR4.

9. The use according to claim 6, characterized in that: The tumor cells of the tumor are MDA-MB-453 breast cancer cells that highly express FGFR4.

10. A pharmaceutical composition for preventing and / or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the 2-formyltetrahydronaphthyridine compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

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