Novel amide pyrrole compounds and their use in medicine

Abstract

The present application relates to a novel amide pyrrole compound and its application in medicine, especially the use as a drug for treating and preventing hepatitis B. Specifically, the present application relates to a compound represented by general formula (I) or a stereoisomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the use thereof as a drug, especially the use as a drug for treating and / or preventing hepatitis B, wherein each variable is as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field. Specifically, it relates to a novel amide-pyrrole compound and its use as a medicine, particularly as a medicine for the treatment and / or prevention of hepatitis B. The invention also relates to compositions containing these novel amide-pyrrole compounds in combination with other antiviral agents, and their use in the treatment and / or prevention of hepatitis B virus (HBV) infection. Background Technology

[0002] Hepatitis B virus (HBV) belongs to the Hepatoviridae family. It can cause acute and / or progressively chronic diseases. HBV can also cause many other pathological and clinical manifestations—especially chronic inflammation of the liver, cirrhosis, and hepatocellular carcinoma. The World Health Organization estimates that 2 billion people worldwide have been infected with HBV, with approximately 350 million chronically infected, and about 1 million people die annually from liver failure, cirrhosis, and hepatocellular carcinoma (HCC) caused by HBV infection.

[0003] Currently, the main treatment for chronic hepatitis B (CHB) is antiviral therapy. Interferon-alpha (IFN-α), pegylated IFN-α, and five nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir) have been approved by the U.S. Food and Drug Administration (FDA) for clinical treatment. Interferon was the first anti-HBV drug approved by the FDA. It primarily works by directly inhibiting the virus and inducing an immune response to clear the virus. However, its application is limited due to its low response rate, various side effects, high cost, and limited treatment options. Nucleoside (acid) analogs against HBV share the characteristic of specifically targeting viral DNA polymerase, exhibiting a strong inhibitory effect on viral replication. Patients tolerate these drugs better than with interferon. However, the widespread and long-term use of nucleoside (acid) analogs can induce DNA polymerase mutations, leading to drug resistance and the emergence of resistant strains, making treatment far from achieving ideal efficacy.

[0004] Therefore, there is still a need for new compounds that can be effectively used as antiviral drugs, especially for the treatment and / or prevention of hepatitis B. Summary of the Invention

[0005] This invention relates to novel amide-pyrrole compounds and their use in the preparation of medicaments for the treatment and prevention of HBV infection. In particular, this invention relates to a novel amide-pyrrole compound and pharmaceutically acceptable compositions thereof, which possess advantages such as good solubility, good stability, minimal induction of hepatic drug-metabolizing enzymes, and low toxicity, and especially exhibits excellent pharmacokinetic properties. The compounds of this invention can effectively inhibit HBV infection and show great promise for anti-HBV applications.

[0006] On one hand, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0007]

[0008] Among them, each R 5a R 5b R 5c R 5d R 5e R 2 and R 3 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, SF5, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, trifluoromethoxy, methoxy or ethoxy;

[0009] Ring B is C 6-10 Aryl, heteroaryl composed of 5-6 ring atoms, (I-2) or Wherein, the C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. 6 Replaced;

[0010] Each R 6 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl or carboxyl C 1-6 Alkyl group, wherein the amino group, -C(=O)OC 1-6 Alkyl, -OC1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl and carboxyl groups C 1-6 Each alkyl group is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w1 Replaced;

[0011] Each R 1a R 1b R 1 R 4 R a and R b Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups;

[0012] Each R 2a R 2b and R 2c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C 1-4 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w2 Replaced;

[0013] Each R 3a R 3b R 3c R 4a R 4b and R 4c Independently for C 1-6 Alkyl, C 6-10 Aryl or heteroaryl group composed of 5-6 ring atoms, wherein the C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w3 Replaced;

[0014] L1 is a single bond, a methylene group, or an ethylene group; wherein the methylene group and the ethylene group are each independently unsubstituted or converted by 1, 2, or 3 R groups. w4 Replaced;

[0015] L2 is a single bond or -NR b -;

[0016] Each Rw1 R w2 R w3 R w4 and R w5 Independently, it can be deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, or -C(=O)OC. 1-6 Alkyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, carboxyl group C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0017] Ring A is a cyclohexyl group, a monocyclic heterocyclic group composed of 5-6 ring atoms, a fused bicyclic heterocyclic group composed of 8-10 ring atoms, or a bridged bicyclic heterocyclic group composed of 6-10 ring atoms. The cyclohexyl group, the monocyclic heterocyclic group composed of 5-6 ring atoms, the fused bicyclic heterocyclic group composed of 8-10 ring atoms, and the bridged bicyclic heterocyclic group composed of 6-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, 4, or 5 R atoms. x Replaced;

[0018] Each R x Independently, it can be deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2, or -C(=O)OC. 1-6 Alkyl, -C 1-4 Alkylene-N(R) a )S(=O)2C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 2-6 alkenyl, C 2-6 alkynyl group, carboxyl group C 1-6 Alkyl or C 1-6 Haloalkyl groups, wherein -CONH2, -C(=O)OC 1-6 Alkyl, -C 1-4 Alkylene-N(R) a )S(=O)2C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 2-6 alkenyl, C 2-6 alkynyl group, carboxyl group C 1-6 Alkyl and C1-6 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w5 What it replaced.

[0019] In some embodiments, the ring B of the present invention is phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyrimidinyl. In this embodiment, the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, and pyrimidinyl groups are each independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. 6 Replaced;

[0020] Among them, each R 1a R 2a R 3a R 4a R 1b R 2b R 3b R 4b R 2c R 3c R 4c and R 6 It has the meaning described in this invention.

[0021] In some embodiments, the Rs described in this invention 6 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 1-4 Alkyl, -OC 2-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl or carboxyl C 1-4 Alkyl group, wherein the amino group, -C(=O)OC 1-4 Alkyl, -OC 2-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl and carboxyl groups C 1-4Each alkyl group is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w1 Replaced, of which each R w1 It has the meaning described in this invention.

[0022] In some embodiments, the Rs described in this invention 6 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -OCH2CH2CH2-OCH3, -OCH2CH2CH2-OCH2CH3, -OCH2CH2CH2CH2-OCH3, -OCH2CH2CH2CH2-OCH2CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl groups, methoxy groups, ethoxy groups, 1-propoxy groups, 2-propoxy groups, 1-butoxy groups, 2-methyl-1-propoxy groups, 2-butoxy groups, -OCH2F groups, -OCH2Cl groups, -OCHF2 groups, -OCHCl2 groups, -OCF3 groups, -OCH2CH2F groups, -OCH2CH2Cl groups, -OCH2CHF2 groups, -OCH2CHCl2 groups, -OCHFCH2F groups, -OCHClCH2Cl groups, -OCH2CF3 groups, -OCH(CF3)2 groups, -OCF2CH2CH3 groups, -OCH2CH2CH2F groups, -OCH2CH2CHF2 groups, -OCH2CH2CF3 groups, C 2-4 alkenyl, C 2-4 alkynyl or carboxyl C 1-4 Alkyl groups, wherein the amino group, -C(=O)O methyl group, -C(=O)O ethyl group, -C(=O)O n-propyl group, -C(=O)O isopropyl group, -OCH2CH2CH2-OCH3 group, -OCH2CH2CH2-OCH2CH3 group, -OCH2CH2CH2CH2-OCH3 group, -OCH2CH2CH2CH2-OCH2CH3 group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, C 1-4 Halogenated alkyl groups, methoxy groups, ethoxy groups, 1-propoxy groups, 2-propoxy groups, 1-butoxy groups, 2-methyl-1-propoxy groups, 2-butoxy groups, -OCH2F groups, -OCH2Cl groups, -OCHF2 groups, -OCHCl2 groups, -OCH2CH2F groups, -OCH2CH2Cl groups, -OCH2CHF2 groups, -OCH2CHCl2 groups, -OCHFCH2F groups, -OCHClCH2Cl groups, -OCH2CF3 groups, -OCH(CF3)2 groups, -OCF2CH2CH3 groups, -OCH2CH2CH2F groups, -OCH2CH2CHF2 groups, -OCH2CH2CF3 groups, C 2-4 alkenyl, C2-4 alkynyl and carboxyl groups C 1-4 Each alkyl group is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w1 Replaced, of which each R w1 It has the meaning described in this invention.

[0023] In some embodiments, the Rs described in this invention 3a R 3b R 3c R 4a R 4b and R 4c Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein each of the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl groups is independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 Replaced, of which each R w3 It has the meaning described in this invention.

[0024] In some embodiments, the Rs described in this invention w1 R w2 R w3 R w4 and R w5 Independently, it can be deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, or -C(=O)OC. 1-4 Alkyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0025] In some embodiments, the Rs described in this invention w1 R w2 R w3 R w4 and R w5 Independently, it can be deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0026] In some embodiments, the ring A of the present invention is The formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), and (II-14) therein are each independently unsubstituted or replaced by 1, 2, 3, 4, or 5 R's. x Replaced, of which each R x It has the meaning described in this invention.

[0027] In some embodiments, the Rs described in this invention x Independently, it can be deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2, or -C(=O)OC. 1-4 Alkyl, -C 1-3 Alkylene-N(R) a )S(=O)2C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkylene, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl or C 1-4 Haloalkyl groups, wherein -CONH2, -C(=O)OC 1-4 Alkyl, -C 1-3 Alkylene-N(R) a )S(=O)2C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkylene, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl and C 1-4 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w5Replaced, of which each R a and R w5 It has the meaning described in this invention.

[0028] In some embodiments, the Rs described in this invention x Independently, it can be deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -methylene-N(R) a )S(=O)2methyl,-methylene-N(R a )S(=O)2ethyl,-methylene-N(R a )S(=O)2 n-propyl, -methylene-N(R a )S(=O)2 isopropyl,-methylene-N(R a )S(=O)2 n-butyl,-methylene-N(R a S(=O)2 isobutyl, -ethylene-N(R) a )S(=O)2methyl,-ethylidene-N(R) a )S(=O)2ethyl, -ethylidene-N(R a )S(=O)2 n-propyl, -ethylene-N(R a )S(=O)2 isopropyl, -ethylidene-N(R a )S(=O)2 n-Butyl, -Ethylene-N(R a S(=O)2 isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein -CONH2, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -methylene-N(R) a )S(=O)2methyl,-methylene-N(R a )S(=O)2ethyl,-methylene-N(R a )S(=O)2 n-propyl, -methylene-N(R a )S(=O)2 isopropyl,-methylene-N(Ra )S(=O)2 n-butyl,-methylene-N(R a S(=O)2 isobutyl, -ethylene-N(R) a )S(=O)2methyl,-ethylidene-N(R) a )S(=O)2ethyl, -ethylidene-N(R a )S(=O)2 n-propyl, -ethylene-N(R a )S(=O)2 isopropyl, -ethylidene-N(R a )S(=O)2 n-Butyl, -Ethylene-N(R a S(=O)2 isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl and C 1-4 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w5 Replaced, of which each R a and R w5 It has the meaning described in this invention.

[0029] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients.

[0030] In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0031] In some embodiments, the pharmaceutical composition of the present invention includes, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

[0032] In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simvastatin, clavudine, emtricitabine, famciclovir, interferon, bacalanol CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, roximate, cizonan, eufovac, ampridin, phosphazid, heplisav, interferon α-2b, levamisole, or propanthenium.

[0033] In some embodiments, it comprises a structure, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, of one of the following:

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or relief of viral diseases in patients.

[0045] In some embodiments, the use described in this invention refers to the viral disease as hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0046] In some other embodiments, the uses described in this invention refer to diseases caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0047] On the other hand, the present invention relates to the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of hepatitis B in patients, including administering to patients an effective therapeutic dose of the compound or pharmaceutical composition described herein.

[0048] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.

[0049] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable and effective dose.

[0050] Another aspect of the present invention relates to the use of a compound of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of these symptoms.

[0051] Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compounds of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of those symptoms.

[0052] Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a dose of the compound or pharmaceutical composition of the present invention capable of effectively inhibiting HBV. In some further embodiments, the method further comprises contacting the cells with other anti-HBV therapeutic agents.

[0053] Another aspect of the present invention relates to a treatment method for HBV disease in patients, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment. In some further embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV drug to a patient requiring treatment.

[0054] Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment. In some further embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV drug to a patient requiring treatment.

[0055] Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).

[0056] The compounds involved in this invention, and their pharmaceutically acceptable compositions, can effectively inhibit HBV infection.

[0057] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are within the scope of this invention.

[0058] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the other components of the formulation and the mammal intended for treatment.

[0059] The salts of the compounds of the present invention also include salts used for the preparation or purification of intermediates of the compound of formula (I) or for the isolation of enantiomers of the compound of formula (I), but are not necessarily pharmaceutically acceptable salts.

[0060] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Alternatively, organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc., or combinations thereof, can be used.

[0061] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N2, etc. + (R 14 Salts of 4 and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary, and tertiary ammonia, N... + (R 14 )4 salts, such as R 14 It is H, C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl groups, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium salts, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C. 1-8 Sulfonates and aromatic sulfonates.

[0062] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0063] Definitions and general terms

[0064] This invention will list in detail the relevant literature for the specific details provided, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usages of terms, described techniques, or the scope controlled as described in this application.

[0065] This invention will apply the following definitions unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75. th Ed., 1994, defines it. Additionally, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all content incorporates references.

[0066] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and a class of compounds included in this invention.

[0067] In various parts of this specification, the substituents of the compounds of the present invention are disclosed according to the type or scope of the groups. In particular, the present invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C" 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0068] As used in this invention, the term "alkyl" includes a monovalent hydrocarbon group consisting of a saturated straight-chain or branched chain of 1-20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments have an alkyl group containing 1-12 carbon atoms, others have an alkyl group containing 1-10 carbon atoms, still others have an alkyl group containing 1-8 carbon atoms, still others have an alkyl group containing 1-6 carbon atoms, still others have an alkyl group containing 1-4 carbon atoms, and still others have an alkyl group containing 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH 2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)) 2) 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)C H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0069] The term "carbonyl", whether used alone or in combination with other terms (such as "aminocarbonyl" or "acyloxy"), means -(C=O)-.

[0070] The term "alkylene" refers to a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, it contains 1-4 carbon atoms; in still other embodiments, it contains 1-3 carbon atoms; and in still other embodiments, it contains 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), etc.

[0071] The terms “hydroxyalkyl” and “hydroxyalkoxy” refer to alkyl or alkoxy groups, which, depending on the context, are replaced by one or more hydroxyl groups. The terms “hydroxyalkyl”, “hydroxyalkylene”, and “hydroxyalkyl” can be used interchangeably. Examples of such interchangeability include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH,-CHOHCH3), hydroxypropyl (e.g., -CH2CH2CH2OH,-CH2CHOHCH3,-CHOHCH2CH3), hydroxymethoxy (-OCH2OH), etc.

[0072] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position of C and D is sp. 2 The double bond, wherein the alkenyl group may be independently unsubstituted or substituted by one or more substituents described in this invention, including "cis", "trans" or "Z", "E" isomers, wherein specific examples include, but are not limited to, vinyl (-CH=CH2), propenyl (-CH=CHCH3), allyl (-CH2CH=CH2), etc., wherein the alkenyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0073] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one C-C bond is an sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted by one or more substituents described in this invention, specific examples including, but not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), propynyl (-C≡C-CH3), 1-alkynylbutyryl (-CH2CH2C≡CH), 2-alkynylbutyryl (-CH2C≡CCH3), 3-alkynylbutyryl (-C≡CCH2CH3), etc., wherein the alkynyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0074] The terms "haloalkyl", "haloalkenyl", or "haloalkoxy" refer to alkyl, alkenyl, or alkoxy groups substituted with one or more halogen atoms, wherein alkyl, alkenyl, and alkoxy have the meanings described herein. Examples include, but are not limited to, difluoroethyl (-CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (-CH2CF3,-CF2CH2F,-CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), fluorovinyl (-CH=CHF,-CF=CH2), etc.

[0075] The term "carboxyalkyl" means that an alkyl group is replaced by one or two carboxyl substituents, wherein the alkyl and carboxyl groups have the meanings described in this invention. Such examples include, but are not limited to, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, etc.

[0076] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in still other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0077] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl- 2-Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0078] The term "composed of M-M1 ring atoms" or "composed of M-M1 atoms" indicates that the cyclic group is composed of M-M1 ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "a heteroaryl composed of 6-10 atoms" means that it comprises a heteroaryl group consisting of 6, 7, 8, 9, or 10 ring atoms.

[0079] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3-12 ring carbon atoms, with one or more linkages to the remainder of the molecule. In some embodiments, the cycloalkyl group is a spirobicycloalkyl group consisting of 6-10 atoms; in other embodiments, it is a fused bicycloalkyl group consisting of 6-10 atoms; in other embodiments, it is a cyclic system containing 3-10 ring carbon atoms; in other embodiments, it is a cyclic system containing 3-8 ring carbon atoms; in other embodiments, it is a cyclic system containing 3-7 ring carbon atoms; in other embodiments, it is a cyclic system containing 5-8 ring carbon atoms; in other embodiments, it is a cyclic system containing 3-6 ring carbon atoms; in other embodiments, it is a cyclic system containing 5-6 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and said cycloalkyl groups may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0080] The term "heterocyclic group" includes monocyclic, bicyclic, or polycyclic fused, spirocyclic, or bridged ring systems. The terms "heterocyclic group" and "heterocycle" are used interchangeably herein, referring to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms, and this ring system has one or more connecting sites attached to the remainder of the molecule. The term "heterocyclic group" includes monocyclic heterocyclic groups, bicyclic or polycyclic fused heterocyclic groups, spirocyclic or bridged heterocyclic heterocyclic groups, and also includes polycyclic ring systems in which the heterocycle may be fused with one or more non-aromatic carbocyclic or heterocyclic or one or more aromatic rings or combinations thereof, wherein the connecting atomic groups or sites are on the heterocycle. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. Unless otherwise stated, the -CH2- group of a heterocyclic group may optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic group is a ring system consisting of 3-12 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 4-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 5-6 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-10 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group consisting of 8-10 ring atoms; in some embodiments, the heterocyclic group is a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms; in other embodiments, the heterocyclic group is a ring system consisting of 3-8 ring atoms; in other embodiments, the heterocyclic group is a ring system consisting of 3-6 ring atoms; in other embodiments, the heterocyclic group is a ring system consisting of 5-7 ring atoms. A ring system composed of ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 5-8 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 6-8 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 5-6 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 3 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 4 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 5 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 6 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 7 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 8 ring atoms.

[0081] Examples of heterocycles include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, piperazinyl, homopiperazinyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, homopiperidinyl, oxacyclopropyl, azirroheptanyl, oxacycloheptanyl, thioheptanyl, oxazazolyl, diazazolyl, thioazazolyl, 2-pyrrolinyl, 3- Pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino; wherein examples of carbon atoms on the ring being replaced by oxo (=O) groups include, but are not limited to, pyrimidinidone, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-keto, etc.; wherein examples of carbon atoms on the ring being replaced by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thiono, 1,3,4-oxadiazole-2(3H)-thiono. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0082] The terms “fused bicyclic,” “fused ring,” “fused bicyclic group,” and “fused ring group” are used interchangeably here to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system in which the two rings share a single bond. Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain an aromatic ring or heterocyclic ring (although aromatic groups may act as substituents thereon).

[0083] The terms “spirocyclic,” “spirocyclic,” “spirobicyclic,” or “spirobicyclic” are used interchangeably here to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system in which one ring originates from a specific ring carbon atom on the other ring, and the two rings share only one atom.

[0084] For example, as described in formula a-1 below, a saturated ring system (rings C and B′) is called a “fused bicyclic”, while rings A′ and B share a carbon atom and are called a “spirocyclic” or “spirobicyclic”. Each ring in a fused bicyclic or spirobicyclic group can be a carbocyclic or heterocyclic group, and each ring may optionally be substituted by one or more substituents described in this invention.

[0085]

[0086] The term "fused bicyclic heterocyclic group" refers to a monovalent, saturated or partially unsaturated, non-aromatic fused-ring system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or aromatic heterocyclic ring (although aromatics can act as substituents thereon). Each ring in the ring system comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-10 ring atoms; in some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 8-10 ring atoms. Examples of such groups include, but are not limited to, 3-aza-fused [3.1.0]hexane, 3-aza-bicyclic [3.3.0]octane, hexahydro-furan [3,4-c]pyrrole, hexahydro-thiophene [3,4-c]pyrrole, 3,4,5,6-tetrahydro-cyclopentane [c]thiophene. The fused heterobicyclic group may optionally be replaced by one or more substituents described in this invention.

[0087] The term "bridged bicyclic" refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula (b), where ring A1 and ring A2 share a common alkane chain or a heteroalkane chain, where X 3 The components are C, N, O, P, and S; j is 1, 2, 3, or 4. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or aryl ring (however, aromatics may be used as substituents thereon). Each ring, such as A1 or A2, contains 3-7 atoms, and examples include, but are not limited to, bicyclic [2.2.1]heptyl, 2-methyl-diazabicyclo[2.2.1]heptyl, etc. The bridged bicyclic group may optionally be substituted by one or more substituents described in this invention.

[0088]

[0089] The term "bridged bicyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic system, wherein each ring contains 3-7 carbon atoms. Examples of such systems include, but are not limited to, bicyclic [2.2.1]heptyl groups. The bridged bicyclic group may optionally be substituted by one or more substituents described in this invention.

[0090] The term "bridged bicyclic heterocyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic system, wherein each ring comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the bridged bicyclic heterocyclic group is a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms. Examples of such groups include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptyl, The bridged bicyclic heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0091] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 carbon atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 carbon atoms and has one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic cyclic ring," as aryl can include phenyl, naphthyl, and anthracene. The aryl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0092] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-16 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system comprises a ring of 5-7 ring atoms and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, a heteroaryl is a heteroaryl comprising 5-14 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, a heteroaryl is a heteroaryl comprising 5-12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In still other embodiments, a heteroaryl is a heteroaryl comprising 5-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0093] Other embodiments include, but are not limited to, the following monocyclic groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl. 3-Pyridinyl, 4-Pyridinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl, Pyridazinyl (e.g., 3-pyridazinyl), 2-Thiazolyl, 4-Thiazolyl, 5-Thiazolyl, Tetrazolyl (e.g., 5H-Tetrazolyl, 2H-Tetrazolyl), Triazolyl (e.g., 2-Triazolyl, 5-Triazolyl, 4H-1,2,4-Triazolyl, 1H-1,2,4-Triazolyl, 1,2,3-Triazolyl) 2-Thienyl, 3-Thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including The following bicyclic or tricyclic groups, but not limited to: benzimidazolyl, benzofuranyl, benzothiopheneyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathioyl, dibenzimidazolyl, dibenzofuranyl, or dibenzothiopheneyl, etc. The heteroaryl group may optionally be substituted by one or more substituents described in this invention.

[0094] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases “each and each is independently”, “each and each is independently”, and “each and each is independently” used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0095] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0096] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0097] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0098] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0099] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is rotated. (-) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity. The terms "tautomer" or "tautomeric form" refer to isomers with different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomerism includes interconversions involving recombination of bonding electrons. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0100] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0101] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0102] The term "protecting group" or "Pg" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, a "protecting group for an amino group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, and so on. For a general description of protecting groups, please refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0103] Pharmaceutical compositions, formulations, administration, and uses of the compounds and pharmaceutical compositions of the present invention.

[0104] According to another aspect, the pharmaceutical compositions of the present invention are characterized by compounds of formula (I), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable excipients. The compounds in the pharmaceutical compositions of the present invention are effective in inhibiting hepatitis B virus and are suitable for the treatment of viral diseases, especially acute and chronic persistent HBV infection. Chronic HBV-induced viral diseases can lead to severe pathological changes, and chronic hepatitis B virus infection can lead to cirrhosis and / or hepatocellular carcinoma in many cases.

[0105] For the compounds of the present invention, the areas of disease treatment that may be mentioned include, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, such as hepatitis B virus infection. The compounds of the present invention are particularly suitable for treating chronic hepatitis B infection and acute and chronic hepatitis B virus infection.

[0106] The present invention includes pharmaceutical preparations that, in addition to non-toxic, inert, pharmaceutically suitable excipients, contain one or more compounds of formula (I) of the present invention or pharmaceutical compositions thereof, or contain one or more active ingredients of formula (I) compounds or pharmaceutical compositions thereof.

[0107] The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides the compound of formula (I).

[0108] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0109] As described in this invention, the pharmaceutical compositions of this invention comprise any compound of formula (I) of this invention, further comprising pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0110] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0111] The pharmaceutical compositions of the compounds of the present invention can be administered in any of the following ways: oral administration, inhalation via aerosol, local administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, or intracranial injection or infusion, or administration via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0112] The compounds or pharmaceutical compositions thereof of this invention can be administered in unit doses. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders for injection, inclusion complexes, implants, patches, and liniments.

[0113] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0114] Oral liquids can be formulated as hydrated oil suspensions, solutions, emulsions, syrups, or elixirs, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous excipients (which may contain edible oils such as almond oil), fats such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0115] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0116] For external administration, liquid dosage forms are typically made from a compound and a sterilized excipient. Water is the preferred excipient. Depending on the excipient and drug concentration, the compound can be either dissolved in the excipient or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0117] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more excipients. Excipients that may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Excipients that may be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0118] Generally, it has been proven advantageous, in both human and veterinary medicine, that the total dosage of the active compound of the present invention is about 0.5-500 mg per 24 hours, preferably 1-100 mg / kg body weight, administered in multiple single doses if appropriate, to achieve the desired effect. The amount of active compound in a single dose is preferably about 1-80 mg, more preferably 1-50 mg / kg body weight, but may not follow the above dosages, depending on the type and weight of the patient, the nature and severity of the disease, the type of formulation and the route of administration, and the dosing cycle or time interval.

[0119] The pharmaceutical composition provided by this invention further comprises an anti-HBV drug. The anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or interferon.

[0120] The anti-HBV drugs mentioned include lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simmointerleukin, clavudine, emtricitabine, faprovir, interferon, bacalanol CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, roximate, cizonan, eufovac, amprigin, phosphazid, heplisav, interferon α-2b, levamisole, or propafenone, etc.

[0121] Another aspect of this invention relates to the use of a compound or pharmaceutical composition of the invention in the preparation of a medicament for the prevention, treatment, or relief of hepatitis B disease in a patient, including administering the medication to the patient in a pharmaceutically acceptable and effective dose. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis, and hepatitis B stem cell carcinoma. Acute hepatitis B virus infection can be asymptomatic or present with symptoms of acute hepatitis. Patients with chronic viral infection have active disease that can develop into cirrhosis and hepatitis B cancer.

[0122] Anti-HBV drugs can be administered separately from compositions comprising the compounds of the present invention as part of a multiple-dose regimen. Alternatively, those drugs can be part of a single-dose formulation, mixed with the compounds of the present invention to form a single composition. If administration is part of a multiple-dose regimen, the two active agents can be delivered simultaneously and continuously or over a period of time to achieve the target agent activity.

[0123] The amount of compounds and pharmaceutical compositions that can be combined with excipients to produce single-dose formulations (those comprising a single pharmaceutical composition as described in this invention) varies depending on the indication and specific dosing regimen. Normally, the amount of the pharmaceutical compositions of this invention will not exceed the amount normally administered in a composition containing only one active agent. On the other hand, the amounts of the pharmaceutical compositions disclosed herein range from approximately 50% to 100% of the normal amounts in existing pharmaceutical compositions, containing an agent as the sole active therapeutic agent. In those compositions, the composition will act synergistically with the compounds of this invention.

[0124] The compounds of this invention exhibit potent antiviral activity. These compounds possess unexpected antiviral activity against HBV, making them suitable for treating various viral diseases, particularly those caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity; chronic hepatitis B virus infection is well known to cause cirrhosis and / or hepatocellular carcinoma.

[0125] Examples of indications for treatment with the compounds of the present invention include acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Chronic hepatitis B infection and acute hepatitis B virus infection are particularly preferred.

[0126] This invention also relates to the use of the compounds and pharmaceutical compositions of this invention in the preparation of medicaments for the treatment and prevention of viral diseases, particularly hepatitis B.

[0127] General synthesis methods

[0128] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following synthetic schemes and examples are provided to further illustrate the content of the present invention.

[0129] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0130] In the examples described below, all temperatures are specified in degrees Celsius (°C) unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0131] Silica gel columns were used, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartets), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet), td (three doublets). The coupling constant J is expressed in Hertz (Hz).

[0132] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0133] Low-resolution mass spectrometry (MS) data were also determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0134] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table 1.

[0135] Table 1: Gradient elution conditions

[0136] 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0137] Compound purity was evaluated using an Agilent 1100 series high-performance liquid chromatography (HPLC) system with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column (2.1 × 30 mm, 4 μm), a flow rate of 0.6 mL / min for 10 min, and a concentration of 5-95% (0.1% formic acid acetonitrile solution) or (0.1% formic acid aqueous solution) at a column temperature of 40 °C.

[0138] The following abbreviations are used throughout this invention:

[0139]

[0140] Synthesis method

[0141] The following synthetic scheme outlines the experimental steps for preparing the compounds disclosed in this invention. Specifically, the B and R rings... 5a R 5b R 5c R 5d R 5e R x R 1 R 2 R 3 and R 4 It has the meaning as described in this invention.

[0142] Synthesis Scheme 1

[0143]

[0144] The compound shown in formula (a-6) can be prepared by the method described in Synthesis Scheme 1, wherein Y is O or S; and X is chlorine or bromine. Compound (a-1) (obtained by referring to the synthesis method of compound M in Example 11 of WO2015132276) reacts with compound (a-2) under alkaline conditions (e.g., sodium hydride) to generate compound (a-3); then, compound (a-3) is deprotected by the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to obtain compound (a-4) or its salt; finally, compound (a-5) (obtained by referring to the synthesis method of compound 42 on page 101 of WO2017156255) undergoes a condensation reaction with compound (a-4) or its salt under suitable conditions (e.g., under HATU and DIPEA) to obtain compound (a-6).

[0145] Synthesis Scheme 2

[0146]

[0147] The compound shown in formula (b-4) can be prepared by the method described in synthetic scheme 2, wherein D is optionally surrounded by 1, 2, 3, 4, or 5 Rs.x The replaced ring atoms form an N-containing monocyclic heterocyclic group of 4-7 ring atoms or an N-containing bridged bicyclic heterocyclic group of 6-10 ring atoms; X is chlorine or bromine. Compound (a-5) and compound (b-1) undergo a condensation reaction under suitable conditions (e.g., under HATU and DIPEA) to generate compound (b-2); then, compound (b-2) is deprotected by the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to give compound (b-3) or its salt; finally, compound (b-3) or its salt reacts with compound (a-2) under alkaline conditions (e.g., potassium carbonate) to give compound (b-4).

[0148] Synthesis Scheme 3

[0149]

[0150] The compound shown in formula (b-4) can also be prepared by the method described in synthetic scheme 3, wherein D is optionally replaced by 1, 2, 3, 4, or 5 Rs. x The substituted ring atoms form an N-containing monocyclic heterocyclic group of 4-7 ring atoms or an N-containing bridged bicyclic heterocyclic group of 6-10 ring atoms; X is chlorine or bromine. Compound (a-2) reacts with compound (b-1) under alkaline conditions (e.g., potassium carbonate) to generate compound (c-1); then, compound (c-1) undergoes debonding of the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to give compound (c-2) or its salt; finally, compound (c-2) or its salt reacts with compound (a-5) under suitable conditions (e.g., under HATU and DIPEA) to give compound (b-4). Detailed Implementation

[0151] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0152] Preparation Examples

[0153] In the following preparation examples, the inventors have described in detail the preparation process of the compounds of the present invention using some of the compounds of the present invention as examples.

[0154] Table 1. Compound Numbers and Corresponding Structures

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] Synthesis of Compound 1

[0166]

[0167] Step 1: Synthesis of Compound 1-1

[0168] Compound F1 (1.5 g, 6.20 mmol, obtained by the synthesis method of compound M in Example 11 of WO2015132276) was dissolved in DMF (20 mL). Sodium hydride (0.4 g, 10 mmol, 60 mass%) was added to the system at 0 °C. After reacting for 1 h, 1-(bromomethyl)-2-chloro-4-fluorobenzene (1.7 g, 7.6 mmol) was slowly added to the reaction system. The reaction was then stirred at room temperature for 6 h. Water (5 mL) was added to quench the reaction. DCM (10 mL) and water (10 mL) were then added. The aqueous phase was discarded. The organic phase was washed successively with water (10 mL × 2) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to give a white solid (1.32 g, 55%). MS(ESI,pos.ion)m / z:328.2[M-56+H] + .

[0169] Step 2: Synthesis of Compounds 1-2

[0170] Compound 1-1 (650 mg, 1.69 mmol) was dissolved in DCM (5 mL), followed by the addition of trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure to obtain the title compound as a brown oil (673 mg, 99%), which was directly added to the next step.

[0171] Step 3: Synthesis of Compound 1

[0172] Compound F2 (682 mg, 2.028 mmol, obtained by the synthesis method of compound 42 on page 101 of WO2017156255), DIPEA (0.9 mL, 5 mmol), and HATU (880 mg, 2.199 mmol) were dissolved in DMF (20 mL). After stirring for ten minutes, compounds 1-2 (673 mg, 1.69 mmol) were added to the system. The reaction was stirred at room temperature for 21 h. Water (20 mL) and DCM (20 mL) were added, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid (1 M, 20 mL × 1), sodium hydroxide solution (1 M, 20 mL × 1), and saturated brine (20 mL × 1), respectively. The solution was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (PE / EA (V / V) = 1 / 2) to give the title compound as a white solid (737 mg, 73%). MS(ESI,pos.ion)m / z:602.1[M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ (ppm) 10.46 (s, 1H), 7.86 (dd, J = 13.0, 7.5Hz, 1H), 7 .50–7.33(m,4H),7.27–7.19(m,1H),4.49–4.29(m,3H),3.85–3.63(m,2H),3 .60(d,J=3.6Hz,3H),3.46–3.38(m,1H),3.17–3.07(m,1H),3.06–3.00(m,1H ),2.95–2.85(m,2H),2.83–2.70(m,1H),2.46(s,3H),2.25(d,J=2.1Hz,3H).

[0173] Synthesis of Compound 2

[0174] Replacing 1-(bromomethyl)-2-chloro-4-fluorobenzene with 2-(chloromethyl)-3,4-dimethoxypyridine, the target product was prepared as a white solid (384 mg, 51%), following the synthetic method for compound 1. MS (ESI, pos.ion) m / z: 611.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.49 (s, 1H), 8.53 (t, J = 7.2Hz, 1H), 7.92–7.82 (m, 1H), 7.56(t,J=5.5Hz,1H),7.49–7.33(m,2H),4.57(d,J=10.6Hz,2H),4.41(dd,J=40.6,11. 8Hz,1H),4.10(d,J=3.6Hz,3H),3.87(d,J=6.9Hz,3H),3.83–3.65(m,2H),3.60(s,3H) ,3.55–3.37(m,2H),3.20–3.3.02(m,2H),2.95–2.69(m,2H),2.46(s,3H),2.25(s,3H).

[0175] Synthesis of Compound 3

[0176] Replacing 1-(bromomethyl)-2-chloro-4-fluorobenzene with 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine, the target product was prepared according to the synthetic method of reference compound 1, yielding a white solid (358 mg, 44%). MS (ESI, pos.ion) m / z: 663.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.50(s,1H),8.71(s,1H),7.87(s,1H),7.58(s,1H),7.43(s,2H),5.16(s,2H),4.62(d,J=9.3Hz,2H),4.41(d d,J=38.9,10.4Hz,1H),3.96–3.64(m,2H),3.60(s,3H),3.55–3.35(m ,2H),3.20–3.05(m,1H),3.02–2.75(m,3H),2.46(s,3H),2.25(s,6H).

[0177] Synthesis of Compound 4

[0178] Replacing 1-(bromomethyl)-2-chloro-4-fluorobenzene with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine, the target product was prepared using the same synthetic method as compound 1, yielding a white solid (356 mg, 44%). MS (ESI, pos.ion) m / z: 653.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ(ppm)10.50(s,1H),8.74–8.58(m,1H),7.97–7.80(m,1H) ),7.60–7.53(m,1H),7.46–7.38(m,2H),4.62(d,J=10.8Hz,2H),4.50–4.33(m,3H ),3.88–3.65(m,2H),3.60(s,3H),3.51(s,3H),3.45–3.35(m,1H),3.26(s,3H),3 .20–3.06(m,2H),3.02–2.72(m,2H),2.46(s,3H),2.30–2.17(m,6H),2.06(s,2H)

[0179] Synthesis of Compound 5

[0180]

[0181] Replacing 1-(bromomethyl)-2-chloro-4-fluorophenyl)-2-(thiazo-2-yl)-1,4-dihydropyrimidin-5-carboxylate with compound F3 (i.e., (R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazo-2-yl)-1,4-dihydropyrimidin-5-carboxylate, obtained by referring to the synthetic method of compound W2 in Example 11 of WO2015078391A1), the target product was prepared as a yellow solid (351 mg, 66%). MS (ESI, pos.ion) m / z: 823.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.46(d,J=4.8Hz,1H),9.62(s,0.5H),9.05(d,J=17.8Hz,0.5H),8.03– 7.97(m,1H),7.95–7.81(m,2H),7.43(s,4H),7.25–7.13(m,1H),6.07–5.90(m,1H),4.70–4.59(m,1H) ,4.55–4.30(m,2H),3.90–3.68(m,3H),3.60(d,J=6.4Hz,3H),3.55(d,J=8.0Hz,3H),3.50–3.42(m,1H ),3.28–3.07(m,2H),3.02–2.87(m,1H),2.85–2.72(m,1H),2.45(d,J=5.6Hz,3H),2.30–2.17(m,3H).

[0182] Synthesis of Compound 6

[0183]

[0184] Compound F4 (synthesized by replacing (S)-piperazine-2-carboxylic acid dihydrochloride with (R)-piperazine-2-carboxylic acid dihydrochloride, following the same synthetic method as F1) and compound F3, respectively, replacing compounds F1 and 1-(bromomethyl)-2-chloro-4-fluorobenzene, followed the same synthetic method as compound 1, yielded the target product as a yellow solid (350 mg, 71%). MS (ESI, pos.ion) m / z: 823.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.69 (d, J = 7.6Hz, 1H), 8.11 (d, J = 17.3Hz, 1H), 7.85 (d, J = 3.0Hz, 1H), 7.78–7.73 (m, 1H), 7.4 6(dd,J=2.9,1.5Hz,1H),7.28–7.23(m,2H),7.21–7.12(m,2H),6.95–6.88(m,1H),6.21(d,J=2.2Hz,1H),4.44(dd,J=17. 7,6.4Hz,1H),4.18–4.10(m,1H),3.95(d,J=17.6Hz,1H),3.71(d,J=2.2Hz,3H),3.62(d,J=2.4Hz,3H),3.56(d,J=8.3Hz, 2H),3.51–3.43(m,2H),3.02–2.86(m,1H),2.82(s,2H),2.70–2.60(m,1H),2.51(d,J=1.6Hz,3H),2.42(d,J=2.1Hz,3H).

[0185] Synthesis of Compound 7

[0186]

[0187] Replacing 1-(bromomethyl)-2-chloro-4-fluorobenzene with compound F5 (obtained according to steps 1 and 2 of Example 39, WO2015144093A1), and following the synthetic method of compound 1, the target product was prepared as a yellow solid (220 mg, 53%). MS (ESI, pos.ion) m / z: 823.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.98 (d, J = 15.4Hz, 1H), 7.86 (d, J = 3.0Hz, 1H), 7.76–7.68 (m ,1H),7.65–7.42(m,2H),7.39–7.33(m,1H),7.20–7.14(m,2H),7.02–6.88(m,1H),6.20 –6.08(m,1H),4.85–4.55(m,3H),4.15–3.80(m,3H),3.72(d,J=4.5Hz,3H),3.66–3.60( m,3H),3.30–3.10(m,3H),2.94–2.74(m,2H),2.51(d,J=3.1Hz,3H),2.44–2.39(m,3H).

[0188] Synthesis of Compound 8

[0189] Step 1: Synthesis of F6

[0190]

[0191] Compound F1 (10 g, 41.4 mmol) and anhydrous toluene (200 mL) were added sequentially to a reaction flask. Under nitrogen protection, phosphorus pentasulfide (4.61 g, 20.7 mmol) was added, and the mixture was heated to 115 °C and maintained at this temperature for 6 h. The mixture was then cooled to room temperature, and water (100 mL) and dichloromethane (200 mL) were added. The mixture was extracted and separated into layers. The organic layer was concentrated, and the concentrated residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give a white solid (3.12 g, 29.2%). MS (ESI, pos.ion) m / z: 258.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 6.58 (s, 1H), 4.37 (d, J = 10.8Hz, 1H), 4.32–4.00 (m, 2H), 3.96–3.84 (m, 1H) ,3.73(t,J=9.5Hz,1H),3.28–3.18(m,1H),3.07–2.94(m,1H),2.84(s,1H),2.71(s,1H),1.47(s,9H).

[0192] Step 2: Synthesis of Compound 8

[0193] Replacing compound F1 with compound F6 and following the synthetic method for compound 1, the target product was prepared as a white solid (40 mg, 16%). MS (ESI, pos.ion) m / z: 618.1 [M+H] + ;1 H NMR(400MHz, CDCl3)δ(ppm)7.76–7.68(m,1H),7.58–7.46(m,2H),7.20–7.13 (m,2H),7.04–6.97(m,1H),5.09–4.92(m,2H),4.75–4.58(m,2H),4.05–3.90 (m,1H),3.75–3.60(m,2H),3.71(d,J=6.2Hz,3H),3.30–3.18(m,2H),3.11–2 .88(m,1H),2.73–2.65(m,1H),2.50(d,J=6.7Hz,3H),2.41(d,J=7.9Hz,3H).

[0194] Synthesis of Compound 9

[0195]

[0196] Step 1: Synthesis of Compound 9-1

[0197] Compound F2 (1.0 g, 3.0 mmol) was dissolved in DMF (10 mL), followed by the addition of DIPEA (1.6 mL, 8.7 mmol) and HATU (2.4 g, 6.0 mmol). After stirring for two minutes, piperazine-1-carboxylic acid tert-butyl ester (830 mg, 4.456 mmol) was added to the system. The reaction was stirred at room temperature for 13 h, and then water (10 mL) was added to quench the reaction. DCM (20 mL) was then added, and the mixture was allowed to stand for separation. The aqueous phase was extracted with DCM (20 mL). The organic phases were combined and washed twice with 1 M dilute hydrochloric acid (20 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the target compound as a white solid (1.13 g, 75%). MS (ESI, pos.ion) m / z: 449.60 [M-56+H] + .

[0198] Step 2: Synthesis of Compound 9-2

[0199] Compound 9-1 (371 mg, 0.74 mmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 h, and the solvent was evaporated to obtain the crude product (381 mg, 100%), which was then directly added to the next step.

[0200] Step 3: Synthesis of Compound 9

[0201] Compound F3 (364 mg, 0.82 mmol) and compound 9-2 (381 mg, 0.74 mmol) were dissolved in anhydrous ethanol (4 mL) at room temperature, followed by the addition of potassium carbonate (339 mg, 2.45 mmol). The mixture was stirred at 40 °C for 4 h, then filtered through a diatomaceous earth layer to obtain the solid. The solid was washed with DCM (10 mL), the solvent was evaporated, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 2) to give the title compound as a yellow solid (210 mg, 37%). MS (ESI, pos.ion) m / z: 768.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.47 (s, 1H), 9.69 (s, 1H), 8.03 (d, J = 3.1Hz, 1H), 7. 95(d,J=3.1Hz,1H),7.87(dd,J=12.5,7.2Hz,1H),7.48–7.35(m,4H),7.17(td,J=8. 5,2.5Hz,1H),6.05(s,1H),4.08–3.88(m,2H),3.67(s,2H),3.61(s,3H),3.52(s,3H ),3.42–3.36(m,2H),2.65(s,2H),2.59(d,J=6.0Hz,2H),2.48(s,3H),2.28(s,3H).

[0202] Synthesis of Compound 10

[0203] By replacing compound F3 with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine, and following the synthetic method for compound 9, the target product was prepared as a white solid (284 mg, 80%). MS (ESI, pos.ion) m / z: 598.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.52(s,1H),8.55(d,J=6.1Hz,1H),7.87(dd,J=11.8,7.1Hz,1H),7.51–7.31(m,3H),4.31(t,J=5.1Hz,2H),4 .17(s,3H),3.74(s,3H),3.61(s,3H),3.55–3.43(m,5H),2.86(d,J=2 1.9Hz,4H),2.47(s,3H),2.26(s,3H),2.19(s,3H),2.07–1.95(m,2H).

[0204] Synthesis of Compound 11

[0205] By replacing compound F3 with 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine, and following the synthetic method for compound 9, the target product was prepared as a white solid (52 mg, 21%). MS (ESI, pos.ion) m / z: 608.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.82 (s, 1H), 8.70 (d, J = 4.6Hz, 1H), 7.79–7.72 (m, 1H), 7.34–7.30 (m, 1H), 7.17–7.10 (m, 2H), 4.62 (q, J =7.5Hz,2H),4.02(s,2H),3.85(s,2H),3.67(s,3H),3.56(s,2H),2.89–2.84(m,2H),2.82–2.76(m,2H),2.51(s,3H),2.34(s,6H).

[0206] Synthesis of Compound 12

[0207] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with piperazine-1-carboxylic acid tert-butyl ester, and following the synthetic method for compound 9, the target product was prepared as a yellow solid (280 mg, 46%). MS (ESI, pos.ion) m / z: 782.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ(ppm)8.18(d,J=19.7Hz,1H),7.90(d,J=3.0Hz,1H),7.78–7.70(m, 1H),7.64–7.60(m,1H),7.26–7.24(m,1H),7.23–7.12(m,2H),7.05–6.95(m,1H),6.19(d, J=7.8Hz,1H),4.60–4.30(m,4H),4.05–3.97(m,1H),3.70(s,3H),3.63(s,3H),3.59–3.48 (m,2H),3.17–2.96(m,2H),2.51(d,J=4.0Hz,3H),2.40(d,J=8.7Hz,3H),1.73–1.58(m,3H)

[0208] Synthesis of Compound 13

[0209] Replacing piperazine-1-carboxylic acid tert-butyl ester with 2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (670 mg, 95%), following the synthetic method of compound 9. MS (ESI, pos.ion) m / z: 794.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)7.87(d,J=7.9Hz,1H),7.77–7.58(m,1H),7.49–7.30(m,2H),7.25–7.12(m,2H),7.08–6.81(m,2H),6.16(d,J=9.7Hz,1H) ,4.96–4.73(m,2H),4.38–3.74(m,4H),3.72–3.65(m,3H),3.63(s,3H),2. 63–2.36(m,6H),2.35–2.05(m,2H),1.35–1.25(m,2H),0.94–0.78(m,2H).

[0210] Synthesis of Compound 14

[0211] Replacing piperazine-1-carboxylic acid tert-butyl ester with 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (670 mg, 95%), following the synthetic method of compound 9. MS (ESI, pos.ion) m / z: 794.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.10 (d, J = 3.7Hz, 1H), 7.89 (t, J = 3.0Hz, 1H), 7.79–7.70 (m, 1H), 7.59 (t, J = 2.7Hz, 1H ),7.36–7.30(m,1H),7.27–7.22(m,1H),7.21–7.11(m,1H),7.02-6.94(m,1H),6.22(d,J=1.8Hz,1H),4.91–4.78 (m,1H),4.32(dd,J=16.5,5.3Hz,1H),4.22–4.07(m,2H),3.70(d,J=1.5Hz,3H),3.62(s,3H),3.36–2.99(m,4H), 2.49(d,J=1.9Hz,3H),2.47–2.42(m,1H),2.40(s,3H),2.14–2.07(m,1H),1.30–1.25(m,1H),0.90–0.85(m,1H).

[0212] Synthesis of Compound 15

[0213] Replacing compound F3 with compound F7 (obtained according to steps 1 to 2 of Example 8 in WO2015078391), and following the synthetic method of compound 9, the target product was prepared as a yellow solid (570 mg, 75%). MS (ESI, pos.ion) m / z: 854.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.93–7.84 (m, 2H), 7.78–7.71 (m, 1H), 7.55 (d, J = 2.9Hz, 1H), 7.44–7. 37(m,1H),7.24–7.19(m,1H),7.15(dd,J=9.8,7.5Hz,1H),7.03–6.98(m,1H),6.29(s,1H),4.95( q,J=7.1Hz,1H),4.42(s,2H),4.25–4.17(m,2H),4.14–4.00(m,2H),3.80(s,2H),3.72(d,J=2.5H z,3H),3.28–3.10(m,4H),2.52(s,3H),2.42(s,3H),1.32(d,J=7.1Hz,3H),1.28(t,J=7.1Hz,3H).

[0214] Synthesis of Compound 16

[0215] Replacing piperazine-1-carboxylic acid tert-butyl ester with (1R,4R)-2,5-diazabicyclo[2.2.1]octane-2-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (150 mg, 50%), following the synthetic method of compound 9. MS (ESI, pos.ion) m / z: 780.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 9.54 (d, J = 13.3Hz, 1H), 8.04 (d, J = 10.0Hz, 1H), 7.85–7.64 (m, 2H), 7.41 (dd, J = 14. 7,3.1Hz,1H),7.29–7.25(m,1H),7.23–7.11(m,2H),6.98–6.89(m,1H),6.18(d,J=5.4Hz,1H),5.01–4.36(m,1H ),4.26(d,J=17.4Hz,1H),4.14(d,J=17.4Hz,1H),3.74–3.66(m,5H),3.58(d,J=16.9Hz,3H),3.55–3.46(m,1H ),3.14–2.97(m,2H),2.51(d,J=16.6Hz,3H),2.43(d,J=14.0Hz,3H),2.14(t,J=9.7Hz,1H),1.95–1.85(m,1H).

[0216] Synthesis of Compound 17

[0217] Replacing piperazine-1-carboxylic acid tert-butyl ester with (1S,4S)-2,5-diazabicyclo[2.2.1]octane-2-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (230 mg, 77%), following the synthetic method of compound 9. MS (ESI, pos.ion) m / z: 780.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)9.62(d,J=10.5Hz,1H),8.22(d,J=16.2Hz,1H),7.84–7.51(m,2H),7.43(dd ,J=15.4,3.1Hz,1H),7.28–7.18(m,2H),7.17–7.09(m,2H),6.95–6.88(m,1H),6.20(d,J=7.6Hz,1H),4 .50–4.31(m,2H),4.00–3.80(m,2H),3.70(s,3H),3.65–3.42(m,5H),3.22–3.10(m,1H),3.03–2.90(m, 1H), 2.51 (d, J = 18.3Hz, 3H), 2.44 (d, J = 27.2Hz, 3H), 2.14–2.05 (m, 1H), 1.87 (dd, J = 16.7, 10.3Hz, 1H).

[0218] Synthesis of Compound 18

[0219] Replacing (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester with piperazine-1-carboxylic acid tert-butyl ester, and following the synthetic method for compound 9, the target product was prepared as a yellow solid (290 mg, 59%). MS (ESI, pos.ion) m / z: 782.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ(ppm)9.72(d,J=10.0Hz,1H),7.86(t,J=3.5Hz,1H),7.79–7.71(m,1H),7.67(s,1H),7.49–7.45(m ,1H),7.31–7.27(m,1H),7.20–7.13(m,2H),6.95–6.88(m,1H),6.22(d,J=5.2Hz,1H),4.35–4.26(m,1H),4.15(dd,J=17.7 ,7.3Hz,1H),4.02(dd,J=17.7,3.9Hz,1H),3.73(d,J=4.8Hz,3H),3.62(d,J=1.6Hz,3H),3.57–3.47(m,1H),3.45–3.33(m ,1H),3.25–3.17(m,1H),3.15–3.08(m,1H),2.93–2.73(m,2H),2.54(d,J=4.5Hz,3H),2.47(d,J=3.0Hz,3H),1.28(d,3H).

[0220] Synthesis of Compound 19

[0221] Replacing piperazine-1-carboxylic acid tert-butyl ester with 3,6-diazabicyclo[3.1.1]octane-6-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (360 mg, 49%), following the synthetic method of compound 9. MS (ESI, pos.ion) m / z: 780.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 9.65 (d, J = 5.4Hz, 1H), 7.95–7.82 (m, 2H), 7.76–7.68 (m, 1H), 7.46 (d, J=3.1Hz,1H),7.28–7.23(m,1H),7.20–7.10(m,2H),6.96–6.86(m,1H),6.18(d,J=6.5Hz,1H),4. 29–4.09(m,1H),4.05–3.94(m,1H),3.92–3.79(m,3H),3.74(d,J=2.0Hz,3H),3.72–3.60(m,2H), 3.50(d,J=10.4Hz,3H),3.03–2.92(m,1H),2.59(d,J=3.1Hz,3H),2.52(s,3H),1.78–1.69(m,2H).

[0222] Synthesis of Compound 20

[0223]

[0224] Step 1: Synthesis of Compound 20-1

[0225] Compound F3 (608 mg, 1.37 mmol), potassium carbonate (755 mg, 5.46 mmol), and (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (410 mg, 2.05 mmol) were dissolved in DMF (6 mL). The mixture was stirred at room temperature for 15 h. Ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was discarded, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 1) to give the target compound as a yellow solid (600 mg, 78%). MS (ESI, pos.ion) m / z: 564.2 [M+H] + .

[0226] Step 2: Synthesis of compound 20-2

[0227] Compound 20-1 (600 mg, 1.06 mmol) was dissolved in DCM (14 mL), followed by the addition of trifluoroacetic acid (7 mL). The mixture was stirred at room temperature for 0.5 h, and the solvent was evaporated to obtain a brown oily substance (615 mg, 100%), which was then directly added to the next step.

[0228] Step 3: Synthesis of Compound 20

[0229] Compound F2 (357 mg, 1.06 mmol), DIPEA (0.7 mL, 4 mmol), and HATU (554 mg, 1.38 mmol) were dissolved in DCM (10 mL). After stirring for ten minutes, compound 20-2 (615 mg, 1.06 mmol) was added to the system. The mixture was stirred at room temperature for 15 hours, and then washed with water (20 mL). The organic phase was then washed with dilute hydrochloric acid (1 M, 20 mL × 2), sodium hydroxide (1 M, 10 mL), and saturated brine (10 mL), respectively. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the target compound as a yellow solid (200 mg, 24%). MS (ESI, pos.ion) m / z: 782.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.15 (s, 1H), 7.93–7.86 (m, 1H), 7.79-7.71 (m, 1H), 7.60 (t, J = 3.4Hz, 1H),7.36(dd,J=14.2,7.5Hz,1H),7.27–7.22(m,1H),7.21–7.10(m,2H),7.05–6.98(m,1H),6.18( d,J=7.7Hz,1H),5.02–4.82(m,1H),4.48–4.35(m,3H),4.01–3.74(m,4H),3.70(d,J=2.4Hz,3H), 3.64(s,3H),3.48–3.35(m,1H),2.51(d,J=3.4Hz,3H),2.37(s,3H),1.60(dd,J=34.2,5.5Hz,3H).

[0230] Synthesis of Compound 21

[0231] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (105 mg, 25%), following the synthetic method of compound 20. MS (ESI, pos.ion) m / z: 794.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.39 (d, J = 8.4Hz, 1H), 7.93–7.87 (m, 1H), 7.80–7.72 (m, 1H), 7.60 (dd, J = 6.1, 3 .0Hz,1H),7.47–7.38(m,1H),7.21–7.08(m,2H),7.03(td,J=8.4,2.3Hz,1H),6.16(s,1H),4.71–4.48(m,3 Synthesis of Compound 22 (m, 2H), 4.45–4.33 (m, 2H), 4.22–4.12 (m, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J = 2.5 Hz, 3H), 3.59–3.55 (m, 1H), 2.54 (d, J = 4.0 Hz, 3H), 2.49–2.40 (m, 2H), 2.37 (d, J = 5.7 Hz, 3H), 2.28–2.05 (m, 2H)

[0232] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, and following the synthetic method for compound 20, the target product was prepared as a yellow solid (590 mg, 78%). MS (ESI, pos.ion) m / z: 782.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)9.54(s,1H),7.82(dd,J=12.1,9.0Hz,2H),7.78–7.71(m,1H),7.46(dd,J=3.0,1.6 Hz,1H),7.23–7.13(m,3H),6.97–6.88(m,1H),6.21(d,J=1.8Hz,1H),4.85–4.75(m,1H),4.58–4.52(m,1H),4.0 8 (dd, J = 17.1, 2.3 Hz, 1H), 3.93–3.83 (m, 2H), 3.72 (s, 3H), 3.60 (d, J = 2.5 Hz, 3H), 3.58–3.53 (m, 1H), 3.40–3.29 (m, 1H), 3.07–3.01 (m, 1H), 2.80–2.65 (m, 1H), 2.53 (s, 3H), 2.46 (d, J = 6.0 Hz, 3H), 1.54–1.47 (m, 3H). Synthesis of compound 23

[0233] By replacing piperazine-1-carboxylate tert-butyl ester and compound F5 with (R)-3-methylpiperazine-1-carboxylate tert-butyl ester and compound F3, respectively, and following the synthetic method for compound 20, the target product was prepared as a yellow solid (230 mg, 50%). MS (ESI, pos.ion) m / z: 768.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.56 (s, 1H), 8.26 (s, 1H), 7.85 (d, J = 3.1Hz, 1H), 7.79–7. 73(m,1H),7.47(d,J=3.1Hz,1H),7.30–7.25(m,1H),7.18–7.12(m,2H),6.92(td,J=8 .3,2.5Hz,1H),6.21(s,1H),4.12(d,J=17.2Hz,1H),3.93–3.81(m,3H),3.71(s,3H), 3.61(s,3H),3.54(brs,2H),2.69(brs,2H),2.62(brs,2H),2.50(s,3H),2.41(s,3H).

[0234] Synthesis of Compound 24

[0235] Step 1: Synthesis of compound F8:

[0236]

[0237] Compound F3 (145.99 g, 328.1 mmol), toluene (1200 mL), and DDQ (82.0 g, 361.2 mmol) were added sequentially to a dry reaction flask. The mixture was heated to 110 °C and stirred for 1.5 h. After cooling to room temperature, the reaction solution was washed sequentially with 10% sodium hydroxide aqueous solution (500 mL × 2) and saturated saline solution (500 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to obtain a pale yellow solid (80.2 g, 55.2%).

[0238] Step 2: Synthesis of Compound 24

[0239] By replacing piperazine-1-carboxylic acid tert-butyl ester and compound F8 with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and compound F3, respectively, the target product was prepared according to the synthetic method of compound 20, yielding a brown solid (330 mg, 78%). MS (ESI, pos.ion) m / z: 766.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.09 (d, J = 3.1Hz, 1H), 8.05 (s, 1H), 7.78–7.71 (m, 1H), 7.61 (d, J = 3.1Hz, 1H), 7.41 (dd, J = 8.5, 5.9Hz, 1H), 7.27– 7.20(m,2H),7.17–7.10(m,2H),4.03(s,2H),3.68(s,6H),3.64(s,2H ),3.32(s,2H),2.61(brs,2H),2.52(s,2H),2.46(s,3H),2.37(s,3H).

[0240] Synthesis of Compound 25

[0241] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with 3,6-diazabicyclo[3.1.1]octane-6-carboxylic acid tert-butyl ester, the target product was prepared as a yellow solid (300 mg, 44%), following the synthetic method of compound 20. MS (ESI, pos.ion) m / z: 780.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.51 (d, J = 7.3Hz, 1H), 7.80 (t, J = 2.8Hz, 1H), 7.78–7.67 (m, 2H), 7.46 (d d,J=2.9,1.5Hz,1H),7.31–7.28(m,1H),7.22–7.13(m,3H),6.98–6.90(m,1H),6.21(d,J=2.6Hz,1H ),4.73–4.53(m,2H),4.35–4.08(m,2H),3.72(d,J=1.0Hz,3H),3.61(d,J=4.6Hz,3H),3.43–3.34(m ,2H),3.32–3.21(m,2H),2.79–2.72(m,1H),2.64–2.58(m,1H),2.50(d,J=3.3Hz,3H),2.47(s,3H).

[0242] Synthesis of Compound 26

[0243] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester, and following the synthetic method for compound 20, the target product was prepared as a yellow solid (430 mg, 90%). MS (ESI, pos.ion) m / z: 798.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ(ppm)9.67(d,J=11.1Hz,1H),8.23–8.00(m,1H),7.84(d,J=3.0Hz,1H),7.79–7.66(m,1H),7.47 (d,J=2.9Hz,1H),7.27–7.22(m,1H),7.19–7.09(m,2H),6.97–6.87(m,1H),6.19(d,J=7.4Hz,1H),4.45(d,J=17.6Hz, 1H),4.10–3.92(m,2H),3.87–3.72(m,2H),3.70(d,J=6.4Hz,3H),3.62(d,J=2.6Hz,3H),3.59–3.44(m,2H),3.23–3.1 2(m,1H),3.09–3.00(m,1H),2.87–2.77(m,1H),2.65(d,J=12.7Hz,1H),2.50(d,J=6.7Hz,3H),2.39(d,J=4.0Hz,3H).

[0244] Synthesis of Compound 27

[0245] Synthetic route of compound F9:

[0246]

[0247] Step 1: Synthesis of compound F9-1

[0248] Compound F9-0 (5.0 g, 14.3 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -20 °C, and sodium hydride (1.1 g, 28 mmol, 60 mass%) was slowly added. After reacting for 5 min, iodomethane (1.3 mL, 21 mmol) was added. After the addition was complete, the mixture was slowly heated to room temperature and the reaction continued for 5 h. The reaction was quenched with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to obtain the target compound as a colorless oil (2.81 g, 54%). MS (ESI, pos.ion) m / z: 365.2 [M+H] + .

[0249] Step 2: Synthesis of compound F9

[0250] Compound F9-1 ​​(2.51 g, 6.89 mmol), 10% Pd / C (251 mg), and methanol (20 mL) were added sequentially to a dry reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure to give the target compound as a white solid (1.58 g, 99%). MS (ESI, pos.ion) m / z: 231.2 [M+H] + .

[0251] Step 3: Synthesis of Compound 27

[0252] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with compound F9, and following the synthetic method for compound 20, the target product was prepared as a yellow solid (350 mg, 72%). MS (ESI, pos.ion) m / z: 812.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.54 (d, J = 4.7Hz, 1H), 8.63 (s, 0.5H), 8.37 (s, 0.5H), 7.84 (dd, J = 4.1, 3.3Hz, 1H), 7.80–7.71 (m ,1H),7.47(dd,J=4.3,3.3Hz,1H),7.37–7.29(m,2H),7.20–7.11(m,2H),6.98–6.88(m,1H),6.18(d,J=1.2Hz,1H),4.88–4. 81(m,0.5H),4.53–4.48(m,0.5H),3.98–3.87(m,3H),3.84–3.78(m,1H),3.69(d,J=4.5Hz,3H),3.61(s,3H),3.57–3.42(m, 1H),3.32–3.19(m,4H),3.17–3.05(m,1H),2.97–2.70(m,1H),2.55–2.50(m,1H),2.49(d,J=4.2Hz,3H),2.43–2.37(m,4H).

[0253] Synthesis of Compound 28

[0254] Replacing piperazine-1-carboxylic acid tert-butyl ester with compound F9, and following the synthetic method for compound 9, the target product was prepared as a yellow solid (320 mg, 80%). MS (ESI, pos.ion) m / z: 812.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ(ppm)9.69(d,J=7.6Hz,1H),8.11(d,J=17.3Hz,1H),7.87–7.83(m,1H),7.79-7.73(m,1H),7.4 6(dd,J=2.9,1.5Hz,1H),7.28–7.22(m,2H),7.21–7.11(m,2H),6.96–6.87(m,1H),6.21(d,J=2.2Hz,1H),4.44(dd,J= 17.7,6.4Hz,1H),4.15–4.02(m,1H),3.95(d,J=17.6Hz,1H),3.71(d,J=2.2Hz,3H),3.62(d,J=2.4Hz,3H),3.58–3.4 2(m,5H),3.24(d,J=31.5Hz,3H),3.02–2.85(m,2H),2.72–2.57(m,1H),2.51(d,J=1.6Hz,3H),2.42(d,J=2.1Hz,3H).

[0255] Synthesis of Compound 29

[0256] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester, the target compound was prepared as a yellow solid (30 mg, 7%), following the synthetic method for compound 20. MS (ESI, pos.ion) m / z: 798.2 [M+H] + .

[0257] Synthesis of Compound 30

[0258] Replacing (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester with piperazine-1-carboxylic acid tert-butyl ester, and following the synthetic method for compound 9, the target product was prepared as a yellow solid (145 mg, 16%). MS (ESI, pos.ion) m / z: 798.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.93–8.73 (m, 1H), 7.88 (d, J = 2.6Hz, 1H), 7.85–7.73 (m, 1H), 7.65–7.61 (m, 1H), 7.37– 7.26(m,2H),7.23–7.17(m,1H),7.13(dd,J=18.2,9.0Hz,1H),7.05–6.98(m,1H),6.16(s,1H),4.55(d,J=22.9Hz,2 H),4.45–4.35(m,1H),4.30–4.20(m,1H),4.19–4.05(m,2H),3.93–3.74(m,2H),3.67(d,J=3.1Hz,3H),3.63(d,J=3 .7Hz,3H),3.42–3.34(m,1H),3.31–3.22(m,1H),3.15–3.05(m,1H),2.52(d,J=13.0Hz,3H),2.38(d,J=3.9Hz,3H).

[0259] Synthesis of Compound 31

[0260]

[0261] Step 1: Synthesis of compound 31-1

[0262] Compound F10 (500 mg, 0.91 mmol, obtained according to the synthesis method in step 1 of Example 1 in WO2020135439) was dissolved in DCM (10 mL). Then, NBS (169 mg, 0.95 mmol) was added to the system in portions. The mixture was stirred at 40 °C for 3 h, and the solvent was evaporated to obtain a yellow oil (550 mg, 95.8%), which was directly added to the next step. MS (ESI, pos.ion) m / z: 530.1 [M+H-100] + .

[0263] Step 2: Synthesis of compound 31-2

[0264] Compound 31-1 (550 mg, 0.87 mmol), DIPEA (0.6 mL, 4 mmol), and compound 9-2 (450 mg, 0.87 mmol) were dissolved in DCM (6 mL) at room temperature. After stirring for 15 h at room temperature, water (10 mL) and ethyl acetate (15 mL) were added. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give a yellow solid (520 mg, 62.7%). MS (ESI, pos.ion) m / z: 954.3 [M+H] + .

[0265] Step 3: Synthesis of compound 31-3

[0266] Compound 31-3 (520 mg, 0.55 mmol) and sodium hydroxide (110 mg, 2.75 mmol) were dissolved in methanol (6 mL), water (2 mL), and THF (4 mL) at room temperature. The mixture was then heated to 70 °C and stirred for 10 h. Water (10 mL) and ethyl acetate (15 mL) were added, and the pH of the solution was adjusted to 4–5 with 1 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow solid (330 mg, 70.9%). MS (ESI, pos.ion) m / z: 854.1 [M+H] + .

[0267] Step 4: Synthesis of Compound 31

[0268] Compound 31-3 (330 mg, 0.39 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of 1,4-dioxane hydrogen chloride solution (4 mL, 16 mmol, 4 mol / L). The mixture was stirred at room temperature for 18 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography (DCM / CH3OH (V / V) = 25 / 1) to give a yellow solid (53 mg, 18%). MS (ESI, pos.ion) m / z: 754.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.39 (s, 1H), 7.88 (d, J = 2.7Hz, 1H), 7.72–7.64 (m, 1H), 7.58 (d, J = 2.8Hz, 1H), 7.27–7.22 (m, 2H), 7.12 (dd, J = 10.6, 8.5Hz, 2 H),6.89–6.80(m,1H),6.11(s,1H),4.58–4.40(m,2H),3.88–3.75(m,2H),3 .67(s,3H),3.62–3.40(m,6H),3.20–3.10(m,2H),2.49(s,3H),2.30(s,3H).

[0269] Synthesis of Compound 32

[0270]

[0271] Step 1: Synthesis of Compound 32-1

[0272] Compound F2 (500 mg, 1.49 mmol) and HATU (895 mg, 2.24 mmol) were dissolved in DMF (5 mL). DIPEA (578 mg, 4.46 mmol) and (S)-1-tert-butyl-2-methylpiperazine-1,2-dicarboxylic acid ester (363 mg, 1.49 mmol) were added to the solution, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 3) to give the title compound as a brown solid (650 mg, 78%). MS (ESI, pos.ion): m / z 507.2 [M-56+H] + .

[0273] Step 2: Synthesis of compound 32-2

[0274] Compound 32-1 (600 mg, 1.07 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide monohydrate (90 mg, 2.15 mmol) was added, and the mixture was stirred at room temperature for 2 h. Water (100 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL × 2). The pH of the aqueous phase was adjusted to 3–4 with 1 M hydrochloric acid, resulting in the precipitation of a large amount of solid. After stirring for 30 min, the mixture was filtered, and the filter cake was dried to obtain the title compound as a brown solid (550 mg, 94%). MS (ESI, pos.ion): m / z 493.2 [M-56+H] + .

[0275] Step 3: Synthesis of compound 32-3

[0276] Compound 32-2 (200 mg, 0.36 mmol), HATU (212 mg, 0.55 mmol), and DIPEA (95 mg, 0.73 mmol) were dissolved in DMF (5 mL), followed by the addition of ammonium chloride (39 mg, 0.73 mmol). The mixture was stirred at room temperature for 12 h, and the reaction was quenched by adding water (20 mL). Ethyl acetate (80 mL) was then added. The organic layer was washed with 1 M dilute hydrochloric acid (50 mL) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give the title compound as a brown solid (150 mg, 75%). MS (ESI, pos.ion): m / z 492.2 [M-56+H] + .

[0277] Step 4: Synthesis of compound 32-4

[0278] 32-3 (200 mg, 0.37 mmol) was suspended in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was slowly added. The mixture was stirred at room temperature for 20 min. The solution was directly evaporated to dryness to obtain the title compound trifluoroacetate as a brown oil (200 mg, 98%).

[0279] Step 5: Synthesis of Compound 32

[0280] Compound 32-4 (200 mg, 0.36 mmol) and DIPEA (140 mg, 1.08 mmol) were dissolved in dichloromethane (10 mL), and compound F3 (175 mg, 0.39 mmol) was added. The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give the title compound as a yellow solid (180 mg, 62%). MS (ESI, pos.ion): m / z 811.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ(ppm)9.64–9.49(m,1H),8.58–8.26(m,1H),7.90–7.80(m,1H),7.78–7. 70(m,1H),7.60–7.40(m,1H),7.35–7.25(m,1H),7.20–7.10(m,2H),7.03–6.85(m,2H),6.21– 6.12(m,1H),6.00–5.83(m,1H),4.39–4.19(m,1H),3.96–3.72(m,1H),3.68(s,3H),3.65–3.5 2(m,5H),3.48–3.04(m,4H),2.87–2.54(m,1H),2.48(d,J=3.9Hz,3H),2.37(d,J=6.3Hz,3H).

[0281] Synthesis of Compound 33

[0282] Replacing compound 32-3 with compound 32-2, and following steps 4 and 5 of the synthesis of compound 32, the target product was prepared as a yellow solid (200 mg, 69%). MS (ESI, pos.ion) m / z: 812.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.00–8.71 (m, 1H), 7.92 (dd, J = 8.3, 2.9Hz, 1H), 7.79–7.69 (m, 1 H),7.65(t,J=3.1Hz,1H),7.37–7.29(m,2H),7.19–7.07(m,2H),7.04–6.92(m,1H),6.22(s ,1H),4.58(d,J=16.5Hz,1H),4.38(dd,J=29.4,16.7Hz,1H),4.27–3.96(m,2H),3.97–3.75 (m,2H),3.70–3.51(m,8H),3.11–2.74(m,1H),2.46(d,J=6.6Hz,3H),2.30(d,J=5.0Hz,3H).

[0283] Synthesis of Compound 34

[0284] Replacing piperazine-1-carboxylic acid tert-butyl ester with (2S,4S)-1-tert-butyl-2-methyl-4-aminopyrrolidine-1,2-dicarboxylic acid ester, the target product was prepared as a yellow solid (72 mg, 71%) following the synthetic method for compound 9. MS (ESI, pos.ion) m / z: 826.0 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 9.61 (s, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.72 (s, 1H), 7.67–7.57 (m, 2H), 7.3 2–7.21(m,2H),7.15–7.01(m,3H),6.92–6.84(m,1H),6.14(d,J=6.7Hz,1H),4.71–4.60(m,1H),4.35 (d,J=17.4Hz,1H),4.12(d,J=17.4Hz,1H),3.74–3.61(m,4H),3.57(d,J=4.7Hz,6H),3.18(d,J=9.5H z,1H),2.95(dd,J=9.3,4.1Hz,1H),2.76–2.65(m,1H),2.29(s,3H),2.23(s,3H),2.18–2.08(m,1H).

[0285] Synthesis of Compound 35

[0286] Replacing (R)-3-methylpiperazine-1-carboxylate with methyl (2R,4R)-4-((tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylate, and following the synthetic method for compound 20, the target product was prepared as a yellow solid (60 mg, 59%). MS (ESI, pos.ion) m / z: 826.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.68 (s, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.69–7.59 (m, 2H), 7.55 (s, 1H) ,7.31–7.21(m,2H),7.16–7.03(m,3H),6.94–6.84(m,1H),6.15(d,J=6.1Hz,1H),4.72–4.62(m, 1H),4.36(d,J=17.4Hz,1H),4.13(d,J=17.5Hz,1H),3.78–3.64(m,4H),3.59(s,6H),3.19(d,J= 9.7Hz,1H),3.02–2.90(m,1H),2.78–2.66(m,1H),2.31(s,3H),2.25(s,3H),2.17–2.10(m,1H).

[0287] Synthesis of Compound 36

[0288] Compound 34 (0.2 g, 0.24 mmol) and tetrahydrofuran (5 mL) were added sequentially to a dry reaction flask. After stirring until homogeneous, a solution of lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 12 h. Then, water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution, and the layers were extracted and separated. The organic layer was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / CH3OH (V / V) = 10 / 1) to obtain the target product as a yellow solid (120 mg, 61%). MS (ESI, pos.ion) m / z: 812.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.01 (s, 1H), 7.91–7.61 (m, 3H), 7.35–7.20 (m, 2H), 7.19–6.95 (m, 3H), 6.11 (d, J = 33.5Hz, 1H), 4. 63(s,2H),3.91(d,J=14.5Hz,1H),3.82–3.41(m,7H),3.27–3.09(m,1H),2.82–2.59(m,1H),2.36(s,3H),2.31–2.14(m,5H).

[0289] Synthesis of Compound 37

[0290] Replacing compound 34 with compound 35 and following the synthetic method for compound 36, the target product was prepared as a yellow solid (120 mg, 68%). MS (ESI, pos.ion) m / z: 812.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)8.99(s,1H),7.95–7.64(m,3H),7.35–7.23(m,2H),7.15–6.95(m,3H),6.15(s,1H),4.63(s,2H),3.9 1(d,J=13.2Hz,1H),3.81–3.56(m,6H),3.54–3.41(m,1H),3.25–3.10(m,1H),2.66(s,1H),2.45–2.31(m,4H),2.29–2.19(m,4H).

[0291] Synthesis of Compound 38

[0292] Synthetic route of compound F11:

[0293]

[0294] Step 1: Synthesis of compound F11-1

[0295] Compound F11-0 (1.35 g, 4.28 mmol) and triethylamine (866 mg, 8.56 mmol) were dissolved in dichloromethane (15 mL). Methylsulfonyl chloride (588 mg, 5.13 mmol) was added under ice-water bath conditions. After addition, the mixture was stirred at room temperature for 15 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the title compound as a white solid (1.21 g, 72%). MS (ESI, pos.ion): m / z 416.1 [M+Na] + .

[0296] Step 2: Synthesis of compound F11-2

[0297] Compound F11-1 (1.21 g, 3.07 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at room temperature for 20 h, and then concentrated under reduced pressure to obtain the trifluoroacetate of the title compound as a brown oil (1.18 g, 91.1%). MS (ESI, pos.ion): m / z 194.1 [M+H] +

[0298] Step 3: Synthesis of compound F11

[0299] Compound F11-2 (1.10 g, 2.61 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.32 g, 13.0 mmol) was added. Then, (Boc)₂O (513 mg, 2.35 mmol) was slowly added under ice-water bath conditions. After the addition was complete, the reaction was continued at this temperature for 14 h. The solution was evaporated to dryness, and the residue was subjected to silica gel column chromatography (DCM / MeOH (V / V) = 10 / 1) to give the title compound as a white solid (630 mg, 82%). MS (ESI, pos.ion): m / z 294.2 [M+H] + .

[0300] Step 4: Synthesis of Compound 38

[0301] Replacing (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester with compound F11, and following the synthetic method for compound 20, the target product was obtained as a yellow solid (130 mg, 50%). MS (ESI, pos.ion) m / z: 875.0 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 9.52 (d, J = 63.3Hz, 1H), 8.60 (d, J = 32.8Hz, 1H), 7.93–7.85 (m, 1H), 7.76–7.63 (m, 1 H),7.52–7.40(m,1H),7.33–7.24(m,2H),7.21–7.09(m,2H),7.00–6.88(m,2H),6.20–6.17(m,1H),4.98–4.42( m,1H),4.19–3.93(m,2H),3.88–3.79(m,1H),3.69–3.64(m,4H),3.60(d,J=4.2Hz,3H),3.55–3.43(m,1H),3.1 2–3.02(m,1H),2.98–2.87(m,1H),2.84–2.65(m,2H),2.65–2.61(m,2H),2.58–2.47(m,4H),2.45–2.35(m,4H).

[0302] Synthesis of Compound 39

[0303]

[0304] Replacing piperazine-1-carboxylic acid tert-butyl ester with compound F11, and following the synthetic method for compound 9, the target product was prepared as a yellow solid (120 mg, 51%). MS (ESI, pos.ion) m / z: 875.0 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)9.50(d,J=6.6Hz,1H),8.62(d,J=22.7Hz,1H),7.83(d,J=2.7Hz,1H),7.75–7.66(m,1 H),7.45(t,J=3.4Hz,1H),7.31–7.23(m,2H),7.16–7.07(m,2H),6.97–6.85(m,1H),6.16(d,J=8.9Hz,1H),5.97– 5.51(m,1H),4.51–4.41(m,1H),4.22–3.97(m,2H),3.70–3.63(m,4H),3.59(s,3H),3.56–3.45(m,2H),3.37–3.2 9(m,2H),3.07–2.99(m,1H),2.97–2.88(m,4H),2.62–2.52(m,1H),2.46(d,J=5.7Hz,3H),2.32(d,J=5.7Hz,3H).

[0305] Biological tests

[0306] Evaluation of the cytotoxicity and HBV DNA replication inhibition activity of compounds in HepAD38 cells (qPCR method)

[0307] HBV cell line and culture conditions

[0308] HepAD38: Ladner et al. (Ladner, Otto et al. 1997) ligated the tetracycline-sensitive cytomegalovirus (CMV) promoter to the PBR322 plasmid and linked it to ayw subtype HBV DNA to form the ptetHBV plasmid. This plasmid was transfected into HepG2 cells to obtain the HepAD38 cell line. Due to the disruption of the pre-C region gene, the HBV DNA yield was approximately 11 times higher than that of HepG2.2.15 cells. HBV replication can be regulated using tetracycline, and the culture time required is only half that of HepG2.2.15 cells, making it suitable for studying the HBV replication process and intermediates, as well as screening anti-HBV drugs. HepAD38 cells were cultured in DMEM / F-12K medium containing 10% FBS and 1% penicillin antibiotics (also containing 300 ng / ml Tetracycline and 400 μg / ml G418).

[0309] Viral particle DNA secreted by HepAD38 cells can be quantified using qPCR, thereby detecting the effect of compounds on viral replication.

[0310] In vitro cytotoxicity assay

[0311] HepAD38 cells were resuscitated and, after reaching confluence and good condition, digested, counted, and diluted with DMEM / F-12K medium containing 10% FBS and 1% penicillin antibiotics to a concentration of 1×10⁻⁶. 5 Cell suspension was seeded at a rate of 100 μL per well in a 96-well plate (covering the entire plate), and incubated at 37°C in a 5% CO2 incubator for 24 h. After 24 h, the old culture medium was discarded, and 200 μL of fresh DMEM / F-12K medium containing 2% FBS and 1% antibiotics was added.

[0312] Compound preparation and cell treatment in in vitro cytotoxicity assays: The compound was dissolved in DMSO to a final concentration of 20 mM, and then subjected to eight 4-fold dilutions, with the highest concentration being 20 mM. 1 μL of each serially diluted compound was added to each well of the cell plate, with the highest final concentration being 100 μM (200-fold dilution). Staurosporine (Selleck, CAS No. 62996-74-1) was used as a positive control compound, with a maximum concentration of 1 μM. 1 μL of DMSO was added to each negative control well, resulting in a final concentration of 0.5%.

[0313] After 72 hours, the old culture medium was discarded, and culture medium containing 10% CCK8 solution was added. The mixture was incubated for 20-40 minutes, and the OD values ​​were measured using a microplate reader. The data were exported to calculate the inhibition rate. The CCK values ​​of the compounds were then calculated using a nonlinear regression model generated by Graphpad Prism 5 software and a curve was plotted. 50 The experimental results are shown in Table 1.

[0314] In vitro anti-HBV activity assay

[0315] After HepAD38 cells were revived and in good condition, Tetracycline (final concentration 300 ng / ml) and G418 (final concentration 400 μg / ml) were added to the culture medium. Virus expression was inhibited in the presence of Tetracycline. After confluence, the cells were digested, counted, and diluted to a concentration of 2 × 10⁻⁶ cells using DMEM / F-12K medium containing 10% FBS (containing Tetracycline at a final concentration of 300 ng / ml and G418 at a final concentration of 400 μg / ml, plus 1% penicillin antibody). 5 Cell suspension was seeded at a rate of 100 μL per well in a 96-well plate (covering the entire plate), and incubated at 37°C in a 5% CO2 incubator for 24 h. After 24 h, the old culture medium was discarded, and 200 μL of fresh DMEM / F-12K medium containing 2% FBS and 1% antibiotics was added.

[0316] Compound preparation and cell treatment in the antiviral assay: The compound was dissolved in DMSO to 20 mM, further diluted with DMSO to 800 μM, and then subjected to eight 4-fold dilutions, with the highest concentration being 800 μM. 1 μL of each serially diluted compound was added to each well of the cell plate, with the highest final concentration being 4 μM (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound, with a highest concentration of 4 μM. 1 μL of DMSO was added to each negative control well, resulting in a final concentration of 0.5%.

[0317] HBV DNA Q-PCR

[0318] Quantitative PCR (q-PCR) was performed using the Sansure Biotech 48-sample (PCR-fluorescent probe method) one-step hepatitis B virus nucleic acid quantitative assay kit. 2.5 μL of supernatant was aspirated for q-PCR. Before use, the kit reagents were thawed and vortexed to mix. After centrifugation, the enzyme mixture was placed on ice until ready to use, ensuring subsequent steps were performed on ice. 2.5 μL of sample release agent and 2.5 μL of test sample supernatant (experimental group, control group, standard curve group) were added to each well of the q-PCR plate. Viral DNA copy number was obtained for each well after the q-PCR reaction. The concentration-viral copy number was processed using Graphpad Prism 5 software, and the EC50 of the compound on viral replication was calculated using a four-parameter nonlinear regression model. 50 The experimental results are shown in Table 1.

[0319] Table 1: Results of in vitro anti-HBV activity and cytotoxicity experiments of the compounds of this invention

[0320] 1 55 N / A 2 157 98 3 45 N / A 4 190 N / A 5 120 ＞100 6 84 ＞100 8 131 N / A 9 29 ＞100 10 129 N / A 11 86 N / A 12 21 ＞100 13 145 ＞100 14 86 ＞100 16 46 ＞100 17 81 ＞100 18 20 ＞100 19 20 ＞100 20 48 ＞100 21 40 ＞100 22 80 ＞100 24 120 ＞100 25 152 ＞100 26 27 N / A 27 109 ＞100 28 58 ＞100 29 34 N / A 30 80 ＞100 32 55 62 34 167 ＞100 38 164 ＞100

[0321] Note: N / A indicates not measured.

[0322] Conclusion: Experimental results show that the compound of the present invention has good inhibitory activity against HBV and low cytotoxicity.

Claims

1. A compound, which is a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (I), (I) in, each R 5a , R 5b , R 5c , R 5d , R 5e , R 2 , and R 3 are independently hydrogen, deuterium, F, Cl, Br, I, CN, methyl, or methoxy; Ring B is phenyl, pyridyl, (I-1) or (I-3), wherein the phenyl and pyridyl groups are each independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. 6 Replaced; R 6 independently deuterium, F, Cl, Br, I, CN, -OH, amino, -OCH2CH2CH2CH2- OCH3, methyl, ethyl, methoxy, ethoxy, or -OCH2CF3; each R 1a , R 1 , and R 4 is independently hydrogen, deuterium, methyl, or ethyl; Each R 2a and R 2c It can be methyl, ethyl, n-propyl, or isopropyl independently; Each R 3a and R 3c Thiazole independently; Each R 4a and R 4c Independently, it is phenyl, wherein the phenyl group is not substituted or is surrounded by 1, 2 or 3 R groups. w3 Replaced; L1 is a methylene group; L2 is a single bond; R w3 It can be deuterium, F, Cl, Br, CN, -OH, amino, methyl, or ethyl; Ring A is (II-1) (II-2) (II-3) (II-4) (II-5) (II-6) (II-7) (II-8) (II-9) (II-10) or (II-14), wherein each of the following formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), and (II-14) is independently not substituted or is replaced by one or two R. x Replaced; R x Independently, it can be deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, -CONH2, or -methylene-N(R) a )S(=O)2methyl,-methylene-N(R) a S(=O)2-ethyl, hydroxymethyl, hydroxyethyl, amino, methyl, ethyl, methoxymethyl, or ethoxymethyl; each R a It can be either hydrogen or deuterium.

2. The compound according to claim 1, comprising one of the following structures: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (twenty one), (twenty two), (twenty three), (twenty four), (25) (26) (27) (28) (29) (30) (31) (32) (33) (38) (39) (48) (49) (50) (51) (52) (53) (54) (55) (56) or (57) or its stereoisomers, tautomers or pharmaceutically acceptable salts.

3. A compound having one of the following structures: (40) (41) (42) (44) (45) (46) or its stereoisomers, tautomers or pharmaceutically acceptable salts.

4. A pharmaceutical composition comprising the compound of any one of claims 1-3, and pharmaceutically acceptable excipients thereof.

5. The pharmaceutical composition according to claim 4, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alloferon, simvastatin, clavudine, emtricitabine, famciclovir, bacalan CP, interferon α, interferon β-1a, interleukin-2, mirtovalidone, nitrozonide, ribavirin, cizonan, eufovac, amplivir, phosphazid, heplisav, interferon α-2b, levamisole, or propafenone.

6. Use of the compound of any one of claims 1-3 or the pharmaceutical composition of any one of claims 4-5 in the preparation of a medicament for the prevention, treatment, or relief of a patient’s viral disease, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

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