WO2024153112A1

WO2024153112A1 - Pde4 inhibitor, and preparation method therefor and use thereof in medicine

Info

Publication number: WO2024153112A1
Application number: PCT/CN2024/072708
Authority: WO
Inventors: 陈鑫德; 孙鲲; 崔美玉; 杨鸿睿; 郝欣; 周玲
Original assignee: 瑞石生物医药有限公司
Priority date: 2023-01-17
Filing date: 2024-01-17
Publication date: 2024-07-25

Abstract

The present disclosure relates to a PDE4 inhibitor, and a preparation method therefor and the use thereof in medicine. Specifically, the present disclosure relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof as a PDE4 inhibitor, particularly in the preparation of a drug for treating PDE4-related diseases.

Description

PDE4 inhibitor, preparation method thereof and medical application thereof

Technical Field

The present disclosure belongs to the field of medicine and relates to PDE4 inhibitors, preparation methods thereof and their applications in medicine. Specifically, the present disclosure relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and its application as a PDE4 inhibitor, in particular, its application in the preparation of a drug for treating a disease associated with PDE4.

Background technique

Phosphodiesterases (PDEs) are responsible for catalyzing the hydrolysis of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP), and regulating cAMP and cGMP-related signaling pathways. Among them, PDE4 is a member of the 11 known PDEs family, which contains 4 subtypes: PDE4A, PDE4B, PDE4C and PDE4D. PDE4 is highly specific for cAMP, and by catalyzing the hydrolysis of cAMP, it regulates the function of transcription factors (such as NF-κB) and the expression of inflammatory mediators (such as INF-α, IFN-γ, IL-12, IL-10). Therefore, PDE4 is involved in a variety of physiological and pathological processes, such as promoting the activation of monocytes and macrophages, neutrophil infiltration, proliferation of vascular smooth muscle, vasodilation, and myocardial contraction.

In recent years, many PDE4 inhibitors have been approved for marketing or are in clinical research. For example, roflumilast is approved for severe chronic obstructive pulmonary disease (COPD) to reduce the number of sudden attacks or prevent the deterioration of COPD symptoms, and apremilast is approved for the treatment of adults with active psoriatic arthritis. Although PDE4 inhibitors have shown good pharmacological activity, they also cause many side effects, such as induced gastrointestinal symptoms such as vomiting and diarrhea.

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

At present, certain progress has been made in the treatment of inflammatory diseases, allergic diseases, autoimmune diseases and other fields, but there are still a large number of patients who need better and more effective clinical treatment drugs and programs. In view of this, the present disclosure designs a series of compounds based on the prior art to provide PDE4 inhibitors with novel structures, better efficacy, high bioavailability and strong drugability, which are used to effectively treat PDE4-related diseases or conditions, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis diseases, skin inflammatory diseases, inflammatory bowel diseases and diseases related to smooth muscle contractility.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

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

Ring B is phenyl or 5-6 membered heteroaryl;

Ring C is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _3-8 membered cycloalkyl and 3-8 membered heterocyclyl;

R ¹ is 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 heterocyclyl;

each R ² is independently 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 heterocyclyl; or

Two adjacent ^R2 together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

each R ³ is independently 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 heterocyclyl; or

Two adjacent R3 ^'s together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

each R ⁴ is independently selected from H atom, -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 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 heterocyclyl;

Each R ⁵ is independently selected from H atom, -OH, -COOH, -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 heterocyclyl; or

Two adjacent R ^5's together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

L ¹ is selected from a chemical bond, -C _1-6 alkylene-, -O-, -C _1-6 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 alkylene is each independently 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 1-6} _6-10 membered aryl, 5-10 membered heteroaryl, C _3-8 membered cycloalkane substituted by one or more substituents of a 3- to 8-membered heterocyclic group;

Each R ⁶ is independently selected from 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 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.

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:

wherein ring A, ring B, L ¹ , R ¹ to R ⁵ , m, n, p and q are as defined in the general formula (I).

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

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

Ring B is phenyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl and pyridazinyl.

Selected from indazolyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, triazolopyridinyl, pyrazolopyridine, isoindolyl, dihydroisoquinolyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl and dihydrobenzothienyl.

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

L ¹ is selected from a chemical bond, -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 substituted with one or more substituents selected from C _1-6 alkyl, halogen, nitro, -OH, -COOH, -NH ₂ , -CN, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

In certain embodiments, in the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, L ¹ is selected from a chemical bond, -C _1-6 alkylene- and -C _1-6 alkylene- substituted by C _1-6 alkyl.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, L ¹ is selected from a chemical bond, -CH ₂ -, -CH(CH ₃ )- and -CH ₂ -CH ₂ -.

R ¹ is selected from the group consisting of H atom, -OH, -COOH, -NH ₂ , -CN, halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, R ¹ is selected from H atom, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, R ¹ is a H atom or a methyl group.

each R ² is independently selected from H atom, -OH, -COOH, -NH ₂ , -CN, halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl; or

Two adjacent ^R2 and the part directly connected thereto together form a 4-7 membered cycloalkyl or 4-7 membered heterocyclic ring base.

In certain embodiments, each R ² in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is independently selected from H atom, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy; or

Two adjacent ^R2 together with the moiety to which they are directly attached form a tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, cyclopentyl or cyclohexyl group.

In some embodiments, each R ² in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is ^{independently} H atom or methoxy; or

Two adjacent ^R2 together with the part to which they are directly attached form a tetrahydrofuranyl group.

Each R ³ is independently selected from H atom, -OH, -COOH, -NH ₂ , -CN, halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R ³ is independently selected from H atom, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy.

In certain embodiments, each R ³ in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is independently an H atom.

Each R ⁴ is independently selected from H atom, -OH, -COOH, -NH ₂ , -CN, halogen, nitro, =O, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R ⁴ is independently selected from H atom, -OH, -CN, halogen, =O, C _1-6 alkyl and C _1-6 alkoxy.

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

Each R ⁵ is independently selected from H atom, -OH, -COOH, -CN, halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R ⁵ is independently selected from H atom, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy.

In certain embodiments, in the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R ⁵ is independently H atom or C _1-6 alkyl.

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

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

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);

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);

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

in:

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

Y is a halogen, preferably an I atom.

In particular,

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).

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).

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).

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, Me ₃ SiCl, and TMSOTf.

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.

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

The present disclosure also relates to the use of the 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 a disease associated with PDE4.

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 A pharmaceutical composition for use as a medicament.

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, which is used for treating diseases related to PDE4.

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 general formula (I) or (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

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

Particularly, the PDE4-related disease is selected from asthma, chronic bronchitis, chronic obstructive pneumonia, 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.

The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. 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.

As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

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.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be granulating agents, disintegrants, binders and lubricants. The tablets may be uncoated or may be coated by 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.

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

Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants 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.

Oil suspensions can be prepared by suspending the active ingredient in 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. Antibiotics may be added. Oxidants preserve these compositions.

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, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

The disclosed compounds may 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 which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

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.

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 factors: 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 dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

Terminology

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

The term "alkyl" refers to a saturated straight 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., _C1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., _C1-12 alkyl), and more preferably an alkyl group having 1 to 6 carbon atoms (i.e., _C1-6 alkyl). Non-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.

A "monovalent group" refers to a compound that "formally" eliminates a monovalent atom or group. A "subunit" refers to a compound that "formally" eliminates two monovalent or one divalent atoms or groups.

The term "alkylene" refers to the remaining part after removing two hydrogen atoms from an alkane molecule, wherein the alkyl group 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 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 alkylene), and 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 .

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., _C2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., _C2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the alkyl group 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., _C2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., _C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

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

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or 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 is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), a cycloalkyl having 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl), or a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

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

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

The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -OO-, -OS- or -SS-), provided that at least one all-carbon ring is contained and the point of attachment is on the all-carbon ring, and it 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., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, 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 monospirocycloalkyl. Non-limiting examples include:

The term "fused cycloalkyl" refers to a polycyclic 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., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The condensed cycloalkyl includes bicyclic condensed cycloalkyl and polycyclic condensed cycloalkyl (such as tricyclic condensed cycloalkyl, tetracyclic condensed cycloalkyl, etc.), preferably bicyclic condensed cycloalkyl or tricyclic condensed cycloalkyl, 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 condensed cycloalkyl. Non-limiting examples include:

The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in 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., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 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:

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), 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 nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), and has 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).

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

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

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 in the ring (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 does not include -O-O-, -O-S- or -S-S-), 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 of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), and more preferably has a spiro heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 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:

wait.

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 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 nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form nitrogen oxides; Oxo, i.e., forming sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more of a cycloalkyl, aryl or heteroaryl group, wherein the point of attachment is on the monocyclic heterocyclic group, 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 heterocyclic group). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic 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 heterocyclic groups. Non-limiting examples include:

wait.

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 in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -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., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it 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:

wait.

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), and 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.

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 does not include -O-O-, -O-S- or -S-S-), 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 group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5- to 10-membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5- or 6-membered monocyclic heteroaryl group), or preferably a heteroaryl group having 8 to 10 ring atoms (i.e. an 8- to 10-membered polycyclic heteroaryl group).

The monocyclic heteroaryl group includes, but is not limited to, furanyl, 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.

The polycyclic heteroaryl group includes, but is not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazine, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2,4]triazolo[1,5-a]pyridinyl, etc.

The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. 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, etc.

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

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

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

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

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

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=0".

The term "carbonyl" refers to C=O.

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

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

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with 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 may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

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

"Optional" or "optional" means that the event or environment described later can but does not necessarily occur, and includes both situations where the event or environment occurs or does not occur. For example, "alkyl optionally substituted by halogen or cyano" includes the situation where alkyl is substituted by halogen or cyano and the situation where alkyl is not substituted by halogen and cyano.

"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 replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) 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).

A "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein or a pharmaceutically acceptable salt thereof. A mixture with 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

"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 when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or 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.

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 and on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by a person skilled in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for 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.

As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

Detailed ways

The disclosed compounds of formula (I) can be synthesized by various methods familiar to those skilled in the art of organic synthesis. Some exemplary synthesis methods of compounds of formula (I) are given in the following specific examples, and these methods are well known in the field of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, those skilled in the art can easily design the synthesis routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.

The present disclosure is further described below in conjunction with 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; the instruments and equipment used in the synthesis experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

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

1) Synthesis of Compound A-2

At room temperature, compound A-1 (10.00 g, 42.91 mmol) was dissolved in diethyl ethoxymethylenemalonate (18 mL), and the reaction solution was stirred at 95°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with n-hexane (30 mL×3) and dried to obtain compound A-2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

2) Synthesis of Compound A-3

Diphenyl ether (75 mL) was heated to 220°C, and compound A-2 (12.00 g, 29.76 mmol) was slowly added in batches, and 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 was precipitated. Cyclohexane (50 mL) was added, stirred and slurried, and filtered. The filter cake was washed with cyclohexane (20 mL × 3), and the filter cake was dried to obtain compound A-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 8.39 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).

3) Synthesis of Compound A-4

At room temperature, compound A-3 (10.00 g, 28.00 mmol) and 2 mol/L sodium hydroxide (67.00 mL, 134.00 mmol) aqueous solution were added to ethanol (34 mL), and 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 to the residue until pH ~ 2, and a large amount of solid was precipitated. The filter cake was washed with water (20 mL × 3) and dried to obtain compound A-4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.99 (s, 1H), 12.77 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 2.54 (s, 3H).

4) Synthesis of Compound A-5

At room temperature, compound A-4 (2.00 g, 6.08 mmol) was dissolved in thionyl chloride (30 mL), N, N-dimethylformamide (0.3 mL) was added, and 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 tetrahydrofuran solution of ammonia (50 mL), and 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.

5) Synthesis of Intermediate A

At room temperature, compound A-5 (2.00 g, 5.37 mmol, 93% purity) and m-methoxyaniline (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] ⁺ .

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

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] ⁺ .

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

1) Synthesis of Compound 1-1

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, the filter cake was vacuum dried, the filtrate was concentrated under reduced pressure, the obtained 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-d ₆ ) 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).

2) Synthesis of Compound 1-2

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, it was filtered while hot, the filter cake was washed with ethyl acetate (10 mL×3), and the organic phase was concentrated under reduced pressure. The obtained 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, CDCl ₃ ) δ7.65 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.4Hz, 2H), 7.52 (d, J = 2.0Hz, 1H), 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).

3) Synthesis of Compound 1-3

At room temperature, compound 1-2 (450 mg, 1.49 mmol, 97% purity) was dissolved in methanol (10 mL), di-tert-butyl dicarbonate (650 mg, 2.98 mmol) was added, and 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 obtained 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 (400 MHz, CDCl ₃ ) δ7.70 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.58-7.51 (m, 3H), 7.40 (dd, J = 8.4, 1.6 Hz, 1H), 6.75 (s, 1H), 3.83 (s, 3H), 1.55 (s, 9H).

4) Synthesis of Compound 1-4

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, nitrogen was replaced, the tube was sealed and stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The 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] ⁺ .

5) Synthesis of Compound 1-5

At room temperature, compound 1-4 (400 mg, 0.88 mmol, 93% purity) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, cooled to -70 ° C, and 1 mol/L potassium tert-butoxide tetrahydrofuran solution (2.50 mL, 2.50 mmol) was slowly dripped in. 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 The residue was concentrated under reduced pressure to obtain compound 1-5. MS-ESI: m/z 356.1 [M+H] ⁺ .

6) Synthesis of Compound 1-6

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), cuprous iodide (15 mg, 0.05 mmol) and triethylamine (94 mg, 0.93 mmol) were added, replaced with nitrogen, and stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature, poured into water (40 mL) for dilution, 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 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] ⁺ .

7) Synthesis of Compound 1-7

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 the reaction was completed, the reaction solution was poured into water (20 mL) and diluted, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, 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 obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1), and then separated by preparative high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient ratio: 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] ⁺ .

8) Synthesis of Compound 1

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 the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was separated by preparative high performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex luna C18150*25mm*10μm; mobile phase: water (0.2% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 19-43%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 1. MS-ESI: m/z 593.2[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) 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).

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

1) Synthesis of Compound 2-1

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 mixed in anhydrous N,N-dimethylformamide (60 mL) in sequence, and 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 × 2). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 2-1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.35 (s, 1H), 8.47-8.42 (m, 2H), 8.41-8.35 (m, 2H), 8.02 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.8, 1.2 Hz, 1H).

2) Synthesis of Compound 2

Compound 2 was prepared by referring to the synthetic method of Example 1. MS-ESI: m/z 593.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (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=8.4 Hz, 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=7.2 Hz, 1H), 5.58 (s, 2H), 3.63 (s, 3H), 2.69 (s, 3H).

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

1) Synthesis of compound 3-1

At room temperature and under nitrogen protection, 6-bromoindazole (3.00 g, 15.23 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0 ° C. Under a weak nitrogen flow, sodium hydrogen (0.91 g, 22.84 mmol, 60% purity) was slowly added, and 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 a saturated aqueous ammonium chloride solution (40 mL) to quench, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 3-1. ¹ H NMR (400MHz, CDCl ₃ ) δ7.90(s,1H),7.82(s,1H),7.49(d,J＝8.8Hz,1H),7.37(d,J＝8.4Hz,2H),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).

2) Synthesis of Compound 3

Compound 3 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 593.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.75(s,1H),9.07(s,1H),8.55(s,1H),8.36(s,1H),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).

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

1) Synthesis of compound 4-1

At room temperature and under nitrogen protection, 6-bromoindazole (3.00 g, 15.23 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction mixture was cooled to 0 ° C, sodium hydrogen (0.91 g, 22.84 mmol, 60% purity) was slowly added under a weak nitrogen flow, stirred at 0 ° C for 30 minutes, tert-butyl (4- (bromomethyl) phenyl) carbamate (5.23 g, 18.27 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (40 mL) to quench, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the product compound 4-1. ¹ H NMR (400MHz, CDCl ₃ ) 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).

2) Synthesis of compound 4

Compound 4 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 593.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.73 (s, 1H), 9.07 (s, 1H), 8.36 (dd, J=7.2, 1.6 Hz, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.21 (dd, J=8.4, 0.8 Hz, 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),3.6 0(s,3H),2.70(s,3H).

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

1) Synthesis of compound 5-1

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, and the reaction solution was stirred at 70 ° C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (100 mL) and water (60 mL) were added for dilution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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, CDCl ₃ ) 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).

2) Synthesis of compound 5

Compound 5 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 593.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ10.80 (s, 1H), 8.93 (s, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.23 (dd, J=8.4, 1.2 Hz, 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).

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)

1) Synthesis of compound 6-1

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), and the reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution for dilution, and ethyl acetate (50 mL×2) was used for extraction. 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 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, CDCl ₃ ) 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).

2) Synthesis of Compound 6 and Compound 7

Compound 6-8 was prepared by referring 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 (chromatographic column: Daicel Chiralpak AS (250 mm*30 mm*10 μm); mobile phase: supercritical carbon dioxide, acetonitrile/ethanol (0.1% monohydrated ammonia); 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 eluted peak, and compound 7 is the second eluted peak). Compound 6: MS-ESI: m/z 607.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.0 Hz,1H),7.01(d,J=8.4 Hz,2H),6.68(d,J＝7.6Hz,1H),6.60(s,1H),6.53(d,J＝7.6Hz,1H),6.45(d,J＝8.4Hz,2H),6.10-6.00(m,1H),5.03(s,2H),3.60(s,3H),2.69(s,3H),1 .88(d,J＝6.8Hz,3H). Compound 7: MS-ESI: m/z607.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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

1) Synthesis of compound 8-1

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 reacted at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was diluted with water (100 mL), and extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The 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-d ₆ ) 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).

2) Synthesis of Compound 8

Compound 8 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 579.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

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

1) Synthesis of compound 9-1

At room temperature, 6-bromo-3-methylindazole (1.00 g, 4.74 mmol) and (4-tert-butyloxycarbonyl-aminophenyl)boronic acid (1.35 g, 5.69 mmol) were dissolved in dichloromethane (30 mL), and copper acetate (1.29 g, 7.11 mmol) and pyridine (1.12 g, 14.21 mmol) were added, and the reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 9-1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

2) Synthesis of compound 9

Compound 9 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 593.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.81(s,1H),9.07(s,1H),8.38-8.24(m,2H),8.04(s,1H),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 ).

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

1) Synthesis of compound 10-1

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

2) Synthesis of compound 10

Compound 10 was prepared by referring to the synthetic method of Example 1. MS-ESI: 604.1 m/z [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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)

1) Synthesis of compound 11-1

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, and nitrogen was replaced. The reaction mixture was stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), 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 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] ⁺ .

2) Synthesis of compound 11-2

At room temperature, compound 11-1 (700 mg, 1.66 mmol, 90% purity) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, 1,1-carbonyldiimidazole (539 mg, 3.32 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the 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 (400 MHz, DMSO-d ₆ ) δ9.64 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.44-7.36 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 1.50 (s, 9H).

3) Synthesis of compound 11

Compound 11 was prepared by referring to the synthetic method of Example 1. MS-ESI: m/z 596.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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

1) Synthesis of compound 12-1

At room temperature, 6-bromoindazole (3.00 g, 15.23 mmol) and (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 reacted at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was diluted with water (100 mL), 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 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, CDCl ₃ ) 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).

2) Synthesis of compound 12

Compound 12 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 579.2 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )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),7.4 8-7.42(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).

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

1) Synthesis of compound 13-1

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

2) Synthesis of compound 13-2

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, and then 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (379 mg, 0.47 mmol) was added, and nitrogen was replaced. The reaction solution was stirred at 70°C for 16 hours. The reaction solution was cooled to room temperature, 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 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, CD ₃ OD) δ 8.52 (s, 1H), 7.65-7.60 (m, 3H), 7.54 (d, J = 9.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 8.8, 1.2 Hz, 1H), 1.55 (s, 9H).

3) Synthesis of compound 13

Compound 13 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 579.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.09 (s, 1H), 8.77 (d, J=0.8 Hz, 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).

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)

1) Synthesis of compound 14-1

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), followed by addition of glacial acetic acid (80 mg, 1.33 mmol), and the reaction solution was stirred at 80 ° C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of solid precipitated. Ethanol (100 mL) was added for dilution, filtered, and 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-d ₆ ) δ 11.49 (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).

2) Synthesis of compound 14-2

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, and 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 residue was purified by silica gel column chromatography (dichloromethane/methanol =10/1). The crude product was 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, CDCl ₃ ) δ7.65 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.52 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.4, 1.6 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 4.12-3.87 (m, 2H), 3.83 (s, 3H).

3) Synthesis of compound 14

Compound 14 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 580.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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),2.7 0(s,3H).

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

1) Synthesis of compound 15-1

At room temperature, 6-bromoisoindolin-1-one (2000 mg, 9.43 mmol) was dissolved in dioxane (20 mL) and dimethyl sulfoxide (20 mL), followed by the addition of 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), nitrogen replacement, and the reaction solution was stirred at 120 ° C for 16 hours. After the reaction was completed, it was diluted with ethyl acetate (150 mL), filtered, and the filtrate was washed with saturated brine (120 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain compound 15-1. MS-ESI: m/z 303.0 [M+H] ⁺ .

2) Synthesis of Example 15

Compound 15 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 594.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.81 (s, 1H), 9.08 (s, 1H), 8.33 (d, J=1.2 Hz, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.77 (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).

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)

1) Synthesis of compound 16-1

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), followed by the addition of 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), nitrogen replacement, and the reaction mixture was stirred at 120 ° C for 16 hours. The reaction solution was diluted with ethyl acetate (150 mL), filtered, and the filtrate was washed with saturated brine (120 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.98 (d, J=2.0 Hz, 1H), 7.68 (dd, J=8.0, 2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.04-6.96 (m, 2H), 6.58 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 3.81 (t, J=6.4 Hz, 2H), 3.05 (t, J=6.4 Hz, 2H).

2) Synthesis of compound 16

Compound 16 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 608.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.79 (s, 1H), 9.08 (s, 1H), 8.35 (d, J=1.6 Hz, 1H), 8.30 (brs, 1H), 8.26 (d, J=1.6 Hz, 1H), 7.98 (d, J=1.2 Hz, 1H), 7.85-7.70 (m, 2H), 7.58 (d, J=8.4 Hz, 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).

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

1) Synthesis of compound 17-1

At room temperature and under nitrogen protection, 4-bromo-2,3-dihydro-isoindolyl-1-one (6.00g, 28.29mmol), tert-butyl N-(4-iodophenyl)carbamate (13.55g, 42.44mmol), cuprous iodide (1.08g, 5.66mmol), N,N-dimethylethylenediamine (1.00g, 11.32mmol) and cesium carbonate (23.05g, 70.74mmol) were mixed in dimethyl sulfoxide (30mL) and dioxane (30mL), and the reaction mixture was stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature, filtered through a silica gel column, and the filtrate was collected and concentrated under reduced pressure. The residue was diluted with water (50mL) and extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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] ⁺ .

2) Synthesis of compound 17

Compound 17 was prepared by referring to the synthetic method of Example 1. MS-ESI: m/z 594.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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) .

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

1) Synthesis of compound 18-1

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), followed by the addition of (3-iodo-phenyl)-carbamic acid tert-butyl ester (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), nitrogen replacement, and the reaction mixture was stirred at 120 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (100 mL) for dilution, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 18-1. MS-ESI: m/z 303.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ7.87 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.06 (dd, J=8.0, 0.8 Hz, 1H), 6.58-6.51 (m, 1H), 4.74 (s, 2H).

2) Synthesis of Compound 18

Compound 18 was prepared by referring to the synthetic method of Example 1. MS-ESI: m/z 594.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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

1) Synthesis of compound 19-1

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), and the reaction mixture was stirred at room temperature for 16 hours. Water (60 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The 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] ⁺ .

2) Synthesis of compound 19

Compound 19 was prepared by referring to the synthetic method of Example 1. MS-ESI: m/z 608.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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

1) Synthesis of Compound 20-1

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), and the reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution for dilution, and ethyl acetate (50 mL×2) was used for extraction. 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 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] ⁺ .

2) Synthesis of Compound 20

Compound 20 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 608.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.80 (s, 1H), 9.10 (s, 1H), 8.34 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.03 (dd, J=7.2, 0.4 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.83 (dd, J=8.0, 0.8 Hz, 1H), 7.80 (s, 1H), 7.74 (t, J=7.6 Hz, 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).

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)

1) Synthesis of Example 21-1

At room temperature, 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). The reaction mixture was stirred at 120°C for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (500 mL), and the filtrate was concentrated under reduced pressure. Water (30 mL) was added for dilution, and ethyl acetate (30 mL×2) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=0/1) to obtain compound 21-1. MS-ESI: m/z 317.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ8.14 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.26-7.21 (m, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 3.93 (t, J=6.8 Hz, 2H), 3.90-3.60 (m, 2H), 3.22 (t, J=6.8 Hz, 2H).

2) Synthesis of Compound 21

Compound 21 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 608.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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),2.7 1(s,3H).

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

Compound 22 was prepared by referring to the synthesis method of Example 1. MS-ESI: m/z 591.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )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),7.37-7.3 0(m,3H),6.83-6.75(m,3H),6.40(d,J＝8.0Hz,1H),6.33(d,J＝7.6Hz,1H),5.53(s,2H),4.39(t,J＝8.4Hz,2H),2.78(t,J＝8.8Hz,2H),2.68(s,3H).

Biological evaluation

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

Test Example 1: In vitro PDE4B1 enzyme activity detection experiment

1.1 Experimental Materials

1.2 Experimental procedures

First, prepare a 10mM compound stock solution in a test tube with 90% DMSO (10% water) and use it to prepare a series of dilutions with a dilution gradient of 1:3. Transfer 0.2μL of compound solution to a 384-well reaction plate, and transfer 0.2μL of 100% DMSO to both the negative and positive controls. Then add 10μL of 2x PDE4B1 enzyme solution (final concentration 0.04nM) to the wells, and replace the enzyme solution with 10μL of 1x reaction buffer for the no enzyme activity control wells. Centrifuge at 1000rpm for 1 minute and incubate at room temperature for 15 minutes. Then add 10μL of 2x FAM-cAMP substrate solution (substrate final concentration 0.1μM, compound final concentration starts from 100nM and goes down to 0.05nM) to each well of the 384-well reaction plate, centrifuge at 1000rpm for 1 minute, and react at 25℃ for 30 minutes. After the reaction, 60 μL of the reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the plate was incubated at room temperature for 60 minutes with shaking at 600 rpm in the dark. After the incubation, the RLU data was read and the inhibition rate was calculated, and the IC ₅₀ value was calculated based on the concentration and inhibition rate fitting curve.

1.3 Experimental Results

The inhibition of PDE4B1 enzyme activity in vitro by the examples disclosed herein was determined by the above test, and the measured IC ₅₀ values are shown in Table 1. The experimental results show that the test compounds disclosed herein have significant inhibitory activity on the enzyme activity of PD4EB1.

Table 1: Inhibitory activity of test compounds on PDE4B1 enzyme

Claims

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

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

Ring B is phenyl or 5-6 membered heteroaryl;

Ring C is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 membered cycloalkyl and 3-8 membered heterocyclyl;

R 1 is 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 heterocyclyl;

each R 2 is independently 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 heterocyclyl; or

Two adjacent R2 together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

each R 3 is independently 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 heterocyclyl; or

Two adjacent R3 's together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

each R 4 is independently selected from H atom, -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 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 heterocyclyl;

Each R 5 is independently selected from H atom, -OH, -COOH, -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 heterocyclyl; or

Two adjacent R 5's together with the part to which they are directly connected form a 4-7 membered cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

L1 is selected from a chemical bond, -C1-6 alkylene-, -O-, -C1-6 alkylene-O-, -OC1-6 alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)- , -S(O) 2- , -C1-6 alkylene-C(O)-, -C(O) -C1-6 alkylene -, -C 1-6 alkylene-S(O) 2 - and -S(O) 2 -C 1-6 alkylene-, wherein the C 1-6 alkylene groups are each independently optionally substituted with 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 heterocyclyl;

Each R 6 is independently selected from 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 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.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

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

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

Ring B is phenyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl and pyridazinyl.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: Selected from indazolyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, triazolopyridinyl, pyrazolopyridine, isoindolyl, dihydroisoquinolyl, indolyl, quinoline benzofuranyl, dihydrobenzofuranyl, benzothiophenyl and dihydrobenzothiophenyl;

Preferably, Selected from
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein L 1 is selected from a chemical bond, -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 substituted with one or more substituents selected from C 1-6 alkyl, halogen, nitro, -OH, -COOH, -NH 2 , -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, -CH 2 -, -CH(CH 3 )- and -CH 2 -CH 2 -.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein:

R 1 is selected from the group consisting of H atom, -OH, -COOH, -NH 2 , -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 H atom, -OH, halogen, C 1-6 alkyl and C 1-6 alkoxy;

More preferably, R 1 is a H atom or a methyl group.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein:

each R 2 is independently selected from H atom, -OH, -COOH, -NH 2 , -CN, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; or

Two adjacent R2 's together with the part to which they are directly connected form a 4-7 membered cycloalkyl or 4-7 membered heterocyclic group;

Preferably, each R 2 is independently selected from H atom, -OH, halogen, C 1-6 alkyl and C 1-6 alkoxy; or

Two adjacent R2 together with the moiety to which they are directly attached form a tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, cyclopentyl or cyclohexyl group;

More preferably, each R 2 is independently an H atom or a methoxy group; or

Two adjacent R2 together with the part to which they are directly attached form a tetrahydrofuranyl group.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein:

Each R 3 is independently selected from H atom, -OH, -COOH, -NH 2 , -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, each R 3 is independently selected from H atom, -OH, halogen, C 1-6 alkyl and C 1-6 alkoxy;

More preferably, each R 3 is independently a H atom.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein:

Each R 4 is independently selected from H atom, -OH, -COOH, -NH 2 , -CN, halogen, nitro, =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 H atom, -OH, -CN, halogen, =O, C 1-6 alkyl and C 1-6 alkoxy;

More preferably, each R 4 is independently H atom, -CN, =O and methyl.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein:

Each R 5 is independently selected from H atom, -OH, -COOH, -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, each R 5 is independently selected from H atom, -OH, halogen, C 1-6 alkyl and C 1-6 alkoxy;

More preferably, each R 5 is independently a H atom or a C 1-6 alkyl group.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from:
A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, comprising:

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);

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);

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

in:

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

Y is a halogen, preferably an I atom.
A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of the compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a PDE4-related disease.
The use according to claim 14, wherein 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, inflammatory skin diseases, inflammatory bowel disease;

Particularly, the PDE4-related disease is selected from asthma, chronic bronchitis, chronic obstructive pneumonia, 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.