CN114014842A - A kind of heterocyclic ketone compound and its composition and its preparation method and application - Google Patents

Abstract

The present invention relates to a heterocyclic ketone compound and its pharmaceutical composition, preparation method and use. The present invention specifically discloses a pyridone represented by general formula I, or a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof. The heterocyclic ketone compound of the present invention is an efficient and highly selective BRD4 inhibitor, and has a good therapeutic effect on inflammation, autoimmune diseases and various cancers, such as prostate cancer and the like. The present invention also discloses the preparation of the compound represented by the general formula I.

Description

A kind of heterocyclic ketone compound and its composition and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a heterocyclic ketone compound and a composition thereof as well as a preparation method and application thereof.

Background technique

Bromodomain and extra-terminal domain (BET) belong to the bromodomain protein family and play an important role in regulating the cell cycle and mediating gene transcription, and then participate in the regulation of tumorigenesis and development. It is a potential drug target.

The human BET family consists of BRD2, BRD3, BRD4, and BRDT. The BET protein family consists of two conserved bromodomains (BD1, BD2) and an ultraterminal domain (ET). BRD2 is mainly expressed in spermatocytes and round spermatids and regulates the development of neurons; BRD3 is highly expressed in the ovary, uterus, placenta and brain, and transcriptionally regulates the hematopoietic process; BRDT specifically exists in the testis and affects the gene expression of sperm. Compared to the other three members, BRD4 is the most extensively studied. BRD4 is overexpressed in a variety of tumors, such as ovarian cancer, melanoma, etc. It recognizes and binds to histone acetylated lysine, recruits chromatin regulators, promotes gene transcription, and promotes the occurrence and development of tumors. Studies have shown that many human diseases are closely related to BRD4 protein, such as tumors, autoimmune or inflammatory diseases, and viral infections. Among them, tumors associated with BRD4 protein include breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal and gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer and Hematopoietic system tumors.

Therefore, the development of drugs that inhibit the binding of bromodomains to acetylated lysine residues on histones can be effectively used to treat the above-mentioned diseases.

SUMMARY OF THE INVENTION

Purpose of invention

The present invention provides a BRD4 inhibitor that is partially different from the prior art, and one of the technical problems to be solved by the present invention is to provide a novel pyridone compound, which provides the possibility for subsequent drug development.

Technical solutions

A kind of compound as shown in general formula I, its pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate, it is characterized in that, structural formula is as shown in formula I,

in,

R ¹ is hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl; wherein said C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl may be optionally replaced by one or more substituted with substituents independently selected from deuterium, halogen, hydroxyl, amino, cyano and the like;

Z is CR ⁵ or NR ⁶ ;

Y is ^CR7 or ^NR8 ;

R ⁵ -R ⁷ are independently selected from hydrogen, deuterium atom, halogen, amino, nitro, cyano, hydroxyl, haloalkoxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy;

R ⁸ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl; wherein said C ₁ -C ₆ Alkyl, C2 _{- C6alkenyl} , C2 _{- C6alkynyl} , C3 _{- C6cycloalkyl} may be optionally one or more independently selected from deuterium, halogen, hydroxy, amino, cyano Substituents are substituted;

独立地是单键或双键，条件是:each

is independently a single or double bond, provided that:

为单键时，Z为CR⁵,Y为NR⁸；R⁵和R⁸取代如上面所述；(1) When

When being a single bond, Z is CR ⁵ , Y is NR ⁸ ; R ⁵ and R ⁸ are substituted as described above;

为双键时，Z和Y可以是C、N的任意组合；(2) When

When it is a double bond, Z and Y can be any combination of C and N;

R ² is independently selected from hydrogen, deuterium atom, halogen, amino, -OR ⁹ , C _6- C ₁₂ aromatic ring, C ₆ -C ₁₂ heteroaromatic ring; wherein said C _6- C ₁₂ aromatic ring, C ₆ -C ₁₂ heteroaromatic ring is independently one or more selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, C ₁ -C ₃ alkyl, -N(R ^10-1 )C(O)R ^10-2 , -N(R ^10-3 )S(O) ₂ R ^10-4 , -CON(R ^10-5 ) ₂ and other substituents are substituted;

R ⁹ is C ₁ -C ₄ alkyl, C ₃ -C ₁₂ cycloalkane, C ₃ -C ₁₂ heterocycloalkane; wherein the C ₃ -C ₁₂ cycloalkane and C ₃ -C ₁₂ heterocycloalkane can be Monocyclic, paracyclic, spirocyclic, bridged ring; the C ₃ -C ₆ heterocycloalkane is "one or more of heteroatoms selected from N, O or S, and the number of heteroatoms is 1-3 3-6 membered "heterocycloalkyl; the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane, C ₃ -C ₆ heterocycloalkane can be optionally selected by one or more independently From halogen, amino, oxo, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, -N(R ^9-1 )C(O)R ^9-2 , or, -N (R ^9-3 )S(O) ₂ R ^9-4 and other substituents are substituted;

R ^9-1 to R ^9-4 are independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkane, C ₃ -C ₆ cycloalkyl or "hetero atoms are selected from N, O or S One or more of 3-6-membered "heterocycloalkyl groups with 1-3 heteroatoms; wherein the C ₃ -C ₆ cycloalkyl groups or "hetero atoms are selected from N, O or S One or more of the 3-6-membered "heterocycloalkyl" with 1-3 heteroatoms can be optionally substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, amino and the like;

R ^10-1 to R ^10-5 are independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkane, or C ₃ -C ₆ cycloalkane;

R ³ is hydrogen, unsubstituted or R ¹¹ substituted C ₁ -C ₆ alkyl, -C(O)N(R ^11-1 )(R ^11-2 ), -N(R ^11-3 )COR ^{11- 4} , -N( ^11-5 )SO ₂ R ^11-6 , or,

R ^11-1 to R ^11-8 are independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ deuterated alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

Ring A is selected from saturated C ₃ -C ₆ carbocycles, saturated C ₃ -C ₆ heterocycles, unsaturated C ₅ -C ₁₀ carbocycles, aromatic rings; wherein the saturated C ₃ -C ₆ heterocycles, The unsaturated C ₅ -C ₁₀ carbocyclic ring is a hetero ring with "hetero atoms selected from one or more of N, O or S, and the number of hetero atoms is 1-3"; the saturated C ₃ -C ₆ carbocycles, saturated C3 _{- C6} heterocycles, unsaturated _C5 - _C10 carbocycles, aromatic rings independently by one or more independently selected from halogen, amino, nitro, cyano, hydroxyl, oxygen Substituents such as substituted groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, etc.;

W is independently selected from C(R ¹² ) _n , N, O, S; wherein n represents 0, 1, 2; R ¹² is hydrogen or C ₁ -C ₃ alkane, C _1- C ₃ deuterated alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

R ⁴ is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkane, C ₁ -C ₃ alkoxy;

P stands for 0, 1, 2 or 3;

Described halogen is selected from fluorine, chlorine, bromine, iodine;

In the present invention, any one of the compounds represented by general formula I, pharmaceutically acceptable salts, prodrugs, isomers, racemates, precursors or solvates thereof is characterized in that said The compound shown in formula I is any of the following compounds:

5-(1-Benzyl-1H-indazol-6-yl)-1-methylpyrimidin-2(1H)-one (I-1)

5-(1-Benzyl-1H-indazol-6-yl)-1-methyltetrahydropyrimidin-2(1H)-one (I-2)

5-(1-Benzyl-1H-indazol-6-yl)-1,3-dimethyltetrahydropyrimidin-2(1H)-one (I-3)

6-(1-Benzyl-1H-indazol-6-yl)-5-ethoxy-2-methylpyridazin-3(2H)-one (I-4)

5-(1-Benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-5)

N-(4-(5-(1-Benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)methane Sulfonimide (I-6)

trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Oxy)cyclohexyl)acetamide (I-7)

trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Oxy)cyclohexyl)-N-methylacetamide (I-8)

trans-N-((4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl ) oxy) cyclohexyl) methylsulfonamide (I-9)

trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Oxy)cyclohexyl)cyclopropanecarboxamide (I-10)

trans-4-(8-Acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-5-(1-benzyl-1H-indazol-6-yl)- 1-Methylpyridin-2(1H)-one (I-11)

trans-5-(1-benzyl-1H-indazol-6-yl)-1-methyl-4-(8-(methylsulfonyl)-8-azabicyclo[3.2.1]octane- 3-yl)oxy)pyridin-2(1H)-one (I-12)

4-((1-Acetylpiperidin-4-yl)oxy)-5-(1-benzyl-1H-indazol-6-yl)-1-methylpyridin-2(1H)-one (I -13)

(R)-4-Ethoxy-1-methyl-5-(1-(1-phenethyl)-1H-indazol-6-yl)pyridin-2(1H)-one (I-14)

5-(1-(2,4-Difluorobenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-15)

5-(1-(2,6-Dimethylbenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-16)

5-(1-Benzyl-1H-indol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-17)

4-Ethoxy-1-methyl-5-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)pyridin-2(1H)-one (I-18)

trans-6-(4-((4-acetamidocyclohexyl)oxo)-1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-1-benzyl-N -Methyl-1H-indazole-4-carboxamide (I-19)

trans-N-(4-((5-(1-benzyl-4-(hydroxymethyl)-1H-indazol-6-yl)-1-methyl-2-carbonyl-1,2- Dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-20)

trans-N-(4-((5-(1-benzyl-4-(2-hydroxypropan-2-yl)-1H-indazol-6-yl)-1-methyl-2-carbonyl -1,2-Dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-21)

trans-N-(4-((5-(1-(2,6-dimethylbenzyl)-4-(2-hydroxypropan-2-yl)-1H-indazol-6-yl) -1-Methyl-2-carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-22)

The compound structure is as follows:

The present invention also provides a kind of preparation method of compound shown in formula I, it is characterized in that, it comprises the following steps as follows:

The definitions of Z, Y, R ¹ , R ² , R ³ , R ⁴ , A, and W are as described above.

Intermediate 1 and intermediate 2 are obtained by Suzuki coupling in an oxygen-free solvent to obtain I, the reaction time is preferably 8-12 hours, the reaction temperature is preferably 100°C-110°C, and the reaction solvent is preferably 1,4-dioxane and water. The preparation of I adopts conventional preparation methods.

In the present invention, after the substitution reaction is completed, preferably, it may further include a post-processing step. The conditions and operations of the described post-processing can be conventional post-processing conditions and operations in the field, which include the following steps: cooling the reaction solution, adding a solvent, extracting an organic layer, drying, filtering, and removing the solvent in the filtrate to obtain an organic layer. The residue can be separated and purified. The cooling is preferably to room temperature. The solvent is preferably saline, such as saturated saline. The conditions and operations for the extraction can be conventional conditions and operations in the art, and the solvent for the extraction is preferably an ester solvent, such as ethyl acetate. The drying conditions and operations can be conventional conditions and operations in the art, and the drying reagents can be conventional reagents in the art, such as anhydrous sodium sulfate. The filtering conditions and operations can be conventional conditions and operations in the field. The conditions and operations for removing the solvent can be conventional conditions and operations in the art, such as evaporating the solvent to dryness. The separation and purification is preferably column chromatography separation.

Unless otherwise specified, the "room temperature" in the present invention refers to 20-30°C.

The invention also provides a pharmaceutical composition, which comprises a compound represented by general formula I, or a pharmaceutically acceptable salt, ester prodrug, isomer, racemate, precursor or solvate thereof, and Pharmaceutically acceptable excipients.

The present invention also provides the application of a compound represented by general formula I, or a pharmaceutically acceptable salt, ester or pharmaceutical composition thereof, in the preparation of BET inhibitors, especially in the preparation of BRD4 protein inhibitors .

The present invention also provides the use of a compound represented by formula I, or a pharmaceutically acceptable salt or ester thereof, in preparing a medicine. The present invention also provides a compound represented by formula I, or a pharmaceutically acceptable salt or ester thereof, which can be used for tumors.

The present invention also provides an application of the above-mentioned drug combination in preparing a drug for treating tumors.

In the present invention, the tumors include but are not limited to breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal and gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, Prostate cancer and hematopoietic system tumors. The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed. The pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.

Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.

The pharmaceutical compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant Intradermal, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in controlled release or delayed release dosage forms (eg, liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.

In the compounds of the present invention, when any variable occurs more than once in any component, its definition at each occurrence is independent of the definition at each other occurrence. Likewise, combinations of substituents and variables are permissible so long as such combinations stabilize the compound. A line drawn into a ring system from a substituent indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atoms adjacent to the ring. It is understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide chemically stable and easily synthesized target compounds from readily available starting materials by skill in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.

The term "pharmaceutically acceptable salts" refers to salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit/risk ratio, Medically acceptable salts such as amines, carboxylic acids and other types of compounds are well known in the art.

The term "pharmaceutically acceptable ester" refers to a compound consisting of a compound with an acid, such as a phosphate, carboxylate, sulfonate, and the like.

The compounds of the present invention may form salts. "Salt" in this application refers to acid salts formed with inorganic or organic acids, and basic salts formed with inorganic or organic bases. Additionally, when the compound has a basic moiety (eg, pyridine, imidazole, etc.) and an acidic moiety (eg, a carboxylic acid), zwitterions ("inner salts") can form, also included in the term "salt" as used herein . The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of compounds are formed by reaction with an appropriate inorganic or organic base. Pharmaceutically acceptable, non-toxic, physiologically acceptable salts are preferred, although other salts are also useful. Exemplary non-toxic acid salts include those from inorganic acids such as hydrochloric, sulfuric, hydrobromic, sulfamic, phosphoric, nitric, and the like, as well as from organic acids such as acetic, propionic, succinic, glycolic, Acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, glycerophosphoric acid, salicylic acid, p-aminobenzene Salts prepared from sulfonic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid, among others . Exemplary non-toxic base salts include salts from inorganic bases such as aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, Sodium salts, zinc salts, etc., also include salts from organic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, For example, arginine, sugar beet, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, Ethylenediamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Methylglucamine, Histidine, Lysine, Isopropylamine, Morpholine, Piperidine, Polyamine Resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine, etc.

The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Alkyl groups containing 1 to 3 carbon atoms are preferred, and methyl and ethyl groups are most preferred. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like, and Various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano , nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl groups.

The term "substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

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

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention. The reagents and raw materials used in the present invention are all commercially available.

Detailed ways

In order to better understand the present invention, the present invention is further illustrated by the following examples, but the content of the present invention is not limited to the following examples.

Example 1: 5-(1-Benzyl-1H-indazol-6-yl)-1-methylpyrimidin-2(1H)-one (I-1)

Step 1: Synthesis of intermediate 1-benzyl-6-bromo-1H-indazole (A-002)

6-Bromo-1H-indazole (A-001) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. Benzyl bromide (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-002 as a white solid with a yield of 67%. ¹ H NMR (300MHz, Chloroform-d) δ8.01 (d, J=1.0Hz, 1H), 7.60 (dd, J=8.5, 0.7Hz, 1H), 7.53 (m, 1H), 7.35-7.26 (m ,3H),7.24(dd,J=8.5,1.5Hz 1H),7.21-7.16(m,2H),5.55(s,2H).

ESI-MS(m/z): 287.0[M+H]+

Step 2: Synthesis of intermediate 1-benzyl-6-(2-methoxypyrimidin-5-yl)-1H-indazole (A-003)

A-002 (2.0g, 6.96mmol, 1eq), 2-methoxy-5-pyrimidineboronic acid (1.28g, 1.2eq), potassium carbonate (1.92g, 2eq) and Pd(dppf)Cl2 ( _50.9mg ) , 1% mmol), added to 100mL eggplant-shaped bottle. 27 mL of dioxane, 3 mL of water were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 8 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-003 as a white solid with a yield of 79%. ¹ H NMR (300MHz, Chloroform-d) δ 8.71 (s, 2H), 8.10 (d, J=0.8Hz, 1H), 7.85 (dd, J=8.28, 0.68Hz, 1H), 7.41-7.38 (m ,1H),7.36–7.27(m,4H),7.25–7.19(m,2H),5.66(s,2H),4.07(s,3H).ESI-MS(m/z):317.1[M+H ]+

Step 3: Synthesis of Intermediate 5-(1-benzyl-1H-indazol-6-yl)pyrimidin-2(1H)-one (A-004)

A-003 (1.70g, 5.37mmol, 1eq) was added to the eggplant-shaped flask, 9mL of hydrobromic acid and 11mL of glacial acetic acid were added, and the mixture was heated to reflux for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid A-004 with a yield of 90%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.05(s, 2H), 8.16(s, 1H), 8.15(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.46(dd, J=8.5, 1.4Hz, 1H), 7.34–7.20(m, 5H), 5.69(s, 2H).

ESI-MS(m/z): 303.1[M+H]+

Step 4: Synthesis of 5-(1-benzyl-1H-indazol-6-yl)-1-methylpyrimidin-2(1H)-one (I-1)

A-004 (2.50g, 8.81mmol, 1eq) and cesium carbonate (1.2eq) were placed in a 100ml single-necked flask, 15mL of DMF was added and stirred at room temperature, iodomethane (1.2eq) was added dropwise, and the reaction was carried out at room temperature for 10min to stop the reaction , 100 mL of ethyl acetate was added, washed with saturated sodium chloride solution (15 ml × 5), concentrated, and purified by column chromatography to obtain white solid I-1 with a yield of 73%. mp 182.6-184.2°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.86 (d, 1H, J=3.3 Hz), 8.08 (s, 1H), 7.85 (d, 1H, J=3.3 Hz), 7.83 (d,1H,J=8.6Hz),7.36-7.27(m,4H),7.23-7.13(m,3H),5.99(s,1H),5.65(s.2H),3.66(s,3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 165.0, 156.0, 146.1, 139.8, 136.4, 133.3, 131.3, 128.6, 127.7, 126.9, 123.6, 122.1, 119.0, 118.3, 106.1, 52.7, 39.3; HRMS (ESI) calcd for C ₁₉ H ₁₇ N ₄ O ⁺ [M+H] ⁺ 317.1397, found 317.1390.

Example 2: 5-(1-Benzyl-1H-indazol-6-yl)-1-methyltetrahydropyrimidin-2(1H)-one (I-2)

Step 1: Synthesis of 5-(1-benzyl-1H-indazol-6-yl)-1-methyltetrahydropyrimidin-2(1H)-one (I-2)

I-1 (500 mg, 1.58 mmol, 1 eq) and 10% palladium hydroxide were placed in a single-necked flask, 10 mL of methanol was added, hydrogen was replaced, and the reaction was carried out at room temperature overnight in a hydrogen atmosphere. After the completion of the reaction by spot plate monitoring, suction filtration and concentration to obtain a white solid I-1 with a yield of 86%. mp 94.3-95.0°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.01 (d, 1H, J=0.7Hz), 7.70 (d, 1H, J=8.4Hz), 7.34-7.23 (m, 3H) ,7.22-7.15(m,3H),7.00(dd,1H,J=8.4,1.1Hz),5.77(s,1H),5.58(s,2H),3.50-3.40(m,3H),3.40-3.30 (m, 2H), 2.95 (s, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 156.6, 139.8, 138.2, 136.7, 133.3, 128.8, 127.9, 127.2, 123.8, 121.6, 120.5, 107.6, 53.7, 53.0, 46.5, 39.1, 35.2; HRMS(ESI) calcd for C ₁₉ H ₂₁ N ₄ O ⁺ [M+H] ⁺ 321.1710, found 321.1709.

Example 3: 5-(1-Benzyl-1H-indazol-6-yl)-1,3-dimethyltetrahydropyrimidin-2(1H)-one (I-3)

Step 1: Synthesis of 5-(1-benzyl-1H-indazol-6-yl)-1,3-dimethyltetrahydropyrimidin-2(1H)-one (I-3)

I-2 (100mg, 0.31mmol, 1eq), cesium carbonate (1.2eq) was dissolved in 2mL DMF, iodomethane (29uL, 1.5eq) was added dropwise, and stirred for 1.5h. The reaction was stopped, 20 mL of ethyl acetate was added for extraction, washed with saturated sodium chloride solution (5 ml × 5), concentrated, and purified by column chromatography to obtain white solid I-3 with a yield of 72%. mp 108.0-109.6°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.03 (d, 1H, J=0.7Hz), 7.71 (d, 1H, J=8.4Hz), 7.35-7.23 (m, 3H) ,7.22-7.14(m,3H),7.02(dd,1H,J=8.4,1.2Hz),5.59(s,2H),3.56-3.30(m,5H),2.96(s,6H); ¹³ C NMR (101MHz, CDCl ₃ ) δ156.3, 139.7, 138.2, 136.6, 133.2, 128.7, 127.8, 127.1, 123.7, 121.6, 120.4, 107.5, 54.0, 52.9, 38.9, 35.8; HRMS(ESI) calcd for C ₂₀ H ₂₃ N ₄ O ⁺ [M+H] ⁺ 335.1866, found335.1861.

Example 4: 6-(1-Benzyl-1H-indazol-6-yl)-5-ethoxy-2-methylpyridazin-3(2H)-one (I-4)

Step 1: Intermediate 1-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-indazole (A-005) Synthesis

A-002 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-005 as a white solid with a yield of 74%. ESI-MS(m/z): 335.2[M+H]+

Step 2: Synthesis of 6-(1-benzyl-1H-indazol-6-yl)-5-ethoxy-2-methylpyridazin-3(2H)-one (I-4)

A-005 (1eq), 6-bromo-5-ethoxy-2-methylpyridazin-3(2H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%) mmol), added to a single-necked bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-4 as a white solid with a yield of 71%. mp 151.0-152.0°C; ¹ HNMR (300MHz, CDCl ₃ ) δ 8.08(s, 1H), 7.79(d, 1H, J=8.4Hz), 7.75(s, 1H), 7.50(dd, 1H.J =8.4,1.0Hz),7.35-7.27(m,3H),7.23-7.16(m,2H),6.25(s,1H),5.64(s,2H),4.03(q,2H,J=7.0Hz) , 3.81 (s, 3H), 1.32 (t, 3H, J=7.0 Hz); ¹³ C NMR (75 Hz, CDCl ₃ ) 165.1, 156.0, 146.0, 139.8, 136.4, 133.3, 131.4, 128.6, 127.7, 126.9, 123.7 , 122.1, 119.0, 118.4, 106.1, 52.8, 39.4; HRMS(ESI) calcd for C ₂₁ H ₂₁ N ₄ O ₂ ⁺ [M+H] ⁺ 361.1659, found 361.1658.

Example 5: 5-(1-Benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-5)

Step 1: Synthesis of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-5)

Combine A-005 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-5 as a white solid with a yield of 84%. mp 49.1-50.0°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.37 (s, 1H), 7.35-7.27 (m, 3H),7.23-7.14(m,4H),5.99(s,1H),5.61(s.2H),4.00(q,2H,J＝7.0Hz),3.54(s,3H),1.26(t,3H) , J=7.0 Hz); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.8, 163.7, 139.6, 137.7, 136.8, 133.1, 132.1, 128.6, 127.6, 126.9, 123.3, 122.4, 120.5, 115.1, 109.4, 97.2, 64.1, 52.7, 36.6, 13.9; HRMS(ESI) calcd for C ₂₂ H ₂₂ N ₃ O ₂ ⁺ [M+H] ⁺ 360.1707, found 360.1705.

Example 6: N-(4-(5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Phenyl)methanesulfonimide (I-6)

Step 1: Synthesis of intermediate 5-(1-benzyl-1H-indazol-6-yl)-4-chloro-1-methylpyridin-2(1H)-one (A-006)

A-005 (1eq), 5-bromo-4-chloro-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol), Add to single neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-006 as a white solid with a yield of 67%. ¹ H NMR (300MHz, Chloroform-d) δ 8.08 (d, J=1.0Hz, 1H), 7.77 (dd, J=8.3, 0.8Hz, 1H), 7.35-7.27 (m, 4H), 7.24-7.19 (m, 2H), 7.11(dd, J=8.3, 1.4Hz, 1H), 6.77(s, 1H), 5.63(s, 2H), 3.57(s, 3H).

ESI-MS(m/z): 350.1[M+H]+

Step 2: N-(4-(5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)benzene Synthesis of yl)methanesulfonimide (I-6)

A-006 (100mg, 0.28mmol, 1eq), 4-methanesulfonamidophenylboronic acid pinacol ester (99.8mg, 0.34mmol, 1.2eq), Pd2(dba _{)3 (} 2mol%), P( Cy) ₃ (6%), and potassium carbonate (3eq) were added to a single-necked flask, dioxane and tert-butanol (4:1, 0.2M) were added, and the reaction was carried out at 120° C. for 12h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-6 as a white solid with a yield of 87%. mp 216.9-219.0°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.94 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H, J=8.1 Hz) ,7.58(s,1H),7.41-7.27(m,3H),7.20(d,2H),7.11(s,4H),6.78(d,1H,J＝8.1Hz),6.47(s,1H), 5.58(s, 2H), 3.58(s, 3H), 3.02(s, 3H)

¹³ C NMR (101 MHz, CDCl ₃ ) δ 161.1, 151.4, 140.1, 139.5, 138.4, 137.4, 135.0, 133.2, 132.9, 129.6, 128.5, 127.50, 127.47, 120.9, 122.2, 120.3, 118.5, 11.018 , 36.5; HRMS(ESI) calcd for C ₂₇ H ₂₅ N ₄ O ₃ S ⁺ [M+H] ⁺ 485.1642, found 485.1636.

Example 7: N-((1r,4r)-4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-di Hydropyridin-4-yl)oxy)cyclohexyl)acetamide (I-7)

Step 1: Synthesis of intermediate 5-(1-benzyl-1H-indazol-6-yl)-4-fluoro-1-methylpyridin-2(1H)-one (A-007) A-005 (1eq), 5-bromo-4-fluoro-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) in a single-neck flask . Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-007 as a white solid with a yield of 45%. ¹ H NMR (300MHz, Chloroform-d) δ8.09 (d, J=1.0Hz, 1H), 7.81 (dd, J=8.4, 0.8Hz, 1H), 7.43 (d, J=9.3Hz, 1H), 7.38-7.29(m, 4H), 7.25-7.20(m, 2H), 7.17(dt, J=8.4, 1.6Hz, 1H), 6.37(d, J=12.1Hz, 1H), 5.65(s, 2H) ,3.62(s,3H).

ESI-MS(m/z): 334.1[M+H]+

Step 2: Intermediate trans-tert-butyl-4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydro Synthesis of Pyridin-4-yl)oxy)cyclohexyl)carbamate (A-008)

Dissolve trans-tert-butyl-(4-hydroxycyclohexyl)carbamate (2.0 g, 9.3 mmol, 1.2 eq) in 40 mL of THF, place it in a low temperature reaction bath at 0 °C, and slowly add sodium hydride (744 mg, 60%, dispersed in liquid paraffin), stirred at 0 °C for 30 min. Then A-007 (2.58 g, 7.75 mmol, 1 eq) was dissolved in 10 mL of THF, added dropwise to the reaction system, and the reaction flask was moved to 60° C. to react overnight. After the completion of the reaction was monitored by spot plate, the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-008 as a white solid with a yield of 75%. δ8.08(d,J＝1.0Hz,1H),7.36-7.30(m,5H),7.21(s,1H),7.19(dd,J＝7.4,2.1Hz,1H),7.16-7.12(m, 2H), 6.00(s, 1H), 5.63(s, 2H), 4.50-4.36(m, 1H), 4.25-4.09(m, 2H), 3.55(s, 3H), 2.19-2.05(m, 4H) ,1.62-1.50(m,2H),1.27(s,9H),1.28-1.16(m,2H).ESI-MS(m/z):529.3[M+H]+

Step 3: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4 Synthesis of -yl)oxy)cyclohexyl)acetamide (I-7)

A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1eq), triethylamine (4eq) was dissolved in 0.2M THF, acetyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography gave I-7 as a white solid with a two-step yield of 60%. mp 206.0-208.2°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.06(s, 1H), 7.73(d, 1H, J=8.4Hz), 7.35-7.28(m, 4H), 7.22(s, 1H), 7.18-7.14(m, 2H), 7.12(d, 1H, J=8.4Hz), 6.12-6.04(m, 1H), 5.96(s, 1H), 5.61(s, 2H), 4.22-4.13 ¹³ CNMR (101MHz, CDCl ₃ )δ169.5,163.7,139.5,138.1,136.8,133.1,132.0,128.7,127.7,126.7,123.4,122.4,120.7,115.7,109.5,97.6,75.5,52.8,46.9,36. 23.3; HRMS(ESI) calcd for C ₂₈ H ₃₁ N ₄ O ₃ ⁺ [M+H] ⁺ 471.2391, found 471.2388.

Example 8: N-((1r,4r)-4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-di Hydropyridin-4-yl)oxy)cyclohexyl)-N-methylacetamide (I-8)

Step 1: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4 Synthesis of -yl)oxy)cyclohexyl)-N-methylacetamide (I-8)

I-7 (80 mg, 0.17 mmol, 1 eq) was dissolved in 5 mL of DMF, placed in a low temperature reaction bath at 0°C, sodium hydride (27.2 mg, 60%, dispersed in liquid paraffin) was slowly added, and stirred for 30 min. Iodomethane (32uL, 3eq) was added dropwise at 0°C, moved to 50°C to react overnight. The reaction was stopped, 15 mL of ethyl acetate was added for extraction, washed with saturated sodium chloride solution (5 ml × 5), concentrated, and purified by column chromatography to obtain white solid I-8 with a yield of 78%. mp 79.4-81.0°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.73 (d, 1H, J=8.5Hz), 7.39-7.28 (M, 3H), 7.24-7.09 ( m, 4H), 5.99(s, 1H), 5.62(s, 2H), 4.57-4.39(m, 1H), 4.22-4.04(m, 1H), 3.53(s, 3H), 2.84(s, 1H) , 2.80(s, 1H), 2.24-2.05(m, 2H), 2.09(s, 3H), 1.73-1.61(m, 2H), 1.55-1.23(m, 4H); ¹³ C NMR (101 Hz CDCl ₃ ) 170.4,163.74,163.65,139.4,138.0,136.8,133.1,132.0,128.7,127.8,126.7,123.4,122.3,120.6,115.6,109.5,97.6,75.7,56.1,52.8,50.5,36 26.9, 22.4; HRMS(ESI) calcd for C ₂₉ H ₃₃ N ₄ O ₃ ⁺ [M+H] ⁺ 485.2547, found 485.2541.

Example 9: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine- 4-yl)oxy)cyclohexyl)methylsulfonamide (I-9)

Step 1: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4 Synthesis of -yl)oxy)cyclohexyl)methylsulfonamide (I-9)

A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF, methylsulfonyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-7 with a two-step yield of 69%. mp 218.0-220.0°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.17(s, 1H), 7.85-7.76(m, 2H), 7.71(s, 1H), 7.42-7.28(m, 3H), 7.27-7.19(m, 3H), 7.14(d, 1H, J=7.1Hz), 6.06(s, 1H), 5.72(s, 2H), 4.48-4.32(m, 1H), 3.46(s, 3H) ,3.25-3.08(m,1H),2.96(s,3H),2.07-1.93(m,2H),1.92-1.79(m,2H),1.52-1.34(m,2H),1.33-1.16(m, 2H); ¹³ C NMR (75MHz, DMSO) δ 162.9, 162.6, 139.6, 139.4, 137.8, 133.0, 132.3, 128.6, 127.4, 127.0, 122.6, 122.4, 120.3, 113.4, 109.7, 96.8, 74.2, 51.7, 5 , 35.9, 30.4, 28.8; HRMS(ESI) calcd for C ₂₇ H ₃₁ N ₄ O ₄ S ⁺ [M+H] ⁺ 507.2061, found507.2060.

Example 10: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine- 4-yl)oxy)cyclohexyl)cyclopropanecarboxamide (I-10)

Step 1: trans-N-(4-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4 Synthesis of -yl)oxy)cyclohexyl)cyclopropanecarboxamide (I-10)

A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1eq), triethylamine (4eq) was dissolved in 0.2M THF, cyclopropylcarbonyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-10 with a two-step yield of 75%. mp 119.4-121.2°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.73 (d, 1H, J=8.1 Hz), 7.36-7.28 (m, 4H), 7.23-7.08 ( m, 4H), 6.00(s, 1H), 5.62(s, 2H), 5.48(d, 1H, J=7.1Hz), 4.25-4.12(m, 1H), 3.84-3.71(m, 1H), 3.54 (s, 3H), 2.11-1.94 (m, 5H), 1.35-1.194H), 1.01-0.92 (m, 2H), 0.79-0.69 (m, 2H); ¹³ C NMR (75MHz, CDCl ₃ )δ172. HRMS( ESI) calcd for C ₃₀ H ₃₃ N ₄ O ₃ ⁺ [M+H] ⁺ 497.2547, found 497.2542.

Example 11: trans-4-(8-Acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-5-(1-benzyl-1H-indazole-6 -yl)-1-methylpyridin-2(1H)-one (I-11)

Step 1: Intermediate trans-tert-butyl(3-((5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydro Synthesis of Pyridin-4-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (A-009)

Dissolve trans-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (2.0 g, 9.3 mmol, 1.2 eq) in 40 mL of THF and place it at 0 °C for low temperature reaction In the bath, sodium hydride (744 mg, 60%, dispersed in liquid paraffin) was slowly added, and the mixture was stirred at 0° C. for 30 min. Then A-007 (2.58 g, 7.75 mmol, 1 eq) was dissolved in 10 mL of THF, added dropwise to the reaction system, and the reaction flask was moved to 60° C. to react overnight. After the completion of the reaction was monitored by spot plate, the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-009 as a white solid with a yield of 78%. ¹ H NMR (300MHz, Chloroform-d) δ8.08 (d, J=0.9Hz, 1H), 7.74 (dd, J=8.3, 0.8Hz, 1H), 7.35-7.25 (m, 5H), 7.17-7.09 (m, 3H), 5.88(s, 1H), 5.62(s, 2H), 4.55(t, J=4.5Hz, 1H), 4.07–3.87(m, 2H), 3.53(s, 3H), 2.05- 1.92(m,2H),1.81-1.69(m,2H),1.44(s,9H),1.24-1.18(m,2H).

ESI-MS(m/z): 541.3[M+H]+

Step 2: trans-4-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-5-(1-benzyl-1H-indazole-6- Synthesis of yl)-1-methylpyridin-2(1H)-one (I-11)

A-009 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1eq), triethylamine (4eq) was dissolved in 0.2M THF, acetyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-11 as a white solid with a two-step yield of 46%. mp 120.0-121.2°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.09 (d, 1H, J=0.8Hz), 7.75 (d, 1H, J=8.4Hz), 7.35-7.27 (m, 4H) ,7.22-7.08(m,4H),5.85(s,1H),5.62(s,2H),4.60-4.52(m,1H),4.48-4.41(m,1H),3.92-3.85(m,1H) ,3.53(s,3H),2.15-2.06(m,1H),2.00(s,3H),1.96-1.90(m,2H),1.86-1.77(m,1H),1.39-1.22(m,4H) ; ¹³ C NMR (101MHz, CDCl ₃ )δ165.3,162.9,162.6,139.43,139.39,137.8,133.1,132.39,128.5,127.4,127.0,122.74,122.65,120.3,113.9,110.3.1,5.6,75. 49.3, 35.8, 35.3, 33.7, 27.8, 26.2, 21.3; HRMS(ESI) calcd for C ₂₉ H ₃₁ N ₄ O ₃ ⁺ [M+H] ⁺ 483.2391, found 483.2389.

Example 12: trans-5-(1-benzyl-1H-indazol-6-yl)-1-methyl-4-(8-(methylsulfonyl)-8-azabicyclo[3.2.1 ]octan-3-yl)oxy)pyridin-2(1H)-one (I-12)

Step 1: trans-5-(1-benzyl-1H-indazol-6-yl)-1-methyl-4-(8-(methylsulfonyl)-8-azabicyclo[3.2.1] Synthesis of octan-3-yl)oxy)pyridin-2(1H)-one (I-12) A-009 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2h, and vacuum filtered A white solid was obtained. This solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF, methylsulfonyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-12 with a two-step yield of 55%. mp 189.0-190.6°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.74 (d, 1H, J=8.3 Hz), 7.34-7.27 (m, 4H), 7.21-7.06 ( m, 4H), 5.85(s, 1H), 5.62(s, 2H), 4.53(t, 1H, J=4.8Hz), 4.00(s, 2H), 3.53(s, 3H), 2.79(s, 3H) _The ^_ , 40.2, 36.8, 36.4, 28.1, 21.0, 14.1; HRMS(ESI) calcd for C ₂₈ H ₃₁ N ₄ O ₄ S ⁺ [M+H] ⁺ 519.2061, found 519.2060.

Example 13: 4-((1-Acetylpiperidin-4-yl)oxy)-5-(1-benzyl-1H-indazol-6-yl)-1-methylpyridine-2(1H) - Ketone (I-13)

Step 1: Intermediate 4-(5-(1-benzyl-1H-indazol-6-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy Synthesis of Piperidine-1-Carboxylic Acid Tert-Butyl Ester (A-010)

Dissolve 4-hydroxypiperidine-1-carboxylate tert-butyl ester (2.0g, 9.3mmol, 1.2eq) in 40mL of THF, put it in a low temperature reaction bath at 0°C, slowly add sodium hydride (744mg, 60%, dispersed in liquid paraffin), stirring at 0 °C for 30 min. Then A-007 (2.58 g, 7.75 mmol, 1 eq) was dissolved in 10 mL of THF, added dropwise to the reaction system, and the reaction flask was moved to 60° C. to react overnight. After the completion of the reaction was monitored by spot plate, the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-010 as a white solid with a yield of 72%. ¹ H NMR (300MHz, Chloroform-d) δ8.07 (d, J=1.0Hz, 1H), 7.73 (dd, J=8.4, 0.8Hz, 1H), 7.35-7.28 (m, 4H), 7.21 (s ,1H),7.20–7.11(m,3H),5.99(s,1H),5.61(s,2H),4.53-4.43(m,1H),3.53(s,3H),3.45–3.23(m,4H) ),1.99-1.81(m,2H),1.68-1.53(m,2H),1.45(s,9H).ESI-MS(m/z):515.3[M+H]+

Step 2: 4-((1-Acetylpiperidin-4-yl)oxy)-5-(1-benzyl-1H-indazol-6-yl)-1-methylpyridine-2(1H)- Synthesis of Ketone (I-13)

A-010 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1eq), triethylamine (4eq) was dissolved in 0.2M THF, acetyl chloride (1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-11 with a two-step yield of 72%. mp 162.4-163.0°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.07 (d, 1H, J=0.8Hz), 7.74 (d, 1H, J=8.5Hz), 7.34-7.28 (m, 4H) ,7.21(s,1H),7.20-7.11(m,3H),6.00(s,1H),5.61(s.2H),4.60-4.50(m,1H),3.54(s,3H),3.46-3.35 (m, 1H), 3.33-3.23 (m, 2H), 2.04 (s, 3H), 1.91-1.77 (m, 2H), 1.75-1.63 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 168 HRMS (ESI)calcd for C ₂₇ H ₂₉ N ₄ O ₃ ⁺ [M+H] ⁺ 457.2234, found 457.2234.

Example 14: (R)-4-Ethoxy-1-methyl-5-(1-(1-phenethyl)-1H-indazol-6-yl)pyridin-2(1H)-one ( I-14)

Step 1: Synthesis of intermediate (R)-6-bromo-1-(1-phenethyl)-1H-indazole (A-011)

6-Bromo-1H-indazole (A-001) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. (R)-(1-bromoethyl)benzene (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature, and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-011 as a white solid with a yield of 48%. ¹ H NMR (300MHz, Chloroform-d) δ8.03 (d, J=1.0Hz, 1H), 7.58 (dd, J=8.5, 0.7Hz, 1H), 7.49–7.45 (m, 1H), 7.34–7.19 (m, 6H), 5.74 (q, J=7.1Hz, 1H), 2.03 (d, J=7.1Hz, 3H), ESI-MS (m/z): 301.0[M+H]+

Step 2: Intermediate (R)-1-(1-phenethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)- Synthesis of 1H-Indazole (A-013)

A-011 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-013 as a white solid with a yield of 79%. ESI-MS(m/z): 349.2[M+H]+

Step 3: (R)-4-ethoxy-1-methyl-5-(1-(1-phenethyl)-1H-indazol-6-yl)pyridin-2(1H)-one (I -14) synthesis

Combine A-013 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-14 as a white solid with a yield of 80%. mp 151.3-152.5°C; ¹ HNMR (300MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.70 (d, 1H, J=8.4Hz), 7.32 (s, 1H), 7.31-7.19 (m, 5H) ), 7.17-7.11(m, 2H), 5.97(s, 1H), 5.83(q, 1H, J=7.0Hz), 3.97(q, 2H, J=7.0Hz), 3.50(s, 3H), 2.05 (d, 3H, J=7.0 Hz), 1.25 (t, 3H, J=7.0 Hz); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.8, 163.7, 142.1, 139.2, 137.7, 132.7, 131.8, 128.5, 127.4, 126.0, 123.4, 122.5, 120.4, 115.2, 109.6, 97.2, 64.1, 57.9, 36.6, 21.3, 13.9; HRMS(ESI) calcd for C ₂₃ H ₂₄ N ₃ O ₂ ⁺ [M+H] ⁺ 374.1863, found 374.1859.

Example 15: 5-(1-(2,4-Difluorobenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I -15)

Step 1: Synthesis of intermediate 6-bromo-1-(2,4-difluorobenzyl)-1H indazole (A-014)

6-Bromo-1H-indazole (A-001) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. 1-(Bromomethyl)-2,4-difluorobenzene (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature, and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-014 as a white solid with a yield of 64%. ¹ H NMR (300MHz, Chloroform-d)δ8.00(d,J=1.0Hz,1H),7.62-7.60(m,1H),7.58(d,J=8.6Hz,1H),7.25(dd,J =8.6,1.5Hz,1H),7.06(td,J=8.5,6.2Hz,1H),6.88–6.76(m,2H),5.53(s,2H).

ESI-MS(m/z): 323.0[M+H]+

Step 2: Intermediate 1-(2,4-Difluorobenzyl)-6-(4,4,5,5-Tetramethyl-1,3,2-Dioxybenzaldehyde-2-yl)-1H Synthesis of Indazole (A-015)

A-014 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-015 as a white solid with a yield of 79%. ESI-MS(m/z): 371.2[M+H]+

Step 3: 5-(1-(2,4-Difluorobenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I- 15) Synthesis

Combine A-015 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-15 as a white solid with a yield of 61%. mp135.2-137.0℃ ^.1HNMR (300MHz, _CDCl3 )δ8.05(s,1H),7.73(d,1H,J=8.4Hz),7.45(s,1H),7.19(d,1H,J =8.4Hz), 7.12-7.02(m, 1H), 6.89-6.73(m, 2H), 6.00(s, 1H), 5.60(s, 2H), 4.03(q, 2H, J=7.0Hz), 3.57 (s, 3H), 2.32 (s, 6H), 1.31 (t, 3H, J=7.0 Hz).; ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.9, 163.8 (dd, J=11.9, 11.9 Hz), 161.4 (dd, J=7.7, 7.7Hz), 158.9 (d, J=11.6Hz), 139.6, 137.8, 133.7, 132.6, 130.5 (dd, J=5.4, 5.4Hz), 123.3, 122.7, 120.7, 119.9 (dd , J=3.9, 3.9Hz), 115.1, 111.7 (dd, J=3.8, 3.8Hz), 109.2, 103.9 (t, J=25.4Hz), 97.4, 64.3, 45.5 (d, J=4.3Hz), 36.8 , 14.0; HRMS(ESI) calcd for C ₂₂ H ₂₀ F ₂ N ₃ O ₂ +[M+H] ⁺ 396.1518, found396.1516.

Example 16: 5-(1-(2,6-Dimethylbenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one ( I-16)

Step 1: Synthesis of intermediate 6-bromo-1-(2,6-dimethylbenzyl)-1H indazole (A-016)

6-Bromo-1H-indazole (A-001) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. 2-(bromomethyl)-1,3-xylene (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature, and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-016 as a white solid with a yield of 54%. ¹ H NMR (300 MHz, Chloroform-d) δ 7.94 (d, J=1.0 Hz, 1H), 7.56 (dd, J=8.5, 0.7 Hz, 1H), 7.39 (m, 1H), 7.22 (dd, J =8.5,1.6Hz,1H),7.22-7.16(m,1H),7.11(s,1H),7.10(d,J=7.45Hz,1H)5.49(s,2H),2.31(s,6H). ESI-MS(m/z): 315.0[M+H]+

Step 2: Intermediate 1-(2,6-Dimethylbenzyl)-6-(4,4,5,5-Tetramethyl-1,3,2-Dioxybenzaldehyde-2-yl)- Synthesis of 1H Indazole (A-017)

A-016 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-017 as a white solid with a yield of 84%. ESI-MS(m/z): 363.2[M+H]+

Step 3: 5-(1-(2,6-dimethylbenzyl)-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I -16) synthesis

Combine A-017 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-16 as a white solid with a yield of 72%. mp 180.5-182.0°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.68 (d, 1H, J=8.3 Hz), 7.26-7.14 (m, 3H), 7.14-7.04 (m ,3H),6.00(s,1H),5.54(s,2H),4.03(q,2H,J＝7.0Hz),3.52(s,3H),2.32(s,6H),1.35(t,3H, J=7.0 Hz); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.8, 163.7, 139.6, 137.9, 137.7, 132.9, 132.0, 131.9, 128.4, 128.2, 123.0, 122.3, 120.4, 115.2, 109.2, 97.2, 64.1 , 36.6, 20.1, 14.0; HRMS(ESI) calcd for C ₂₄ H ₂₆ N ₃ O ₂ ⁺ [M+H] ⁺ 388.2020, found 388.2015.

Example 17: 5-(1-Benzyl-1H-indol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-17)

Step 1: Synthesis of intermediate 1-benzyl-6-bromo-1H-indole (A-019)

6-Bromo-1H-indole (A-018) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. 2-(bromomethyl)-1,3-xylene (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature, and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-019 as a white solid with a yield of 88%. ¹ H NMR (300MHz, Chloroform-d) δ 7.50 (dd, J=8.4, 0.5Hz, 1H), 7.43 (m, 1H), 7.35-7.26 (m, 3H), 7.20 (dd, J=8.4, 1.7Hz, 1H), 7.12–7.06 (m, 3H), 6.52 (dd, J=3.2, 0.9Hz, 1H), 5.28 (s, 2H). ESI-MS (m/z): 286.0[M+H ]+

Step 2: Preparation of the intermediate 1-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H indole (A-020) synthesis

A-019 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-017 as a white solid with a yield of 76%. ESI-MS(m/z): 334.2[M+H]+

Step 3: Synthesis of 5-(1-benzyl-1H-indol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one (I-17)

Combine A-020 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-17 as a white solid with a yield of 57%. mp 69.0-71.2°C; ¹ HNMR (300MHz, CDCl ₃ ) δ 7.64 (d, 1H, J=8.2Hz), 7.35-7.27 (m, 4H), 7.19-7.15 (m, 2H), 7.15-7.08 (m,3H),6.57(d,1H,J=3.1Hz),5.98(s,1H),5.34(s.2H),3.97(q,2H,J=7.0Hz),3.52(s,3H) , 1.22 (t, 3H, J=7.0 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.2, 163.9, 137.4, 137.3, 136.2, 128.9, 128.7, 127.8, 127.5, 127.2, 126.5, 121.0, 120.5, 116.2, 110.3, 101.6, 97.1, 64.0, 49.9, 36.7, 13.9; HRMS(ESI) calcd for C ₂₃ H ₂₃ N ₂ O ₂ ⁺ [M+H] ⁺ 359.1754, found 359.1754.

Example 18: 4-Ethoxy-1-methyl-5-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)pyridin-2(1H)-one (1- 18)

Step 1: Synthesis of intermediate 6-bromo-2,3-dihydro-1H-inden-1-ol (A-022)

6-Bromo-2,3-dihydro-1H-inden-1-one (A-021) (2.0 g, 9.48 mmol, 1 eq) was dissolved in 20 mL of methanol and placed in a low temperature reaction bath at 0°C. Sodium borohydride (360.2 mg, 1 eq) was added in small portions and stirred for 1 h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-022 as a white solid with a yield of 92%. ¹ H NMR (300MHz, Chloroform-d) δ7.54 (d, J=1.9Hz, 1H), 7.37 (dd, J=8.0, 1.9Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 5.22(q,J＝6.4Hz,1H),2.99(ddd,J＝16.2,8.6,4.5Hz,1H),2.76(dt,J＝16.0,7.6Hz,1H),2.51(dddd,J＝12.9, 8.3,6.9,4.5Hz,1H),1.95(dddd,J=13.5,8.7,6.9,5.6Hz,1H),1.79(d,J=6.9Hz,1H).

ESI-MS(m/z)213.0[M+H]+

Step 2: Synthesis of intermediate 6-bromo-1-phenoxy-2,3-dihydro-1H-indene (A-023)

A-022 (1.0g, 4.7mmol, 1eq), phenol (1eq), triphenylphosphine (1.1eq) were dissolved in 20mL of DCM, placed in a low temperature reaction bath at 0°C, and DEAD (1.1eq) was added dropwise , the reaction is 12h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-023 as a white solid with a yield of 61%. ESI-MS(m/z): 289.0[M+H]+

Step 3: Intermediate 4,4,5,5-Tetramethyl-2-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)-1,3,2-dioxo Synthesis of Benzaldehyde (A-024)

A-023 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-024 as a white solid with a yield of 76%. ESI-MS(m/z): 337.2[M+H]+

Step 4: 4-ethoxy-1-methyl-5-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)pyridin-2(1H)-one (I-18 )Synthesis

Combine A-024 (1eq), 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2% mmol) ) into a single-neck bottle. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain I-18 as a white solid with a yield of 82%. mp 51.0-51.6°C; ¹ HNMR (300MHz, CDCl ₃ ) δ 7.45(s, 1H), 7.40-7.28(m, 4H), 7.17(s, 1H), 7.10-6.94(m, 3H), 5.98 (s, 1H), 5.79(d, 1H), 4.01(q, 2H, J=7.0Hz), 3.52(s, 3H), 3.23-3.10(m, 1H), 3.02-2.89(m, 1H), 2.69-2.55 (m, 1H), 2.32-2.18 (m, 1H), 1.34 (t, 3H, J=7.0 Hz); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.8, 163.6, 158.1, 142.8, 141.8, 137.2 , 132.3, 129.6, 129.3, 125.6, 124.4, 120.6, 115.5, 114.9, 97.0, 81.1, 63.9, 36.4, 32.3, 29.8, 13.8; HRMS(ESI) calcd for C ₂₃ H ₂₄ NO ₃ ⁺ [M+H] ⁺ 362.1751, found 362.1748.

Example 19: trans-6-(4-((4-acetamidocyclohexyl)oxo)-1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-1-benzene Methyl-N-methyl-1H-indazole-4-carboxamide (I-19)

Step 1: Intermediate trans-tert-butyl (4-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)cyclohexyl)carbamic acid Synthesis of Esters (A-025)

Dissolve trans-tert-butyl 4-hydroxycyclohexyl)carbamate (1.5g, 6.97mmol, 1.2eq) in 40mL of THF, place it in a low temperature reaction bath at 0°C, slowly add sodium hydride (557.6mg, 60%, dispersed in liquid paraffin, 2.4eq), stirred at 0°C for 30min. Then 5-bromo-4-fluoro-1-methylpyridin-2(1H)-one (1.19 g, 5.81 mmol, 1 eq) was dissolved in 8 mL of THF, added dropwise to the reaction system, and reacted at room temperature for 2 h. After spotting the plate to monitor the completion of the reaction, the mixture was extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-025 as a white solid with a yield of 83%. ¹ H NMR (300MHz, Chloroform-d) δ7.44(s, 1H), 5.92(s, 1H), 4.57(d, J=7.9Hz, 1H), 4.26-4.16(m, 1H), 3.66-3.51 (m,1H),3.47(s,3H),2.19-2.06(m,4H),1.72-1.57(m,2H),1.45(s,9H),1.38-1.20(m,2H).ESI-MS (m/z): 401.1[M+H]+

Step 2: Intermediate trans-N-(4-((5-bromo-1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (A -026) synthesis

A-025 (1.9 g, 4.74 mmol) was dissolved in 2M EA/HCl (40 mL), stirred at room temperature for 2 h, and vacuum filtered to obtain a white solid. This solid (1eq), triethylamine (1.91g, 4eq) was dissolved in 20mL THF, acetyl chloride (558mg, 1.5eq) was added dropwise and stirred at room temperature overnight. After the completion of the reaction was monitored by spot plate, the solvent was spin-dried, extracted with ethyl acetate (3×30 mL), washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography gave A-026 as a white solid with a two-step yield of 84%. ¹ H NMR (300MHz, Chloroform-d) δ7.44(s, 1H), 5.93(s, 1H), 5.60(d, J=7.9Hz, 1H), 4.28-4.14(m, 1H), 3.94-3.80 (m, 1H), 3.48 (s, 3H), 2.21-2.01 (m, 4H), 1.97 (d, J=5.6Hz, 3H), 1.75–1.58 (m, 2H), 1.38–1.21 (m, 2H) ).ESI-MS(m/z): 343.1[M+H]+

Step 3: Synthesis of intermediate methyl 1-benzyl-6-bromo-1H-indazole-4-carboxylate (A-028)

Methyl 6-bromo-1H-indazole-4-carboxylate (A-027) (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. Benzyl bromide (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-028 as a white solid with a yield of 44%. ¹ H NMR(300MHz, Chloroform-d)δ8.51(d,J=1.0Hz,1H),8.00(d,J=1.6Hz,1H),7.72-7.70(m,1H),7.37-7.27(m ,3H),7.20-7.14(m,2H),5.59(s,2H),4.02(s,3H).ESI-MS(m/z):345.0[M+H]+

Step 4: Synthesis of intermediate 1-benzyl-6-bromo-N-methyl-1H-indazole-4-carboxamide (A-029)

A-028 (500 mg, 1.45 mmol, 1 eq) and sodium hydroxide (116 mg, 2 eq) were dissolved in 10 mL of THF and 2 mL of water, and stirred at room temperature for 1 h. After monitoring the completion of the reaction by spotting, neutralize with 2M HCl, extract with ethyl acetate (3×50 mL), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Suction filtration and concentration. Another addition of methylamine hydrochloride (97.8mg, 3eq), EDCI (306mg, 1.1eq), dissolved in 15mL of THF, stirred at room temperature overnight. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography gave A-029 as a white solid with a two-step yield of 73%. ¹ H NMR (300MHz, Chloroform-d) δ8.12(s,1H), 7.45(s,1H), 7.36-7.23(m,4H), 7.20-7.14(m,2H), 5.54(s,2H) ,4.98(d,J＝5.6Hz,3H),2.22(t,J＝5.8Hz,1H).

ESI-MS(m/z): 344.0[M+H]+

Step 5: Intermediate 1-benzyl-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H- Synthesis of Indazole-4-Carboxamide (A-030)

A-029 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-030 as a white solid with a yield of 74%. ESI-MS(m/z): 392.2[M+H]+

Step 6: trans-6-(4-(4-acetamidocyclohexyl)oxo)-1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-1-benzyl Synthesis of -N-methyl-1H-indazole-4-carboxamide (I-19)

A-030 (1eq), A-026 (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-19 with a yield of 26%.

mp142.0-143.5℃; ^1H NMR(300MHz,DMSO)δ8.49(d,1H,J=4.4Hz),8.38(s,1H),7.86(s,1H),7.81(s,1H), 7.76(d,1H,J＝7.3Hz),7.58(s,1H),7.37-7.21(m,3H),7.16(d,2H,J＝7.0Hz),6.03(s,1H),5.71(s ,2H),4.46-4.27(m,1H),3.59-3.47(m,1H),3.43(s,3H),2.85(d,3H,J＝4.4Hz),2.00-1.85(m,2H), 1.78(s, 3H), 1.75-1.64(m, 2H), 1.57-1.19(m, 4H); ¹³ C NMR (151MHz, CDCl3) δ 171.6, 168.9, 165.1, 164.7, 140.5, 139.6, 137.1, 133.93, 133.86 , 132.2, 129.4, 128.5, 127.0, 126.9, 122.4, 121.7, 116.1, 113.6, 97.7, 76.4, 53.3, 47.4, 37.2, 29.9, 29.7, 26.8, 22.8; HRMS(ESI) calcd for C ₃₀ H ₃₄ N ₅ O ₄ ⁺ [M+H] ⁺ 528.2605, found528.2607.

Example 20: trans-N-(4-((5-(1-benzyl-4-(hydroxymethyl)-1H-indazol-6-yl)-1-methyl-2-carbonyl- 1,2-Dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-20)

Step 1: Intermediate (1-benzyl-6-bromo-1H-indazol-4-yl)methanol (A-031)

A-028 (500 mg, 1.45 mmol) was dissolved in 20 mL of THF, lithium aluminum hydride (55 mg, 1 eq) was added at 0°C, and the mixture was stirred at room temperature overnight. After monitoring the reaction at half a point, saturated ammonium chloride was added dropwise at 0 °C to quench, ethyl acetate was added to dilute, magnesium sulfate was added, and the mixture was stirred for 30 min. After suction filtration, the filtrate was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered and concentrated. After purification by column chromatography, a colorless liquid A-031 was obtained with a yield of 76%. ¹ H NMR (300MHz, Chloroform-d) δ8.12(s,1H), 7.45(s,1H), 7.36-7.23(m,4H), 7.20-7.14(m,2H), 5.54(s,2H) , 4.98 (d, J=5.6Hz, 3H), 2.22 (t, J=5.8Hz, 1H). ESI-MS(m/z): 317.0[M+H]+

Step 2: Intermediate (1-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4 -Base) Synthesis of Methanol (A-032)

A-031 (1eq), pinacol biborate (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a 100mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-032 as a white solid with a yield of 74%. ESI-MS(m/z): 365.2[M+H]+

Step three: trans-N-(4-((5-(1-benzyl-4-(hydroxymethyl)-1H-indazol-6-yl)-1-methyl-2-carbonyl-1 Synthesis of ,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-20)

A-032 (1eq), A-026 (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-20 with a yield of 16%. mp 139.0-140.4°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.07(s, 1H), 7.57(s, 1H), 7.41-7.29(m, 5H), 7.25(s, 1H), 7.06( s, 1H), 5.99(s, 1H), 5.59(s, 2H), 5.42(d, 1H, J=7.7Hz), 4.91(s, 2H), 4.32-4.16(m, 1H), 3.87-3.69 (m, 1H), 3.52 (s, 3H), 2.21-1.97 (m, 4H), 1.96 (s, 3H), 1.60-1.44 (m, 2H), 1.31-1.05 (m, 2H); ¹³ C NMR (75MHz, CDCl ₃ )δ169.6,164.0,149.4,137.9,135.6,133.1,131.8,128.9,128.4,128.0,122.5,121.3,119.9,116.3,116.2,97.7,76.4,64.0,5,2.6,47.0 29.2, 23.4; HRMS(ESI) calcd for C ₂₉ H ₃₃ N ₄ O ₄ +[M+H] ⁺ 501.2496, found 501.2494.

Example 21: trans-N-(4-((5-(1-benzyl-4-(2-hydroxypropan-2-yl)-1H-indazol-6-yl)-1-methyl -2-Carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-21)

Step 1: Synthesis of intermediate 2-(1-benzyl-6-bromo-1H-indazol-4-yl)propan-2-ol (A-033)

A-028 (1.0 g, 2.9 mmol) was dissolved in 10 mL of THF, 1 M methylmagnesium bromide (8.7 mL, 3 eq) was added dropwise at 0°C, and stirred for 4 h. After the completion of the reaction was monitored by spot plate, saturated aqueous ammonium chloride solution was quenched, extracted with ethyl acetate (3×50 mL), washed with saturated brine 3 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-033 as a white solid with a yield of 92%. ¹ H NMR (300MHz, Chloroform-d) δ8.30(t, J=0.8Hz, 1H), 7.43(t, J=1.2Hz, 1H), 7.38-7.27(m, 3H), 7.24(d, J =1.5Hz,1H),7.22–7.17(m,2H),5.53(s,2H),1.72(s,6H).

ESI-MS(m/z): 345.1[M+H]+

Step 2: Intermediate 2-(1-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole Synthesis of -4-yl)propan-2-ol (A-034)

A-033 (1 eq), pinacol biborate (1.2 eq), potassium carbonate (2 eq) and Pd(dppf)Cl2 (2% mmol) were added to a 100 mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-034 as a white solid with a yield of 74%. ESI-MS(m/z): 393.2[M+H]+

Step three: trans-N-(4-((5-(1-benzyl-4-(2-hydroxypropan-2-yl)-1H-indazol-6-yl)-1-methyl- Synthesis of 2-carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-21)

A-034 (1eq), A-026 (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-21 with a yield of 30%. mp 139.4-140.0°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.36-7.28 (m, 3H), 7.25-7.12 (m, 5H), 5.98 (s, 1H), 5.60(s, 2H), 5.58-5.12(m, 1H), 4.25-4.10(m, 1H), 3.83-3.66(m, 1H), 3.52(s, 3H), 2.30(s, 1H), 2.11- 1.92(m, 4H), 1.97(s, 3H), 1.77(s, 6H), 1.43-1.14(m, 4H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 169.6, 163.8, 142.6, 140.3, 138.1, 136.8 HRMS(ESI)calcd for C ₃₁ HRMS(ESI)calcd for C 31 ₃₇ N ₄ O ₄ ⁺ [M+H] ⁺ 529.2809, found529.2803.

Example 22: N-((1r,4r)-4-((5-(1-(2,6-dimethylbenzyl)-4-(2-hydroxypropan-2-yl)-1H- Indazol-6-yl)-1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-22)

Step 1: Synthesis of intermediate methyl 6-bromo-1-(2,6-dimethylbenzyl)-1H-indazole-4-carboxylate (A-035)

A-027 (1 eq) was dissolved in dry DMSO (0.7M) and placed in a low temperature reaction bath at 0°C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30 min. 2-(bromomethyl)-1,3-xylene (1.2eq) was slowly added dropwise at 0°C, the reaction flask was moved to room temperature, and stirred for 4h. After the completion of the reaction was monitored by spotting, the reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-035 as a white solid with a yield of 38%. ESI-MS(m/z): 373.0[M+H]+

Step 2: Synthesis of intermediate 2-(6-bromo-1-(2,6-dimethylbenzyl)-1H-indazol-4-yl)propan-2-ol (A-036)

A-035 (1.0 g, 2.9 mmol) was dissolved in 10 mL of THF, 1 M methylmagnesium bromide (8.7 mL, 3 eq) was added dropwise at 0°C, and the mixture was stirred for 4 h. After the completion of the reaction was monitored by spot plate, saturated aqueous ammonium chloride solution was quenched, extracted with ethyl acetate (3×50 mL), washed with saturated brine 3 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-036 as a white solid with a yield of 87%. ESI-MS(m/z): 373.1[M+H]+

Step 3: Intermediate 2-(1-(2,6-dimethylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Synthesis of 2-yl)-1H-indazol-4-yl)propan-2-ol (A-037)

A-036 (1 eq), pinacol biborate (1.2 eq), potassium carbonate (2 eq) and Pd(dppf)Cl2 (2% mmol) were added to a 100 mL eggplant-shaped flask. Add 0.2M dioxane, heat to 95°C, and react for 12h. After spotting the plate to monitor the completion of the reaction, extract with 100 mL of ethyl acetate, wash with saturated brine 5 times, and dry the organic phase over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain A-037 as a white solid with a yield of 74%. ESI-MS(m/z): 421.3[M+H]+

Step 4: trans-N-(4-((5-(1-(2,6-dimethylbenzyl)-4-(2-hydroxypropan-2-yl)-1H-indazole-6 Synthesis of -yl)-1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)oxo)cyclohexyl)acetamide (I-22)

A-037 (1eq), A-026 (1.2eq), potassium carbonate (2eq) and Pd(dppf)Cl2 (2%mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. The vacuum was changed to nitrogen, and the reaction was carried out at 100 °C for 12 h. After the completion of the reaction was monitored by dot plate, the solvent was spin-dried, extracted with 100 mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration, and purification by column chromatography to obtain yellow solid I-22 with a yield of 32%.

mp 164.6-166.0°C; ¹ H NMR (300MHz, CDCl ₃ ) δ 8.27(s, 1H), 7.25-7.07(m, 5H), 7.04(s, 1H), 5.99(s, 1H), 5.70( d, 1H, J＝7.9Hz), 5.52(s, 2H), 4.30-4.18(m, 1H), 3.85-3.70(m, 1H), 3.53(s, 3H), 2.32(s, 1H), 2.19 -1.98(m, 4H), 1.96(s, 3H), 1.73(s, 6H), 1.57-1.19(m, 4H); ¹³ C NMR (151MHz, DMSO) δ 168.6, 163.2, 162.7, 143.1, 140.5, 139.5 HRMS(ESI) )calcd for C ₃₃ H ₄₁ N ₄ O ₄ ⁺ [M+H] ⁺ 557.3122, found 557.3122.

Example 23: In vitro activity test of BRD4 (BD1) enzyme level

The BRD4 (BD1) enzyme level activity of each compound in the above embodiment is tested, and the specific operations are as follows:

experimental method:

binding reaction process

(1) Prepare 1×Assay buffer.

(2) Preparation of compound concentration gradient: the final concentration of the test compound is 10 μM starting, 3-fold dilution, 10 concentrations, and a single-well test is set for each concentration. In 384-well Source plate, the solution was serially diluted to the corresponding 1000-fold final concentration, and then 20nL was transferred to 384-well reaction plate with Echo550 for testing. Transfer 20 nL of 100% DMSO to Max wells, and transfer 20 nL of the highest concentration of positive compounds to Min wells.

(3) Prepare 4× protein solution with 1× reaction solution.

(4) Add 5 μL of 4× protein solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 minutes.

(5) Prepare 4× polypeptide solution with 1× reaction solution.

(6) Add 5 μL of 4× polypeptide solution to each well of the reaction plate, and centrifuge at 1000 rpm for 1 min.

(7) Add 10 μL of detection solution, centrifuge at 1000 rpm for 60 seconds, gently shake and mix, and incubate at room temperature for 60 minutes.

(8) Read with EnVision.

data processing:

%Inhibition=(Signal_max-Signal_sample)/(Signal_max-Signal_min) X 100

Fitting the dose-response curve: take the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis, use the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 to fit the dose-response curve, thereby obtaining the compound pair. IC50 values for protein binding inhibition.

Note: JQ-1 is a BET inhibitor, purchased from Jiangsu Aikang Biomedical Research and Development Co., Ltd., as a positive control.

The specific results are shown in the table:

Example 24 In vitro antiproliferative activity of the compound

1. Experimental steps

(1) The PBS solution was autoclaved and stored in a refrigerator at 4°C.

(2) Weigh trypsin and trypsin digestion solution, add ultrapure water to fully dissolve, and filter with a microporous filter to obtain the solution

body and stored in the refrigerator at -20°C.

(3) Weigh the medium powder and NaHCO ₃ respectively, add ultrapure water to fully dissolve, add 10% double antibody, filter with a microporous membrane to obtain the culture medium, store it in the refrigerator at 4°C, and add 10% fetal bovine serum.

(4) Take the 22RV1 cells or LNcap cells out of the liquid nitrogen tank, immediately place them in a constant temperature water bath at 37 degrees Celsius, shake them to melt, then pour the cells into the culture flask, and add the culture medium (containing 10% fetal bovine serum). )dilution. Transfer the diluted medium to a centrifuge tube, centrifuge at 1000 r/min for 5 minutes, discard the supernatant, add fresh medium, pipette and mix, transfer to a culture flask and incubate in a 5% CO ₂ , 37°C incubator cultivated in. When the cells adhered to the bottom of the bottle, the passage was started. A small amount of fresh medium (containing 10% fetal bovine serum) was added to terminate the digestion. Evenly, evenly divided into two culture flasks to continue culturing.

(5) Take log-phase cells, discard the old medium, add trypsin solution to digest for 3 minutes, add fresh medium containing 10% fetal bovine serum to stop digestion, transfer the solution to a centrifuge tube, and centrifuge at 1000 r/min for 5 minutes , discard the supernatant. The medium was added to prepare a cell suspension, and the cells were counted. After counting, cells were seeded in 96-well plates at a concentration of 5,000-10,000 cells per well. Place the plated 96-well plate in a 37°C, 5% CO2 incubator for 24h. The drugs were serially diluted with culture medium to 160 μmol/L, 80 μmol/L, 40 μmol/L, 20 μmol/L, 10 μmol/L, 5 μmol/L and then added to 96-well plates, 100 μL per well, and each concentration was set to three. duplicate holes. The control group was added with the medium containing the medium of the corresponding concentration, and the same volume of blank medium was added to the zero-adjusted well, placed in a 5% CO ₂ , 37° C. incubator for 3 days, and the medium was replaced every two days. 20 μL of MTT (5 mg/mL) was added to each well, mixed well, and incubated for 4 h in a 5% CO ₂ , 37° C. incubator in the dark. The liquid in the 96-well plate was removed, 200 μL of DMSO was added to each well, and it was shaken on a micro-shaker to completely dissolve the crystals at the bottom. Then put the 96-well plate into the microplate reader for detection, and measure the absorbance at 490nm.

2. Data processing

Draw the curve and calculate the inhibitory rate and IC ₅₀ of the drug on the cells.

Inhibition rate=[(average OD value of control group-average OD value of experimental group)/(average OD value of control group-average OD value of blank control group)]×100%.

3. Experimental results

The inhibitory activities of the compounds on human prostate cancer cell line 22RV1 and LNcap cells are as follows:

Compound number 22RV1IC₅₀(μM) LNcapIC₅₀(μM) I-5 8.27±0.28 7.33±0.49 I-6 16.99±1.36 9.22±0.65 I-7 14.38±3.2 15.74±2.50 I-8 10.66±0.16 13.55±1.66 I-13 49.6±1.05 26.32±1.62 I-14 11.32±0.73 12.59±1.38 I-15 19.23±1.38 18.53±2.22 I-22 16.35±0.82 20.32±1.62 JQ-1 28.29±2.66 18.38±2.23

Claims (8)

1. A compound shown as a general formula I, and pharmaceutically acceptable salt, prodrug, isomer, raceme, precursor or solvate thereof, is characterized in that the structural formula is shown as the formula I,

wherein,

R¹is hydrogen, C₁-C₃Alkyl radical, C₃-C₆A cycloalkyl group; wherein said C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano, and the like;

z is CR⁵Or NR⁶；

Y is CR⁷Or NR⁸；

R⁵-R⁷Independently selected from hydrogen, deuterium atom, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C₁-C₃Alkyl radical, C₁-C₃An alkoxy group;

R⁸independently selected from hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆A cycloalkyl group; wherein said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano, and the like;

each one of which is

Independently a single or double bond, with the proviso that:

(1) when in use

When it is a single bond, Z is CR⁵Y is NR⁸；R⁵And R⁸The substitution is as described above;

(2) when in use

When double bonds, Z and Y may be any combination of C, N;

R²independently selected from hydrogen, deuterium atoms, halogens, amino groups, -OR⁹、C_6-C₁₂Aromatic ring, C₆-C₁₂A heteroaromatic ring; wherein said C_6-C₁₂Aromatic ring, C₆-C₁₂The heteroaromatic rings are independently substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, C₁-C₃Alkyl, -N (R)^10-1)C(O)R^10-2、-N(R^10-3)S(O)₂R^10-4、-CON(R^10-5)₂And the like;

R⁹is C₁-C₄Alkyl radical, C₃-C₁₂Cycloalkanes, C₃-C₁₂A heterocyclic alkane; wherein said C₃-C₁₂Cycloalkanes, C₃-C₁₂The heterocyclic alkane can be monocyclic, bicyclic, spiro, bridged; said C₃-C₆The heterocyclic alkane is 3-6 membered heterocyclic alkyl with 1-3 heteroatoms selected from one or more of N, O or S; said C₁-C₆Alkyl radical, C₃-C₆Cycloalkanes, C₃-C₆The heterocycloalkane is optionally substituted with one or more substituents independently selected from halogen, amino, oxo, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, -N (R)^9-1)C(O)R^9-2Or, -N (R)^9-3)S(O)₂R^9-4And the like;

R^9-1～R^9-4independently selected from hydrogen, C₁-C₃Alkyl radical, C₁-C₃Alkyl halides, C₃-C₆Cycloalkyl or 3-6 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O or S; wherein said C₃-C₆Cycloalkyl or "3-6 membered heterocycloalkyl having 1-3 heteroatoms selected from N, O or S, optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, etc.;

R^10-1～R^10-5independently selected from hydrogen, C₁-C₃Alkyl radical, C₁-C₃Alkyl halides, or C₃-C₆Cycloalkane of (a);

R³is hydrogen, unsubstituted or R¹¹Substituted C₁-C₆Alkyl, -C (O) N (R)^11-1)(R^11-2)、-N(R^11-3)COR^11-4、-N(^11-5)SO₂R^11-6Or (b) or (c),

R^11-1～R^11-8Independently selected from hydrogen, C₁-C₃Alkyl radical, C_1-C₃Deuterated alkyl, C₁-C₃Haloalkyl or C₃-C₆A cycloalkyl group;

the A ring being selected from saturated C₃-C₆Carbocyclic, saturated C₃-C₆Heterocyclic, unsaturated C₅-C₁₀Carbocyclic, aromatic rings; wherein said saturated C₃-C₆Heterocyclic, unsaturated C₅-C₁₀The carbocycle is a heterocyclic ring with 1-3 heteroatoms selected from one or more of N, O or S; said saturated C₃-C₆Carbocyclic, saturated C₃-C₆Heterocyclic, unsaturated C₅-C₁₀The carbocycle and the aromatic ring are independently substituted by one or more substituents independently selected from halogen, amino, nitro, cyano, hydroxyl, oxo, alkoxy, haloalkoxy, hydroxyalkyl and the like;

w is independently selected from C (R)¹²)_nN, O, S; wherein n represents 0, 1, 2; r¹²Is hydrogen or C₁-C₃Alkane, C_1-C₃Deuterated alkyl, C₁-C₃Haloalkyl or C₃-C₆A cycloalkyl group;

R⁴independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C₁-C₃Alkyl radical, C₁-C₃Alkyl halides, C₁-C₃An alkoxy group;

p represents 0, 1,2 or 3;

the halogen is selected from fluorine, chlorine, bromine and iodine.

2. The compound of claim 1, a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor, or solvate thereof, wherein R is as defined in claim¹Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, isopropyl, preferably methyl;

and/or when R¹Is C₃-C₆When there is a cycloalkyl group, said C₃-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl;

z is CR⁵Or NR⁶；

Y is CR⁷Or NR⁸；

R⁵-R⁷Independently selected from hydrogen, deuterium atom, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C₁-C₃Alkyl radical, C₁-C₃An alkoxy group;

R⁸independently selected from hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆A cycloalkyl group; wherein said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano, and the like;

each one of which is

Independently a single or double bond, with the proviso that:

(3) when in use

When it is a single bond, Z is CR⁵Y is NR⁸；R⁵And R⁸The substitution is as described above;

(4) when in use

When double bonds, Y and Z may be any combination of C, N;

and/or when R²Is C_6-C₁₂Aromatic ring, said C_6-C₁₂The aromatic ring is benzene ring or naphthalene ring;

and/or when R²Is C_6-C₁₂A heteroaromatic ring of said C_6-C₁₂The heteroaromatic ring is pyridine ring, pyrimidine ring, piperazine ring, quinoline ring, quinoxaline ring, indole ring, benzimidazole ring, benzoxazole ring, benzisoxazole ring, benzothiazole ring, benzisothiazole ringA group, a benzofuran ring, a benzothiophene ring, preferably a pyridine ring, a piperazine ring;

and/or when R⁹Is C₁-C₄When alkyl, said C₁-C₄Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, preferably ethyl;

and/or when R⁹Is C₃-C₁₂In the case of cycloalkanes, said C₃-C₁₂Cycloalkanes to C₃-C₆An alkane of (a);

and/or when R⁹Is C₃-C₁₂When heterocyclic alkanes, said C₃-C₁₂The heterocyclic alkane is ethylene oxide, nitrogenous butane, tetrahydrofuran, tetrahydropiperidine, 2-azaspiro [4.5 ]]Decane, 8-azabicyclo [3.2.1]Octane;

and/or when R^9-1～R^9-4Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R^9-1～R^9-4Is C₁-C₃Haloalkyl, said C_1-C₃Haloalkyl is-CF₃；

And/or when R^9-1～R^9-4Is C₃-C₆Cycloalkyl radical, said C_3-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R^9-1～R^9-4Is one or more of heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl with 1-3 heteroatoms is pyrrolidinyl, piperidinyl, tetrahydrofuryl, azetidinyl, piperazinyl, morpholinyl, N-methylpiperazinyl;

and/or when R^10-1～R^10-5Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R^10-1～R^10-5Is C₁-C₃Alkyl halides, said C_1-C₃Alkyl halidesThe radical being-CF₃；

And/or when R^10-1～R^10-5Is C₃-C₆Cycloalkane of (2), said C_3-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R³Is unsubstituted or R¹¹Substituted C₁-C₄When it is alkyl, said R¹¹Is one or more, when there are more than one R¹¹When R is said¹¹May be the same or different;

and/or when R³Is unsubstituted or R¹¹Substituted C₁-C₆When alkyl, said C₁-C₆Alkyl is C₁-C₄Alkyl groups of (a);

and/or when R^11-1～R^11-8Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R^11-1～R^11-8Is C₁-C₃Deuterated alkyl, said C_1-C₃Deuterated alkyl is-CH₂D；

And/or when R^11-1～R^11-8Is C₁-C₃Alkyl halides, said C_1-C₃Haloalkyl is-CF₃；

And/or when R^11-1～R^11-8Is C₃-C₆Cycloalkane of (2), said C_3-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or, when ring A is saturated, C₃-C₆Carbocyclic ring of said C_3-C₆The carbocycle is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl;

and/or, when ring A is saturated, C₃-C₆Heterocycle of said C_3-C₆The heterocycle is a tetrahydropyrrole ring, a tetrahydrofuran ring, an azetidine ring, a piperazine ring, a tetrahydropyridine ring or an N-methylpiperazine ring;

and/or, when ring A is unsaturated C₅-C₁₀Carbocyclic ring of said unsaturated C₅-C₁₀The carbocycle is pyrrole, pyrazole, imidazole, pyridine, piperidine, pyrimidine, pyridazine, thiazine, indole, benzofuran, benzimidazole, quinoline, benzopyrimidine, benzothiazole, benzopyrazine, imidazopyridine, indazole, benzothiophene;

and/or when R³Is unsubstituted or R¹¹Substituted C₁-C₆When alkyl, said C₁-C₆Alkyl is C₁-C₄Alkyl groups of (a);

and/or when R¹²Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R¹²Is C₁-C₃Deuterated alkyl, said C_1-C₃Deuterated alkyl is-CH₂D；

And/or when R¹²Is C₁-C₃Alkyl halides, said C_1-C₃Haloalkyl is-CF₃；

And/or when R¹²Is C₃-C₆Cycloalkane of (2), said C_3-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R¹²Is C₁-C₃Alkyl radical, said C₁-C₃Alkyl is methyl, ethyl, propyl or isopropyl, preferably methyl;

and/or when R⁴Is C₁-C₃Deuterated alkyl, said C_1-C₃Deuterated alkyl is-CH₂D；

And/or when R⁴Is C₁-C₃Alkyl halides, said C_1-C₃Haloalkyl is-CF₃；

And/or when R⁴Is C₁-C₃Alkoxy radical, said C₁-C₃Alkoxy is methoxy;

p represents 0, 1,2 or 3;

the hydroxyalkyl is C₁-C₃Hydroxyalkyl is

The halogen is selected from fluorine, chlorine, bromine and iodine.

3. The compound of formula I, a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof, according to claims 1 to 3, wherein the compound of formula I is any one of the following compounds:

5- (1-benzyl-1H-indazol-6-yl) -1-methylpyrimidin-2 (1H) -one (I-1)

5- (1-benzyl-1H-indazol-6-yl) -1-methyltetrahydropyrimidin-2 (1H) -one (I-2)

5- (1-benzyl-1H-indazol-6-yl) -1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (I-3)

6- (1-benzyl-1H-indazol-6-yl) -5-ethoxy-2-methylpyridazin-3 (2H) -one (I-4)

5- (1-benzyl-1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-5)

N- (4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) methanesulfonamide (I-6)

trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide (I-7)

trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) -N-methylacetamide (I-8)

trans-N- ((4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) methanesulfonamide (I-9)

trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) cyclopropanecarboxamide (I-10)

Trans-4- (8-acetyl-8-azabicyclo [3.2.1] octan-3-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-11)

Trans-5- (1-benzyl-1H-indazol-6-yl) -1-methyl-4- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) oxy) pyridin-2 (1H) -one (I-12)

4- ((1-acetylpiperidin-4-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-13)

(R) -4-ethoxy-1-methyl-5- (1- (1-phenylethyl) -1H-indazol-6-yl) pyridin-2 (1H) -one (I-14)

5- (1- (2, 4-difluorobenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-15)

5- (1- (2, 6-dimethylbenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-16)

5- (1-benzyl-1H-indol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-17)

4-ethoxy-1-methyl-5- (3-phenoxy-2, 3-dihydro-1H-inden-5-yl) pyridin-2 (1H) -one (I-18)

Trans-6- (4- ((4-acetamido-cyclohexyl) oxo) -1-methyl-6-carbonyl-1, 6-dihydropyridin-3-yl) -1-benzyl-N-methyl-1H-indazole-4-carboxamide (I-19)

trans-N- (4- ((5- (1-benzyl-4- (hydroxymethyl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-20)

trans-N- (4- ((5- (1-benzyl-4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-21)

trans-N- (4- ((5- (1- (2, 6-dimethylbenzyl) -4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-22).

4. A process for the preparation of a compound, pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof according to any one of claims 1 to 3, comprising the steps of:

wherein, Z, Y, R¹、R²、R³、R⁴A, W, as defined in claim 1.

5. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable excipient.

6. Use of a compound according to claims 1-3, a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment of a disease associated with bromodomains and the superterminal domain (BET).

7. Use of a compound of formula I as shown in claims 1-3, a pharmaceutically acceptable salt, prodrug, isomer, racemate, precursor or solvate thereof or a pharmaceutical composition of claim 5 for the manufacture of a medicament for the treatment of BET-related diseases.

8. The use according to claim 7, wherein the related diseases are breast cancer, brain cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, hematopoietic tumors, arthritis, autoimmune diseases, hepatitis, and the like.