PDE4 inhibitor, preparation method thereof and application of PDE4 inhibitor in medicine

Abstract

The invention relates to a PDE4 inhibitor, a preparation method of the PDE4 inhibitor and application of the PDE4 inhibitor in medicine. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound as a PDE4 inhibitor, especially application of the compound in preparation of drugs for treating PDE4-related diseases. # imgabs0 #

Description

PDE4 inhibitors, preparation methods and medical applications thereof Technical Field

[0001] The present disclosure relates to the field of medicine and relates to PDE4 inhibitors, methods for preparing the same, and their use in medicine. Specifically, the present disclosure relates to a compound represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as PDE4 inhibitors, particularly in the preparation of medicaments for treating PDE4-related diseases. Background Art

[0002] Phosphodiesterases (PDEs) are responsible for catalyzing the hydrolysis of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP), regulating cAMP- and cGMP-related signaling pathways. PDE4 is a member of a family of 11 known PDEs, comprising four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is highly specific for cAMP and, by catalyzing its hydrolysis, regulates the function of transcription factors (such as NF-κB) and the expression of inflammatory mediators (such as INF-α, IFN-γ, IL-12, and IL-10). Therefore, PDE4 participates in a variety of physiological and pathological processes, such as promoting monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction.

[0003] In recent years, many PDE4 inhibitors have been approved for marketing or are in clinical trials. For example, roflumilast is approved for the treatment of severe chronic obstructive pulmonary disease (COPD) to reduce the number of flare-ups or prevent worsening of COPD symptoms, and apremilast is approved for the treatment of adults with active psoriatic arthritis. While PDE4 inhibitors have demonstrated promising pharmacological activity, they can also cause numerous side effects, such as induced gastrointestinal symptoms like vomiting and diarrhea.

[0004] Published patent applications for PDE4 inhibitors include WO2004103998A1, WO2011143105A, etc.

[0005] While some progress has been made in the treatment of inflammatory diseases, allergic diseases, and autoimmune diseases, a significant number of patients remain in need of better and more effective clinical treatments and regimens. In light of this, the present disclosure designs a series of compounds based on existing technologies to provide PDE4 inhibitors with novel structures, improved efficacy, high bioavailability, and strong drugability for the effective treatment of PDE4-related diseases or conditions, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis, inflammatory skin diseases, inflammatory bowel disease, and diseases related to smooth muscle contractility.

[0006] Summary of the Invention

[0007] The present invention aims to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008] in:

[0009] Ring A is a 4-7 membered heterocyclyl or a 5-6 membered heteroaryl;

[0010] Ring B is phenyl or a 5-6 membered heteroaryl group;

[0011] Ring C is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0012] R 1 Selected from H atoms, -OH, -COOH, -NR 6 R 7 、-CN、halogen、nitro、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0013] Each R 2 independently selected from H atoms, -OH, -COOH, -NR 6 R 7 、-CN、halogen、nitro、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; or

[0014] Two adjacent R 2 Together with the part to which it is directly connected, it forms a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group or a 5-6 membered heteroaryl group;

[0015] Each R 3 independently selected from H atoms, -OH, -COOH, -NR6 R 7 、-CN、halogen、nitro、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; or

[0016] Two adjacent R 3 Together with the part to which it is directly connected, it forms a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group or a 5-6 membered heteroaryl group;

[0017] Each R 4 independently selected from H atoms, -OH, -COOH, -NR 6 R 7 、-CN、halogen、nitro、=O、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0018] Each R 5 independently selected from H atoms, -OH, -COOH, -CN, halogen, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; or

[0019] Two adjacent R 5 Together with the part to which it is directly connected, it forms a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group or a 5-6 membered heteroaryl group;

[0020] L 1 Selected from chemical bonds, -C 1-6 Alkylene-, -O-, -C1-6 Alkylene-O-, -OC 1-6 Alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-C(O)-, -C(O)-C 1-6 Alkylene-, -C 1-6 Alkylene-S(O)2- and -S(O)2-C 1-6 Alkylene-, wherein the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, nitro, -OH, -COOH, -NR 6 R 7 、-CN、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 substituted by one or more substituents of a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group;

[0021] Each R 6 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0022] Each R 7 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0023] m is 0, 1, 2, 3, 4 or 5;

[0024] n is 0, 1, 2, or 3;

[0025] p is 0, 1, or 2; and

[0026] q is 0, 1, 2, or 3.

[0027] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0028] Among them, ring A, ring B, L1 、R 1 -R 5 , m, n, p and q are as defined in the general formula (I).

[0029] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0030] Ring A is selected from the group consisting of pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, thiazolyl, pyranyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, and tetrahydropyranyl; and

[0031] Ring B is phenyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl and pyridazinyl.

[0032] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0033] Selected from indazolyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, triazolopyridinyl, pyrazolopyridine, isoindolinyl, dihydroisoquinolinyl, indolinyl, quinolinyl, isoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl and dihydrobenzothienyl.

[0034] In some embodiments, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof Selected from

[0035] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0036] L 1 Selected from chemical bonds, -C 1-6 Alkylene-, -O-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, and -S(O)2-, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl, halogen, nitro, -OH, -COOH, -NH2, -CN, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 The hydroxyalkyl group is substituted with one or more substituents.

[0037] In some embodiments, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is 1 Selected from chemical bonds, -C 1-6 Alkylene- and C 1-6 Alkyl-substituted-C 1-6 Alkylene-.

[0038] In some embodiments, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is 1 Selected from a chemical bond, -CH2-, -CH(CH3)- and -CH2-CH2-.

[0039] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0040] R 1 Selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl.

[0041] In some embodiments, R 1 Selected from H atoms, -OH, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0042] In some embodiments, R 1 is a H atom or a methyl group.

[0043] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0044] Each R 2 independently selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl; or

[0045] Two adjacent R 2 Together with the directly connected part, it forms a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclic group.

[0046] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 2 independently selected from H atoms, -OH, halogen, C 1-6 Alkyl and C 1-6 alkoxy; or

[0047] Two adjacent R 2 Together with the moieties to which it is directly attached, it forms a tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, cyclopentyl or cyclohexyl group.

[0048] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 2 Independently 2 is an H atom or a methoxy group; or

[0049] Two adjacent R 2 Together with the moiety to which it is directly attached, it forms a tetrahydrofuranyl group.

[0050] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0051] Each R 3 independently selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl.

[0052] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 3 independently selected from H atoms, -OH, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0053] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 3 are independently H atoms.

[0054] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0055] Each R 4 independently selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, nitro, =O, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl

[0056] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 4 independently selected from H atoms, -OH, -CN, halogen, =O, C 1-6 Alkyl and C 1-6 Alkoxy.

[0057] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 4 independently H atoms, -CN, =O and methyl groups.

[0058] In some embodiments of the present disclosure, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof,

[0059] Each R 5 independently selected from H atoms, -OH, -COOH, -CN, halogen, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl.

[0060] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 5 independently selected from H atoms, -OH, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0061] In certain embodiments, each R in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof 5 are independently H atoms or C 1-6 alkyl.

[0062] Typical compounds of the present disclosure include, but are not limited to:

[0063] The present disclosure also provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0064] 1) A compound represented by the general formula (I-1) and a compound represented by the general formula (I-2) are subjected to a metal-catalyzed coupling reaction to obtain a compound represented by the general formula (I-3);

[0065] 2) The compound represented by the general formula (I-3) is subjected to an oxidation reaction to obtain the compound represented by the general formula (I-4);

[0066] 3) The compound represented by the general formula (I-4) is subjected to a deprotection reaction to obtain the compound represented by the general formula (I);

[0067] in:

[0068] X is an amino protecting group, preferably selected from tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;

[0069] Y is a halogen, preferably an I atom.

[0070] In particular,

[0071] In step 1), the compound represented by the general formula (I-1) and the compound represented by the general formula (I-2) undergo a coupling reaction under metal catalysis conditions to obtain the compound represented by the general formula (I-3).

[0072] In step 2), the compound represented by the general formula (I-3) is oxidized in the presence of an oxidizing agent such as potassium monopersulfate or m-chloroperbenzoic acid to obtain a compound represented by the general formula (I-4).

[0073] In step 3), the compound represented by the general formula (I-4) is subjected to a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (I).

[0074] Reagents providing acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf.

[0075] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.

[0076] The present disclosure also provides a pharmaceutical composition comprising a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0077] The present disclosure also relates to the use of a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a drug for treating diseases associated with PDE4.

[0078] The present disclosure also relates to a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0079] The present disclosure also relates to a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating diseases associated with PDE4.

[0080] The present disclosure also relates to a method for treating a disease associated with PDE4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0081] In some embodiments of the present disclosure, the PDE4-related disease is selected from inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and diseases related to smooth muscle contractility; preferably, the inflammatory disease is selected from arthritis, skin inflammatory diseases, and inflammatory bowel disease;

[0082] Particularly, the PDE4-related disease is selected from asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, adult respiratory distress syndrome, atopic dermatitis, psoriasis, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn's disease and overactive bladder.

[0083] The active compound can be prepared into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0084] As a general guide, the active compound is preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0085] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, wherein the excipient is selected from the following ingredients: filler (diluent), binder, wetting agent or disintegrant, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0086] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0087] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0088] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0089] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0090] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0091] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0092] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0093] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0094] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0095] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0096] Terminology

[0097] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0098] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2, 4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0099] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0100] The term "alkylene" refers to the portion of an alkane molecule remaining after removing two hydrogen atoms, wherein alkyl is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0101] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like.

[0102] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0103] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.

[0104] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), a cycloalkyl group having 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl), or a cycloalkyl group having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

[0105] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0106] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0107] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0108] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0109] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0110] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group) or a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0111] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0112] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0113] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0114] wait.

[0115] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0116] wait.

[0117] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0118] wait.

[0119] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., 6- to 10-membered aromatic group), more preferably an aromatic group having 8 to 10 ring atoms (i.e., 8- to 10-membered polycyclic aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.

[0120] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl), or preferably a heteroaryl having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic heteroaryl).

[0121] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0122] Non-limiting examples of the polycyclic heteroaryl group include indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0123] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0124] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0125] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0126] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0127] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0128] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0129] The term "hydroxy" refers to -OH.

[0130] The term "mercapto" refers to -SH.

[0131] The term "amino" refers to -NH2.

[0132] The term "cyano" refers to -CN.

[0133] The term "nitro" refers to -NO2.

[0134] The term "oxo" or "oxo" refers to "=0".

[0135] The term "carbonyl" refers to C=O.

[0136] The term "carboxy" refers to -C(O)OH.

[0137] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0138] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0139] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both and Two configurations.

[0140] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0141] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0142] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0143] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0144] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0145] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0146] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise. DETAILED DESCRIPTION

[0147] The compounds of formula (I) disclosed herein can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of formula (I), which are well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0148] The present disclosure is further illustrated below with reference to examples; however, these examples do not limit the scope of the present disclosure. Unless otherwise stated, all reactants used in the examples were obtained from commercial sources; and the instruments and equipment used in the synthesis experiments and product analysis and testing were conventional instruments and equipment commonly used in organic synthesis.

[0149] Intermediate A: 6-iodo-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

[0150] 1) Synthesis of Compound A-2

[0151] At room temperature, compound A-1 (10.00 g, 42.91 mmol) was dissolved in diethyl ethoxymethylenemalonate (18 mL), and the reaction mixture was stirred at 95°C for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with n-hexane (30 mL x 3) and dried to obtain compound A-2. 1 H NMR (400MHz, DMSO-d6) δ10.83(d,J=13.6Hz,1H),8.43(d,J=13.6Hz,1H),7.66(d,J=1.2Hz,1H),7.60(d,J=8. 4Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 4.21 (q, J = 6.8Hz, 2H), 4.12 (q, J = 7.2Hz, 2H), 2.26 (s, 3H), 1.28-1.21 (m, 6H).

[0152] 2) Synthesis of Compound A-3

[0153] Diphenyl ether (75 mL) was heated to 220°C, and compound A-2 (12.00 g, 29.76 mmol) was slowly added in portions. The reaction mixture was stirred at 250°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of solid precipitated. Cyclohexane (50 mL) was added, stirred, and slurried, and then filtered. The filter cake was washed with cyclohexane (20 mL x 3) and dried to obtain compound A-3. 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.39(s,1H),8.30(d,J=2.0Hz,1H),7.91(s,1H),4.22(q,J=7.2Hz,2H),2.47(s,3H),1.28(t,J=7.2Hz,3H).

[0154] 3) Synthesis of Compound A-4

[0155] Compound A-3 (10.00 g, 28.00 mmol) and a 2 mol / L aqueous solution of sodium hydroxide (67.00 mL, 134.00 mmol) were added to ethanol (34 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Concentrated hydrochloric acid was slowly added dropwise to the residue until the pH reached ~2. A large amount of solid precipitated, which was filtered. The filter cake was washed with water (20 mL x 3) and dried to obtain compound A-4.1 H NMR (400MHz, DMSO-d6) δ14.99(s,1H),12.77(s,1H),8.63(s,1H),8.42(s,1H),8.08(s,1H),2.54(s,3H).

[0156] 4) Synthesis of Compound A-5

[0157] At room temperature, compound A-4 (2.00 g, 6.08 mmol) was dissolved in thionyl chloride (30 mL), and N,N-dimethylformamide (0.3 mL) was added. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Under an ice bath, the residue was slowly added to a solution of ammonia in tetrahydrofuran (50 mL). The reaction solution was slowly warmed to room temperature and stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound A-5.

[0158] 5) Synthesis of Intermediate A

[0159] At room temperature, compound A-5 (2.00 g, 5.37 mmol, 93% purity) and m-anisidine (1.32 g, 10.73 mmol) were dissolved in ethanol (24 mL), and the reaction mixture was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (20 mL) and dried to obtain intermediate A. MS-ESI: m / z 434.1 [M+H] + .

[0160] Intermediate B: 4-((2,3-dihydrobenzofuran-4-yl)amino)-6-iodo-8-methylquinoline-3-carboxamide

[0161] At room temperature, compound A-5 (0.40 g, 0.97 mmol, 84%) and 2,3-dihydro-4-aminobenzofuran (0.26 g, 1.94 mmol) were dissolved in ethanol (12 mL) and stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (20 mL) and dried to obtain intermediate B. MS-ESI: m / z 446.0 [M+H] + .

[0162] Example 1: 6-((2-(4-aminophenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (1)

[0163] 1) Synthesis of Compound 1-1

[0164] At room temperature, 4-bromo-2-methylaminoaniline (500 mg, 2.49 mmol) and 4-nitrobenzaldehyde (376 mg, 2.49 mmol) were dissolved in ethanol (15 mL). Sodium metabisulfite (1.42 g, 7.46 mmol) was added, and the reaction mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL) and ethyl acetate (30 mL), filtered, and the filter cake was dried under vacuum. The filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1), then combined with the filter cake and concentrated under reduced pressure to obtain compound 1-1. MS-ESI: m / z 332.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.45-8.37 (m, 2H), 8.21-8.14 (m, 2H), 8.01 (d, J = 2.0Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.43 (dd, J = 8.4, 1.6Hz, 1H), 3.94 (s, 3H).

[0165] 2) Synthesis of Compound 1-2

[0166] At room temperature, compound 1-1 (680 mg, 1.92 mmol, 94% purity) was dissolved in ethanol (8 mL) and water (2 mL). Iron powder (322 mg, 5.77 mmol) and ammonium chloride (823 mg, 15.40 mmol) were added, and the reaction mixture was stirred at 80°C for 1 hour. After the reaction was completed, the mixture was filtered while hot, the filter cake was washed with ethyl acetate (10 mL x 3), and the organic phase was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 1-2. MS-ESI: m / z 301.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,2H),7.52(d,J=2.0Hz,1 H), 7.38 (dd, J=8.4, 1.6Hz, 1H), 6.80 (d, J=8.4Hz, 2H), 4.12-3.87 (m, 2H), 3.83 (s, 3H).

[0167] 3) Synthesis of Compounds 1-3

[0168] At room temperature, compound 1-2 (450 mg, 1.49 mmol, 97% purity) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (650 mg, 2.98 mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1-3. MS-ESI: m / z 402.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 8.4Hz, 2H), 7.66 (d, J = 8.4Hz, 1H), 7.58-7.5 1(m,3H),7.40(dd,J=8.4,1.6Hz,1H),6.75(s,1H),3.83(s,3H),1.55(s,9H).

[0169] 4) Synthesis of Compounds 1-4

[0170] At room temperature, compound 1-3 (460 mg, 1.09 mmol, 95% purity) and methyl 3-mercaptopropionate (131 mg, 1.09 mmol) were dissolved in dioxane (20 mL). Tris(dibenzylideneacetone)dipalladium (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and triethylamine (220 mg, 2.17 mmol) were added. The atmosphere was purged with nitrogen, and the tube was sealed and stirred at 100°C for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 1-4. MS-ESI: m / z 442.1 [M+H] + .

[0171] 5) Synthesis of Compounds 1-5

[0172] At room temperature, compound 1-4 (400 mg, 0.88 mmol, 93% purity) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, and cooled to -70°C. A 1 mol / L solution of potassium tert-butoxide in tetrahydrofuran (2.50 mL, 2.50 mmol) was slowly added dropwise, and the reaction mixture was stirred at -70°C for 1 hour. After the reaction was completed, the reaction solution was warmed to room temperature, diluted with water (20 mL), washed with ethyl acetate (10 mL × 3), and the organic phase was discarded. The aqueous phase was adjusted to pH ~5 with 1 mol / L dilute hydrochloric acid aqueous solution and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-5. MS-ESI: m / z 356.1 [M+H] + .

[0173] 6) Synthesis of Compounds 1-6

[0174] At room temperature, compound 1-5 (200 mg, 0.47 mmol, 83% purity) and intermediate A (202 mg, 0.47 mmol) were dissolved in N,N-dimethylacetamide (10 mL), and cuprous iodide (15 mg, 0.05 mmol) and triethylamine (94 mg, 0.93 mmol) were added. The atmosphere was replaced with nitrogen and stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (40 mL) and diluted, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 1-6. MS-ESI: m / z 661.4 [M+H] + .

[0175] 7) Synthesis of Compounds 1-7

[0176] At room temperature, compound 1-6 (140 mg, 0.16 mmol, 77% purity) was dissolved in N,N-dimethylformamide (5 mL). Potassium monopersulfate (301 mg, 0.49 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium thiosulfate aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) and then by preparative HPLC (ammonium bicarbonate / acetonitrile / water system, column: Waters Xbridge 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: acetonitrile phase (0-10min, 38-68%); flow rate: 30mL / min; column temperature: room temperature) to obtain compound 1-7. MS-ESI: m / z 693.3 [M+H] + .

[0177] 8) Synthesis of Compound 1

[0178] At room temperature, compound 1-7 (8 mg, 0.01 mmol) was dissolved in dichloromethane (0.4 mL), trifluoroacetic acid (0.10 mL) was added, and the reaction solution was stirred at 25°C for 10 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was separated by preparative HPLC (formic acid / acetonitrile / water system, column: Phenomenex luna C18150*25mm*10μm; mobile phase: water (0.2% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-8 min, 19-43%); flow rate: 25 mL / min; column temperature: room temperature) to obtain compound 1. MS-ESI: m / z 593.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.01(s,1H),8.30(s,1H),8.10(s,1H),8.06(s,1H),7.71(d,J=8.8Hz,1H),7.61(d,J=8.4Hz,2H),7.55(dd,J=8 .0,1.6Hz,1H),7.13(t,J=8.0Hz,1H),6.86(d,J=8.4Hz,2H),6.65-6.56(m,1H),6.48(s,1H),3.98(s,3H),3.52(s,3H),2.76(s,3H).

[0179] Example 2: 6-((2-(4-aminophenyl)-2H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (2)

[0180] 1) Synthesis of Compound 2-1

[0181] At room temperature, 6-bromoindazole (6.00 g, 30.45 mmol), p-fluoronitrobenzene (8.59 g, 60.90 mmol), and potassium carbonate (12.63 g, 91.36 mmol) were sequentially mixed in anhydrous N,N-dimethylformamide (60 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 2-1. 1H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 8.47-8.42 (m, 2H), 8.41-8.35 (m, 2H), 8.02 (s, 1H), 7.79 (d, J = 8.8Hz, 1H), 7.24 (dd, J = 8.8, 1.2Hz, 1H).

[0182] 2) Synthesis of Compound 2

[0183] Compound 2 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 593.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),9.07(s,1H),9.00(s,1H),8.39(s,1H),8.30(s,1H),8.23(s,1H),7.88(d,J=8.4Hz,1H),7. 81-7.70(m,3H),7.21-7.12(m,2H),6.77-6.68(m,3H),6.61(s,1H),6.56(d,J=7.2Hz,1H),5.58(s,2H),3.63(s,3H),2.69(s,3H).

[0184] Example 3: 6-((2-(4-aminobenzyl)-2H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (3)

[0185] 1) Synthesis of Compound 3-1

[0186] Under nitrogen at room temperature, 6-bromoindazole (3.00 g, 15.23 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0°C and, under a weak nitrogen stream, sodium hydroxide (0.91 g, 22.84 mmol, 60% purity) was slowly added. The mixture was stirred at 0°C for 30 minutes. A solution of tert-butyl (4-(bromomethyl)phenyl)carbamate (5.23 g, 18.27 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (40 mL) for quenching and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to provide compound 3-1. 1H NMR (400MHz, CDCl3) δ7.90(s,1H),7.82(s,1H),7.49(d,J=8.8Hz,1H),7.37(d,J=8.4Hz,2 H),7.25(d,J=8.4Hz,2H),7.15(d,J=9.2Hz,1H),6.60(brs,2H),5.52(s,2H),1.52(s,9H).

[0187] 2) Synthesis of compound 3

[0188] Compound 3 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 593.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.07(s,1H),8.55(s,1H),8.36(s,1 H),8.29(s,1H),8.17(s,1H),7.99(s,1H),7.86(d,J=8.4Hz,1H),7.76(brs ,1H),7.17-7.07(m,4H),6.66(d,J=8.0Hz,1H),6.59(s,1H),6.55(s,1H), 6.51(d,J=8.4Hz,2H),5.50(s,2H),5.15(s,2H),3.60(s,3H),2.68(s,3H).

[0189] Example 4: 6-((1-(4-aminobenzyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (4)

[0190] 1) Synthesis of compound 4-1

[0191] Under nitrogen at room temperature, 6-bromoindazole (3.00 g, 15.23 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0°C and, under a weak nitrogen stream, sodium hydroxide (0.91 g, 22.84 mmol, 60% purity) was slowly added. The mixture was stirred at 0°C for 30 minutes. A solution of tert-butyl (4-(bromomethyl)phenyl)carbamate (5.23 g, 18.27 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was quenched by pouring into saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the product, compound 4-1. 1H NMR (400MHz, CDCl3) δ8.01(s,1H),7.61(d,J=8.4Hz,1H),7.54(s,1H),7.32(d,J=8.8Hz,2H) ,7.25(dd,J=8.8,1.6Hz,1H),7.16(d,J=8.4Hz,2H),6.49(s,1H),5.51(s,2H),1.52(s,9H).

[0192] 2) Synthesis of compound 4

[0193] Compound 4 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 593.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),9.07(s,1H),8.36(dd,J=7.2,1.6Hz,2H),8.30(s,1H) ,8.22(s,1H),7.98(s,1H),7.91(d,J=8.4Hz,1H),7.77(s,1H),7.21(dd,J=8.4,0.8Hz,1H), 7.12(t,J=8.0Hz,1H),6.99(d,J=8.4Hz,2H),6.67(dd,J=8.4,2.0Hz,1H),6.59(s,1H),6.53 (d, J=7.6Hz, 1H), 6.46 (d, J=8.4Hz, 2H), 5.57 (s, 2H), 5.06 (s, 2H), 3.60 (s, 3H), 2.70 (s, 3H).

[0194] Example 5: 6-((1-(3-aminobenzyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (5)

[0195] 1) Synthesis of compound 5-1

[0196] At room temperature, 6-bromoindazole (1.38 g, 6.99 mmol) and potassium carbonate (1.93 g, 13.98 mmol) were mixed in acetonitrile (40 mL), and then 2-Boc-amino-bromomethylbenzene (2.00 g, 6.99 mmol) was added. The reaction solution was stirred at 70°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 5-1. MS-ESI: m / z 402.1 [M+H] +. 1 H NMR (400MHz, CDCl3) δ8.00(d,J=0.8Hz,1H),7.60(d,J=8.4Hz,1H),7.53(s,1H),7.31(d,J=8.0Hz,1H), 7.28-7.25(m,1H),7.24-7.15(m,2H),6.79(d,J=7.6Hz,1H),6.50(brs,1H),5.52(s,2H),1.50(s,9H).

[0197] 2) Synthesis of compound 5

[0198] Compound 5 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 593.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.80(s,1H),8.93(s,1H),8.28(d,J=1.6Hz,1H),8.10(d,J=0.8Hz ,1H),8.00(s,1H),7.86(d,J=1.2Hz,1H),7.75(d,J=8.8Hz,1H),7.23(dd,J=8.4,1.2Hz, 1H),7.14-7.05(m,2H),6.70-6.65(m,1H),6.64-6.61(m,1H),6.60-6.58(m,1H),6.57-6 .54(m,1H),6.53-6.47(m,2H),6.25-5.61(m,2H),5.57(s,2H),3.63(s,3H),2.73(s,3H).

[0199] Examples 6 and 7: (S)-6-((1-(1-(4-aminophenyl)ethyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide and (R)-6-((1-(1-(4-aminophenyl)ethyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (6 and 7)

[0200] 1) Synthesis of compound 6-1

[0201] At room temperature, 6-bromoindazole (1.90 g, 9.64 mmol), 1-(1-bromoethyl)-4-nitrobenzene (2.22 g, 9.64 mmol), and cesium carbonate (6.28 g, 19.29 mmol) were mixed in anhydrous N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 6-1. MS-ESI: m / z 346.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.8Hz,1H),8.07(s,1H),7.62(d,J=8.4Hz,1H),7.48(s,1H), 7.38(d,J=8.4Hz,2H),7.27(dd,J=8.8,1.6Hz,1H),5.88-5.78(m,1H),2.07(d,J=6.8Hz,3H).

[0202] 2) Synthesis of Compound 6 and Compound 7

[0203] Compound 6-8 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 607.3 [M+H] + Compound 6-8 (306 mg) was separated by supercritical fluid chromatography (column: Daicel Chiralpak AS (250 mm*30 mm*10 μm); mobile phase: supercritical carbon dioxide, acetonitrile / ethanol (0.1% ammonia monohydrate); gradient ratio: acetonitrile / ethanol phase 60%; flow rate: 70 mL / min; column temperature: room temperature) to obtain compound 6 and compound 7. (Compound 6 is the first eluting peak, and compound 7 is the second eluting peak). Compound 6: MS-ESI: m / z 607.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.07(s,1H),8.37(s,1H),8.34-8.22(m,3H),7.95(s ,1H),7.90(d,J=8.4Hz,1H),7.77(s,1H),7.19(d,J=8.4Hz,1H),7.12(t,J=8.0Hz,1H),7.0 1 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 8.4 Hz, 2H), 6.10-6.00 (m, 1H), 5.03 (s, 2H), 3.60 (s, 3H), 2.69 (s, 3H), 1.88 (d, J = 6.8 Hz, 3H). Compound 7: MS-ESI: m / z 607.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.73 (s, 1H), 9.07 (s, 1H), 8.37 (d, J = 1.2Hz, 1H), 8. 33-8.26(m,2H),8.25(s,1H),7.95(s,1H),7.90(d,J=8.8Hz,1H),7.77(s,1H ),7.19(dd,J=8.4,0.8Hz,1H),7.13(t,J=8.0Hz,1H),7.01(d,J=8.4Hz,2H), 6.68(dd,J=8.0,2.4Hz,1H),6.62-6.58(m,1H),6.53(dd,J=8.0,1.2Hz,1H), 6.45(d,J=8.4Hz,2H),6.10-6.00(m,1H),5.02(s,2H),3.60(s,3H),2.69(s,3H),1.88(d,J=7.2Hz,3H).

[0204] Example 8: 6-((1-(3-aminophenyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (8)

[0205] 1) Synthesis of compound 8-1

[0206] At room temperature, 6-bromoindazole (3.00 g, 15.23 mmol), (3-((tert-butyloxycarbonyl)amino)phenyl)boronic acid (5.41 g, 22.84 mmol), copper acetate (4.15 g, 22.84 mmol), and pyridine (3.61 g, 45.68 mmol) were mixed in dichloromethane (100 mL) and allowed to react open to room temperature for 16 hours. The reaction mixture was filtered, the filtrate was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 8-1. MS-ESI: m / z 388.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.40(d,J=0.8Hz,1H),8.05(s,1H),7.94-7.89(m,1H),7.87(d,J=8.4Hz ,1H),7.56-7.50(m,1H),7.47(t,J=8.0Hz,1H),7.42(dd,J=8.4,1.6Hz,1H),7.40-7.34(m,1H),1.50(s,9H).

[0207] 2) Synthesis of Compound 8

[0208] Compound 8 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 579.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.06(s,1H),8.49(s,1H),8.39-8.26(m,2H),8 .19(s,1H),8.08(s,1H),8.06(d,J=8.8Hz,1H),7.78(s,1H),7.42(d,J=8.4Hz,1H),7. 31(t,J=8.0Hz,1H),7.01-6.91(m,2H),6.88(d,J=7.6Hz,1H),6.72(dd,J=8.0,1.2Hz, 1H), 6.60 (s, 1H), 6.49 (t, J = 8.4Hz, 2H), 6.10-5.15 (m, 1H), 3.54 (s, 3H), 2.68 (s, 3H).

[0209] Example 9: 6-((1-(4-aminophenyl)-3-methyl-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (9)

[0210] 1) Synthesis of compound 9-1

[0211] At room temperature, 6-bromo-3-methylindazole (1.00 g, 4.74 mmol) and (4-tert-butoxycarbonyl-aminophenyl)boronic acid (1.35 g, 5.69 mmol) were dissolved in dichloromethane (30 mL). Copper acetate (1.29 g, 7.11 mmol) and pyridine (1.12 g, 14.21 mmol) were added. The reaction mixture was allowed to react in the open air at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 9-1. 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),7.86(d,J=1.2Hz,1H),7.78(d,J=8.4Hz,1H),7.67 -7.62(m,2H),7.61-7.57(m,2H),7.35(dd,J=8.8,1.6Hz,1H),2.56(s,3H),1.50(s,9H).

[0212] 2) Synthesis of compound 9

[0213] Compound 9 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 593.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.07(s,1H),8.38-8.24(m,2H),8.04(s,1 H),7.97(d,J=8.8Hz,1H),7.92(s,1H),7.77(s,1H),7.36(dd,J=8.4,1.2Hz,1H), 7.32(d,J=8.4Hz,2H),6.94(t,J=8.0Hz,1H),6.79(d,J=8.8Hz,2H),6.60(s,1H), 6.46(td,J=8.8,2.0Hz,2H),5.48(s,2H),3.58(s,3H),2.68(s,3H),2.58(s,3H).

[0214] Example 10: 6-((1-(4-aminophenyl)-3-cyano-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (10)

[0215] 1) Synthesis of compound 10-1

[0216] At room temperature, 6-bromoindazole-3-carbonitrile (2.00 g, 9.01 mmol) and (4-tert-butoxycarbonyl-aminophenyl)boronic acid (3.20 g, 13.51 mmol) were dissolved in dichloromethane (60 mL). Anhydrous copper acetate (2.45 g, 13.51 mmol) and pyridine (2.20 mL, 27.02 mmol) were added. The reaction mixture was left to react at room temperature for 16 hours. The mixture was diluted with water (50 mL), and the organic phase was washed with water (50 mL x 2) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to provide compound 10-1. 1 H NMR (400MHz, CDCl3) δ7.89 (d, J = 0.8Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.65-7.56 (m, 4H), 7.53 (dd, J = 8.8, 1.2Hz, 1H), 6.68 (s, 1H), 1.56 (s, 9H).

[0217] 2) Synthesis of Compound 10

[0218] Compound 10 was prepared according to the synthetic method of Example 1. MS-ESI: 604.1 m / z [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),9.08(s,1H),8.31(brs,1H),8.28(d,J=1 .6Hz,1H),8.17(d,J=8.8Hz,1H),8.09(s,2H),7.78(brs,1H),7.64(dd,J=8.8,1 .2Hz,1H),7.44(d,J=8.8Hz,2H),6.94(t,J=8.0Hz,1H),6.83(d,J=8.8Hz,2H),6 .60(t,J=2.0Hz,1H),6.48-6.40(m,2H),5.74(s,2H),3.57(s,3H),2.69(s,3H).

[0219] Example 11: 6-((3-(4-aminophenyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (11)

[0220] 1) Synthesis of compound 11-1

[0221] At room temperature, 2-amino-4-bromophenol (2.30 g, 12.2 mmol) and tert-butyl-N-(4-iodophenyl)carbamate (3.00 g, 9.40 mmol) were dissolved in N,N-dimethylformamide (30 mL). Potassium phosphate (3.99 g, 18.80 mmol) and cuprous iodide (0.36 g, 1.88 mmol) were added. The atmosphere was purged with nitrogen, and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 11-1. MS-ESI: m / z 379.0 [M+H] + .

[0222] 2) Synthesis of compound 11-2

[0223] At room temperature, compound 11-1 (700 mg, 1.66 mmol, 90% purity) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and 1,1-carbonyldiimidazole (539 mg, 3.32 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 11-2. MS-ESI: m / z 349.0 [M-55] + . 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 7.65 (d, J = 8.8Hz, 2H), 7.49 (d, J = 8.4Hz, 2H), 7.44-7.36 (m, 2H), 7.13 (d, J = 1.6Hz, 1H), 1.50 (s, 9H).

[0224] 3) Synthesis of Compound 11

[0225] Compound 11 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 596.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.07(s,1H),8.30(s,1H),8.23(d,J=1. 2Hz,1H),7.99(s,1H),7.77(s,1H),7.61(s,2H),7.21(d,J=8.8Hz,2H),7.13( s,1H),6.89(t,J=8.0Hz,1H),6.76(d,J=8.4Hz,2H),6.67(s,1H),6.49(dd,J= 8.4, 2.0Hz, 1H), 6.38 (d, J = 7.8Hz, 1H), 5.58 (s, 2H), 3.65 (s, 3H), 2.67 (s, 3H).

[0226] Example 12: 6-((1-(4-aminophenyl)-1H-indazol-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (12)

[0227] 1) Synthesis of compound 12-1

[0228] At room temperature, 6-bromoindazole (3.00 g, 15.23 mmol), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (5.41 g, 22.84 mmol), copper acetate (4.15 g, 22.84 mmol), and pyridine (3.61 g, 45.68 mmol) were mixed in dichloromethane (100 mL) and allowed to react open to room temperature for 16 hours. The reaction mixture was filtered, the filtrate was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 12-1. MS-ESI: m / z 388.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.4Hz, 1H ),7.72-7.66(m,2H),7.65-7.60(m,2H),7.39(dd,J=8.8,1.2Hz,1H),1.51(s,9H).

[0229] 2) Synthesis of compound 12

[0230] Compound 12 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 579.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ10.82(s,1H),8.92(s,1H),8.25(d,J=1.6Hz,1H),8.22(d,J= 0.8Hz,1H),8.17(s,1H),7.96-7.93(m,1H),7.81(dd,J=8.4,0.4Hz,1H),7.48- 7.42(m,2H),7.30(dd,J=8.8,1.6Hz,1H),6.98-6.92(m,1H),6.91-6.87(m,2H) ,6.55-6.45(m,3H),6.23-5.54(m,2H),3.92(s,2H),3.58(s,3H),2.74(s,3H).

[0231] Example 13: 6-((3-(4-aminophenyl)imidazo[1,2-a]pyridin-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (13)

[0232] 1) Synthesis of compound 13-1

[0233] At room temperature, 6-bromo-imidazo[1,2-a]pyridine (3000 mg, 15.23 mmol) was dissolved in acetonitrile (30 mL). N-iodosuccinimide (3.49 g, 15.53 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with methyl tert-butyl ether (30 mL), filtered, and the solid dried to obtain compound 13-1. 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),7.75(s,1H),7.60(d,J=9.6Hz,1H),7.42(dd,J=9.6,1.6Hz,1H).

[0234] 2) Synthesis of compound 13-2

[0235] At room temperature, compound 13-1 (3.00 g, 9.29 mmol), 4-(Boc-amino)phenylboronic acid (1.98 g, 8.36 mmol), potassium carbonate (1.28 g, 9.29 mmol), and water (10 mL) were added to dioxane (30 mL) in sequence. A mixture of 1,1-bis(diphenylphosphino)ferrocenepalladium chloride and dichloromethane (379 mg, 0.47 mmol) was then added. The atmosphere was purged with nitrogen, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (60 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 13-2. MS-ESI: m / z 388.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.52 (s, 1H), 7.65-7.60 (m, 3H), 7.54 (d, J = 9.6Hz, 1H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 8.8, 1.2Hz, 1H), 1.55 (s, 9H).

[0236] 3) Synthesis of Compound 13

[0237] Compound 13 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 579.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 9.09 (s, 1H), 8.77 (d, J = 0.8Hz, 1H), 8.35-8.27 (m,2H),8.08(d,J=0.8Hz,1H),7.82-7.74(m,2H),7.71(d,J=9.6Hz,1H),7.35(d,J=8.4Hz,2H),7.18(dd,J=9.2,1.6Hz,1H),6.95(t,J=8.4Hz,1H ), 6.80 (d, J = 8.4Hz, 2H), 6.59 (t, J = 2.0Hz, 1H), 6.50 (dd, J = 7.6, 1.6Hz, 1H), 6.43 (dd, J = 8.4, 2.4Hz, 1H), 5.56 (s, 2H), 3.56 (s, 3H), 2.70 (s, 3H).

[0238] Example 14: 6-((3-(4-aminophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (14)

[0239] 1) Synthesis of compound 14-1

[0240] At room temperature, 2-hydrazino-5-bromopyridine (5.00 g, 26.59 mmol) and 4-nitrobenzaldehyde (4.82 mg, 31.91 mmol) were dissolved in ethanol (20 mL). Glacial acetic acid (80 mg, 1.33 mmol) was then added, and the reaction mixture was stirred at 80°C for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, and a large amount of solid precipitated. Ethanol (100 mL) was added for dilution, and the mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 14-1. MS-ESI: m / z 320.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.49 (s, 1H), 8.27-8.19 (m, 3H), 8.10 (s, 1H), 7.90 (d, J = 8.8Hz, 2H), 7.86 (dd, J = 8.8, 2.0Hz, 1H), 7.29 (d, J = 9.2Hz, 1H).

[0241] 2) Synthesis of compound 14-2

[0242] At room temperature, compound 14-1 (2.00 g, 6.23 mmol) was dissolved in dichloromethane (20 mL), and bis(trifluoroacetyloxy)iodobenzene (2.96 g, 6.85 mmol) was slowly added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 mL) and diluted, and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1). The crude product was then slurried with (ethyl acetate / dichloromethane = 10 / 1), filtered, and the filter cake was dried to obtain compound 14-2. MS-ESI: m / z 301.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,2H),7.52(d,J=2.0Hz,1 H), 7.38 (dd, J=8.4, 1.6Hz, 1H), 6.80 (d, J=8.4Hz, 2H), 4.12-3.87 (m, 2H), 3.83 (s, 3H).

[0243] 3) Synthesis of Compound 14

[0244] Compound 14 was prepared according to the synthesis method of Example 1. MS-ESI: m / z 580.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.08(s,1H),8.71(s,1H),8.32(s,2H),8.13 (s,1H),7.89(d,J=9.6Hz,1H),7.79(s,1H),7.60(d,J=8.4Hz,2H),7.27(dd,J=9.6, 1.2Hz,1H),6.97(t,J=8.0Hz,1H),6.83(d,J=8.4Hz,2H),6.60(s,1H),6.53(d,J=8. 0Hz, 1H), 6.42 (dd, J = 8.0, 1.6Hz, 1H), 6.00-5.50 (m, 1H), 3.55 (s, 3H), 2.70 (s, 3H).

[0245] Example 15: 6-((2-(4-aminophenyl)-3-oxoisoindol-5-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (15)

[0246] 1) Synthesis of compound 15-1

[0247] At room temperature, 6-bromoisoindolin-1-one (2000 mg, 9.43 mmol) was dissolved in dioxane (20 mL) and dimethyl sulfoxide (20 mL). Tert-butyl-N-(4-iodophenyl)carbamate (3.01 g, 9.43 mmol), cuprous iodide (599 mg, 1.89 mmol), N,N-dimethylethylenediamine (166 mg, 1.89 mmol), and cesium carbonate (6146 mg, 18.86 mmol) were then added. The atmosphere was purged with nitrogen, and the reaction mixture was stirred at 120°C for 16 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (150 mL), filtered, and the filtrate washed with saturated brine (120 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to yield compound 15-1. MS-ESI: m / z 303.0[M+H] + .

[0248] 2) Synthesis of Example 15

[0249] Compound 15 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 594.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.08(s,1H),8.33(d,J=1.2Hz,1H),8.30(s,1H),8 .05(s,1H),8.02(d,J=1.2Hz,1H),7.94(dd,J=8.0,1.6Hz,1H),7.83(d,J=8.0Hz,1H),7.7 7(s,1H),7.47(d,J=8.8Hz,2H),7.18(t,J=8.4Hz,1H),6.73(dd,J=8.4,2.0Hz,1H),6.67 -6.58(m,3H),6.53(d,J=7.6Hz,1H),5.12(s,2H),4.98(s,2H),3.61(s,3H),2.70(s,3H).

[0250] Example 16: 6-((2-(4-aminophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (16)

[0251] 1) Synthesis of compound 16-1

[0252] At room temperature, 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (4.00 g, 17.69 mmol) was dissolved in dioxane (40 mL) and dimethyl sulfoxide (40 mL). Tert-butyl-N-(4-iodophenyl)carbamate (8.47 g, 26.54 mmol), cuprous iodide (1.12 g, 3.54 mmol), N,N-dimethylethylenediamine (0.62 g, 7.08 mmol), and cesium carbonate (11.53 g, 35.39 mmol) were then added. The atmosphere was purged with nitrogen, and the reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with ethyl acetate (150 mL), filtered, and the filtrate washed with saturated brine (120 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 16-1. MS-ESI: m / z 317.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=2.0Hz,1H),7.68(dd,J=8.0,2.0Hz,1H),7.32(d,J=8.0Hz,1H),7 .04-6.96(m,2H),6.58(d,J=8.4Hz,2H),5.12(s,2H),3.81(t,J=6.4Hz,2H),3.05(t,J=6.4Hz,2H).

[0253] 2) Synthesis of Compound 16

[0254] Compound 16 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 608.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.08(s,1H),8.35(d,J=1.6Hz,1H),8.30(brs,1H) ,8.26(d,J=1.6Hz,1H),7.98(d,J=1.2Hz,1H),7.85-7.70(m,2H),7.58(d,J=8.4Hz,1H), 7.18(t,J=8.0Hz,1H),7.02(d,J=8.4Hz,2H),6.70(dd,J=8.4,2.4Hz,1H),6.65-6.49(m, 4H), 5.20 (s, 2H), 3.83 (t, J = 6.4Hz, 2H), 3.61 (s, 3H), 3.17 (t, J = 6.4Hz, 2H), 2.70 (s, 3H).

[0255] Example 17: 6-((2-(4-aminophenyl)-1-oxoisoindol-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (17)

[0256] 1) Synthesis of compound 17-1

[0257] Under nitrogen, 4-bromo-2,3-dihydro-isoindolyl-1-one (6.00 g, 28.29 mmol), tert-butyl N-(4-iodophenyl)carbamate (13.55 g, 42.44 mmol), cuprous iodide (1.08 g, 5.66 mmol), N,N-dimethylethylenediamine (1.00 g, 11.32 mmol), and cesium carbonate (23.05 g, 70.74 mmol) were mixed in dimethyl sulfoxide (30 mL) and dioxane (30 mL) at room temperature. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a silica gel column, and the filtrate was collected and concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 17-1. MS-ESI: m / z 303.0 [M+H] + .

[0258] 2) Synthesis of compound 17

[0259] Compound 17 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 594.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.10(s,1H),8.33(s,2H),8.13(s,1H ),8.02(d,J=7.2Hz,1H),7.87(d,J=7.6Hz,1H),7.83-7.77(m,1H),7.74(t,J =7.2Hz,1H),7.49(d,J=8.8Hz,2H),6.96(t,J=8.0Hz,1H),6.67(d,J=8.8Hz, 2H),6.58-6.44(m,3H),5.16(s,2H),4.98(s,2H),3.49(s,3H),2.72(s,3H).

[0260] Example 18: 6-((2-(3-aminophenyl)-1-oxoisoindol-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (18)

[0261] 1) Synthesis of compound 18-1

[0262] At room temperature, 4-bromo-2,3-dihydro-isoindolyl-1-one (1.46 g, 6.89 mmol) was dissolved in dioxane (20 mL) and N,N-dimethylformamide (20 mL). Tert-butyl (3-iodophenyl)carbamate (2.20 g, 6.89 mmol), cuprous iodide (0.44 g, 1.38 mmol), N,N-dimethylethylenediamine (0.12 g, 1.38 mmol), and cesium carbonate (4.49 g, 13.8 mmol) were then added. The atmosphere was purged with nitrogen, and the reaction mixture was stirred at 120°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 18-1. MS-ESI: m / z 303.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.87(d,J=7.6Hz,1H),7.72(d,J=7.6Hz,1H),7.50(s,1H),7.41(t,J=7. 6Hz, 1H), 7.21 (t, J = 8.0Hz, 1H), 7.06 (dd, J = 8.0, 0.8Hz, 1H), 6.58-6.51 (m, 1H), 4.74 (s, 2H).

[0263] 2) Synthesis of Compound 18

[0264] Compound 18 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 594.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.11(s,1H),8.41-8.30(m,2H),8.15(s,1H),8.05(d,J=7.6Hz,1H),7.87(d,J=8.0Hz,1H),7.84-7.71(m, 2H),7.18-7.06(m,3H),6.95(t,J=7.6Hz,1H),6.54(d,J=7.2Hz,1H),6. 51-6.42(m,3H),5.28(brs,2H),5.02(s,2H),3.45(s,3H),2.73(s,3H).

[0265] Example 19: 6-((2-(4-aminobenzyl)-1-oxoisoindol-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (19)

[0266] 1) Synthesis of compound 19-1

[0267] At room temperature, 4-bromo-2,3-dihydro-isoindolyl-1-one (1.50 g, 7.07 mmol), tert-butyl (4-(bromomethyl)phenyl)carbamate (2.02 g, 7.07 mmol), and cesium carbonate (4.61 g, 14.15 mmol) were mixed in anhydrous N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 19-1. MS-ESI: m / z 417.1 [M+H] + .

[0268] 2) Synthesis of Compound 19

[0269] Compound 19 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 608.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.10(s,1H),8.34(s,1H),8.23(s,1H),8.03-7.96(m,2H),7.84-7.77(m,2H),7.75-7.68(m,1H),7.02(t ,J=7.6Hz,1H),6.97(d,J=8.0Hz,2H),6.62-6.57(m,1H),6.56-6.46(m ,4H),5.07(s,2H),4.55(s,2H),4.39(s,2H),3.55(s,3H),2.71(s,3H).

[0270] Example 20: 6-((2-(3-aminobenzyl)-1-oxoisoindol-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (20)

[0271] 1) Synthesis of Compound 20-1

[0272] At room temperature, 4-bromo-2,3-dihydro-isoindolyl-1-one (2.00 g, 9.43 mmol), tert-butyl (3-(bromomethyl)phenyl)carbamate (2.70 g, 9.43 mmol), and cesium carbonate (6.15 g, 18.86 mmol) were mixed in anhydrous N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 20-1. MS-ESI: m / z 417.1 [M+H] + .

[0273] 2) Synthesis of Compound 20

[0274] Compound 20 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 608.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.10(s,1H),8.34(s,1H),8.24(d,J=2.0Hz,1H),8.03( dd,J=7.2,0.4Hz,1H),8.00(d,J=1.2Hz,1H),7.83(dd,J=8.0,0.8Hz,1H),7.80(s,1H),7.74(t ,J=7.6Hz,1H),7.04(t,J=8.0Hz,1H),6.99(t,J=8.0Hz,1H),6.61-6.56(m,1H),6.53-6.45(m ,4H),6.43(d,J=7.6Hz,1H),5.11(s,2H),4.60(s,2H),4.44(s,2H),3.55(s,3H),2.70(s,3H).

[0275] Example 21: 6-((2-(4-aminophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (21)

[0276] 1) Synthesis of Example 21-1

[0277] 5-Bromo-3,4-dihydroisoquinolin-1(2H)-one (2.00 g, 8.85 mmol), tert-butyl-N-(4-iodophenyl)carbamate (4.24 g, 13.27 mmol), cuprous iodide (337 mg, 1.77 mmol), N,N-dimethylethylenediamine (312 mg, 3.54 mmol), and cesium carbonate (7 mg, 22.12 mmol) were mixed in dimethyl sulfoxide (15 mL) and anhydrous dioxane (15 mL) at room temperature. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (500 mL), and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 21-1. MS-ESI: m / z 317.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.14(d,J=7.6Hz,1H),7.70(d,J=7.6Hz,1H),7.26-7.21(m,1H),7.14(d,J=8 .4Hz, 2H), 6.71 (d, J = 8.4Hz, 2H), 3.93 (t, J = 6.8Hz, 2H), 3.90-3.60 (m, 2H), 3.22 (t, J = 6.8Hz, 2H).

[0278] 2) Synthesis of Compound 21

[0279] Compound 21 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 608.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),9.12(s,1H),8.35(s,1H),8.25(d,J=7.6Hz, 1H),8.22(d,J=1.2Hz,1H),8.08(d,J=8.0Hz,1H),7.88(s,1H),7.80(s,1H),7.63( t,J=8.0Hz,1H),7.07(t,J=8.4Hz,1H),6.99(d,J=8.8Hz,2H),6.63-6.51(m,5H),5 .11(s,2H),3.70(t,J=6.4Hz,2H),3.60(s,3H),3.08(t,J=6.0Hz,2H),2.71(s,3H).

[0280] Example 22: 6-((1-(4-aminophenyl)-1H-indazol-6-yl)sulfonyl)-4-((2,3-dihydrobenzofuran-4-yl)amino)-8-methylquinoline-3-carboxamide (22)

[0281] Compound 22 was prepared according to the synthetic method of Example 1. MS-ESI: m / z 591.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ10.96(s,1H),9.09(s,1H),8.42(s,1H),8.35(s,1H), 8.27(d,J=1.6Hz,1H),8.07-8.01(m,2H),7.98(s,1H),7.80(s,1H),7.37- 7.30(m,3H),6.83-6.75(m,3H),6.40(d,J=8.0Hz,1H),6.33(d,J=7.6Hz,1 H), 5.53 (s, 2H), 4.39 (t, J = 8.4Hz, 2H), 2.78 (t, J = 8.8Hz, 2H), 2.68 (s, 3H).

[0282] Biological evaluation

[0283] The following further describes and explains the contents of the present disclosure in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0284] Test Example 1: In vitro PDE4B1 enzyme activity detection experiment

[0285] 1.1 Experimental Materials

[0286] 1.2 Experimental Procedure

[0287] Prepare a 10 mM stock solution of the compound in 90% DMSO (10% water) in a test tube and use this to prepare a 1:3 serial dilution series. Transfer 0.2 μL of the compound solution to a 384-well reaction plate. Transfer 0.2 μL of 100% DMSO to each negative and positive control. Then, add 10 μL of a 2x PDE4B1 enzyme solution (final concentration 0.04 nM) to each well. For the no-enzyme control well, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes. Next, add 10 μL of a 2x FAM-cAMP substrate solution (final substrate concentration 0.1 μM, compound concentrations starting at 100 nM and going down to 0.05 nM) to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 30 minutes. After the reaction is complete, add 60 μL of the reaction stop solution to each well of the 384-well reaction plate to terminate the reaction. Incubate at room temperature with a shaker at 600 rpm in the dark for 60 minutes. After the incubation, read the RLU data and calculate the inhibition rate. The IC is calculated based on the concentration and inhibition rate fitting curve. 50 value.

[0288] 1.3 Experimental Results

[0289] The examples disclosed herein were used to determine the inhibition of PDE4B1 enzyme activity in vitro using the above assays. The IC 50 The values ​​are shown in Table 1. The experimental results show that the test compound disclosed herein has significant inhibitory activity on the enzymatic activity of PD4EB1.

[0290] Table 1: Inhibitory activity of test compounds against PDE4B1 enzyme

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ring A is a 4- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group; Ring B is a phenyl group or a 5- to 6-membered heteroaryl group; Ring C is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 -membered cycloalkyl and 3- to 8-membered heterocyclic group; R 1 Selected from H atom, -OH, -COOH, -NR 6 R 7 , -CN, halogen, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; Each R 2 is independently selected from an H atom, -OH, -COOH, -NR 6 R 7 , -CN, halogen, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 membered cycloalkyl, and 3- to 8-membered heterocycloalkyl; or Two adjacent Rs 2 together with the part directly connected thereto form a 4-7 membered cycloalkyl group, 4-7 membered heterocyclic group or 5-6 membered heteroaryl group; Each R 3 is independently selected from an H atom, -OH, -COOH, -NR 6 R 7 , -CN, a halogen, a nitro group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, C 3-8 membered cycloalkyl and a 3- to 8-membered heterocyclic group; or Two adjacent Rs 3 together with the part directly connected thereto form a 4- to 7-membered cycloalkyl group, 4- to 7-membered heterocyclic group or 5- to 6-membered heteroaryl group; Each R 4 is independently selected from an H atom, -OH, -COOH, -NR 6 R 7 , -CN, a halogen, a nitro group, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 membered cycloalkyl and 3- to 8-membered heterocyclic group; Each R 5 is independently selected from an H atom, -OH, -COOH, -CN, a halogen, a nitro group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 membered cycloalkyl, and 3- to 8-membered heterocyclic group; or Two adjacent Rs 5 together with the part directly connected thereto form a 4-7 membered cycloalkyl group, 4-7 membered heterocyclic group or 5-6 membered heteroaryl group; L 1 Selected from chemical bonds, -C 1-6 alkylene-, -O-, -C 1-6 alkylene-O-, -O-C 1-6 alkylene-, -C(O)-, -O-C(O)-, -C(O)-O-, -S-, -S(O)-, -S(O)2-, -C 1-6 alkylene-C(O)-, -C(O)-C 1-6 alkylene -, -C 1-6 alkylene - S(O)2 - and - S(O)2 - C 1-6 alkylene, wherein said C 1-6 alkylene groups are each independently optionally substituted by one or more substituents selected from C 1-6 alkyl, halogen, nitro, -OH, -COOH, -NR 6 R 7 , -CN, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-8 membered cycloalkyl, 3 - 8 - membered heterocyclic group; Each R 6 is independently selected from an H atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; Each R 7 is independently selected from an H atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3; p is 0, 1 or 2; and q is 0, 1, 2 or 3.

2. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: Among them, Ring A, Ring B, L 1 , R 1 -R 5 , m, n, p and q are as defined in claim 1.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Ring A is selected from pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, pyranyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl and tetrahydropyranyl; and Ring B is a phenyl group, pyridyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl and pyridazinyl.

4. A compound of formula (I) as claimed in any one of claims 1 - 3 or a pharmaceutically acceptable salt thereof, wherein, selected from indazolyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, triazolopyridinyl, pyrazolopyridine, isoindolinyl, dihydroisoquinolinyl, indolinyl, quinolinyl, isoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl and dihydrobenzothienyl; Preferably, Selected from 5. A compound of formula (I) as claimed in any one of claims 1 - 4 or a pharmaceutically acceptable salt thereof, wherein, L 1 selected from chemical bonds, -C 1-6 alkylene-, -O-, -C(O)-, -O-C(O)-, -C(O)-O-, -S-, -S(O)-, and -S(O)2-, where the C 1-6 alkylene is optionally substituted with one or more substituents selected from C 1-6 alkyl, halogen, nitro, -OH, -COOH, -NH2, -CN, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; Preferably, L 1 is selected from a chemical bond, -C 1-6 alkylene-, and -C 1-6 alkylene- substituted by C 1-6 alkyl; Preferably, L 1 is selected from a chemical bond, -CH2-, -CH(CH3)-, and -CH2-CH2-.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein, R 1 selected from H atom, -OH, -COOH, -NH2, -CN, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; Preferably, R 1 is selected from an H atom, -OH, a halogen, C 1-6 alkyl, and C 1-6 alkoxy; More preferably, R 1 is a H atom or a methyl group.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, Each R 2 is independently selected from an H atom, -OH, -COOH, -NH2, -CN, a halogen, a nitro group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; or Two adjacent Rs 2 together with the part directly connected thereto form a 4- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; Preferably, each R 2 is independently selected from an H atom, -OH, a halogen, a C 1-6 alkyl group, and a C 1-6 alkoxy group; or Two adjacent Rs 2 together with the part directly connected thereto form a tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, cyclopentyl or cyclohexyl; More preferably, each R 2 is independently an H atom or a methoxy group; or Two adjacent Rs 2 Together with the parts directly connected thereto, form a tetrahydrofuranyl group.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein, Each R 3 is independently selected from an H atom, -OH, -COOH, -NH2, -CN, a halogen, a nitro group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; Preferably, each R 3 is independently selected from an H atom, -OH, a halogen, C 1-6 alkyl, and C 1-6 alkoxy; More preferably, each R 3 is independently an H atom.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein, Each R 4 is independently selected from an H atom, -OH, -COOH, -NH2, -CN, a halogen, a nitro group, =O, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl Preferably, each R 4 is independently selected from an H atom, -OH, -CN, a halogen, =O, C 1-6 alkyl, and C 1-6 alkoxy; More preferably, each R 4 independently is an H atom, -CN, =O, and a methyl group.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein, Each R 5 is independently selected from an H atom, -OH, -COOH, -CN, a halogen, a nitro group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; Preferably, each R 5 is independently selected from an H atom, -OH, a halogen, C 1-6 alkyl, and C 1-6 alkoxy; More preferably, each R 5 is independently an H atom or a C 1-6 alkyl group.

11. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, which is selected from:

12. A method for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, comprising: 1) The compound of formula (I-1) and the compound of formula (I-2) are subjected to a metal-catalyzed coupling reaction to obtain the compound of formula (I-3); 2) The compound of formula (I-3) is subjected to an oxidation reaction to obtain the compound of formula (I-4); 3) The compound of formula (I-4) is subjected to a deprotection reaction to obtain the compound of formula (I); Wherein: X is an amino protecting group, preferably selected from tert-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl; Y is a halogen, preferably an I atom.

13. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, and one or more pharmaceutically acceptable carriers, diluents or excipients.

14. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11 or the pharmaceutical composition according to claim 13 in the preparation of a drug for the treatment of PDE4-related diseases.

15. The use according to claim 14, wherein the PDE4-related diseases are selected from inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and diseases related to smooth muscle contractility; preferably, the inflammatory diseases are selected from arthritic diseases, skin inflammatory diseases, inflammatory bowel disease; Specifically, the PDE4-related diseases are selected from asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, adult respiratory distress syndrome, atopic dermatitis, psoriasis, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn's disease, and overactive bladder.

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