HPK1 inhibitor with five-membered aromatic heterocyclic piperidine / homopiperidine and preparation method and use thereof

Abstract

The present invention relates to an HPK1 inhibitor having a five-membered aromatic heterocyclic piperidine / homopiperidine, a preparation method thereof and a use thereof. Specifically, the compound of the present invention has a structure shown in Formula 1, wherein the definitions of each group and substituent are as described in the specification; the present invention also discloses a preparation method of the compound and a use thereof in anti-tumor.

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to an HPK1 inhibitor having a five-membered aromatic heterocyclic piperidine / homopiperidine, and a preparation method and use thereof. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a member of the MAP4K family and belongs to the serine / threonine protein kinase class. HPK1 is an immunosuppressive regulatory kinase that is mainly expressed in hematopoietic cells, including early hematopoietic progenitor cells.

[0003] In T cells, HPK1 is a negative signal regulator of the T cell receptor (TCR). After TCR activation, cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, which then activates SLP76 and serves as a docking site for the negative regulatory protein 14-3-3π, ultimately leading to the instability of the TCR signaling complex, thereby downregulating the TCR signal. In addition, HPK1 kinase activity can inhibit CD4 + T cells, CD8 + The immune function of T cells and dendritic cells (DCs) triggers anti-tumor immune responses by inhibiting the activity of HPK1 kinase. HPK1 can also be activated by prostaglandins (PGE2) secreted by tumors, thereby contributing to immune escape of tumor cells. In addition, HPK1 can also promote tumor cell proliferation and invasion and metastasis of tumor cells by inhibiting AP-1. It can be seen that HPK1 is an important regulatory protein of TCR signaling, dominates T cell-mediated immune responses, and is an important and potential target for targeted anti-tumor immunity.

[0004] Currently, there is no drug on the market targeting this target. The present invention discloses a class of HPK1 inhibitors with novel structure and high inhibitory activity. Summary of the invention

[0005] The purpose of the present invention is to provide a compound represented by formula 1, a preparation method thereof and an anti-tumor use thereof.

[0006] In a first aspect of the present invention, a compound is provided, wherein the compound is a compound represented by Formula 1, or a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof,

[0007]

[0008] in,

[0009] X is selected from the group consisting of CH, N;

[0010] A1 and A2 are independently selected from the following group: S, N, CH2, CH, NH, O;

[0011] A3 is selected from the group consisting of C, CH, N;

[0012] is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0013] R1 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl-, substituted or unsubstituted C1-C6 alkylene-, substituted or unsubstituted C3-C8 cycloalkyl-(C=O)-, a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and substituted or unsubstituted C3-C8 cycloalkyl-(C=O)-, substituted or unsubstituted C1-C6 alkyl-(C=O)-, substituted or unsubstituted C2-C6 alkenyl-(C=O)-, substituted or unsubstituted C2-C6 alkynyl-(C=O)-, R b -(substituted or unsubstituted C1-C3 alkylene)-(C=O)-, substituted or unsubstituted -S(=O)2-,

[0014] The substitution independently refers to substitution by 1, 2, 3 or 4 substituents selected from the following group: hydrogen, halogen, hydroxyl, -N(C1-C3 alkyl)2, -NH2, cyano, -(C1-C3 alkylene)-OH, -(C1-C3 alkylene)-CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0015] R b Selected from the following group: hydrogen, halogen, hydroxyl, amino, cyano, C1-C3 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] m is 0, 1, 2 or 3;

[0017] n is 0, 1, 2 or 3;

[0018] p is 0, 1, 2 or 3.

[0019] In another preferred embodiment,

[0020] X is CH;

[0021] A1 and A2 are independently selected from the following group: S, N, CH, NH, O;

[0022] A3 is selected from the following group: C, N.

[0023] In another preferred embodiment, Select from the following group:

[0024] In another preferred embodiment,

[0025] R1 is selected from the following group: H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-, substituted or unsubstituted C1-C3 alkylene-, substituted or unsubstituted C3-C6 cycloalkyl-(C=O)-, a 4-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and substituted or unsubstituted C3-C6 cycloalkyl-(C=O)-, substituted or unsubstituted C1-C3 alkyl-(C=O)-, substituted or unsubstituted C2-C4 alkenyl-(C=O)-, substituted or unsubstituted C2-C4 alkynyl-(C=O)-, R b -(substituted or unsubstituted C1-C3 alkylene)-(C=O)-, substituted or unsubstituted -S(=O)2-,

[0026] The substitution independently refers to substitution by 1, 2, 3 or 4 substituents selected from the following group: hydrogen, halogen, hydroxyl, -N(C1-C3 alkyl)2, -NH2, cyano, -(C1-C3 alkylene)-OH, -(C1-C3 alkylene)-CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0027] R b Selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C1-C3 alkyl, C3-C6 cycloalkyl;

[0028] m is 0, 1, 2 or 3;

[0029] n is 0, 1, 2 or 3.

[0030] In another preferred embodiment, the halogenated C1-C3 alkyl group is a F-substituted C1-C3 alkyl group, preferably a fully F-substituted C1-C3 alkyl group.

[0031] In another preferred embodiment, the halogenated C1-C3 alkyl group is a perhalogenated C1-C3 alkyl group.

[0032] In another preferred embodiment, the compound is selected from the following group:

[0033]

[0034]

[0035]

[0036] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention.

[0037] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a drug for treating tumors.

[0038] In another preferred embodiment, the tumor is selected from the group consisting of breast cancer, colorectal cancer, hematological malignancies, lung cancer, melanoma, ovarian cancer, pancreatic cancer, and kidney cancer.

[0039] In another preferred embodiment, the lung cancer is non-small cell lung cancer;

[0040] The kidney cancer is renal cell carcinoma.

[0041] The fourth aspect of the present invention provides a HPK1 inhibitor comprising one or more compounds described in the first aspect of the present invention.

[0042] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0043] After long-term and in-depth research, the inventors obtained a compound with novel structure and excellent HPK1 inhibitory activity through structural optimization. On this basis, the inventors completed the present invention.

[0044] the term

[0045] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0046] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0047] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0048] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0049] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0050] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0051] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0052] In the present invention, the term "heterocyclic group" refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0053] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0054] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0055] In the present invention, the term "halo" means substituted with halogen.

[0056] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0057] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0058] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:".

[0059] Compound

[0060] The present invention provides a compound, which is a compound represented by Formula 1, or a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof.

[0061]

[0062] wherein each group is as defined above.

[0063] In another preferred embodiment, in the compound, X, A1, A2, A3, R1, R b Any one of m and n is independently a corresponding group in the specific compound described in the present invention.

[0064] In another preferred embodiment, the compound is preferably the compound prepared in each embodiment.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0066] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0067] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0068] It should be understood that the compounds of the present invention can be prepared by the methods shown in the examples, and can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by technicians in the field to which the present invention belongs.

[0069] It should be understood that the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0070] Pharmaceutical compositions and methods of administration

[0071] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds.

[0072] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0073] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0074] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0075] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0076] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0077] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0078] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0079] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0080] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0081] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0082] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0083] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0084] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0085] The treatment method of the present invention can be used alone or in combination with other treatment methods (such as CAR-T cell therapy) or therapeutic drugs.

[0086] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0087] Compared with the prior art, the present invention has the following main advantages:

[0088] (1) The compound has significantly excellent HPK1 inhibitory activity;

[0089] (2) The compound has a novel structure and is easy to prepare.

[0090] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0091] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0092] 1H-NMR was measured with a Bruker 400 or 700 instrument; potassium carbonate, triethylamine, sodium hydroxide, sodium sulfate, sodium hydroxide and hydrochloric acid were purchased from Sinopharm Chemical Reagent Co., Ltd., and the remaining reagents were produced by Shanghai Bid Pharmaceutical Technology Co., Ltd. All solvents were redistilled before use, and the anhydrous solvents used were obtained by drying according to standard methods; unless otherwise specified, all reactions were carried out under nitrogen protection and followed by TLC, and post-treatment was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate; the purification of products was carried out using silica gel (200-300 mesh) column chromatography, except for the instructions; the silica gel (200-300 mesh) was produced by Qingdao Ocean Chemical Plant, and the GF-254 thin layer silica gel plate was produced by Yantai Jiangyou Silica Gel Development Co., Ltd.

[0093] Preparation Example

[0094] The following preparation examples exemplify the preparation of some compounds of Formula 1 of the present invention, and each compound is represented by A1 to A28.

[0095] 1. Synthesis of Compound A1

[0096]

[0097] Step 1: Dissolve compound 1a (350 mg, 0.67 mmol), compound 1b (187.43 mg, 0.80 mmol), sodium carbonate (213.03 mg, 2.01 mmol), 1,1'-bis(diphenylphosphino)ferrocene (37.14 mg, 0.07 mmol) in a mixed solution of 1,4-dioxane (20 mL) and water (5 mL). Replace with nitrogen several times and reflux at 90 ° C for 6 h. After the reaction is completed, quench the reaction with water, then extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, spin dry, and silica gel column chromatography (PE: EA = 10: 1) to obtain 240.33 mg of yellow oily liquid (yield: 65.4%). MS (ESI): [M+H] + m / z 549.2. [Synthesis reference of compound 1a: WO 2019 / 206049]

[0098] Step 2: Dissolve compound 1c (200 mg, 0.36 mmol), iron powder (101.78 mg, 1.82 mmol), and ammonium chloride (97.49 mg, 1.82 mmol) in 75% ethanol (10 mL). Reflux at 70°C for 4 h. After the reaction is complete, quench the reaction with water, filter through diatomaceous earth, and then extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography on silica gel (DCM: MeOH = 60: 1) yields 103.9 mg of a white solid (yield: 54.9%).

[0099] Step 3: Compound 1d (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (4 mL), and the round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the nitrogen was replaced several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 18.3 mg of white solid was obtained (yield: 23.9%). 1 H NMR (400MHz, CDCl3) δ8.14(d,J=1.8Hz,1H),7.57(d,J=1.8Hz,1H),7.47(s,1H),7.40(t,J=2.1Hz,0.39H),7.38(t,J=2.3Hz,0.58H) ,7.36–7.30(m,2H),5.08(s,2H),5.03(s,2H),3.68(s,2H),2.96(t,J=5.8Hz,2H),2.84(t,J=5.7Hz,2H),2.52(s,3H),1.61(s,6H).

[0100] 2. Synthesis of Compound A2

[0101]

[0102] Step 1: Dissolve compound 1a (315 mg, 0.6 mmol), compound 2a (231 mg, 0.72 mmol), sodium carbonate (191.7 mg, 1.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene (33.4 mg, 0.06 mmol) in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). Replace with nitrogen several times and reflux at 90 ° C for 6 h. After the reaction is completed, quench the reaction with water, then extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, spin dry, and chromatograph on a silica gel column (PE: EA = 10: 1) to obtain 120 mg of a yellow oily liquid (yield: 31.4%). 1H NMR (400MHz, CDCl3) δ8.48(d,J=1.7Hz,1H),8.09(s,1H),7.48(s,1H),7.43–7.37(m,2H),7.34(d,J=2.5Hz,1H),5.28(s,2H),5.11(dd,J =5.6,3.2Hz,1H),4.71(s,2H),3.97(dt,J=10.5,4.8Hz,1H),3.79(s,2H),3.51(dt,J=11.1,5.0Hz,1H),2.96(s,2H),1.64–1.45(m,21H).

[0103] Step 2: Dissolve compound 2b (120 mg, 0.19 mmol), iron powder (52.8 mg, 0.95 mmol), and ammonium chloride (50.6 mg, 0.95 mmol) in 75% ethanol (10 mL). Reflux at 70°C for 4 h. After the reaction is complete, quench the reaction with water, filter through diatomaceous earth, and then extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography on silica gel (PE: EA = 10: 1) yields 105 mg of a white solid (yield: 91.8%).

[0104] Step 3: Compound 2c (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (4 mL), and a round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the nitrogen was replaced several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. Silica gel column chromatography (DCM: MeOH = 180: 1) was performed to obtain 20.4 mg of a white solid (yield: 29.62%). 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),7.58(s,1H),7.50(s,1H),7.42(d,J=6.5Hz,1H),7.35(d,J=6 .2Hz,2H),5.19–5.08(m,4H),4.64(s,2H),3.77(s,2H),2.91(s,2H),1.63(s,6H),1.50(s,9H).

[0105] Step 4: Compound 2d (100 mg, 0.19 mmol) was dissolved in DCM (dichloromethane, 5 mL), TFA (trifluoroacetic acid, 5 mL) was added dropwise under stirring, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction system was spin-dried without further purification to obtain 78.6 mg of yellow oily liquid (yield: 97.31%).

[0106] Step 5: Compound 2e (78.6 mg, 0.19 mmol), 2,2-difluorocyclopropanecarboxylic acid (29.7 mg, 0.24 mmol), and HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate, 142.1 mg, 0.38 mmol) were dissolved in DMF (N,N-dimethylformamide, 5 mL), and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 16.2 mg of a white solid (yield: 16.52%). 1 H NMR (400MHz, CDCl3) δ8.12(d,J=1.8Hz,1H),7.61(d,J=1.8Hz,0.33H),7.57(d,J= 1.8Hz,0.71H),7.49(s,1H),7.43–7.40(m,1H),7.38–7.32(m,2H),5.39(s,2H),5. 12(s,2H),4.93–4.79(m,2H),4.09–3.85(m,2H),3.06–3.01(m,1.55H),2.97–2.94 (m,0.69H),2.69–2.56(m,1H),2.25–2.17(m,1H),1.79–1.68(m,1H),1.63(s,6H).

[0107] 3. Synthesis of Compound A3

[0108]

[0109] Compound 2e (60 mg, 0.14 mmol), 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (23.8 mg, 0.19 mmol), and HATU (108.5 mg, 0.29 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give 17.3 mg of a white solid (yield: 22.85%). 1H NMR (400MHz, CDCl3) δ8.14(s,1H),7.58(s,0.3H),7.55(s,0.7H),7.48(s,1H),7. 44–7.39(m,1H),7.38–7.31(m,2H),5.20(s,2H),5.11(s,2H),4.85(s,0.7H),4.80 (s,1.4H),3.97–3.94(m,4H),3.79(d,J=8.4Hz,2H),2.99(s,1.3H),2.91(s,0.7H) ,2.51(br,2H),2.22(s,2H),1.84(t,J=3.4Hz,0.7H),1.77(s,0.3H),1.63(s,6H).

[0110] 4. Synthesis of Compound A4

[0111]

[0112] Compound 2e (60 mg, 0.14 mmol), 3-cyanopropionic acid (18.4 mg, 0.19 mmol), and HATU (108.5 mg, 0.29 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to obtain 13.5 mg of a white solid (yield: 18.86%). 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.57(d,J=1.6Hz,0.36H),7.54(d,J=1.8Hz,0.7 2H),7.49(s,1H),7.41(m,1H),7.38–7.31(m,2H),5.20(s,2H),5.11(s,2H),4.82( s,1.46H),4.66(s,0.72H),3.98(t,J=5.8Hz,0.73H),3.78(t,J=5.8Hz,1.44H),2. 99(t,J=5.9Hz,1.45H),2.93(t,J=5.9Hz,0.75H),2.87–2.70(m,4H),1.63(s,6H).

[0113] 5. Synthesis of Compound A5

[0114]

[0115] Compound 2e (60 mg, 0.14 mmol), 1-trifluoromethylcyclopropane-1-carboxylic acid (28.6 mg, 0.19 mmol), and HATU (108.5 mg, 0.29 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give 11.2 mg of a white solid (yield: 14.11%). 1 H NMR (700MHz, CDCl3) δ8.08(d,J=1.7Hz,1H),7.62(s,1H),7.49(s,1H),7.44–7.42(m,1H),7.36(d,J=1.0Hz,1.16H),7.35(d,J=1 .3Hz,0.86H),5.75(s,2H),5.14(s,2H),4.86(s,2H),4.04(s,2H),2.99(s,2H),1.63(s,6H),1.40(t,J=6.5Hz,2H),1.25(s,2H).

[0116] 6. Synthesis of Compound A6

[0117]

[0118] Compound 2e (60 mg, 0.14 mmol), 3,3-difluorocyclobutanecarboxylic acid (23.3 mg, 0.19 mmol), and HATU (108.5 mg, 0.29 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to obtain 16.3 mg of a white solid (yield: 21.21%). 1H NMR(700MHz, CDCl3) δ8.10(d,J=1.8Hz,0.66H),8.09(d,J=1.8Hz,0.32H),7.62(d,J=1.8Hz,0.32H),7.5 7(d,J=1.8Hz,0.68H),7.49(s,1H),7.44–7.41(m,1H),7.36–7.34(m,2H),5.58(s,2H),5.13(d,J=2.9Hz ,2H),4.83(s,1.43H),4.62(s,0.64H),3.98(t,J=5.8Hz,0.65H),3.74(t,J=5.8Hz,1.44H),3.20–3.16( m,0.77H),3.14–3.10(m,0.35H),3.03–2.96(m,2H),2.97–2.89(m,1H),2.84–2.73(m,2H),1.63(s,6H).

[0119] 7. Synthesis of Compound A7

[0120]

[0121] Step 1: Dissolve compound 2e (160 mg, 0.38 mmol), compound 7a (112.4 mg, 0.49 mmol), and HATU (289.3 mg, 0.76 mmol) in DMF (10 mL) and react at room temperature for 2 h. After the reaction is completed, quench the reaction with water, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, spin dry, and chromatograph on a silica gel column (DCM: MeOH = 25: 1) to obtain 73.5 mg of a white solid (yield: 30.67%). 1 H NMR (700MHz, CDCl3) δ8.13(s,1H),7.57(s,1H),7.49(s,1H),7.41(d,J=6.8Hz,1 H),7.35(d,J=7.6Hz,2H),5.33(s,2H),5.12(s,2H),4.87–4.75(m,2H),3.96(t, J=5.8Hz,2H),3.69(d,J=10.9Hz,1H),3.57(s,1H),3.46(d,J=11.4Hz,2H),3.03 –2.91(m,2H),2.55(s,2H),2.17(s,1H),2.09(s,1H),1.62(s,6H),1.47(s,9H).

[0122] Step 2: Compound 7b (50 mg, 0.08 mmol) was dissolved in DCM (5 mL), TFA (5 mL) was added dropwise with stirring, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction system was adjusted to neutral with saturated sodium bicarbonate solution, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 18.7 mg of a white solid (yield: 44.52%). 1 H NMR(700MHz, CDCl3)δ8.16(s,1H),7.53(s,1H),7.46(s,1H),7.40(m,1H),7.36–7.31(m, 2H),5.07(s,2H),5.03(s,2H),4.89(s,0.71H),4.78(s,1.31H),3.97(t,J=5.7Hz,1.33H) ,3.94(t,J=6.0Hz,0.78H),3.19(d,J=11.1Hz,2H),3.10(d,J=11.0Hz,2H),3.00(t,J=5. 7Hz,1.36H),2.90(s,0.70H),2.10(s,2H),1.96(s,0.64H),1.94(s,0.39H),1.62(s,6H).

[0123] 8. Synthesis of Compound A8

[0124]

[0125] Compound 2e (143 mg, 0.34 mmol), methoxyacetic acid (39.8 mg, 0.44 mmol), and HATU (258.6 mg, 0.68 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give 28.7 mg of a white solid (yield: 17.1%). 1H NMR(700MHz, CDCl3)δ8.13(s,0.62H),8.12(s,0.31H),7.56(s,0.34H),7.53(s,0.67H),7.46 (s,1H),7.39(s,0.42H),7.38(s,0.56H),7.32(m,2H),5.17(s,2H),5.08(s,2H),4.79(s,1.39 H),4.72(s,0.69H),4.21(s,1.36H),4.17(s,0.69H),3.95(t,J=5.5Hz,0.69H),3.80(t,J=5.7 Hz, 1.37H), 3.44 (s, 2H), 3.42 (s, 1H), 2.96 (t, J = 5.1Hz, 1.42H), 2.93 (s, 0.79H), 1.62 (s, 6H).

[0126] 9. Synthesis of Compound A9

[0127]

[0128] Compound 2e (96.7 mg, 0.23 mmol), glycolic acid (22.7 mg, 0.30 mmol), and HATU (178.9 mg, 0.17 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to obtain 11.2 mg of a white solid (yield: 10.2%). 1 H NMR(700MHz, CDCl3)δ8.05(s,0.62H),8.05(s,0.39H),7.48(s,0.38H),7.45(s,0 .71H),7.40(s,1H),7.32(s,0.46H),7.32(s,0.63H),7.29–7.22(m,2H),5.11(s, 2H),5.01(s,2H),4.77(s,1.46H),4.40(s,0.74H),4.22(s,1.47H),4.16(s,0.79 H), 3.94 (t, J = 5.9Hz, 0.75H), 3.53 (t, J = 5.8Hz, 1.60H), 2.88 (s, 2H), 1.54 (s, 6H).

[0129] 10. Synthesis of Compound A10

[0130]

[0131] Compound 2e (109.3 mg, 0.26 mmol), potassium D-threonate (46.0 mg, 0.34 mmol), and HATU (197.7 mg, 0.52 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain 21.6 mg of compound A10 as a white solid (yield: 15.4%). 1 H NMR (500MHz, CDCl3) δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44(d,J=1.5Hz,1H),7.43–7.42(m,0.66H),7.42–7.41(m ,0.37H),7.40(q,J=1.3Hz,1H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5H z,1H),5.16–5.05(m,2H),4.71(d,J=9.5Hz,1H),4.67(s,1H),4.46–4.42(m,2H),4.41(d,J=0.7Hz,0.79H),4.40(d,J=0.7Hz, 0.2H), 4.36 (s, 1H), 4.24 (t, J = 7.5Hz, 1H), 3.97–3.89 (m, 1H), 3.83–3.66 (m, 4H), 2.66–2.62 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H).

[0132] 11. Synthesis of Compound A11

[0133]

[0134] Compound 2e (55 mg, 0.13 mmol), 2-bromoethanol (32.7 mg, 0.26 mmol) and potassium carbonate (36.2 mg, 0.26 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 26.8 mg of a white solid (yield: 44.1%). 1H NMR (700MHz, CDCl3) δ8.16(d,J=1.8Hz,1H),7.56(d,J=1.9Hz,1H),7.50(s,1H),7.42(t,J=1.8Hz,0.44H),7.41(t,J=1.7Hz,0.59H),7.38–7.33(m ,2H),5.11(s,2H),5.00(s,2H),3.88(s,2H),3.76(t,J=5.2Hz,2H),3.04 (t,J=5.8Hz,2H),3.00–2.96(m,2H),2.85(t,J=5.3Hz,2H),1.63(s,6H).

[0135] 12. Synthesis of Compound A12

[0136]

[0137] Compound 2e (55 mg, 0.13 mmol), 2-(2-bromoethoxy)ethanol (44.2 mg, 0.26 mmol) and potassium carbonate (36.2 mg, 0.26 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 18.7 mg of a white solid (yield: 28.12%). 1 H NMR (700MHz, CDCl3) δ8.12(d,J=1.8Hz,1H),7.54(d,J=1.9Hz,1H),7.47(s,1 H),7.40(t,J=2.2Hz,0.43H),7.39(t,J=2.4Hz,0.5H),7.36–7.31(m,2H),5.0 7(s,2H),5.04(s,2H),3.82(s,2H),3.73–3.71(m,4H),3.64–3.61(m,2H),2.9 8(t,J=5.6Hz,2H), 2.95(t,J=5.6Hz,2H), 2.83(t,J=5.4Hz,2H), 1.62(s,6H).

[0138] 13. Synthesis of Compound A13

[0139]

[0140] Compound 2e (48 mg, 0.12 mmol), bromo-diethylene glycol (48.6 mg, 0.23 mmol) and potassium carbonate (31.6 mg, 0.23 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 28.4 mg of a white solid (yield: 45.02%). 1 H NMR (700MHz, CDCl3) δ8.09(d,J=1.8Hz,1H),7.53(d,J=1.8Hz,1H),7.46(s,1H),7.38(t ,J=1.6Hz,0.44H),7.37(t,J=1.6Hz,0.54H),7.34–7.29(m,2H),5.14(s,2H),5.06(s,2 H),3.83(s,2H),3.73–3.70(m,4H),3.68–3.66(m,2H),3.65–3.63(m,2H),3.62–3.59(m ,2H),2.99(t,J=5.8Hz,2H),2.93(t,J=6.2Hz,2H),2.85(t,J=5.5Hz,2H),1.60(s,6H).

[0141] 14. Synthesis of Compound A14

[0142]

[0143] Compound 2e (72.5 mg, 0.17 mmol), 3-bromo-1,1,1-trifluoro-2-propanol (66.5 mg, 0.34 mmol) and potassium carbonate (47.7 mg, 0.34 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 30.5 mg of a white solid (yield: 33.22%). 1H NMR (700MHz, DMSO-d6) δ8.05(d,J=1.9Hz,1H),7.53(m,2H),7.46(d,J=1.9Hz,1H),7.42–7.37(m,1H),7.34(d,J=7.7Hz,1H),6.34(s,2H),6.2 4(d,J=6.4Hz,1H),5.47(s,1H),5.23(s,2H),4.23(br,1H),3.85–3.75(m,2H),2.92(t,J=5.8Hz,2H),2.77(m,3H),2.72(m,1H),1.46(s,6H).

[0144] 15. Synthesis of Compound 15

[0145]

[0146] Compound 2e (72.5 mg, 0.17 mmol), 3-bromo-trifluoro-2-propanol (66.5 mg, 0.34 mmol) and potassium carbonate (47.7 mg, 0.34 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 20.4 mg of a white solid (yield: 22.21%). 1 H NMR(700MHz,DMSO-d6)δ8.05(d,J=1.9Hz,1H),7.53(m,2H),7.46(d,J=1.9Hz,1 H),7.40(t,J=8.0Hz,1H),7.34(dt,J=7.6,1.5Hz,1H),6.34(s,2H),6.25(d,J=6 .4Hz,1H),5.47(s,1H),5.23(s,2H),4.23(br,1H),3.80(q,J=15.2Hz,2H),3.30 (s,1H),2.92(t,J=5.8Hz,2H),2.78(s,3H),2.72(m,J=8.3Hz,1H),1.47(s,6H).

[0147] 16. Synthesis of Compound A16

[0148]

[0149] Compound 2e (60 mg, 0.14 mmol), 2-bromoethyl methyl ether (39.7 mg, 0.29 mmol) and potassium carbonate (39.4 mg, 0.29 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 18: 1) to obtain 21.6 mg of a white solid (yield: 31.63%). 1 H NMR (700MHz, CDCl3) δ8.13 (s, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.4Hz, 1H), 7.32 (m, 2H), 5.06 (s, 4H), 3.81 (s, 2H), 3.59 (t, J = 5.4Hz, 2H), 3.37 (d, J = 1.3Hz, 3H), 2.95 (d, J = 4.5Hz, 2H), 2.94 (s, 2H), 2.82 (m, 2H), 1.61 (s, 6H).

[0150] 17. Synthesis of Compound A17

[0151]

[0152] Compound 2e (48 mg, 0.11 mmol), N,N-dimethylaminoethyl bromide hydrobromide (34.7 mg, 0.23 mmol) and potassium carbonate (31.6 mg, 0.23 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 8.6 mg of a white solid (yield: 15.32%). 1 H NMR (700MHz, CDCl3) δ8.13(d,J=1.6Hz,1H),7.54(s,1H),7.49(s,1H),7.41(d,J=7.1Hz,1H),7.37-7.33(m,2H),5.1 4(s,2H),5.10(s,2H),3.85(s,2H),3.19(s,4H),3.01–2.97(m,2H),2.94(d,J=6.7Hz,2H),2.90(s,6H),1.62(s,6H).

[0153] 18. Synthesis of Compound A18

[0154]

[0155] Compound 2e (48 mg, 0.11 mmol), compound 18a (45.9 mg, 0.23 mmol) and potassium carbonate (31.6 mg, 0.23 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 12.4 mg of a white solid (yield: 20.09%). 1 H NMR(500MHz, CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.43–7.42(m,0.68H),7.42–7.41(m,0.32H),7.41 –7.39(m,2H),7.37(t,J=1.6Hz,0.55H),7.35(t,J=1.6Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5Hz,1H),5. 16–5.04(m,2H),4.70(d,J=6.8Hz,1H),4.67(s,1H),4.05–3.93(m,3H),3.12–3.06(m,2H),3.04–2.99(m,1H),2.94–2 .89(m,1H),2.72(t,J=7.1Hz,2H),2.44–2.32(m,1H),2.29–2.17(m,1H),1.92–1.80(m,1H),1.67(s,3H),1.62(s,3H).

[0156] 19. Synthesis of Compound A19

[0157]

[0158] Compound 2e (72 mg, 0.17 mmol), 3-bromo-1,2-diphenol (53.1 mg, 0.34 mmol) and potassium carbonate (47.3 mg, 0.34 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 12: 1) to obtain 18.0 mg of a white solid (yield: 21.26%). 1H NMR (700 MHz, deuterated methanol) δ 8.04 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.54 (s, 1H), 7.47 (m, 1H), 7.37 (s, 1H), 7.37 (d, J = 1.3 Hz, 1H), 5.21 (s, 2H), 3.94–3.84 (m, 3H), 3.55 (qd, J = 11.2, 5.3 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.8 Hz, 2H), 2.79 (dd, J = 13.1, 4.0 Hz, 1H), 2.69 (dd, J = 13.0, 8.0 Hz, 1H), 1.56 (s, 6H).

[0159] 20. Synthesis of Compound A20

[0160]

[0161] Compound 2e (72 mg, 0.17 mmol), compound 20a (56.5 mg, 0.34 mmol) and potassium carbonate (47.3 mg, 0.34 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 9.4 mg of a white solid (yield: 10.88%). 1 H NMR(500MHz, CDCl3)δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.43(m,1.65H),7.42–7.41(m ,0.34H),7.41–7.40(m,1H),7.37(t,J=1.7Hz,0.57H),7.36(t,J=1.6Hz,0.42H),6.78(d,J=12.3Hz,1H ),6.41(d,J=12.5Hz,1H),5.10(t,J=1.0Hz,2H),4.67(s,1H),4.05(t,J=5.4Hz,1H),3.93(s,2H),3.34 (d,J=5.5Hz,2H),3.06(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.52(s,2H),1.81(s,4H),1.64(s,6H).

[0162] 21. Synthesis of Compound A21

[0163]

[0164] Compound 2e (60.5 mg, 0.14 mmol), 1-cyclopropylbromomethanecarbonitrile (50.1 mg, 0.29 mmol) and potassium carbonate (39.8 mg, 0.29 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 17.3 mg of a white solid (yield: 23.41%). 1 H NMR (500MHz, CDCl3) δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42(m,1.71H),7. 42–7.41(m,0.35H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.58H),7.36(t,J=1.6Hz,0.43H),6 .78(d,J=12.3Hz,1H),6.41(d,J=12.5Hz,1H),5.10(t,J=1.0Hz,2H),4.67(s,1H),3.99(s,2H ),3.11(t,J=7.1Hz,2H),2.83(s,2H),2.71(t,J=7.1Hz,2H),2.18–2.04(m,4H),1.64(s,6H).

[0165] 22. Synthesis of Compound A22

[0166]

[0167] Compound 2e (60.5 mg, 0.14 mmol), compound 22a (47.2 mg, 0.29 mmol) and potassium carbonate (39.8 mg, 0.29 mmol) were dissolved in dry acetonitrile (10 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 12.0 mg of a white solid (yield: 16.56%). 1H NMR(500MHz, CDCl3)δ8.12(d,J=1.4Hz,1H),7.48–7.44(m,1H),7.43(d,J=1.5Hz,1H),7.42–7.4 1(m,0.63H),7.41–7.39(m,1.34H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.41H),6.78(d, J=12.5Hz,1H),6.44(d,J=12.3Hz,1H),5.08(t,J=1.0Hz,2H),4.67(s,1H),3.90(s,2H),3.43(s ,2H),3.03(t,J=7.0Hz,2H),2.73(t,J=7.0Hz,2H),2.38(s,2H),1.93–1.82(m,4H),1.64(s,6H).

[0168] 23. Synthesis of Compound A23

[0169]

[0170] Step 1: Compound 23a (300 mg, 1.08 mmol) and potassium cyanate (262.5 mg, 3.24 mmol) were dissolved in a mixed solution of ethanol (9 mL) and water (1 mL), and refluxed at 78°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 60: 1) to obtain 68.5 mg of a red oily liquid (yield: 26.43%). 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 3.95 (s, 1H), 3.75 (t, J = 7.1Hz, 2H), 3.71 (s, 1H), 2.39 (t, J = 7.1Hz, 2H), 1.46 (s, 9H).

[0171] Step 2: Compound 23b (50 mg, 0.21 mmol) and phosphorus oxybromide (298.3 mg, 1.04 mmol) were dissolved in pyridine (5 mL) and refluxed at 110°C for 2 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 200: 1) to obtain 16 mg of a red oily liquid (yield: 25.36%). 1 H NMR (400MHz, CDCl3) δ4.47 (s, 2H), 3.77 (t, J = 7.0 Hz, 2H), 2.98 (t, J = 7.1 Hz, 2H), 1.46 (s, 9H).

[0172] Step 3: Compound 1a (280 mg, 0.54 mmol), compound 23c (194.9 mg, 0.64 mmol), sodium carbonate (170.4 mg, 1.61 mmol), 1,1'-bis(diphenylphosphino)ferrocene (29.7 mg, 0.05 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 ml) and water (2 ml). The mixture was replaced with nitrogen several times and refluxed at 90°C for 6 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 76.8 mg of yellow oily liquid was obtained (yield: 23.2%). 1 H NMR (400MHz, CDCl3) δ8.72(d,J=1.4Hz,1H),7.81(d,J=1.4Hz,1H),7.48(t,J =7.5Hz,1H),7.43–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.27–5.14(m,2H ),4.94(t,J=6.9Hz,1H),4.48(d,J=4.9Hz,2H),3.75(q,J=7.0Hz,2H),3.73–3 .58(m,2H),2.98(m,2H),1.80–1.67(m,2H),1.65–1.53(m,10H),1.47(s,9H).

[0173] Step 4: Dissolve compound 23d (60 mg, 0.10 mmol), iron powder (27.1 mg, 0.48 mmol), and ammonium chloride (25.9 mg, 0.48 mmol) in 75% ethanol (10 mL). Reflux at 70°C for 4 h. After the reaction is complete, quench the reaction with water, filter through diatomaceous earth, and then extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. 43.5 mg of a white solid is obtained (yield: 76.2%). 1H NMR(700MHz, CDCl3)δ8.31(d,J=1.4Hz,1H),7.52(d,J=1.5Hz,1H),7.48–7.44(m,2H), 7.41(ddq,J=6.4,1.6,0.8Hz,1H),7.36(dt,J=7.3,1.6Hz,1H),6.51(d,J=12.4Hz,1H), 5.99(d,J=12.5Hz,1H),5.18–5.04(m,2H),4.94(t,J=7.0Hz,1H),4.46(d,J=8.6Hz,2H ),3.79–3.60(m,4H),2.98(m,2H),1.80–1.67(m,2H),1.65–1.54(m,10H),1.47(s,9H).

[0174] Step 5: Compound 23e (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (4 mL), and a round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the atmosphere was replaced with nitrogen several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 12.8 mg of a white solid was obtained (yield: 46.6%). 1 H NMR (400MHz, CDCl3) δ8.14(d,J=1.8Hz,1H),7.57(d,J=1.8Hz,1H),7.47(s,1H),7.39(m,1H),7 .36-7.31(m,2H),5.05(d,J=18.6Hz,4H),3.68(s,2H),2.90(m,5H),2.52(s,3H),1.61(s,6H).

[0175] Step 6: Compound 23f (11.2 mg, 0.03 mmol), [1-(bromomethyl)cyclopropyl]acetonitrile (9.6 mg, 0.06 mmol) and potassium carbonate (7.7 mg, 0.06 mmol) were dissolved in dry acetonitrile (5 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 4.3 mg of a white solid (yield: 31.2%). 1H NMR (500MHz, CDCl3) δ8.32(d,J=1.4Hz,1H),7.52(d,J=1.6Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42 (m,0.65H),7.42–7.41(m,0.35H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.55H),7.36(t,J=1.6Hz,0.4 3H),6.52(d,J=12.4Hz,1H),6.12(d,J=12.5Hz,1H),5.11(t,J=1.0Hz,2H),4.67(s,1H),3.84(s,2H) ,3.09(t,J=7.1Hz,2H),2.92–2.88(m,2H),2.56(s,2H),2.39(s,2H),1.93–1.83(m,4H),1.64(s,6H).

[0176] 24. Synthesis of Compound 24

[0177]

[0178] Step 1: Compound 23a (300 mg, 1.08 mmol), urea (194.3 mg, 3.24 mmol), ammonium acetate (249.4 mg, 3.24 mmol), acetic acid (0.19 mL, 3.24 mmol) were dissolved in water (10 mL) and refluxed at 100°C for 12 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 40: 1) to obtain 98.2 mg of a red oily liquid (yield: 38.05%).

[0179] Step 2: Compound 24a (95 mg, 0.39 mmol) and phosphorus oxybromide (569.1 mg, 1.99 mmol) were dissolved in pyridine (5 ml) and refluxed at 110°C for 2 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 80: 1) to obtain 48.7 mg of a yellow oily liquid (yield: 40.59%). 1 HNMR (400MHz, CDCl3) δ4.24 (s, 2H), 3.70 (t, J = 7.1 Hz, 2H), 2.68 (t, J = 7.1 Hz, 2H), 1.46 (s, 9H).

[0180] Step 3: Compound 1a (185 mg, 0.35 mmol), compound 24b (128.4 mg, 0.42 mmol), sodium carbonate (112.6 mg, 1.06 mmol), 1,1'-bis(diphenylphosphino)ferrocene (19.6 mg, 0.04 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 ml) and water (2 ml). The mixture was replaced with nitrogen several times and refluxed at 90°C for 6 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 58.3 mg of yellow oily liquid was obtained (yield: 26.7%). 1 H NMR (400MHz, CDCl3) δ8.80(d,J=1.4Hz,1H),8.02(d,J=1.4Hz,1H),7.50(t,J= 7.4Hz,1H),7.43–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.24–5.16(m,2H) ,4.94(t,J=6.9Hz,1H),4.26(s,2H),3.76–3.67(m,1H),3.66–3.55(m,3H),2. 64(td,J=7.0,1.6Hz,2H),1.79–1.67(m,2H),1.66–1.53(m,10H),1.47(s,9H).

[0181] Step 4: Dissolve compound 24c (48 mg, 0.08 mmol), iron powder (21.7 mg, 0.39 mmol), and ammonium chloride (20.8 mg, 0.39 mmol) in 75% ethanol (10 mL). Reflux at 70°C for 4 h. After the reaction is complete, quench the reaction with water, filter through diatomaceous earth, and then extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography on silica gel (PE: EA = 3: 1) yields 28.6 mg of a white solid (yield: 62.6%). 1H NMR (400MHz, CDCl3) δ8.42(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.46(t,J=7.3Hz,1H), 7.44–7.39(m,2H),7.36(dt,J=7.3,1.6Hz,1H),6.14(d,J=12.3Hz,1H),5.67(d,J=12.5Hz ,1H),5.17–5.03(m,2H),4.94(t,J=7.0Hz,1H),4.25(s,2H),3.76–3.68(m,1H),3.68–3.5 6(m,3H),2.64(td,J=7.0,1.6Hz,2H),1.80–1.66(m,2H),1.67–1.52(m,10H),1.47(s,9H).

[0182] Step 5: Compound 24d (25 mg, 0.04 mmol) was dissolved in tetrahydrofuran (4 mL), and the round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the nitrogen was replaced several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 9.1 mg of white solid was obtained (yield: 53.1%). 1 H NMR (400MHz, CDCl3) δ8.40(d,J=1.4Hz,1H),7.54(d,J=1.6Hz,1H),7.46–7.41( m,1H),7.40(p,J=1.3Hz,1H),7.39–7.35(m,2H),6.14(d,J=12.4Hz,1H),5.67(d ,J=12.5Hz,1H),5.09(t,J=1.0Hz,2H),4.67(s,1H),4.39(d,J=7.6Hz,2H),3.20 (q,J=7.0Hz,2H),2.91–2.82(m,2H),2.65(dt,J=12.4,7.2Hz,1H),1.64(s,6H).

[0183] Step 6: Compound 24e (8.5 mg, 0.02 mmol), L-cyclopropylglycine (3.2 mg, 0.03 mmol), and HATU (16.0 mg, 0.04 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give 4.30 mg of a white solid (yield: 40.8%).1 H NMR (500MHz, CDCl3) δ8.41(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44–7.42(m,0.66H),7.42–7 .41(m,0.36H),7.41–7.39(m,1H),7.37(t,J=1.6Hz,0.56H),7.36(t,J=1.6Hz,0.43H),6.13(d,J=12.3Hz,1H),5.83(d, J=12.3Hz,1H),5.15–5.07(m,2H),4.97–4.91(m,1H),4.67(s,1H),4.60–4.54(m,1H),4.33(s,2H),3.73–3.69(m,2H),3 .67–3.61(m,1H),2.71–2.64(m,2H),2.27–2.18(m,1H),1.67(s,3H),1.62(s,3H),1.55–1.44(m,2H),1.41–1.29(m,2H).

[0184] 25. Synthesis of Compound 25

[0185]

[0186] Step 1: Compound 1a (240 mg, 0.46 mmol), compound 25a (166.6 mg, 0.55 mmol), sodium carbonate (146.1 mg, 1.38 mmol), 1,1'-bis(diphenylphosphino)ferrocene (25.5 mg, 0.05 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The mixture was replaced with nitrogen several times and refluxed at 90 °C for 6 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 172.3 mg of yellow oily liquid was obtained (yield: 60.7%). 1H NMR (400MHz, CDCl3) δ8.34(d,J=1.4Hz,1H),7.57(d,J=1.4Hz,1H),7.50(t,J=7.4Hz,1 H),7.44–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),6.78(s,1H),5.21(dt,J=1.9,1.0H z, 2H), 4.94 (t, J = 6.9 Hz, 1H), 4.40 (d, J = 1.8 Hz, 2H), 3.83 (td, J = 7.1, 1.2 Hz, 2H), 3.74–3.68 (m, 1H), 3.66–3.58 (m, 3H), 1.78–1.67 (m, 2H), 1.65–1.54 (m, 10H), 1.47 (s, 9H). [Synthesis of intermediate 25a, see WO 2020 / 089456 Al]

[0187] Step 2: Compound 25b (150 mg, 0.24 mmol), iron powder (67.8 mg, 1.21 mmol), and ammonium chloride (64.9 mg, 1.21 mmol) were dissolved in 75% ethanol (10 mL). The mixture was refluxed at 70°C for 4 h. After the reaction was completed, the reaction was quenched with water, filtered through celite, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 53.6 mg of white solid was obtained (yield: 37.6%). 1 H NMR(400MHz, CDCl3)δ8.33(d,J=1.6Hz,1H),7.46(t,J=7.3Hz,1H),7.43–7.39(m,3H),7 .36(dt,J=7.3,1.6Hz,1H),6.61(s,1H),6.44(d,J=12.3Hz,1H),6.00(d,J=12.5Hz,1H), 5.10(qt,J=12.5,0.9Hz,2H),4.94(t,J=7.0Hz,1H),4.41(d,J=4.2Hz,2H),3.84(td,J= 7.1,2.0Hz,2H),3.75–3.58(m,4H),1.79–1.67(m,2H),1.65–1.53(m,10H),1.47(s,9H).

[0188] Step 3: Compound 25c (48.6 mg, 0.08 mmol) was dissolved in tetrahydrofuran (4 mL), and the round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the nitrogen was replaced several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 12.8 mg of white solid was obtained (yield: 38.4%).

[0189] Step 4: Compound 25d (12.0 mg, 0.03 mmol), 3-(bromomethyl)-1,1-difluorocyclopentane (11.4 mg, 0.06 mmol) and potassium carbonate (7.9 mg, 0.06 mmol) were dissolved in dry acetonitrile (5 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 5.3 mg of a white solid (yield: 35.62%). 1 H NMR(500MHz, CDCl3)δ8.34(d,J=1.6Hz,1H),7.47(t,J=7.3Hz,1H),7.44–7.42(m,0.68H),7.42–7.41(m,0.33H),7. 41(d,J=1.6Hz,1H),7.41–7.40(m,1H),7.37(t,J=1.6Hz,0.56H),7.36(t,J=1.6Hz,0.43H),6.58(s,1H),6.45(d,J =12.5Hz,1H),6.13(d,J=12.5Hz,1H),5.11(s,2H),4.67(s,1H),4.00–3.92(m,2H),3.66(d,J=12.6Hz,2H),2.92–2 .85(m,2H),2.56–2.46(m,2H),2.33–2.23(m,1H),2.13–1.80(m,4H),1.79–1.70(m,2H),1.67(s,3H),1.62(s,3H).

[0190] 26. Synthesis of Compound 26

[0191]

[0192] Step 1: Compound 1a (303.6 mg, 0.58 mmol), compound 26a (232.4 mg, 0.70 mmol), sodium carbonate (184.8 mg, 1.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene (32.2 mg, 0.06 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The mixture was replaced with nitrogen several times and refluxed at 90°C for 6 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 204.6 mg of yellow oily liquid was obtained (yield: 54.26%). 1 H NMR (400MHz, CDCl3) δ8.35(d,J=1.4Hz,1H),7.59(d,J=1.4Hz,1H),7.48(t,J=7.4Hz ,1H),7.44–7.38(m,2H),7.36(dt,J=7.5,1.6Hz,1H),5.24–5.17(m,2H),4.94(t,J=6 .9Hz,1H),3.74–3.66(m,3H),3.64(tt,J=7.0,2.4Hz,3H),2.94(td,J=7.1,3.5Hz,2H),2.71(dt,J=11.9,7.1Hz,2H),1.79–1.67(m,2H),1.65–1.53(m,10H),1.45(s,9H). [For the synthesis of intermediate 26a, refer to Eur.J.Med.Chem.86(2014)438-448]

[0193] Step 2: Compound 26b (200 mg, 0.31 mmol), iron powder (86.1 mg, 1.54 mmol), and ammonium chloride (82.5 mg, 1.54 mmol) were dissolved in 75% ethanol (10 mL). The mixture was refluxed at 70°C for 4 h. After the reaction was completed, the reaction was quenched with water, filtered through diatomaceous earth, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 118.4 mg of white solid was obtained (yield: 62.07%). 1H NMR(400MHz, CDCl3)δ8.12(d,J=1.4Hz,1H),7.46(t,J=7.3Hz,1H),7.44–7.38(m, 3H),7.36(dt,J=7.3,1.6Hz,1H),6.78(d,J=12.4Hz,1H),6.27(d,J=12.5Hz,1H),5 .15–5.04(m,2H),4.94(t,J=6.9Hz,1H),3.79–3.57(m,6H),2.94(td,J=7.1,3.5H z, 2H), 2.72 (t, J = 7.1Hz, 2H), 1.81–1.66 (m, 2H), 1.66–1.52 (m, 10H), 1.45 (s, 9H).

[0194] Step 3: Compound 26c (112.5 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), and a round-bottom flask was placed in an ice-water bath and dry 4.0 M hydrochloric acid (1 mL) was added dropwise, and the nitrogen was replaced several times, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin drying. 42.3 mg of white solid was obtained (yield: 53.54%).

[0195] Step 4: Compound 26d (35.6 mg, 0.08 mmol), 2-bromoethanol (20.5 mg, 0.16 mmol) and potassium carbonate (22.6 mg, 0.16 mmol) were dissolved in dry acetonitrile (5 mL), replaced with nitrogen several times, and refluxed at 80°C for 3 h. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a silica gel column (DCM: MeOH = 15: 1) to obtain 17.6 mg of a white solid (yield: 44.89%). 1H NMR(500MHz, CDCl3)δ8.12(d,J=1.4Hz,1H),7.48–7.43(m,2H),7.42–7.39(m,2H),7.37(t,J=1.6 Hz,0.57H),7.35(t,J=1.5Hz,0.42H),6.78(d,J=12.5Hz,1H),6.44(d,J=12.3Hz,1H),5.08(t,J=1 .0Hz,2H),4.67(s,1H),4.03(t,J=7.6Hz,1H),3.59(q,J=7.1Hz,2H),3.01(t,J=7.1Hz,2H),2.95( t,J=7.1Hz,2H),2.79(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.63(t,J=7.1Hz,2H),1.64(s,6H).

[0196] 27. Synthesis of Compound 27

[0197]

[0198] Step 1: Dissolve compound 2e (180 mg, 0.43 mmol), (1R, 2R)-2-fluoro-cyclopropanecarboxylic acid (57.9 mg, 0.56 mmol), and HATU (325.5 mg, 0.86 mmol) in DMF (5 mL) and react at room temperature for 2 h. After the reaction is completed, quench the reaction with water, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, spin dry, and chromatograph on a silica gel column (DCM: MeOH = 20: 1) to obtain 17.6 mg of a white solid (yield: 8.11%). 1H NMR(500MHz, CDCl3)δ8.12(d,J=1.5Hz,1H),7.48–7.44(m,2H),7.44–7.42(m,0.73H),7.42–7.41(m,0.32H),7.41– 7.39(m,1H),7.37(t,J=1.6Hz,0.57H),7.36(t,J=1.6Hz,0.42H),6.78(d,J=12.3Hz,1H),6.41(d,J=12.4Hz,1H),5 .15–5.05(m,2H),4.84(q,J=7.0Hz,0.5H),4.75(q,J=7.0Hz,0.5H),4.67(s,1H),4.42(d,J=12.6Hz,2H),3.69(q,J =7.2Hz,2H),2.66–2.58(m,2H),2.26–2.14(m,1H),2.11–2.02(m,1H),2.02–1.92(m,1H),1.67(s,3H),1.62(s,3H).

[0199] 28. Synthesis of Compound 28

[0200]

[0201] Compound 2d (131.16 mg, 0.31 mmol), compound 28a (55.2 mg, 0.41 mmol), and HATU (237.2 mg, 0.62 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give 32.7 mg of a white solid (yield: 23.71%). 1H NMR (500MHz, CDCl3) δ8.12(d,J=1.4Hz,1H),7.47(t,J=7.4Hz,1H),7.44(d,J=1.5Hz,1H),7.44–7.42(m,0.68H),7.42–7.41(m,0 .37H),7.41–7.39(m,1H),7.37(t,J=1.6Hz,0.56H),7.35(t,J=1.5Hz,0.43H),6.78(d,J=12.5Hz,1H),6.27(d,J=12.5Hz,1H),5 .15–5.05(m,2H),4.71(d,J=9.5Hz,1H),4.67(s,1H),4.45–4.43(m,1H),4.43(s,1H),4.41(d,J=0.7Hz,0.77H),4.40(d,J=0.7H z,0.2H),4.36(s,1H),4.24(t,J=7.5Hz,1H),3.97–3.88(m,1H),3.78–3.65(m,4H),2.67–2.60(m,2H),1.67(s,3H),1.62(s,3H).

[0202] 29. The synthesis of compound 29 is the same as compound 4

[0203]

[0204] 1 H NMR (700MHz, CDCl3) δ8.16(d,J=1.8Hz,0.58H),8.13(d,J=1.8Hz,0.37H),7.58(d,J=1.8Hz,0.40H),7.51(d,J=1.8H z,1H),7.50(s,0.60H),7.44–7.39(m,1H),7.39–7.31(m,2H),5.12(s,0.82H),5.11(s,1.25H),5.03(s,1.15H),5.0 2(s,0.80H),4.82(s,0.80H),4.64(s,1.23H),3.97(t,J=5.7Hz,1.26H),3.76(t,J=5.7Hz,0.80H),2.94(t,J=5.6Hz ,0.81H),2.90–2.87(m,1.27H),2.84–2.78(m,2H),2.77–2.71(m,2H),2.52(s,0.38H),2.39(s,0.57H),1.63(s,6H).

[0205] 30. The synthesis of compound 30 is the same as compound 7

[0206]

[0207] 1 H NMR (700 MHz, deuterated methanol) δ8.06–7.99 (m, 1H), 7.52 (s, 1.57H), 7.49 (s, 0.49H), 7.45 (s, 1H), 7.38–7.34 (m, 2H), 5.18 (t, J = 8.6 Hz, 2H), 4.86 (s, 0.86H), 4.70 (s, 1.20H), 4.04 (t, J = 5.4 Hz, 1.22H), 3.93–3.87 (m, 0.85H), 3.38 (d, J = 3.5 Hz, 0.49H), 3.36 (d,J=3.6Hz,0.68H),3.33(s,0.40H),3.31(s,0.50H),3.25–3.22(m,0.64H),3.24–3.21(m,0.52H),3.22–3.19(m,0.49H ),3.20–3.17(m,0.35H),2.98(s,1.22H),2.84(s,0.85H),2.30(d,J=17.3Hz,0.63H),2.19–2.10(m,2.47H),1.55(s,6H).

[0208] 31. The synthesis of compound 31 is the same as compound 8

[0209]

[0210] 1 H NMR(700MHz, CDCl3) δ8.15(d,J=1.8Hz,0.52H),8.10(d,J=1.8Hz,0.47H),7.62(s,0.49H),7.53(s,0.51 H),7.52(s,0.46H),7.50(s,0.52H),7.44–7.39(m,1H),7.39–7.32(m,2H),5.25(s,1H),5.17(s,1H),5.1 3(d,J=13.8Hz,2H),4.81(s,1H),4.69(s,1H),4.21(s,1H),4.20(s,1H),3.96(t,J=5.6Hz,1.23H),3.82( t,J=5.6Hz,0.94H),3.45(s,3H),2.94(t,J=5.7Hz,1H),2.90(t,J=5.8Hz,1H),2.38(s,1H),1.63(s,6H).

[0211] Test Example

[0212] 1. Inhibitory activity of compounds on HPK1 enzyme

[0213] Reagents, consumables and instruments:

[0214] The kinases and substrates used in the experiment were purchased from Promega; the reaction microplates were purchased from PerkinElmer. The multifunctional microplate reader used for plate reading was a product of Molecular Devices, model: SpectraMax Paradigm; the experimental water was distilled water produced by Sinopharm Group.

[0215] Compound preparation:

[0216] The compound was centrifuged at 12000 g for 5 min and DMSO was added to prepare 10 -2 M stock solution, vortex evenly and then sonicate for 10 min before use, and store at -40°C. When testing, the compound is diluted with DMSO from the stock solution to 100 times the tested concentration (DMSO concentration in the system is 1%).

[0217] Test method:

[0218] 1. Enzymatic reaction:

[0219] In a 384-well plate, add 2 μL of enzyme and 1 μL of different concentrations of compounds, set up 0% kinase activity control wells without kinase and compounds and 100% kinase activity control wells without compounds, and incubate at room temperature for 10 minutes. Then add 2 μL of ATP+substrate mixture (substrate final concentration 100 μg / mL, ATP final concentration 10 μM), and incubate at 37°C for 1 hour.

[0220] 2. Detection reaction:

[0221] Add 5 μL ADP-Glo ​​to each well TM Reagent, incubate at room temperature for 40 minutes to remove unreacted ATP. Add 10 μl Kinase Detection Reagent to each well and incubate at room temperature for 30-60 minutes to convert the ADP generated in the reaction into ATP.

[0222] 3. Plate reading:

[0223] The fluorescence signal was detected (luminescence: integration time 0.5 s).

[0224] 4. Calculation:

[0225] The inhibition rate, IC, was calculated for each well by averaging the RLU values ​​representing 0% kinase activity (no enzyme and compound) and 100% kinase activity (no compound). 50 The values ​​were calculated using GraphPad Prism software.

[0226] Table 1 Inhibitory effects of some compounds in the examples on HPK1 enzyme activity

[0227]

[0228]

[0229] The inhibitory activity of compound ZYF0033 on HPK1 enzyme at a concentration of 100 nM was 46.5%, indicating that the IC of the compound on HPK1 enzyme inhibition under this test condition was 50 >100nM.

[0230] The invention discloses a novel HPK1 inhibitor having a five-membered aromatic heterocyclic piperidine / homopiperidine, which has a strong inhibitory effect on HPK1. Compared with the positive control drug compound ZYF0033, the compound of the invention has significantly improved inhibitory activity.

[0231]

[0232] 2. Effects of compounds on the ability of Jurkat cells to secrete IL-2

[0233] Reagents, consumables and instruments:

[0234] The experimental water was distilled water produced by Sinopharm Group; Human IL-2 ELISA Kit (#1110203), anti-CD3 (#100238), and anti-CD28 (#302923) were purchased from Dako Biotechnology Co., Ltd.; RPMI-1640 culture medium (#C22400500BT) and fetal bovine serum (#10099141) were purchased from Thermo Fisher Scientific; other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.; the full-wavelength microplate reader used for plate reading was a product of Molecular Device, model: SpectraMax 190.

[0235] Compound preparation:

[0236] The compound was centrifuged at 12000 g for 5 min and DMSO was added to prepare 10 -2 M stock solution, vortex evenly, sonicate for 10 min before use, and store at -40°C. When testing, the compound was diluted with PBS from the stock solution to 20 times the tested concentration.

[0237] Test method:

[0238] 1) Add 100uL anti-CD3 to a 96-well plate and coat overnight at 4°C.

[0239] 2) Jurkat cells in the logarithmic growth phase were seeded into 96-well culture plates at an appropriate density, with 190uL per well, and 0.1μM of the drug was added. Triplicate wells were set up, and solvent controls of corresponding concentrations and zero wells without cells were set up.

[0240] 3) After culturing for 24 hours, the supernatant was collected by centrifugation and the secretion of IL-2 was detected using an IL-2 ELISA detection kit.

[0241] Table 2 Effects of some compounds in the examples on the ability of Jurkat cells to secrete IL-2

[0242] Compound IL-2 secretion (pg / mL) blank 163.9 ZYF0033 252.5 A3 279.1 A4 296.65

[0243] The compounds A3 and A4 of the present invention can significantly promote the secretion of IL-2 by Jurkat cells at a concentration of 0.1 μM, and their activity is stronger than that of the positive control ZYF0033.

[0244] 3. Compound Metabolic Stability Test

[0245]

[0246] The metabolic stability of the compounds A4 and A9 of the present invention is significantly stronger than that of the positive control ZYF0033.

[0247] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound, characterized in that The compound is a compound represented by Formula 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, in, X is selected from the group consisting of CH, N; is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; R1 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl-, substituted or unsubstituted C1-C6 alkylene-, substituted or unsubstituted C3-C8 cycloalkyl-(C=O)-, a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and substituted or unsubstituted C3-C8 cycloalkyl-(C=O)-, substituted or unsubstituted C1-C6 alkyl-(C=O)-, substituted or unsubstituted C2-C6 alkenyl-(C=O)-, substituted or unsubstituted C2-C6 alkynyl-(C=O)-, R b -(substituted or unsubstituted C1-C3 alkylene)-(C=O)-, substituted or unsubstituted -S(=O)2-, Said substitution independently refers to substitution by 1, 2, 3 or 4 substituents selected from the following group: hydrogen, halogen, hydroxyl, -N(C1-C3 alkyl)2, -NH2, cyano, -(C1-C3 alkylene)-OH, -(C1-C3 alkylene)-CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S; R b Selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C1-C3 alkyl, C3-C8 cycloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

2. The compound according to claim 1, characterized in that X is CH; A1 and A2 are independently selected from the following groups: S, N, O; A3 is C.

3. The compound according to claim 1, characterized in that Select from the following group:

4. The compound according to claim 1, characterized in that R1 is selected from the following group: H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-(C=O)-, a 4-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and substituted or unsubstituted C3-C6 cycloalkyl-(C=O)-, substituted or unsubstituted C1-C3 alkyl-(C=O)-, The substitution independently refers to substitution by 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, hydroxyl, -N(C1-C3 alkyl)2, -NH2, cyano, -(C1-C3 alkylene)-OH, -(C1-C3 alkylene)-CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C8 cycloalkyl; R b Selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C1-C3 alkyl, C3-C6 cycloalkyl; m is 0, 1, 2 or 3; n is 0, 1 or 2.

5. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

6. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

7. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to claim 1.

9. A use of the compound according to claim 1, characterized in that: Used for preparing a drug for treating HPK1-related tumors.

10. The use according to claim 9, characterized in that The tumor is selected from the group consisting of breast cancer, colorectal cancer, hematological malignancies, lung cancer, melanoma, ovarian cancer, pancreatic cancer, and kidney cancer.

11. The use according to claim 10, characterized in that The lung cancer is non-small cell lung cancer; The kidney cancer is renal cell carcinoma.

12. A HPK1 inhibitor, characterized in that Containing one or more compounds according to claim 1.

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