Cyclin-dependent kinase degrader, preparation method therefor and use thereof

Abstract

The present invention provides a cyclin-dependent kinase degrader, a preparation method therefor and the use thereof. Particularly, the present invention provides compounds shown as formula I, the definition of each group being as described in the description. The compounds have excellent inhibitory activity on cyclin-dependent kinases (CDKs), and therefore can be used for preparing a pharmaceutical composition for treating blood cancer or solid tumor cancer.

Description

Cell cycle-dependent kinase degrader and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a class of cell cycle-dependent kinase degraders, and a preparation method and use thereof. Background Art

[0002] Molecular glues (MGDs) are small molecule compounds that can "glue" two proteins together. They typically bind to their surfaces, inducing or stabilizing protein-protein interactions. Some MGDs can recruit target proteins to E3 ubiquitin ligases, where they are degraded through the ubiquitin-protease system. Rapamycin was one of the first reported compounds of this type, having been found to stabilize FK506 binding proteins 12 (FKBP12) and the mammalian target of rapamycin (mTOR). IMiDs and the anticancer drug Indisulam, among others, recruit proteins from the DCAF (DDB1- and CUL4-associated factor) family to induce the degradation of pro-inflammatory and pro-oncogenic proteins such as DNA-binding proteins Ikaros1 / 3, casein kinase 1α (CK1α), and RNA-binding motif protein 23 / 39 (RBM23 / 39), all typical examples of MGD. In the past two years, a series of MGDs have also been reported that can degrade oncogenic proteins such as Cyclin K and B-cell lymphoma 6 (BCL-6).

[0003] In 2019, Ebert's team reported a CDK inhibitor, CR8, that can induce the degradation of the cell cycle protein Cyclin K. This compound can bind to the CDK12-Cyclin K heterodimer target complex and recruit the DDB1-CUL4-RBX1 E3 ligase to ubiquitinate Cyclin K, which is then recognized and degraded by the proteasome. CR8 occupies the ATP-binding pocket of CDK12 and interacts with the BPC domain of DDB1 through the hydrophobic interaction of the terminal phenylpyridine ring. CDK12 acts as a substrate receptor for the E3 ligase, placing Cyclin K in the usual position of a CRL4 ubiquitinated substrate. Long-term exposure of CDK12 to CR8 also leads to its own ubiquitination.

[0004] Cyclin-dependent kinases (CDKs) belong to the serine / threonine protein kinase family and are key kinases involved in cell cycle regulation. CDKs can be divided into two main categories based on their functions: CDK1, 2, 4, and 6, which are involved in cell cycle regulation; and CDK7-13, which are involved in transcriptional regulation. CDK7-Cyclin H, CDK8-Cyclin C, CDK9-Cyclin T, and CDK12 / 13-Cyclin K all regulate the initiation or elongation of transcription by modulating the phosphorylation of RNA polymerase II, prompting the latter to overexpress various oncogenes (such as MYC and RUNX) via super enhancers, thereby maintaining the growth and survival of cancer cells. CDK12 is also a key component in regulating DNA damage repair in cancer cells. Its inactivation not only promotes the efficacy of DNA damage repair inhibitors (such as the PARP inhibitor olaparib), but also enhances the penetration of immune cells in solid tumors.

[0005] In 2016, Gray's team developed a highly specific CDK12 / 13 inhibitor THZ531 based on the compound THZ1. The latter can specifically induce apoptosis in some tumor cells, but still has pharmacokinetic shortcomings, including low bioavailability and short half-life.

[0006] Syros has developed SY-1365, a more specific drug based on THZ1, which is currently in Phase I clinical trials for the treatment of solid tumors. Due to its pharmacokinetic properties, SY-1365 is administered via intravenous injection.

[0007] Therefore, developing highly active and specific molecular glue degraders targeting CDK7, 12 or 13, a series of cancer treatment targets that are undergoing clinical verification, is expected to provide promising targeted drugs for a variety of blood cancers or solid tumors. Summary of the Invention

[0008] The present invention aims to provide a cell cycle kinase inhibitor and its preparation and use, which has excellent cell cycle kinase (CDK) inhibitory activity and can be used to prepare a pharmaceutical composition for treating blood cancer or solid tumor cancer.

[0009] The first aspect of the present invention provides a compound represented by the following formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof

[0010] Where:

[0011] L is selected from the group consisting of a chemical bond, a C1-C4 alkylene group, and L1;

[0012] Wherein L1 is hydroxy substituted or unsubstituted

[0013] X1 is selected from: CH, N;

[0014] Y is selected from the following group: chemical bond, C1-C4 alkylene, wherein X2 is selected from the group consisting of a chemical bond, a substituted or unsubstituted methylene group, an oxygen atom, NH, and NCH3; wherein X3 is selected from the group consisting of a chemical bond, a substituted or unsubstituted C1-C4 alkylene group; and m is 0, 1, 2, 3, or 4;

[0015] Ring A is a C4-C14 cycloalkyl, a 4-14 membered heterocyclyl having 1-3 heteroatoms selected from N, O or S, a C6-C14 aryl, or a 5-14 membered heteroaromatic ring having 1-3 heteroatoms selected from N, O or S; wherein the ring may be monocyclic, bicyclic or tricyclic;

[0016] Each R1 is independently selected from oxo (C=O), C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, halogen, hydroxy, nitro, -NR a R b , substituted or unsubstituted S(O)2, substituted or unsubstituted 5-10 membered heteroaryl; R a and R b Each is independently selected from hydrogen, C1-C4 alkyl, acetyl;

[0017] n is 0, 1, 2, 3, 4 or 5;

[0018] The term "substituted" in the substituted or unsubstituted group refers to the group being substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, cyano, halogen, hydroxyl, and nitro.

[0019] The halogen is F, Cl, Br or I.

[0020] In another preferred embodiment, the compound of formula I has a structure shown in the following formula I-1, I-2, I-3 or I-4:

[0021] wherein p is selected from 1, 2, 3 or 4;

[0022] Ring A, R1, X1, Y, n, and m are all as defined above.

[0023] In another preferred embodiment, the L1 is selected from the following substituted or unsubstituted groups:

[0024] Substitution refers to the replacement of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, hydroxyl, and C1-C4 alkyl.

[0025] In another preferred embodiment, the A ring is selected from the following substituted or unsubstituted groups:

[0026] Wherein substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, hydroxyl, oxo (C=O), C1-C4 alkyl, cyano, -NR a R b ; R a and R b Each is independently selected from hydrogen, C1-C4 alkyl, and acetyl.

[0027] In another preferred embodiment, R1 is selected from the following group: F, Cl, oxo, amino, methyl-substituted amino, carbonylmethyl-substituted amino, cyano, nitro, hydroxy, methoxy, methyl-substituted S(O)2.

[0028] In another preferred embodiment, the compound of formula (I) is selected from the following group:

[0029] The second aspect of the present invention provides a pharmaceutical composition comprising: (1) the compound according to the first aspect of the present invention or its optical isomer, or a pharmaceutically acceptable salt thereof; and 2) a pharmaceutically acceptable carrier.

[0030] The third aspect of the present invention provides the use of the compound or optical isomer thereof, or pharmaceutically acceptable salt thereof, as described in the first aspect of the present invention, or the pharmaceutical composition as described in the second aspect of the present invention, which can be used to prepare a pharmaceutical composition that can be used as a cell cycle-dependent kinase degrader to treat cancer and other diseases related to cell cycle kinase activity.

[0031] In another preferred embodiment, the cell cycle dependent kinase is selected from the following group: CDK 7, CDK 9, CDK 12, CDK 13, and Cyclin K.

[0032] In another preferred embodiment, the cancer and other cell cycle kinase activity-related diseases are selected from the following groups: T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), neuroblastoma, non-small cell lung cancer (NSCLC), colon cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma, ovarian cancer, Ewing's sarcoma, skin cancer, prostate cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, brain tumor, squamous cell carcinoma, peritoneal cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.

[0033] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 shows the structural formulas of compounds CR8, SR4835, and THZ531.

[0035] FIG2 shows the effects of representative compounds in Example 2 on the protein levels of CDK12 / 13 and Cyclin K and downstream signaling pathways in SK-OV-3 and COV362 cells.

[0036] FIG3 shows the growth inhibitory activity of representative compounds against various ovarian cancer and lung cancer cell lines, as well as the inhibitory activity against THZ531-resistant cell lines.

[0037] FIG4 shows the tumor inhibitory activity of compound HQY-14-28 on SKOV3 cell xenografted mice. DETAILED DESCRIPTION

[0038] After extensive and in-depth research, the present inventors have provided a class of cell cycle-dependent kinase degraders, their preparation methods, and uses. These compounds can be used in the targeted treatment of cancer and other diseases associated with cell cycle kinase activity, such as hematologic cancers and solid tumors. Based on these findings, the present invention was completed.

[0039] the term

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0042] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0043] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0044] As used herein, the term "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances that 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 compound of the present invention and with each other without significantly reducing the efficacy of the compound. 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 (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0045] As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C1-C4 alkyl groups represent straight or branched chain alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0046] As used herein, the term "C4-C14 cycloalkyl" refers to a cycloalkyl group having 4 to 14 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be a bicyclic ring, such as a bridged ring or a spirocyclic ring. It can also be a tricyclic ring.

[0047] As used herein, the term "C1-C4 alkoxy" refers to a straight or branched alkoxy group having 1 to 4 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0048] As used herein, the term "4- to 14-membered heterocyclic group having 1-3 heteroatoms selected from N, S, and O" refers to a saturated or partially saturated cyclic group having 4-14 ring atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. The cyclic group may be monocyclic or polycyclic, such as a bridged ring, a spirocyclic ring, or a fused ring. Specific examples include tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl.

[0049] As used herein, the term "C6-C14 aryl group" refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl group, a naphthyl group, or the like.

[0050] As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S, and O" refers to a cyclic aromatic group having 5-10 ring atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. It may be a single ring or a condensed ring. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl.

[0051] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F and Cl. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0052] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or configurational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc.). Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or configurational isomers) are all within the scope of the present invention.

[0053] The present invention will be further described below in conjunction with specific implementation. 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, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0054] Example 1 Synthesis of Compound ZSQ-25-3

[0055] 1.1 Synthesis of compound 1

[0056] 1-Fluoro-2-nitrobenzene (14 g, 100 mmol), isopropyl mercaptan (10.2 ml, 110 mmol), and anhydrous potassium carbonate (27.6 g, 200 mmol) were dissolved in 100 ml of anhydrous DMF and stirred at 110°C for 12 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, washed with 100 mL of water, then 100 mL of saturated sodium chloride solution, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography using PE / EA (7:1) as the eluent gave 18 g of the product as a yellow oil in a 91% yield.

[0057] 1.2 Synthesis of compound 2

[0058] Compound 1 (9.85 g, 50 mmol) was dissolved in 100 mL of methanol and stirred at 0°C. Potassium peroxymonosulfonate (15.37 g, 250 mmol) was dissolved in 100 mL of water and added dropwise to the mixed solution at 0°C. Stirring was continued at 0°C for 1 hour, then moved to room temperature and stirred for 24 hours. After the reaction was completed, the methanol was removed by distillation under reduced pressure, and the mixture was washed with 50 mL of water and 50 mL of saturated sodium chloride solution, followed by extraction with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 8.3 g of a bright yellow oily liquid (72% yield).

[0059] 1.3 Synthesis of compound 3

[0060] Compound 2 (2.29 g, 10 mmol) was dissolved in 20 mL of methanol, and Pd / C (200 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 h. After completion of the reaction, the mixture was filtered through celite and washed with DCM. The filtrate was concentrated and pumped to dryness to afford 1.99 g of a white solid (99% yield).

[0061] 1.4 Synthesis of compound 4

[0062] Dissolve NaH (600 mg, 15 mmol) in 60 mL of dry DMF and stir at 0°C. Dissolve compound 3 (1.99 g, 10 mmol) in 5 mL of dry DMF and add dropwise to the mixture over 10 minutes. Continue stirring at 0°C for 0.5 hours, then add 2,4,5-trichloropyrimidine (2.29 mL, 20 mmol) dropwise. Stir for 1 hour, then bring to room temperature and stir overnight. After completion, quench the reaction with 20 mL of water and concentrate under reduced pressure to remove DMF. Wash the mixture sequentially with 100 mL of water, 100 mL of saturated sodium bicarbonate solution, and 100 mL of saturated sodium chloride solution, then extract with EA. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. Purify the mixture by silica gel column chromatography using PE / EA (3:1) as the eluent to obtain 1.21 g of a white solid in a 35% yield.

[0063] 1.5 Synthesis of compound 5

[0064] Compound 4 (173 mg, 0.5 mmol), (R)-1-Boc-3-aminopiperidine (100 mg, 0.5 mmol), and DIPEA (248 μL, 1.5 mmol) were dissolved in 2 mL of N-methylpyrrolidone. The mixture was heated and stirred at 135°C for 3 h. The cooled solution was directly purified by C18 reverse-phase column chromatography, eluting with H2O / CH3CN (1:9) to obtain 232 mg of a light yellow solid in a 91% yield.

[0065] 1.6 Synthesis of compound 6

[0066] Compound 5 (232 mg, 0.45 mmol) and 1 mL of trifluoroacetic acid were mixed in 5 mL of DCM and stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and purified by C18 reverse-phase column chromatography using H2O / CH3CN (3:1) as the eluent to afford 180 mg of a light yellow solid in a 97% yield.

[0067] 1.7 Synthesis of compound ZSQ-25-3

[0068] Compound 6 (205 mg, 0.44 mmol) was mixed with benzoic acid (54 mg, 0.44 mmol) and DIPEA (0.165 mL, 1 mmol) and dissolved in 2.5 mL of dimethyl sulfoxide. HATU (190 mg, 0.5 mmol) was dissolved in 1 mL of dimethyl sulfoxide and slowly added to the solution. The reaction was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was transferred to a separatory funnel and washed sequentially with 100 mL of water, 100 mL of saturated sodium bicarbonate solution, and 100 mL of saturated sodium chloride solution. The mixture was then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and then separated and purified by high-performance liquid chromatography (H2O / CH3CN (1:1). After lyophilization, 163 mg of a white solid was obtained with a yield of 72%.

[0069] LC-MS (m / z): 514 (M+H) + .

[0070] 1 H NMR(400MHz,DMSO)δ9.80-9.39(m,1H),8.34(s,1H),8.22(s,1H),8.11-7.84(m,4H) ,7.84-7.75(m,2H),7.28(s,1H),4.70(s,2H),3.59-3.08(m,1H),1.25-1.00(m,6H).

[0071] Example 2 Synthesis route of compound HQY-10-35

[0072] 2.1 Synthesis of compound 7

[0073] Aniline (93 mg, 1 mmol) was mixed with N,N′-disuccinimidyl carbonate (768 mg, 3 mmol) and DIPEA (0.496 mL, 3 mmol) in 5 mL of tetrahydrofuran and allowed to react overnight at room temperature. After completion, the mixture was transferred to a separatory funnel and washed sequentially with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. The mixture was then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then purified by silica gel column chromatography using PE / EA (1:1) as the eluent to obtain 188 mg of a light yellow solid in an 80% yield.

[0074] 2.2 Synthesis of compound HQY-10-35

[0075] Compound 7 (117 mg, 0.5 mmol) was mixed with compound 6 (205 mg, 0.5 mmol) and DIPEA (0.165 mL, 1 mmol) and dissolved in 2.5 mL of dichloromethane. The mixture was reacted at room temperature for 1 h. After completion of the reaction, the mixture was transferred to a separatory funnel and washed sequentially with 100 mL of water, 100 mL of saturated sodium bicarbonate solution, and 100 mL of saturated sodium chloride solution. The mixture was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and then separated and purified by high-performance liquid chromatography (H2O / CH3CN (1:1). After lyophilization, 176 mg of a white solid was obtained with a yield of 66%.

[0076] LC-MS (m / z): 529 (M+H) + .

[0077] 1 H NMR(400MHz,DMSO)δ9.62(s,1H),8.76-8.55(m,1H),8.47(s,1H),8.18(s,1H),7.87-7.54( m,3H),7.42(d,J=7.9Hz,2H),7.26(s,1H),7.21(t,J=7.7Hz,3H),6.92(t,J=7.2Hz,1H),4. 19-4.10(m,1H),3.95(d,J=12.5Hz,1H),3.77-3.62(m,1H),3.41(s,1H),2.91-2.75(m,J=2 7.2,15.1Hz,2H),1.95(s,1H),1.78-1.70(m,1H),1.56-1.43(m,2H),1.17(d,J=6.7Hz,6H).

[0078] Example 3 Synthesis of Compound HQY-12-44

[0079] 3.1 Synthesis of compound HQY-12-44

[0080] Compound 6 (82 mg, 0.2 mmol) was mixed with benzyl bromide (51 mg, 0.3 mmol) and DIPEA (0.07 mL, 0.4 mmol) and dissolved in 0.25 mL of dry DMSO. The mixture was reacted at 90°C for 3 h. After completion of the reaction, the mixture was transferred to a separatory funnel and washed sequentially with 20 mL of water, 20 mL of saturated sodium bicarbonate solution, and 10 mL of saturated sodium chloride solution. The mixture was then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by silica gel column chromatography, eluting with DCM / MeOH (10:1). High-performance liquid chromatography (HPLC) with H2O / CH3CN (1:1) was used to separate and lyophilize the mixture to obtain 68 mg of a white solid with a yield of 68%.

[0081] LC-MS (m / z): 500 (M+H) + .

[0082] 1 H NMR (400MHz, DMSO) δ10.11-9.51(m,1H),9.50(s,1H),8.88-8.28(m,1H),8.13(s,1H) ,7.84(d,J=7.9Hz,1H),7.75(t,J=7.9Hz,1H),7.57-7.39(m,6H),7.36(t,J=7.4Hz,1H ),4.37(s,2H),3.48-3.34(m,3H),3.21-2.92(m,1H),2.88-2.78(m,1H),2.73-2.58(m ,1H),1.96-1.91(m,1H),1.80-1.64(m,1H),1.50-1.32(m,1H),1.17(d,J=6.5Hz,6H).

[0083] Example 4 Synthesis of Compound HQY-12-79

[0084] 4.1 Synthesis of compound 8

[0085] (R)-tert-Butyl (6-oxopiperidin-3-yl)carbamate (107 mg, 0.5 mmol) and benzyl bromide (85 mg, 0.5 mmol) were mixed and dissolved in 3 mL of dry DMF. NaH (24 mg, 1 mmol) was added under an ice bath and allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was transferred to a separatory funnel and washed sequentially with 20 mL of water, 20 mL of saturated sodium bicarbonate solution, and 10 mL of saturated sodium chloride solution. The mixture was then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then purified by silica gel column chromatography using PE / EA (1:1) as the eluent to obtain 50 mg of a white solid in a 33% yield.

[0086] 4.2 Synthesis of compound 9

[0087] Compound 8 (50 mg, 0.16 mmol) was mixed with 0.5 mL of trifluoroacetic acid in 2.5 mL of DCM and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by C18 reverse-phase column chromatography using H2O / CH3CN (2:1) as the eluent to afford 32 mg of a light yellow solid in a 96% yield.

[0088] 4.3 Synthesis of compound HQY-12-79

[0089] Compound 4 (55 mg, 0.15 mmol) was mixed with compound 9 (32 mg, 0.15 mmol) and DIPEA (0.05 mL, 0.3 mmol) and dissolved in 1 mL of N-methylpyrrolidone. The mixed solution was heated and stirred at 135 ° C for 6 h. The cooled solution was transferred to a separatory funnel and washed with 10 mL of water, 10 mL of saturated sodium bicarbonate solution, and 10 mL of saturated sodium chloride solution, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and then separated and purified by high performance liquid chromatography H2O / CH3CN (2:1). After freeze-drying, 21 mg of white solid was obtained with a yield of 27%.

[0090] LC-MS (m / z): 514 (M+H) + .

[0091] 1 H NMR (400MHz, DMSO) δ10.46(s,2H),8.25(d,J=8.3Hz,1H),7.99(d,J=7.1Hz,1H),7.83(s,1H),7 .56(t,J=7.5Hz,1H),7.44(t,J=7.6Hz,1H),7.27-7.20(m,2H),4.87-4.69(m,1H),4.53-4.29( m,1H),4.24-3.97(m,1H),3.56-3.42(m,J=11.9,4.5Hz,1H),3.41-3.27(m,1H),3.18(dt,J=13 .6,6.8Hz,1H),2.88-2.70(m,1H),2.63-2.48(m,1H),2.25-1.99(m,2H),1.31(d,J=6.8Hz,6H).

[0092] Example 5 Synthesis of Compound HQY-17-26

[0093] 5.1 Synthesis of Compound HQY-17-26

[0094] Compound 6 (25 mg, 0.044 mmol) and 3-indolecarboxaldehyde (6.4 mg, 0.044 mmol) were mixed and dissolved in 0.25 mL of methanol. After adding half a drop of acetic acid, sodium cyanoborohydride (12.6 mg, 0.2) was added in batches and reacted at room temperature for 1 h. After completion of the reaction, the mixture was transferred to a separatory funnel and washed with 10 mL of water, 10 mL of saturated sodium bicarbonate solution, and 10 mL of saturated sodium chloride solution, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. After separation and purification by silica gel column chromatography, eluted with DCM / MeOH (10:1), and then separated and purified by high performance liquid chromatography (H2O / CH3CN (1:1), lyophilized to obtain 13 mg of a white solid with a yield of 55%.

[0095] LC-MS (m / z): 539 (M+H) + .

[0096] 1 H NMR(400MHz,DMSO)δ11.52(s,1H),10.00-9.54(m,1H),9.50(s,1H),8.91-8.41(m,1H),8.13(s,1H),7 .83(d,J=7.9Hz,1H),7.78(d,J=7.8Hz,1H),7.73(s,1H),7.60(s,1H),7.45(d,J=7.9Hz,1H),7.34(d, J=5.6Hz,1H),7.25-7.04(m,2H),4.52(s,2H),4.26-4.11(m,1H),3.50-3.38(m,3H),3.25-2.94(m,1H ),2.88-2.80(m,1H),2.73-2.60(m,1H),2.09-1.84(m,2H),1.79-1.66(m,1H),1.16(d,J=6.5Hz,6H).

[0097] Comparative Example 6 Synthesis of Control Compound ZSQ-25-49

[0098] The raw material benzoic acid was replaced by acetic acid, and the other reaction steps were the same as in Example 1 to obtain compound ZSQ-25-49.

[0099] LC-MS (m / z): 452 (M+H) + .

[0100] 1H NMR(400MHz, CDCl3)δ9.56(s,1H),8.55(d,J=8.3Hz,1H),8.05(s,1H),7.89(t,J=7.9Hz,1H),7.70-7.58(m,1H),7.26-7.17(m,1H), 5.03(s,1H),3.98-3.80(m,2H),3.30-3.06(m,3H),2.07(d,J=20.8Hz,3H),1.85-1.72(m,2H),1.65-1.57(m,2H),1.33-1.27(m,6H).

[0101] Example 7 Synthesis of Compound HQY-10-14

[0102] The raw material benzoic acid was replaced with 4-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-14.

[0103] LC-MS (m / z): 532 (M+H) + .

[0104] 1 H NMR (400MHz, DMSO) δ9.67-9.43(m,1H),9.00-8.35(m,1H),8.23-8.10(m,1H),7.83(d,J=7.5Hz,1H),7.78-7.72(m,1H),7.54-7. 13(m,6H),4.45-4.35(m,1H),3.73-3.45(m,3H),3.10-3.00(m,1H),2.03-1.85(m,2H),1.74-1.45(m,3H),1.16(d,J=6.2Hz,6H).

[0105] Example 8 Synthesis of Compound HQY-10-15

[0106] The raw material benzoic acid was replaced with 2-pyridinecarboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-15.

[0107] LC-MS (m / z): 515 (M+H) + .

[0108] 1H NMR(400MHz,DMSO)δ9.69-9.49(m,1H),8.85-8.46(m,2H),8.28-8.18(m,1H) ,8.02-7.87(m,1H),7.83(d,J=7.4Hz,1H),7.80-7.63(m,2H),7.58(d,J=7.6 Hz,1H),7.43-7.30(m,2H),3.91-3.62(m,2H),3.54-3.41(m,2H),3.01-2.79 (m,1H),2.05-1.82(m,2H),1.77-1.41(m,3H),1.18(dd,J=12.5,6.8Hz,6H).

[0109] Example 9 Synthesis of Compound HQY-10-16

[0110] The raw material benzoic acid was replaced with 3-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-16.

[0111] LC-MS (m / z): 532 (M+H) + .

[0112] 1 H NMR (400MHz, DMSO) δ9.48 (s, 1H), 8.91-8.60 (m, 1H), 8.25-8.02 (m, 1H), 7.83 (d, J = 7.9Hz, 1H), 7.81-7.50 (m, 2H), 7.42-6. 94(m,5H),3.90-3.75(m,1H),3.65-3.31(m,3H),3.14-2.93(m,1H),1.94(s,2H),1.76-1.39(m,3H),1.16(d,J=6.5Hz,6H).

[0113] Example 10 Synthesis of Compound HQY-10-17

[0114] The raw material benzoic acid was replaced with 2-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-17.

[0115] LC-MS (m / z): 532 (M+H) + .

[0116] 1H NMR (400MHz, DMSO) δ9.69-9.46(m,1H),8.71(d,J=59.4Hz,1H),8.21(s,1H),7.90-7.65(m,3H),7.55-7.22(m,5H),4.59-4.55(m, 1H),3.81-3.62(m,1H),3.49-3.30(m,2H),2.97-2.80(m,1H),2.03-1.77(m,2H),1.74-1.32(m,3H),1.18(dd,J=13.2,6.7Hz,6H).

[0117] Example 11 Synthesis of Compound HQY-10-18

[0118] The raw material benzoic acid was replaced by isonicotinic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-18.

[0119] LC-MS (m / z): 515 (M+H) + .

[0120] 1 H NMR(400MHz,DMSO)δ9.64-9.47(m,1H),8.87-8.68(m,2H),8.34-8.21(m,1H), 8.17-7.98(m,1H),7.83(d,J=7.5Hz,1H),7.75(t,J=7.7Hz,1H),7.70-7.46(m ,2H),7.38-7.31(m,1H),7.31-7.06(m,1H),4.02-3.80(m,1H),3.51-3.13(m, 3H),3.06-2.92(m,1H),1.95(s,2H),1.77-1.38(m,3H),1.17(d,J=6.9Hz,5H).

[0121] Example 12 Synthesis of Compound HQY-10-19

[0122] The raw material benzoic acid was replaced with nicotinic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-19.

[0123] LC-MS (m / z): 515 (M+H) + .

[0124] 1H NMR(400MHz,DMSO)δ9.72-9.43(m,J=36.3Hz,1H),8.78-8.63(m,2H),8.49- 8.07(m,2H),8.01-7.93(m,1H),7.84(d,J=7.2Hz,1H),7.75(t,J=7.4Hz,1H) ,7.64-7.54(m,1H),7.43-7.16(m,2H),3.94-3.62(m,2H),3.52-3.36(m,2H ),3.11-2.93(m,1H),1.95(s,2H),1.76-1.44(m,3H),1.16(d,J=6.4Hz,6H).

[0125] Example 13 Synthesis of Compound HQY-10-34

[0126] The raw material compound 7 was replaced by phenyl chloroformate, and the other reaction steps were the same as in Example 2 to obtain compound HQY-10-34.

[0127] LC-MS (m / z): 530 (M+H) + .

[0128] 1 H NMR (400MHz, DMSO) δ9.54 (s, 1H), 8.98-8.46 (m, 2H), 8.19 (s, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.77-7.62 (m, 1H), 7.51-7.09 (m, 5H), 7.05-6 .76(m,1H),4.07-3.63(m,3H),3.45-3.30(m,1H),3.17-2.79(m,2H),1.96(s,1H),1.83(s,1H),1.68-1.46(m,2H),1.25-0.85(m,6H).

[0129] Example 14 Synthesis of Compound HQY-10-42

[0130] The raw material compound 7 was replaced by N-methyl-N-phenylcarbamoyl chloride, and the other reaction steps were the same as in Example 2 to obtain compound HQY-10-42.

[0131] LC-MS (m / z): 543 (M+H) + .

[0132] 1H NMR(400MHz,DMSO)δ9.74-9.40(m,1H),8.78-8.44(m,1H),8.16(s,1H),7. 91-7.81(m,1H),7.74(t,J=7.7Hz,1H),7.54-7.21(m,4H),7.11-6.95(m,3H ),3.77-3.71(m,1H),3.68-3.28(m,4H),3.05(s,3H),2.68-2.59(m,2H),1 .87-1.79(m,1H),1.55-1.46(m,1H),1.41-1.33(m,1H),1.20-1.14(m,6H).

[0133] Example 15 Synthesis of Compound HQY-10-44

[0134] The raw material benzoic acid was replaced with benzenesulfonic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-44.

[0135] LC-MS (m / z): 550 (M+H) + .

[0136] 1 H NMR(400MHz,DMSO)δ9.75-9.43(m,1H),8.86-8.46(m,1H),8.20(s,1H),7.88- 7.82(m,1H),7.81-7.69(m,J=8.2Hz,4H),7.64(t,J=7.4Hz,2H),7.49-7.22(m, 2H),3.85-3.65(m,2H),3.48-3.40(m,2H),2.30-2.23(m,1H),2.16-2.09(m,1H ),1.84-1.75(m,2H),1.57-1.48(m,1H),1.32-1.24(m,1H),1.22-1.11(m,6H).

[0137] Example 16 Synthesis of Compound HQY-10-47

[0138] The raw material benzoic acid was replaced by cyclohexanecarboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-47.

[0139] LC-MS (m / z): 520 (M+H) + .

[0140] 1H NMR(400MHz,DMSO)δ9.99-9.43(m,1H),8.85-8.50(m,1H),8.18(s,1H),7. 83(d,J=7.7Hz,1H),7.79-7.70(m,1H),7.59-7.28(m,2H),4.47-4.37(m,1H ),4.01-3.62(m,J=68.7Hz,3H),3.48-3.41(m,1H),3.15-2.82(m,2H),2.68 -2.53(m,1H),2.00-1.53(m,7H),1.52-1.22(m,6H),1.18(d,J=6.5Hz,6H).

[0141] Example 17 Synthesis of Compound HQY-10-58

[0142] The raw material aniline was replaced with 4-aminopyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-10-58.

[0143] LC-MS (m / z): 530 (M+H) + .

[0144] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),10.05(s,1H),9.85(s,1H),8.45(d,J=7.7Hz,1H ),8.32-8.21(m,2H),7.96(d,J=7.4Hz,1H),7.93-7.86(m,2H),7.83(s,1H),7.73-7 .66(m,1H),7.45-7.38(m,1H),4.14-4.02(m,1H),3.77-3.61(m,3H),3.58-3.50(m, 1H),3.25-3.17(m,1H),1.98-1.84(m,3H),1.69-1.61(m,1H),1.32(d,J=6.0Hz,6H).

[0145] Example 18 Synthesis of Compound HQY-10-63

[0146] The raw material benzoic acid was replaced with 4-methylaminobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-63.

[0147] LC-MS (m / z): 543 (M+H) + .

[0148] 1H NMR (400MHz, DMSO) δ9.81-9.49(m,1H),8.79-8.38(m,J=145.9Hz,1H),8.25-8.13( m,1H),7.84(d,J=7.4Hz,1H),7.74(s,1H),7.51-7.27(m,2H),7.23-7.09(m,2H),6 .59-6.44(m,2H),3.77-3.60(m,2H),3.45-3.38(m,1H),3.23-2.85(m,3H),2.69(s ,3H),1.99-1.92(m,1H),1.80-1.73(m,1H),1.64-1.39(m,3H),1.19-1.12(m,6H).

[0149] Example 19 Synthesis of Compound HQY-10-65

[0150] The raw material benzoic acid was replaced with 4-aminobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-10-65.

[0151] LC-MS (m / z): 529 (M+H) + .

[0152] 1 H NMR (400MHz, DMSO) δ9.72-9.45 (m, J=48.2Hz, 1H), 8.85-8.43 (m, 1H), 8.21-8.08 (m, 1H), 7.83 (d, J= 7.9Hz,1H),7.78-7.69(m,1H),7.66-7.40(m,J=74.4Hz,1H),7.35(t,J=7.1Hz,1H),7.27-7.09(m,J= 30.6Hz,2H),6.79-6.54(m,2H),3.86-3.65(m,J=37.8Hz,3H),3.46-3.41(m,1H),3.22-2.68(m,4H) ,2.00-1.93(m,1H),1.80-1.72(m,1H),1.61-1.53(m,1H),1.51-1.42(m,1H),1.17(d,J=6.8Hz,6H).

[0153] Example 20 Synthesis of Compound HQY-11-3

[0154] The raw material aniline was replaced with 3-fluoroaniline, and the other reaction steps were the same as in Example 2 to obtain compound HQY-11-3.

[0155] LC-MS (m / z): 547 (M+H) + .

[0156] 1 H NMR(400MHz,DMSO)δ9.67-9.48(m,1H),8.80-8.52(m,2H),8.17(s,1H),7.96-7.45( m,3H),7.41(d,J=12.4Hz,1H),7.24-7.17(m,2H),6.76-6.63(m,1H),4.11(d,J=11.9 Hz,1H),3.93(d,J=13.4Hz,1H),3.57-3.49(m,1H),3.44-3.37(m,1H),2.94-2.79(m, 2H),2.00-1.91(m,1H),1.81-1.70(m,1H),1.61-1.40(m,2H),1.17(d,J=6.7Hz,6H).

[0157] Example 21 Synthesis of Compound HQY-11-58

[0158] The raw material aniline was replaced with 4-aminopyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-11-58.

[0159] LC-MS (m / z): 530 (M+H) + .

[0160] 1 H NMR (400MHz, DMSO) δ9.93 (s, 1H), 9.57 (s, 1H), 8.92-8.53 (m, 1H), 8.26 (d, J = 4.8Hz, 1H), 8.1 7(s,1H),8.00(s,1H),7.86-7.64(m,2H),7.67-7.45(m,2H),7.34(s,1H),7.20(t,J=6.1Hz, 1H),4.13(d,J=12.6Hz,1H),3.96(d,J=13.4Hz,1H),3.75(s,1H),3.47-3.38(m,1H),3.08-2 .96(m,1H),2.05-1.94(m,1H),1.88-1.77(m,1H),1.62-1.47(m,2H),1.17(d,J=6.7Hz,6H).

[0161] Example 22 Synthesis of Compound HQY-11-63

[0162] The raw material aniline was replaced with 2-fluoroaniline, and the other reaction steps were the same as in Example 2 to obtain compound HQY-11-63.

[0163] LC-MS (m / z): 547 (M+H) + .

[0164] 1 H NMR (400MHz, CDCl3) δ10.47(s,1H),10.21(s,1H),8.54(d,J=8.3Hz,1H),8.05(t,J=7.9Hz,1H),7.90(d,J=7.8Hz,1H), 7.81(s,1H),7.68(t,J=7.8Hz,1H),7.24(d,J=7.8Hz,1H),7.11(t,J=7.3Hz,1H),7.02(dd,J=20.1,10.0Hz,2H),6.64(s ,1H),4.23(d,J=11.6Hz,1H),3.96-3.88(m,1H),3.80(d,J=13.1Hz,1H),3.23-3.16(m,2H),3.10-3.05(m,J=10.9Hz,1 H),2.15-2.09(m,1H),2.01-1.94(m,1H),1.87-1.78(m,J=10.9Hz,1H),1.71-1.62(m,1H),1.32(dd,J=9.9,7.2Hz,6H).

[0165] Example 23 Synthesis of Compound HQY-11-69

[0166] The raw material benzoic acid was replaced with 3-trifluoromethylbenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-69.

[0167] LC-MS (m / z): 582 (M+H) + .

[0168] 1H NMR (400MHz, CDCl3) δ10.46(s,1H),9.96(s,1H),8.56(s,1H),7.97(d,J=7.9Hz,1H),7.87-7.70(m,3H),7.69-7.49(m,3H),7.41(t,J=7.4Hz,1 H),4.54-4.08(m,1H),4.04(s,1H),3.48-3.38(m,2H),3.32-3.18(m,2H ),2.08(s,1H),1.91(s,2H),1.54(s,1H),1.33(dd,J=11.7,6.9Hz,6H).

[0169] Example 24 Synthesis of Compound HQY-11-70

[0170] The raw material benzoic acid was replaced with 3,5-difluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-70.

[0171] LC-MS (m / z): 550 (M+H) + .

[0172] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),9.98(s,1H),8.52(s,1H),7.98(d,J=7.5Hz,1H),7.84(s,1H),7.82-7.70(m,1H),7.49-7.37(m,1H),7.05-6. 74(m,3H),4.37-4.21(m,1H),4.02(s,1H),3.49-3.37(m,2H),3.31-3.20 (m,2H),2.07(s,1H),1.98-1.80(m,2H),1.53(s,1H),1.40-1.15(m,6H).

[0173] Example 25 Synthesis of Compound HQY-11-71

[0174] The raw material benzoic acid was replaced with 3-cyanobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-71.

[0175] LC-MS (m / z): 539 (M+H) + .

[0176] 1H NMR (400MHz, CDCl3) δ10.49(s,1H),9.98(s,1H),8.51(s,1H),7.99(d,J=7.8Hz,1H),7.86(s,1H),7.82-7.64(m,4H),7.57(s,1H),7.44(t,J=7.5Hz ,1H),4.22-4.01(m,2H),3.59(s,1H),3.40-3.31(m,2H),3.25-3.20(m,1 H),2.12-2.03(m,1H),2.01-1.89(m,2H),1.54(s,1H),1.37-1.30(m,6H).

[0177] Example 26 Synthesis of Compound HQY-11-72

[0178] The raw material benzoic acid was replaced with 3,4-difluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-72.

[0179] LC-MS (m / z): 550 (M+H) + .

[0180] 1 H NMR (400MHz, CDCl3) δ10.49(s,1H),9.96(s,1H),8.51(s,1H),7.98(d,J=7.6Hz,1 H),7.84(s,1H),7.78(t,J=7.5Hz,1H),7.44(d,J=7.0Hz,1H),7.27(s,1H),7.22(s ,2H),4.26-3.99(m,2H),3.54-3.41(m,2H),3.37-3.30(m,1H),3.24-3.19(m,1H) ,2.11-2.05(m,1H),2.00-1.88(m,2H),1.55(s,1H),1.33(dd,J=10.4,6.9Hz,6H).

[0181] Example 27 Synthesis of Compound HQY-11-91

[0182] The raw material benzoic acid was replaced with 3-cyano-4-fluoro-benzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-91.

[0183] LC-MS (m / z): 557 (M+H) + .

[0184] 1H NMR(400MHz,DMSO)δ9.76-9.46(m,1H),9.19-8.29(m,1H),8.40-7.90(m,2H),7.94 -7.84(m,1H),7.83(d,J=7.8Hz,1H),7.75(t,J=7.6Hz,1H),7.69-7.54(m,1H),7.5 1-7.33(m,1H),7.36-7.15(m,1H),4.27-4.00(m,2H),3.90-3.75(m,1H),3.72-3.2 6(m,3H),3.21-2.95(m,1H),1.95(s,1H),1.75-1.48(m,2H),1.16(d,J=6.4Hz,6H).

[0185] Example 28 Synthesis of Compound HQY-11-92

[0186] The raw material benzoic acid was replaced with 4-fluoropyridine-2-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-92.

[0187] LC-MS (m / z): 533 (M+H) + .

[0188] 1 H NMR(400MHz,DMSO)δ10.04-9.29(m,1H),8.62(s,1H),8.34(d,1H),8.20(s,0 H),7.83(d,J=7.9Hz,2H),7.73(d,J=7.9Hz,1H),7.58(d,1H),7.34(s,1H),4 .52(d,J=12.3Hz,1H),3.58-3.52(m,1H),3.47-3.40(m,1H),3.02(s,1H),2. 88-2.67(m,1H),2.05-1.83(m,2H),1.74-1.42(m,3H),1.18(t,J=8.6Hz,6H).

[0189] Example 29 Synthesis of Compound HQY-11-93

[0190] The raw material benzoic acid was replaced with 4-cyano-3-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-93.

[0191] LC-MS (m / z): 557 (M+H) + .

[0192] 1H NMR(400MHz,DMSO)δ9.83-9.45(m,1H),9.00-8.49(m,1H),8.22(s,1H),8.06-7.9 1(m,1H),7.84(d,J=7.8Hz,1H),7.75(d,J=7.2Hz,1H),7.64(d,J=10.1Hz,1H),7.4 5(d,J=8.3Hz,1H),7.41-7.26(m,2H),3.78-3.68(m,1H),3.45(s,2H),3.35-3.25 (m,1H),3.01(s,1H),2.06-1.85(m,2H),1.77-1.41(m,3H),1.17(d,J=5.5Hz,6H).

[0193] Example 30 Synthesis of Compound HQY-11-97

[0194] The raw material benzoic acid was replaced with 5-fluoronicotinic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-11-97.

[0195] LC-MS (m / z): 533 (M+H) + .

[0196] 1 H NMR (400MHz, DMSO) δ9.46 (s, 1H), 8.83-8.67 (m, 1H), 8.63-8.49 (m, 0H), 8.47-7.94 (m, 2H), 7.82 (d, J = 7.9Hz, 2H), 7.75 (t, J = 7.9Hz, 1 H),7.54(s,1H),7.35(d,J=7.4Hz,1H),3.48-3.37(m,3H),3.28-2.92(m,2H),2.04-1.83(m,2H),1.64(d,3H),1.17(d,J=6.4Hz,6H).

[0197] Example 31 Synthesis of Compound HQY-11-103

[0198] The raw material aniline was replaced with 2-amino-5-fluoropyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-11-103.

[0199] LC-MS (m / z): 548 (M+H) + .

[0200] 1H NMR(400MHz,DMSO)δ9.60(s,1H),9.21(s,1H),8.79-8.50(m,1H),8.19(s,2H), 7.91-7.78(m,2H),7.65(s,1H),7.64(t,J=9.4Hz,1H),7.53-7.21(m,2H),4.13 -4.11(m,1H),3.94(d,J=11.2Hz,1H),3.72-3.64(m,1H),3.43(s,1H),2.94-2. 81(m,2H),1.93(s,1H),1.74(d,J=10.7Hz,1H),1.57-1.43(m,2H),1.16(s,6H).

[0201] Example 32 Synthesis of Compound HQY-12-3

[0202] The raw material aniline was replaced with 2-amino-4-fluoropyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-12-3.

[0203] LC-MS (m / z): 548 (M+H) + .

[0204] 1 H NMR(400MHz,DMSO)δ9.74-9.39(m,2H),8.83-8.47(m,1H),8.31-8.05(m,2H),7.80(s,1H),7 .61(s,1H),7.61-7.57(m,1H),7.57-7.19(m,J=38.5Hz,2H),6.91(t,J=5.9Hz,1H),4.09(d,J =12.6Hz,1H),3.92(d,J=13.7Hz,1H),3.69(s,1H),3.42(s,1H),2.92(dd,J=21.4,11.7Hz,2H ),1.93(s,1H),1.81-1.71(m,1H),1.59-1.41(m,J=22.3,11.8Hz,2H),1.17(d,J=6.3Hz,6H).

[0205] Example 33 Synthesis of Compound HQY-12-7

[0206] The raw material aniline was replaced with 3,5-difluoroaniline, and the other reaction steps were the same as in Example 2 to obtain compound HQY-12-7.

[0207] LC-MS (m / z): 565 (M+H) + .

[0208] 1 H NMR(400MHz,DMSO)δ9.72-9.45(m,1H),8.83(s,1H),8.79-8.50(m,1H),8.1 6(s,1H),7.78(s,1H),7.55(s,1H),7.34(s,1H),7.20(d,J=9.2Hz,3H),6.70 (t,J=9.3Hz,1H),4.08(s,1H),3.90(s,1H),3.41(s,2H),2.96-2.84(m,2H), 2.00-1.92(m,1H),1.81-1.73(m,1H),1.57-1.43(m,2H),1.19-1.14(m,6H).

[0209] Example 34 Synthesis of Compound HQY-12-52

[0210] The raw material benzyl bromide was replaced with 2-chloroquinazoline, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-52.

[0211] LC-MS (m / z): 538 (M+H) + .

[0212] 1 H NMR (400MHz, CDCl3) δ10.45(s,2H),9.10(s,1H),8.46(d,J=8.3Hz,1H),7.93(d,J=7.9Hz,1H),7.88-7.76(m,4H),7.46(dd,J=16.9,8.6Hz,2 H),7.30(d,J=7.6Hz,1H),4.31(d,J=21.4Hz,4H),3.98(s,1H),3.27-3.22(m,1H),2.08(s,2H),1.97(s,1H),1.82(s,1H),1.39-1.32(m,6H).

[0213] Example 35 Synthesis of Compound HQY-12-56

[0214] The raw material (R)-1-Boc-3-aminopiperidine was replaced by trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester, and benzyl bromide was replaced by 2-chloroquinazoline. The other reaction steps were the same as in Example 3 to obtain compound HQY-12-56.

[0215] LC-MS (m / z): 552 (M+H) + .

[0216] 1 H NMR (400MHz, CDCl3) δ11.08 (d, J = 7.2Hz, 1H), 10.49 (s, 1H), 10.21 (s, 1H), 9.2 3(s,1H),8.51(d,J=8.2Hz,1H),7.99(d,J=7.6Hz,1H),7.93-7.85(m,3H),7.8 0(s,1H),7.76(d,J=8.0Hz,1H),7.48(t,J=7.4Hz,2H),4.26(s,1H),3.82(s,1 H),3.25-3.18(m,1H),2.23-2.13(m,4H),1.67(s,4H),1.35(d,J=6.7Hz,6H).

[0217] Example 36 Synthesis of Compound HQY-12-57

[0218] The raw material benzyl bromide was replaced with 4-fluorobenzyl bromide, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-57.

[0219] LC-MS (m / z): 518 (M+H) + .

[0220] 1 H NMR (400MHz, CDCl3) δ10.67(s,1H),10.60(s,1H),8.40(d,J=8.0Hz,1H),7.95(d,J=7.9Hz,1H),7. 90(t,J=7.6Hz,1H),7.79(s,1H),7.44(d,J=7.6Hz,1H),7.41-7.36(m,2H),7.04(t,J=8.3Hz,2H),4 .47(s,1H),4.35(d,J=12.8Hz,1H),4.05(d,J=13.0Hz,1H),3.67-3.57(m,2H),3.22-3.16(m,1H), 2.71-2.56(m,2H),2.26-2.17(m,1H),2.14-1.97(m,2H),1.66-1.49(m,1H),1.31(t,J=6.4Hz,6H).

[0221] Example 37 Synthesis of Compound HQY-12-61

[0222] The raw material (R)-1-Boc-3-aminopiperidine was replaced by (1R,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, and benzoic acid was replaced by aniline. The other reaction steps were the same as in Example 1 to obtain compound HQY-12-61.

[0223] LC-MS (m / z): 528 (M+H) + .

[0224] 1 H NMR (400MHz, CDCl3) δ10.51(s,1H),9.81(s,1H),8.55(d,J=7.9Hz,2H),7.98(d,J=7.8Hz,1H),7. 83(s,1H),7.74(t,J=7.6Hz,1H),7.60(d,J=7.7Hz,2H),7.44(t,J=7.5Hz,1H),7.31(t,J=7.9Hz,2 H),7.07(t,J=7.3Hz,1H),4.20(s,1H),3.26-3.17(m,1H),2.90-2.81(m,1H),2.15-2.08(m,2H),2 .00-1.95(m,1H),1.94-1.90(m,1H),1.76-1.69(m,2H),1.60-1.54(m,2H),1.33(d,J=6.8Hz,6H).

[0225] Example 38 Synthesis of Compound HQY-12-72

[0226] The raw material benzyl bromide was replaced with 2-fluorobenzyl bromide, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-72.

[0227] LC-MS (m / z): 518 (M+H) + .

[0228] 1H NMR (400MHz, CDCl3) δ10.53(s,1H),10.22(s,1H),8.39(s,1H),7.93(d,J=7.5Hz,1H),7.8 7(s,1H),7.82(s,1H),7.50(d,J=7.2Hz,1H),7.45-7.38(m,2H),7.21-7.17(m,1H),7.13( t,J=8.9Hz,1H),4.52-4.43(m,1H),4.29(s,2H),3.68-3.54(m,2H),3.21-3.17(m,1H),2. 77-2.68(m,2H),2.22-2.15(m,1H),2.10-1.98(m,2H),1.58(s,1H),1.31(d,J=6.8Hz,6H).

[0229] Example 39 Synthesis of Compound HQY-12-73

[0230] The raw material benzyl bromide was replaced with 3-fluorobenzyl bromide, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-73.

[0231] LC-MS (m / z): 518 (M+H) + .

[0232] 1 H NMR (400MHz, CDCl3) δ10.63(s,1H),10.51(s,1H),8.39(d,J=8.1Hz,1H),7.94(d,J=7.8Hz,2H),7.79(s,1H),7. 43(t,J=7.5Hz,1H),7.38-7.32(m,1H),7.20(d,J=7.7Hz,1H),7.15(d,J=9.0Hz,1H),7.09(t,J=7.7Hz,1H),4.53 -4.44(m,1H),4.34(d,J=12.8Hz,1H),4.07(d,J=12.5Hz,1H),3.66-3.55(m,2H),3.21-3.16(m,1H),2.71-2.62( m,2H),2.25-2.18(m,1H),2.13-2.05(m,1H),2.03-1.97(m,1H),1.65-1.53(m,1H),1.31(dd,J=6.7,1.6Hz,6H).

[0233] Example 40 Synthesis of Compound HQY-12-74

[0234] The raw material benzyl bromide was replaced with 3-methoxybenzyl bromide, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-74.

[0235] LC-MS (m / z): 530 (M+H) + .

[0236] 1 H NMR (400MHz, CDCl3) δ10.60(s,1H),10.47(s,1H),8.40(d,J=8.0Hz,1H),8.02-7.89(m,2H),7.79(s,1H), 7.41(t,J=7.4Hz,1H),7.31-7.27(m,1H),6.99(s,1H),6.96-6.90(m,2H),4.55-4.44(m,1H),4.31(d,J=1 2.4Hz,1H),4.07(d,J=12.5Hz,1H),3.78(s,3H),3.68-3.58(m,2H),3.20-3.15(m,1H),2.71-2.59(m,2H) ,2.25-2.16(m,1H),2.14-2.04(m,1H),2.02-1.93(m,1H),1.64-1.48(m,1H),1.31(dd,J=6.4,2.4Hz,7H).

[0237] Example 41 Synthesis of Compound HQY-12-84

[0238] The raw material benzyl bromide was replaced with 2-(chloromethyl)benzimidazole, and the other reaction steps were the same as in Example 3 to obtain compound HQY-12-84.

[0239] LC-MS (m / z): 540 (M+H) + .

[0240] 1H NMR (400MHz, CDCl3) δ9.68 (s, 1H), 8.58 (d, J = 8.2Hz, 1H), 7.91 (s, 1H), 7.89 ( s,1H),7.63(t,J=7.4Hz,1H),7.60-7.49(m,2H),7.26-7.19(m,3H),4.26-3.9 6(m,2H),3.85(s,2H),3.21(dt,J=13.6,6.8Hz,1H),2.92-2.71(m,2H),2.27( s,2H),2.05(s,1H),1.96-1.76(m,2H),1.69-1.47(m,2H),1.32-1.27(m,6H).

[0241] Example 42 Synthesis of Compound HQY-12-96

[0242] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl (trans-3-aminocyclohexyl)carbamate, and the other reaction steps were the same as in Example 1 to obtain compound HQY-12-96.

[0243] LC-MS (m / z): 528 (M+H) + .

[0244] 1 H NMR (400MHz, CDCl3) δ12.33(s,1H),10.44(s,1H),9.35(s,1H),8.65(s,1H),8.55( s,1H),8.27(s,1H),8.20(s,1H),7.96(d,J=7.4Hz,1H),7.90(s,1H),7.72(s,1H),7 .39(s,2H),4.38(s,1H),3.25(s,1H),3.06(s,1H),2.32-2.18(m,1H),2.13-2.03( m,1H),2.04-1.96(m,1H),1.96-1.83(m,3H),1.81-1.71(m,3H),1.34-1.29(m,6H).

[0245] Example 43 Synthesis of Compound HQY-13-1

[0246] The raw material benzoic acid was replaced with 3-methylsulfonylbenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-1.

[0247] LC-MS (m / z): 539 (M+H) + .

[0248] 1 H NMR (400MHz, CDCl3) δ10.49(s,1H),9.98(s,1H),8.51(s,1H),7.99(d,J=7.8Hz,1H),7.86(s,1H),7.82-7.64(m,4H),7.57(s,1H),7.44(t,J=7.5Hz ,1H),4.22-4.01(m,2H),3.59(s,1H),3.40-3.31(m,2H),3.25-3.20(m,1 H),2.12-2.03(m,1H),2.01-1.89(m,2H),1.54(s,1H),1.37-1.30(m,6H).

[0249] Example 44 Synthesis of Compound HQY-13-2

[0250] The raw material benzoic acid was replaced with 4-methylsulfonylbenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-2.

[0251] LC-MS (m / z): 592 (M+H) + .

[0252] 1 H NMR (400MHz, CDCl3) δ10.49 (s, 1H), 10.26 (d, J = 7.0Hz, 1H), 8.54 (d, J = 8.3Hz, 1H), 8.03 (d, J = 7. 7Hz,2H),7.99(d,J=7.8Hz,1H),7.88(s,1H),7.78(t,J=7.6Hz,1H),7.67(d,J=7.8Hz,2H),7.43( t,J=7.4Hz,1H),4.18-4.07(m,2H),3.68-3.62(m,1H),3.40-3.32(m,2H),3.25-3.20(m,1H),3.0 9(s,3H),2.10-2.03(m,1H),2.02-1.89(m,2H),1.61-1.49(m,1H),1.34(dd,J=10.3,7.2Hz,6H).

[0253] Example 45 Synthesis of Compound HQY-13-22

[0254] The raw material benzyl bromide was replaced with 3-fluorobenzyl bromide, and the other reaction steps were the same as in Example 4 to obtain compound HQY-13-22.

[0255] LC-MS (m / z): 532 (M+H)+ .

[0256] 1 H NMR (400MHz, CDCl3) δ10.51(s,1H),10.37(s,1H),8.28(d,J=8.5Hz,1H),8.00(d,J=7.8Hz,1H),7.85(s,1H),7 .60(t,J=7.6Hz,1H),7.46(t,J=7.6Hz,1H),7.23(d,J=7.7Hz,1H),7.02(d,J=7.5Hz,1H),6.97-6.90(m,2H),4. 82(d,J=14.4Hz,1H),4.35(d,J=14.7Hz,1H),4.23-4.08(m,1H),3.47-3.44(m,1H),3.40-3.36(m,1H),3.21-3 .17(m,1H),2.81-2.75(m,1H),2.59-2.53(m,1H),2.21-2.15(m,1H),2.09-2.04(m,1H),1.32(d,J=5.7Hz,6H).

[0257] Example 46 Synthesis of Compound HQY-13-23

[0258] The raw material benzoic acid was replaced with phenylacetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-23.

[0259] LC-MS (m / z): 528 (M+H) + .

[0260] 1 H NMR (400MHz, CDCl3) δ10.60-10.35(m,1H),8.95(s,1H),8.41(d,J=8.3Hz,1H),7.94(d,J=8.1H z,1H),7.71(s,1H),7.62(t,J=7.7Hz,1H),7.34(s,1H),7.33(d,J=7.4Hz,2H),7.24(s,1H),7. 18-7.08(m,1H),4.25(d,J=11.5Hz,1H),3.88-3.74(m,3H),3.65(d,J=14.1Hz,1H),3.38-3.11 (m,4H),2.02-1.94(m,1H),1.85-1.71(m,2H),1.47-1.38(m,1H),1.31(dd,J=10.9,6.9Hz,6H).

[0261] Example 47 Synthesis of Compound HQY-13-25

[0262] The raw material benzoic acid was replaced with 3-fluorophenylacetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-25.

[0263] LC-MS (m / z): 546 (M+H) + .

[0264] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),9.49(s,1H),8.43(d,J=8.2Hz,1H),7.94(d,J=7.8Hz,1H),7.79(s,1H),7 .65(t,J=7.7Hz,1H),7.36(t,J=7.7Hz,1H),7.31(d,J=6.5Hz,1H),7.03(d,J=7.5Hz,1H),7.01-6.88(m,2H), 4.33-4.19(m,1H),3.90-3.83(m,1H),3.82-3.69(m,2H),3.68-3.60(m,1H),3.38-3.27(m,1H),3.24-3.16(m ,2H),2.09-1.95(m,1H),1.91-1.74(m,2H),1.45-1.40(m,1H),1.33(d,J=6.9Hz,3H),1.30(d,J=6.8Hz,3H).

[0265] Example 48 Synthesis of Compound HQY-13-53

[0266] The raw material benzoic acid was replaced with 3-hydroxybenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-53.

[0267] LC-MS (m / z): 530 (M+H) + .

[0268] 1H NMR (400MHz, CDCl3) δ10.42 (s, 1H), 9.48-8.97 (m, 1H), 8.46 (s, 1H), 7.96 (d, J = 7.1Hz ,1H),7.91-7.67(m,2H),7.42(t,J=7.6Hz,1H),7.26(s,1H),7.03-6.86(m,2H),6.86 -6.57(m,1H),4.20-3.81(m,2H),3.81-3.70(m,1H),3.60-3.29(m,2H),3.28-3.12(m ,1H),2.09-1.93(m,1H),1.95-1.69(m,2H),1.70-1.46(m,1H),1.31(d,J=6.7Hz,6H).

[0269] Example 49 Synthesis of Compound HQY-13-54

[0270] The raw material benzoic acid was replaced with 2-hydroxybenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-54.

[0271] LC-MS (m / z): 530 (M+H) + .

[0272] 1 H NMR (400MHz, CDCl3) δ10.44(s,1H),10.08(d,J=6.6Hz,1H),8.41(d,J=8.3Hz,1H),7.97(dd,J=7.9,1.4Hz,1H),7.87(s,1H ),7.75-7.68(m,1H),7.41(t,J=7.4Hz,1H),7.32(t,J=7.7Hz,1H),7.27(s,1H),7.25(s,1H),6.98(d,J=8.1Hz,1H),6.84( t,J=7.5Hz,1H),4.28(d,J=11.9Hz,1H),3.98(s,1H),3.93-3.85(m,1H),3.43(t,J=10.4Hz,1H),3.38-3.27(m,1H),3.20( dt,J=13.6,6.8Hz,1H),2.14-2.06(m,1H),2.02-1.95(m,1H),1.93-1.85(m,1H),1.69-1.58(m,1H),1.32(t,J=7.3Hz,6H).

[0273] Example 50 Synthesis of Compound HQY-13-58

[0274] The raw material benzoic acid was replaced with 4-hydroxybenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-58.

[0275] LC-MS (m / z): 530 (M+H) + .

[0276] 1 H NMR (400MHz, DMSO) δ10.06-9.51 (m, 2H), 8.21 (s, 1H), 7.84 (d, J = 6.9Hz, 1H) ,7.75(s,1H),7.68-7.33(m,2H),7.31-6.98(m,2H),6.99-6.44(m,2H),4.10 -4.01(m,1H),3.60-3.38(m,3H),3.18-2.83(m,2H),2.00-1.90(m,1H),1.8 5-1.68(m,1H),1.64-1.54(m,1H),1.52-1.41(m,1H),1.17(d,J=6.4Hz,6H).

[0277] Example 51 Synthesis of Compound HQY-13-62

[0278] The raw material benzoic acid was replaced with 2-(1H-pyrazol-1-yl)acetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-62.

[0279] LC-MS (m / z): 518 (M+H) + .

[0280] 1 H NMR (400MHz, DMSO) δ9.70-9.47(m,1H),8.80-8.47(m,1H),8.28-8.15(m,1H),8.01-7. 73(m,2H),7.73-7.51(m,2H),7.50-7.25(m,2H),6.40-6.15(m,1H),5.34-5.06(m,2H) ,4.02-3.78(m,2H),3.74-3.57(m,1H),3.49-3.38(m,1H),3.14-2.99(m,1H),2.64-2. 53(m,1H),2.01-1.89(m,1H),1.81-1.71(m,1H),1.63-1.38(m,2H),1.20-1.06(m,6H).

[0281] Example 52 Synthesis of Compound HQY-13-63

[0282] The raw material benzoic acid was replaced with 2-(4-fluoro-1H-pyrazol-1-yl)acetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-63.

[0283] LC-MS (m / z): 536 (M+H) + .

[0284] 1 H NMR (400MHz, DMSO) δ9.65-9.44(m,1H),8.83-8.49(m,1H),8.22-8.13(m,1H),7.86-7. 77(m,2H),7.75-7.51(m,2H),7.47-7.26(m,2H),5.23-4.91(m,2H),3.80-3.75(m,1H) ,3.65-3.52(m,1H),3.45-3.39(m,1H),3.08-3.00(m,1H),2.97-2.76(m,1H),2.64-2. 54(m,1H),1.99-1.91(m,1H),1.80-1.73(m,1H),1.61-1.41(m,2H),1.20-1.05(m,6H).

[0285] Example 53 Synthesis of Compound HQY-13-66

[0286] The raw material benzoic acid was replaced with 6-hydroxypyridine-2-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-66.

[0287] LC-MS (m / z): 539 (M+H) + .

[0288] 1 H NMR (400MHz, CDCl3) δ10.49(s,1H),9.98(s,1H),8.51(s,1H),7.99(d,J=7.8Hz,1H),7.86(s,1H),7.82-7.64(m,4H),7.57(s,1H),7.44(t,J=7.5Hz ,1H),4.22-4.01(m,2H),3.59(s,1H),3.40-3.31(m,2H),3.25-3.20(m,1 H),2.12-2.03(m,1H),2.01-1.89(m,2H),1.54(s,1H),1.37-1.30(m,6H).

[0289] Example 54 Synthesis of Compound HQY-13-67

[0290] The raw material benzoic acid was replaced with 2-hydroxypyridine-5-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-67.

[0291] LC-MS (m / z): 531 (M+H) + .

[0292] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),10.23(s,1H),8.48(d,J=8.2Hz,1H),7.99(d,J=7.5Hz ,1H),7.90-7.84(m,2H),7.81(d,J=8.8Hz,1H),7.75(t,J=7.8Hz,1H),7.45(t,J=7.6Hz,1H ),6.72(d,J=8.5Hz,1H),4.18-4.09(m,1H),3.85-3.72(m,2H),3.59-3.45(m,2H),3.25-3. 18(m,1H),2.13-1.99(m,2H),1.98-1.90(m,1H),1.69-1.56(m,1H),1.33(t,J=6.2Hz,6H).

[0293] Example 55 Synthesis of Compound HQY-13-68

[0294] The raw material benzoic acid was replaced with 2-oxo-3H-pyrimidine-4-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-68.

[0295] LC-MS (m / z): 532 (M+H) + .

[0296] 1H NMR(400MHz,DMSO)δ9.66-9.45(m,1H),8.96-8.47(m,1H),8.20(s,1H),8.12-7.99( m,1H),7.83(d,J=8.0Hz,1H),7.79-7.74(m,1H),7.71-7.37(m,1H),7.37-7.32(m,1 H),6.47-6.13(m,1H),4.43-4.41(m,1H),3.79-3.68(m,1H),3.52-3.24(m,3H),3.0 4-2.79(m,1H),2.03-1.75(m,2H),1.74-1.42(m,3H),1.17(dd,J=12.1,7.0Hz,6H).

[0297] Example 56 Synthesis of Compound HQY-13-69

[0298] The raw material benzoic acid was replaced with 2-hydroxyisonicotinic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-69.

[0299] LC-MS (m / z): 531 (M+H) + .

[0300] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),10.34(d,J=6.7Hz,1H),8.50(d,J=8.3Hz,1H),7.98(d,J=8.0Hz,1H),7.8 6(s,1H),7.77(t,J=7.7Hz,1H),7.55(d,J=6.4Hz,1H),7.43(t,J=7.7Hz,1H),6.68(s,1H),6.63(d,J=6.1Hz, 1H),4.29-4.13(m,1H),4.13-3.95(m,1H),3.60-3.48(m,1H),3.47-3.38(m,1H),3.36-3.26(m,1H),3.22(dt ,J=13.4,6.7Hz,1H),2.17-2.05(m,1H),2.03-1.84(m,2H),1.60-1.50(m,1H),1.34(dd,J=11.6,6.9Hz,7H).

[0301] Example 57 Synthesis of Compound HQY-13-82

[0302] The raw material benzoic acid was replaced with 4-fluoro-3-hydroxybenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-82.

[0303] LC-MS (m / z): 548 (M+H) + .

[0304] 1 H NMR (400MHz, CDCl3) δ10.44(s,1H),9.51(s,1H),8.46(s,1H),7.97(d,J=7.9Hz, 1H),7.81(s,1H),7.78-7.69(m,1H),7.43(t,J=7.6Hz,1H),7.22-6.94(m,2H),6. 90(s,1H),4.20-3.77(m,2H),3.67-3.59(m,1H),3.55-3.27(m,2H),3.25-3.16( m,1H),2.17-1.97(m,1H),1.97-1.77(m,2H),1.55(s,1H),1.32(t,J=6.4Hz,6H).

[0305] Example 58 Synthesis of Compound HQY-13-94

[0306] The raw material benzoic acid was replaced with 3-aminobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-13-94.

[0307] LC-MS (m / z): 529 (M+H) + .

[0308] 1 H NMR (400MHz, CDCl3) δ10.47(s,1H),9.96(s,1H),8.53(s,1H),8.00(s,1H),7.96(d,J =7.7Hz,1H),7.85(s,1H),7.82-7.70(m,1H),7.42(t,J=7.4Hz,1H),7.26-7.18(m,1H) ,7.03-6.79(m,3H),4.26-3.99(m,1H),3.72-3.43(m,2H),3.43-3.22(m,1H),3.25-3 .17(m,1H),2.10-2.02(m,1H),1.97-1.82(m,2H),1.55(s,1H),1.32(t,J=8.0Hz,6H).

[0309] Example 59 Synthesis of Compound SCW-4-12

[0310] The raw material aniline was replaced with 3-aminophenol, and the other reaction steps were the same as in Example 2 to obtain compound SCW-4-12.

[0311] LC-MS (m / z): 545 (M+H) + .

[0312] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),10.38(s,1H),8.51-8.19(m,1H),7.97(d,J=8.4Hz,1 H),7.83(s,1H),7.78-7.66(m,1H),7.48-7.41(m,1H),7.27(s,2H),4.74-4.16(m,1H),3 .97-3.84(m,2H),3.35-3.12(m,3H),2.94-2.88(m,1H),2.19-2.11(m,1H),2.09-1.73(m ,3H),1.65-1.56(m,1H),1.35(d,J=6.2Hz,3H),1.30(d,J=6.1Hz,3H),1.27-1.24(m,1H).

[0313] Example 60 Synthesis of Compound SCW-4-21

[0314] The raw material benzoic acid was replaced with 3-fluoro-5-hydroxybenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound SCW-4-21.

[0315] LC-MS (m / z): 548 (M+H) + .

[0316] 1 H NMR(400MHz,DMSO)δ10.07(s,1H),9.46(s,1H),9.07-8.49(m,1H),8.37-8.03(m,1 H),7.81(d,J=7.3Hz,1H),7.77-7.62(m,1H),7.32(t,J=7.2Hz,1H),7.29-6.84(m,1 H),6.71-6.46(m,2H),3.86-3.55(m,2H),3.46-3.41(m,1H),3.21-2.68(m,2H),2. 05-1.81(m,2H),1.76-1.62(m,1H),1.64-1.33(m,2H),1.16(dd,J=8.0,4.3Hz,6H).

[0317] Example 61 Synthesis of Compound SCW-4-61

[0318] The raw material benzoic acid was replaced with 3-fluoro-5-nitrobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound SCW-4-61.

[0319] LC-MS (m / z): 577 (M+H) + .

[0320] 1 H NMR(400MHz,DMSO)δ9.71-9.39(m,1H),8.97-8.47(m,1H),8.28-7.92(m,2H ),7.91-7.83(m,1H),7.82-7.68(m,2H),7.56(s,1H),7.42-7.29(m,1H),3. 84-3.81(m,2H),3.71-3.57(m,2H),3.53-3.20(m,3H),3.19-2.98(m,1H),1 .99-1.91(m,1H),1.80-1.64(m,1H),1.61-1.48(m,1H),1.40-0.97(m,6H).

[0321] Example 62 Synthesis of Compound HQY-14-19

[0322] The raw material aniline was replaced by 2-aminophenol, and the other reaction steps were the same as in Example 2 to obtain compound HQY-14-19.

[0323] LC-MS (m / z): 545 (M+H) + .

[0324] 1H NMR(400MHz,DMSO)δ9.62(s,1H),9.63-9.48(m,1H),8.89-8.45(m,1H),8.19(s,1H),7.95(s,1H),7.81 (s,1H),7.76-7.60(m,1H),7.59-7.44(m,1H),7.43-7.18(m,2H),6.88(d,J=7.1Hz,1H),6.82(d,J=6.8 Hz,1H),6.73(t,J=7.5Hz,1H),4.12-4.08(m,1H),3.94-3.89(m,1H),3.77-3.68(m,1H),3.47-3.38(m, 1H),3.00-2.80(m,2H),1.99-1.89(m,1H),1.81-1.71(m,1H),1.60-1.44(m,2H),1.17(d,J=6.6Hz,6H).

[0325] Example 63 Synthesis of Compound HQY-14-28

[0326] The raw material benzoic acid was replaced with 3-amino-5-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-14-28.

[0327] LC-MS (m / z): 547 (M+H) + .

[0328] 1 H NMR (400MHz, CDCl3) δ10.36(s,1H),9.10(s,1H),8.54-8.22(m,2H),7.92(d,J=7.6Hz,1H),7.83(s,1H),7.74(s,1H),7.60(s,1H),7.43(t ,J=6.3Hz,1H),7.17(s,1H),4.34-3.80(m,2H),3.75-3.49(m,2H),3.47-3.13(m,2H),2.14-1.70(m,3H),1.61-1.52(m,1H),1.28(s,6H).

[0329] Example 64 Synthesis of Compound HQY-14-72

[0330] The raw material benzoic acid was replaced with 4-amino-5-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-14-72.

[0331] LC-MS (m / z): 547 (M+H) +.

[0332] 1 H NMR (400MHz, DMSO) δ9.69-9.45(m,1H),8.93-8.21(m,1H),8.22-8.03(m,1H),7.83(d, J=7.8Hz,1H),7.73(s,1H),7.65-7.31(m,2H),7.16-7.00(m,1H),6.99-6.87(m,1H),6. 77-6.60(m,1H),3.77-3.64(m,2H),3.45-3.39(m,1H),3.30-2.79(m,3H),2.01-1.91( m,1H),1.83-1.73(m,1H),1.64-1.55(m,1H),1.51-1.39(m,1H),1.17(d,J=6.8Hz,6H).

[0333] Example 65 Synthesis of Compound HQY-14-74

[0334] The raw material benzoic acid was replaced with 4-acetylamino-3-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-14-74.

[0335] LC-MS (m / z): 589 (M+H) + .

[0336] 1 H NMR (400MHz, CDCl3) δ10.50(s,1H),9.84(d,J=6.3Hz,1H),8.50(s,1H),8.38(s,1H),7.98(d,J=7.7Hz, 1H),7.90(s,1H),7.76(t,J=7.5Hz,1H),7.53(s,1H),7.44(d,J=7.3Hz,1H),7.27(s,1H),7.19(s,1H),4 .27(s,1H),4.03(s,1H),3.54(s,1H),3.48-3.40(m,1H),3.37-3.28(m,1H),3.22(dt,J=13.7,6.8Hz,1 H),2.26(s,3H),2.14-2.04(m,1H),1.99-1.78(m,2H),1.60-1.48(m,1H),1.33(dd,J=10.1,6.9Hz,6H).

[0337] Example 66 Synthesis of Compound HQY-15-13

[0338] The raw material benzoic acid was replaced with 3-acetylamino-5-fluorobenzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-15-13.

[0339] LC-MS (m / z): 589 (M+H) + .

[0340] 1 H NMR(400MHz,DMSO)δ10.43(s,1H),9.65(s,1H),8.44(s,1H),8.17(s,1H),7.97(d ,J=7.9Hz,1H),7.87-7.67(m,3H),7.44(t,J=7.6Hz,1H),7.27(s,1H),6.78(s,1H ),4.19-3.98(m,1H),3.95-3.71(m,2H),3.59-3.30(m,2H),3.21(dt,J=13.5,6.7 Hz,1H),2.19(s,3H),2.08-1.89(m,3H),1.68-1.52(m,1H),1.32(d,J=5.0Hz,6H).

[0341] Example 67 Synthesis of Compound HQY-15-18

[0342] The raw material benzoic acid was replaced with 3-fluoro-5-(methylamino)benzoic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-15-18.

[0343] LC-MS (m / z): 561 (M+H) + .

[0344] 1 H NMR (400MHz, CDCl3) δ10.45 (s, 1H), 10.00 (s, 1H), 8.64-8.11 (m, 1H), 7.97 (d, J = 7.2Hz ,1H),7.82(s,1H),7.82-7.69(m,1H),7.46-7.36(m,1H),6.51-6.38(m,1H),6.38-5.99 (m,2H),4.46-3.77(m,2H),3.76-3.44(m,2H),3.47-3.22(m,2H),3.23-3.16(m,1H),2. 84(s,3H),2.12-2.02(m,1H),1.97-1.82(m,2H),1.69-1.49(m,1H),1.37-1.29(m,6H).

[0345] Example 68 Synthesis of Compound HQY-16-41

[0346] The raw material aniline was replaced with tert-butyl 2-aminophenylcarbamate, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-41.

[0347] LC-MS (m / z): 544 (M+H) + .

[0348] 1 H NMR (400MHz, DMSO) δ9.62-9.46(m,1H),8.85-8.48(m,2H),8.17(s,1H),7.81(s,1H),7.55(s,1H),7.33(s,1H),7.28-7.06(m,5H ),4.17-4.13(m,1H),3.46-3.41(m,3H),3.04-2.77(m,4H),1.99(s,1H),1.77(s,1H),1.57-1.48(m,2H),1.17(d,J=6.7Hz,6H).

[0349] Example 69 Synthesis of Compound HQY-16-42

[0350] The raw material compound 7 was replaced with 1-piperidinyl chloride, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-42.

[0351] LC-MS (m / z): 521 (M+H) + .

[0352] 1 H NMR (400MHz, DMSO) δ9.77-9.47(m,1H),8.85-8.55(m,1H),8.17(s,1H),7.84(d,J=7.4Hz,1H),7.73(s,1H),7.63-7.29(m,2H),3.74-3.70(m,2 H),3.46-3.41(m,2H),3.13-2.99(m,4H),2.82-2.64(m,2H),1.91(s,1 H),1.73(s,1H),1.61-1.41(m,6H),1.31(s,2H),1.18(d,J=6.7Hz,6H).

[0353] Example 70 Synthesis of Compound HQY-16-51

[0354] The raw material aniline was replaced with (2-amino-4-fluorophenyl)-carbamic acid-1,1-dimethylethyl ester, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-51.

[0355] LC-MS (m / z): 562 (M+H) + .

[0356] 1 H NMR (400MHz, DMSO) δ9.67-9.50(m,1H),8.90-8.50(m,2H),8.17(s,1H),7.82(d,J=7.6Hz,1H),7.58(s,1H),7.34(s,1H),7.30-7.03(m,3H) ,7.04-6.97(m,1H),4.11(s,1H),3.95-3.85(m,3H),3.02-2.79(m,4H ),1.99(s,1H),1.78(s,1H),1.57-1.47(m,2H),1.17(d,J=6.7Hz,6H).

[0357] Example 71 Synthesis of Compound HQY-16-57

[0358] The raw material compound 7 was replaced by 1-pyrrolidinecarbonyl chloride, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-42.

[0359] LC-MS (m / z): 507 (M+H) + .

[0360] 1 H NMR (400MHz, DMSO) δ9.79-9.48(m,1H),8.81-8.47(m,1H),8.19(s,1H),7.84(d,J=6.8Hz,1H),7.72(s,1H),7.71-7.55(m,1H),7.38(s, 1H),3.82-3.69(m,4H),3.28-3.13(m,4H),2.79-2.62(m,2H),1.91(s,1H),1.79-1.62(m,4H),1.63-1.36(m,3H),1.17(d,J=6.7Hz,6H).

[0361] Example 72 Synthesis of Compound HQY-16-58

[0362] The raw material compound 7 was replaced by azepane-1-carbonyl chloride, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-58.

[0363] LC-MS (m / z): 535 (M+H) + .

[0364] 1 H NMR (400MHz, DMSO) δ9.81-9.47(m,1H),8.87-8.47(m,1H),8.18(s,1H),7.84(d,J=7.0Hz,1H),7.74(t,J=7.5Hz,1H),7.70-7.28(m,2H),3. 44(dd,J=13.5,6.7Hz,3H),3.30-3.15(m,5H),2.77-2.59(m,2H),1.90(s,1H),1.73-1.53(m,5H),1.50-1.35(m,6H),1.17(d,J=6.5Hz,6H).

[0365] Example 73 Synthesis of Compound HQY-16-85

[0366] The raw material benzoic acid was replaced with 3-indolecarboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-16-85.

[0367] LC-MS (m / z): 553 (M+H) + .

[0368] 1 H NMR (400MHz, DMSO) δ11.71-11.49(m,1H),9.69-9.45(m,1H),8.82-8.35(m,1H),8.24(s,1H) ,7.81(d,J=7.9Hz,1H),7.75-7.62(m,2H),7.42(d,J=7.8Hz,1H),7.33(s,1H),7.13(t,J=7. 4Hz,1H),7.06(t,J=7.5Hz,1H),4.33-4.14(m,3H),3.85(s,1H),3.67(s,1H),3.43(s,1H),3 .23(s,1H),2.85(s,1H),2.01(s,1H),1.79(s,1H),1.65-1.46(m,2H),1.16(d,J=6.2Hz,6H).

[0369] Example 74 Synthesis of Compound HQY-16-87

[0370] The raw material aniline was replaced with 3-fluoro-2-nitroaniline, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-87.

[0371] LC-MS (m / z): 562 (M+H) + .

[0372] 1 H NMR(400MHz,DMSO)δ9.71-9.46(m,1H),9.18(s,1H),8.79-8.50(m,1H),8.19(s,1H),7.81 (d,J=6.9Hz,1H),7.66(s,1H),7.57(dd,J=14.4,8.3Hz,1H),7.30(s,1H),7.21(d,J=8.6Hz ,1H),7.18(s,1H),4.04(d,J=10.4Hz,1H),3.88(d,J=13.3Hz,1H),3.80-3.63(m,1H),3.4 3(s,1H),2.96-2.79(m,2H),2.00(s,1H),1.74(s,1H),1.46(s,2H),1.16(d,J=6.4Hz,6H).

[0373] Example 75 Synthesis of Compound HQY-16-89

[0374] The raw material aniline was replaced with 2-fluoro-6-nitroaniline, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-89.

[0375] LC-MS (m / z): 562 (M+H) + .

[0376] 1 H NMR (400MHz, DMSO) δ9.73-9.47(m,1H),8.94-8.52(m,1H),8.17(s,1H),7.82(d,J=7.5Hz,1H),7.75 (s,1H),7.71-7.53(m,1H),7.38-7.27(m,1H),6.96(dd,J=14.5,8.0Hz,1H),6.57(d,J=8.0Hz,1H), 6.44(t,J=8.9Hz,1H),4.14(s,1H),3.92(d,J=12.8Hz,1H),3.80-3.67(m,1H),3.48-3.39(m,1H),3 .03-2.80(m,1H),2.80-2.68(m,1H),1.94(s,1H),1.72(s,1H),1.49(s,2H),1.17(d,J=6.8Hz,6H).

[0377] Example 76 Synthesis of Compound HQY-16-90

[0378] The raw material compound 7 was replaced with 4-morpholinecarbonyl chloride, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-90.

[0379] LC-MS (m / z): 553 (M+H) + .

[0380] 1 H NMR(400MHz,DMSO)δ9.83-9.40(m,1H),8.96-8.45(m,1H),8.18(s,1H),7. 83(s,1H),7.74(s,1H),7.35(s,2H),3.70(s,2H),3.56(s,2H),3.46(dd,J= 13.6,6.8Hz,2H),3.40(s,2H),3.20-3.12(m,1H),3.10-2.98(m,3H),2.89- 2.66(m,2H),1.91(s,1H),1.74(s,1H),1.48(s,2H),1.18(d,J=6.7Hz,6H).

[0381] Example 77 Synthesis of Compound HQY-16-91

[0382] The raw material benzoic acid was replaced with phenylacetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-16-91.

[0383] LC-MS (m / z): 528 (M+H) + .

[0384] 1 H NMR (400MHz, DMSO) δ9.70-9.46 (m, 1H), 8.63 (d, 1H), 8.18 (d, J = 11.2Hz, 1H), 7.81 (s, 1H),7.78(d,J=8.7Hz,1H),7.67-7.44(m,1H),7.44-6.80(m,6H),4.49-4.44(m,1H),3 .93-3.87(m,1H),3.74-3.69(m,1H),3.60-3.33(m,2H),3.19-2.77(m,2H),2.60-2.5 4(m,1H),1.95(s,1H),1.76(s,1H),1.59-1.33(m,2H),1.18(dd,J=21.2,14.5Hz,6H).

[0385] Example 78 Synthesis of Compound HQY-16-93

[0386] The raw material benzoic acid was replaced with α,α-difluorophenylacetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-16-93.

[0387] LC-MS (m / z): 564 (M+H) + .

[0388] 1 H NMR (400MHz, DMSO) δ9.71-9.49(m,1H),8.60(d,J=121.4Hz,1H),8.21(s,1H),7.85(d,J=6.9Hz,1H),7.72(s,1H),7.65-7.53(m,4H),7 .38(s,4H),4.35(s,1H),3.62-3.41(m,3H),2.88(d,J=43.3Hz,2H),1.88(d,J=27.5Hz,1H),1.51(d,J=13.3Hz,2H),1.20-1.14(m,6H).

[0389] Example 79 Synthesis of Compound HQY-16-98

[0390] The raw material benzoic acid was replaced with 2,6-difluorophenylacetic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-16-98.

[0391] LC-MS (m / z): 564 (M+H) + .

[0392] 1 H NMR(400MHz,DMSO)δ9.57(s,1H),8.98-8.45(m,1H),8.37-8.00(m,1H),7.81(s,1H),7.65-7.35(m,2H),7.13(t,2H),4.52-4.27(m,2H),4.06 -3.93(m,3H),3.87-3.73(m,2H),3.66-3.29(m,2H),3.21-2.92(m,1H) ,2.05-1.88(m,1H),1.89-1.69(m,1H),1.70-1.26(m,2H),1.08(s,6H).

[0393] Example 80 Synthesis of Compound HQY-16-104

[0394] The raw material aniline was replaced with 2-amino-3-nitropyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-104.

[0395] LC-MS (m / z): 545 (M+H) + .

[0396] 1 H NMR (400MHz, DMSO) δ9.73-9.54(m,1H),8.81-8.27(m,1H),8.13(s,1H),7. 83(d,J=7.9Hz,1H),7.80-7.68(m,2H),7.69-7.61(m,1H),7.39-7.31(m,1 H),7.24-7.19(m,2H),4.44-4.39(m,1H),3.45-3.38(m,1H),1.95-1.82(m ,2H),1.78(d,J=10.7Hz,2H),1.65(s,3H),1.40-1.29(m,2H),1.14(s,6H).

[0397] Example 81 Synthesis of Compound HQY-16-106

[0398] The raw material aniline was replaced with 2-amino-3-nitropyridine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-16-104.

[0399] LC-MS (m / z): 572 (M+H) + .

[0400] 1 H NMR(400MHz,DMSO)δ9.55(d,J=23.4Hz,1H),8.69(d,J=87.2Hz,1H),8.31(s,1H),8 .17(s,1H),7.81(s,1H),7.57(s,3H),7.34(s,1H),7.22(s,2H),4.09(s,1H),3.84( d,J=12.2Hz,1H),3.71(s,1H),3.43(s,1H),3.04(s,1H),2.94(d,J=11.7Hz,1H),2 .83(s,6H),1.97(s,1H),1.83(s,1H),1.54(d,J=9.3Hz,2H),1.16(d,J=6.6Hz,6H).

[0401] Example 82 Synthesis of Compound HQY-17-3

[0402] The raw material benzoic acid was replaced with 5-fluoroindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-3.

[0403] LC-MS (m / z): 571 (M+H) + .

[0404] 1 H NMR (400MHz, DMSO) δ11.84-11.58(m,1H),9.79-9.43(m,1H),8.53(d,J=188.4Hz,1H),8.26-8.1 5(m,1H),7.81(s,1H),7.77-7.58(m,2H),7.49-7.39(m,2H),7.35-7.30(m,1H),6.99(t,J=8.2H z,1H),4.47-4.35(m,1H),4.30-4.16(m,2H),3.73-3.61(m,2H),3.46-3.39(m,1H),2.93-2.84( m,1H),2.06-1.96(m,1H),1.87-1.77(m,1H),1.67-1.58(m,1H),1.54-1.44(m,1H),1.16(s,6H).

[0405] Example 83 Synthesis of Compound HQY-17-6

[0406] The raw material benzoic acid was replaced with 7-azaindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-6.

[0407] LC-MS (m / z): 554 (M+H) + .

[0408] 1 H NMR (400MHz, DMSO) δ12.45-12.12(m,1H),9.86-9.53(m,1H),8.77(s,1H),8.29(s,2H),8.2 4-8.05(m,2H),7.83(d,J=7.2Hz,1H),7.79-7.67(m,1H),7.36(t,J=7.6Hz,1H),7.16(dd,J= 7.9,4.7Hz,1H),4.23-4.06(m,2H),3.89-3.65(m,2H),3.49-3.29(m,2H),2.92-2.81(m,1H ),2.06-1.95(m,1H),1.87-1.77(m,1H),1.69-1.58(m,1H),1.56-1.45(m,1H),1.15(s,6H).

[0409] Example 84 Synthesis of Compound HQY-17-7

[0410] The raw material benzoic acid was replaced with 4-azaindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-7.

[0411] LC-MS (m / z): 554 (M+H) + .

[0412] 1 H NMR(400MHz,DMSO)δ13.41(s,1H),9.50(s,1H),9.05(s,1H),8.80(s,1H),8.70 (s,1H),8.58(s,2H),8.26(s,1H),7.87-7.81(m,1H),7.78-7.68(m,2H),7.43(s ,1H),7.35(s,1H),3.89-3.86(m,1H),3.46-3.32(m,2H),3.19-3.00(m,2H),2.0 7-2.02(m,1H),1.93-1.85(m,1H),1.79-1.69(m,1H),1.60(s,1H),1.16(s,6H).

[0413] Example 85 Synthesis of Compound HQY-17-8

[0414] The raw material benzoic acid was replaced with 1-methylindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-8.

[0415] LC-MS (m / z): 567 (M+H) + .

[0416] 1 H NMR (400MHz, DMSO) δ9.73-9.47(m,1H),8.20-8.07(m,1H),7.81(d,J=7.7Hz,1H),7.76-7 .58(m,3H),7.46(d,J=7.1Hz,1H),7.34(t,J=7.6Hz,1H),7.22-7.14(m,1H),7.10(t,J=7 .4Hz,1H),4.25-4.06(m,4H),3.79(s,3H),3.44-3.39(m,3H),3.09-3.02(m,1H),2.02-1 .92(m,1H),1.84-1.76(m,1H),1.67-1.58(m,1H),1.53-1.43(m,1H),1.20-1.07(m,6H).

[0417] Example 86 Synthesis of Compound HQY-17-9

[0418] The raw material benzoic acid was replaced with 4-fluoroindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-9.

[0419] LC-MS (m / z): 571 (M+H) + .

[0420] 1 H NMR (400MHz, DMSO) δ11.96-11.61(m,1H),9.77-9.40(m,1H),8.75(s,1H),8.17(s,1H),7.82(s,1H),7.77-7.58(m,2H),7.40-7.25(m,2H),7.1 9-6.97(m,1H),6.93-6.73(m,1H),4.05-3.90(m,4H),3.42-3.31(m,2H) ,3.30-2.62(m,1H),2.24-1.59(m,2H),1.63-1.38(m,2H),1.14(s,6H).

[0421] Example 87 Synthesis of Compound HQY-17-11

[0422] The raw material benzoic acid was replaced with 7-fluoroindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-11.

[0423] LC-MS (m / z): 571 (M+H) + .

[0424] 1 H NMR (400MHz, DMSO) δ12.11(s,1H),9.54(d,J=38.4Hz,1H),8.54(d,J=196.9Hz,1H) ,8.13(s,1H),7.81(s,1H),7.64(s,1H),7.45(s,1H),7.39(d,J=46.7Hz,2H),7.00( dd,J=16.3,8.4Hz,2H),4.36(d,J=45.2Hz,2H),3.84(s,2H),3.42(s,1H),3.25(s, 1H),2.87(s,1H),2.01(s,1H),1.80(s,1H),1.61(s,1H),1.51(s,1H),1.16(s,6H).

[0425] Example 88 Synthesis of Compound HQY-17-12

[0426] The raw material benzoic acid was replaced with indazole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-12.

[0427] LC-MS (m / z): 554 (M+H) + .

[0428] 1 H NMR (400MHz, DMSO) δ13.66-13.31(m,1H),9.71-9.42(m,1H),8.94-8.59(m,1H),8.21(s,1H),7.97-7.81(m,2H),7.63(s,2H),7.45-7.19(m,3H ),4.63-4.51(m,1H),3.74-3.60(m,2H),3.57-3.22(m,3H),3.21-2.56( m,1H),2.00(s,1H),1.96-1.78(m,1H),1.70-1.49(m,2H),1.16(s,6H).

[0429] Example 89 Synthesis of Compound HQY-17-24

[0430] The raw material benzyl bromide was replaced with 2-chlorobenzimidazole, and the other reaction steps were the same as in Example 3 to obtain compound HQY-17-24.

[0431] LC-MS (m / z): 554 (M+H) + .

[0432] 1 H NMR (400MHz, DMSO) δ12.88(s,1H),9.69-9.43(m,1H),8.67(s,1H),8.20(s,1H),7.93-7.65(m,2H),7.49-7.31(m,3H),7.27(s,2 H),4.02(d,J=12.5Hz,2H),3.82-3.80(m,1H),3.50-3.23(m,4H),2.06-1.90(m,2H),1.82-1.59(m,2H),1.20(t,J=10.5Hz,6H).

[0433] Example 90 Synthesis of Compound HQY-17-31

[0434] The raw material benzyl bromide was replaced with 2-chlorobenzothiazole, and the other reaction steps were the same as in Example 3 to obtain compound HQY-17-31.

[0435] LC-MS (m / z): 542 (M+H) + .

[0436] 1 H NMR(400MHz,DMSO)δ9.73-9.45(m,1H),8.88-8.42(m,1H),8.22(s,1H),7.92-7.62 (m,3H),7.52-7.31(m,2H),7.29-7.24(m,1H),7.21-7.08(m,1H),7.06(t,J=7.5Hz ,1H),4.13-4.02(m,1H),3.97-3.76(m,2H),3.53-3.40(m,1H),3.34-3.22(m,1H), 3.20-3.11(m,1H),1.99(s,1H),1.89(s,1H),1.70-1.52(m,2H),1.22-1.08(m,6H).

[0437] Example 91 Synthesis of Compound HQY-17-34

[0438] The raw material benzyl bromide was replaced with 2-chloro-6-fluorobenzothiazole, and the other reaction steps were the same as in Example 3 to obtain compound HQY-17-31.

[0439] LC-MS (m / z): 561 (M+H) + .

[0440] 1 H NMR(400MHz,DMSO)δ9.73-9.43(m,1H),8.88-8.42(m,1H),8.21(s,1H),7.8 8-7.58(m,3H),7.48-7.30(m,2H),7.22-7.04(m,2H),4.08-4.03(m,1H),3.8 9-3.74(m,2H),3.52-3.42(m,1H),3.32-3.21(m,1H),3.19-3.10(m,1H),2.0 6-1.96(m,1H),1.93-1.81(m,1H),1.67-1.51(m,2H),1.17(t,J=5.9Hz,6H).

[0441] Example 92 Synthesis of Compound HQY-17-42

[0442] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and benzoic acid was replaced with 3-amino-5-fluorobenzoic acid. The other reaction steps were the same as in Example 1 to obtain compound HQY-17-42.

[0443] LC-MS (m / z): 533 (M+H) + .

[0444] 1 H NMR(400MHz,DMSO)δ9.65-9.38(m,1H),8.97-8.32(m,1H),8.26-8.13(m,1 H),7.87-7.72(m,2H),7.59(s,1H),7.35(d,J=7.5Hz,1H),6.51(s,1H),6.4 3-6.26(m,2H),4.46-4.05(m,1H),3.80-3.64(m,1H),3.66-3.47(m,2H),3 .47-3.26(m,2H),2.19-2.06(m,1H),2.05-1.85(m,1H),1.19-1.04(m,6H).

[0445] Example 93 Synthesis of Compound HQY-17-43

[0446] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and the other reaction steps were the same as in Example 1 to obtain compound HQY-17-43.

[0447] LC-MS (m / z): 500 (M+H) + .

[0448] 1 H NMR (400MHz, DMSO) δ9.65-9.33(m,1H),8.94-8.46(m,1H),8.24-8.10(m,1H),7.95-7.75(m,2H),7.56-7.45(m,3H),7.44-7.28(m,3H),4.37-4. 14(m,1H),3.85-3.63(m,2H),3.61-3.54(m,1H),3.53-3.38(m,2H),3.3 8-3.27(m,1H),2.26-2.11(m,1H),2.08-1.86(m,1H),1.23-0.99(m,6H).

[0449] Example 94 Synthesis of Compound HQY-17-45

[0450] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and the other reaction steps were the same as in Example 2 to obtain compound HQY-17-45.

[0451] LC-MS (m / z): 515 (M+H) + .

[0452] 1 H NMR(400MHz,DMSO)δ9.58(s,1H),9.01-8.55(m,1H),8.21(s,1H),8.14(s,1H),7.84(d,J=7 .3Hz,1H),7.80-7.74(m,1H),7.50(d,J=7.7Hz,2H),7.39-7.32(m,1H),7.21(t,J=7.4Hz,2 H),6.91(t,J=7.2Hz,1H),4.49-4.14(m,1H),3.71-3.62(m,1H),3.60-3.51(m,1H),3.50-3 .40(m,2H),3.40-3.27(m,1H),2.19-2.10(m,1H),2.04-1.92(m,1H),1.17(d,J=6.4Hz,6H).

[0453] Example 95 Synthesis of Compound HQY-17-65

[0454] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and the other reaction steps were the same as in Example 5 to obtain compound HQY-17-65.

[0455] LC-MS (m / z): 525 (M+H) + .

[0456] 1H NMR (400MHz, DMSO) δ11.45(s,1H),10.00-9.76(m,1H),9.46(s,1H),8.17(s,1H),7.87-7.80(m, 1H),7.74(d,J=8.4Hz,1H),7.72(d,J=11.7Hz,1H),7.58(s,1H),7.44(d,J=8.1Hz,1H),7.39-7.2 8(m,1H),7.16(t,J=7.4Hz,1H),7.08(t,J=7.2Hz,1H),4.62-4.51(m,2H),3.65-3.49(m,3H),3. 44-3.35(m,2H),3.21-3.01(m,1H),2.48-2.39(m,1H),2.35-1.84(m,2H),1.14(d,J=6.1Hz,6H).

[0457] Example 96 Synthesis of Compound HQY-17-70

[0458] The raw material (R)-1-Boc-3-aminopiperidine was replaced by (R)-1-Boc-3-aminopyrrolidine, and benzyl bromide was replaced by 2-chlorobenzimidazole. The other reaction steps were the same as in Example 3 to obtain compound HQY-17-70.

[0459] LC-MS (m / z): 512 (M+H) + .

[0460] 1 H NMR (400MHz, DMSO) δ12.88(s,2H),9.53(s,1H),8.72(d,J=8.3Hz,1H),8.21(s,1H),7 .84(d,J=7.1Hz,1H),7.83-7.60(m,2H),7.41(dd,J=5.8,3.1Hz,2H),7.35(d,J=7.3H z,1H),7.26(dd,J=5.8,3.1Hz,2H),4.55(s,1H),3.89(dd,J=10.2,5.7Hz,2H),3.46( dd,J=13.7,6.8Hz,2H),2.37-2.30(m,1H),2.25-2.17(m,1H),1.18(d,J=6.5Hz,6H).

[0461] Example 97 Synthesis of Compound HQY-17-71

[0462] The raw material (R)-1-Boc-3-aminopiperidine was replaced by (3S,4R)-1-Boc-3-amino-4-hydroxypyrrolidine, and benzoic acid was replaced by indole-3-carboxylic acid. The other reaction steps were the same as in Example 1 to obtain compound HQY-17-71.

[0463] LC-MS (m / z): 555 (M+H) + .

[0464] 1 H NMR (400MHz, DMSO) δ11.59(s,1H),9.51(s,1H),8.80(s,1H),8.17(s,1H),8.05(d,J=6.5Hz,1H),7.82(d,J=6.9Hz,2H),7.77-7.54(m,2H),7.42( d,J=8.1Hz,1H),7.32(s,1H),7.15(t,J=7.5Hz,1H),7.08(t,J=7.3Hz,1H ),4.36-4.11(m,3H),4.09-4.01(m,2H),3.62-3.44(m,3H),1.15(s,6H).

[0465] Example 98 Synthesis of Compound HQY-17-75

[0466] The raw material (R)-1-Boc-3-aminopiperidine was replaced by (R)-1-Boc-3-aminopyrrolidine, and benzoic acid was replaced by 5-fluoroindole-3-carboxylic acid. The other reaction steps were the same as in Example 1 to obtain compound HQY-17-75.

[0467] LC-MS (m / z): 557 (M+H) + .

[0468] 1 H NMR(400MHz,DMSO)δ11.74(s,1H),9.58(s,1H),8.88-8.41(m,1H),8.21(s, 1H),7.95(s,1H),7.87-7.73(m,3H),7.48-7.40(m,1H),7.35(s,1H),7.02( dd,J=12.2,5.7Hz,1H),4.42-4.16(m,2H),3.99-3.74(m,2H),3.72-3.56(m ,2H),3.52-3.39(m,1H),2.32-2.12(m,1H),2.08-1.92(m,1H),1.19(s,6H).

[0469] Example 99 Synthesis of Compound HQY-17-83

[0470] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and 3-indolecarboxaldehyde was replaced with 5-fluoroindole-3-carboxaldehyde. The other reaction steps were the same as in Example 5 to obtain compound HQY-17-83.

[0471] LC-MS (m / z): 543 (M+H) + .

[0472] 1 H NMR(400MHz,DMSO)δ11.55(s,1H),10.07-9.78(m,1H),9.46(s,1H),8.17(s,1H),7.86-7 .80(m,1H),7.76-7.66(m,1H),7.64(s,1H),7.62-7.53(m,1H),7.44(dd,J=8.4,4.4Hz,1 H),7.38-7.29(m,1H),7.01(t,J=9.1Hz,1H),4.53(d,J=12.8Hz,2H),3.54-3.48(m,3H), 3.42-3.37(m,2H),3.31-3.24(m,1H),3.18-3.06(m,1H),2.29-1.96(m,2H),1.15(s,6H).

[0473] Example 100 Synthesis of Compound HQY-17-84

[0474] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and 3-indolecarboxaldehyde was replaced with 5-nitroindole-3-carboxaldehyde. The other reaction steps were the same as in Example 5 to obtain compound HQY-17-84.

[0475] LC-MS (m / z): 540 (M+H) + .

[0476] 1H NMR (400MHz, DMSO) δ11.23 (s, 1H), 10.03 (s, 1H), 9.47 (s, 1H), 8.17 (d, J = 4.1Hz, 1H), 7.8 3(t,J=7.5Hz,1H),7.76-7.65(m,1H),7.56(s,1H),7.41-7.30(m,1H),7.27-7.15(m,1H), 6.97-6.86(m,1H),6.61(d,J=6.7Hz,1H),4.56-4.46(m,2H),3.51-3.45(m,3H),3.38-3.2 5(m,3H),3.14-3.05(m,1H),2.47-2.38(m,1H),2.34-1.94(m,3H),1.15(d,J=6.7Hz,6H).

[0477] Example 101 Synthesis of Compound HQY-17-91

[0478] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (R)-1-Boc-3-aminopyrrolidine, and benzyl bromide was replaced with 3-chloro-1,2-benzisoxazole. The other reaction steps were the same as in Example 3 to obtain compound HQY-17-91.

[0479] LC-MS (m / z): 513 (M+H) + .

[0480] 1 H NMR(400MHz,DMSO)δ9.56(s,1H),9.03-8.47(m,1H),8.21(s,1H),7.84(s,2H) ,7.74(s,1H),7.61-7.47(m,2H),7.34(s,1H),7.24(s,1H),4.55-4.39(m,1H) ,3.89(s,1H),3.78(s,1H),3.70(s,1H),3.63-3.58(m,1H),3.47-3.41(m,1H) ,2.99-2.75(m,1H),2.32-2.25(m,1H),2.16-2.07(m,1H),1.19-1.11(m,6H).

[0481] Example 102 Synthesis of Compound HQY-18-18

[0482] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzoic acid was replaced with 4-fluorophthalic anhydride. The other reaction steps were the same as in Example 3 to obtain compound HQY-18-18.

[0483] LC-MS (m / z): 558 (M+H) + .

[0484] 1 H NMR (400MHz, DMSO) δ9.86-9.53(m,1H),8.87-8.61(m,1H),8.20(s,1H),7.96-7.90(m,1H), 7.84(d,J=7.9Hz,2H),7.77(d,J=6.5Hz,1H),7.66(t,J=8.8Hz,1H),7.36(t,J=7.6Hz,1H), 4.81-4.70(m,1H),4.54-4.41(m,1H),3.45(dd,J=13.5,6.6Hz,2H),2.36-2.30(m,1H),2.2 6-2.17(m,1H),2.06-2.00(m,2H),1.94-1.87(m,1H),1.70-1.59(m,1H),1.21-1.13(m,6H).

[0485] Example 103 Synthesis of Compound HQY-18-19

[0486] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzoic acid was replaced with 6-fluoroindole-4-carboxylic acid. The other reaction steps were the same as in Example 1 to obtain compound HQY-18-19.

[0487] LC-MS (m / z): 571 (M+H) + .

[0488] 1H NMR (400MHz, DMSO) δ11.27(s,1H),9.56(s,1H),8.97-8.46(m,1H),8.39-8.20(m,1H),8.20-8.09(m,1H),7.86-7.66(m,2H),7.45-7.13(m, 4H),6.85-6.64(m,1H),4.47-4.20(m,2H),3.46-3.38(m,2H),2.12-2 .03(m,2H),1.95-1.87(m,2H),1.60-1.49(m,2H),1.19-1.09(m,6H).

[0489] Example 104 Synthesis of Compound HQY-18-25

[0490] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with 4-fluoro-2-nitrobenzyl bromide. The other reaction steps were the same as in Example 3 to obtain compound HQY-18-25.

[0491] LC-MS (m / z): 533 (M+H) + .

[0492] 1 H NMR (400MHz, DMSO) δ9.50 (s, 1H), 8.89-8.57 (m, 1H), 8.16 (d, J = 5.4Hz, 1H), 7.89-7.80 (m,1H),7.74(d,J=6.1Hz,1H),7.38-7.31(m,1H),7.19(d,J=6.8Hz,1H),6.52-6.35(m, 2H),4.41-4.25(m,3H),3.99(s,2H),3.72-3.66(m,1H),3.46-3.39(m,1H),2.22-2.14( m,1H),2.12-1.97(m,3H),1.73-1.65(m,1H),1.62-1.53(m,1H),1.17(d,J=6.7Hz,6H).

[0493] Example 105 Synthesis of Compound HQY-18-26

[0494] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzoic acid was replaced with 3-amino-5-fluorobenzoic acid. The other reaction steps were the same as in Example 1 to obtain compound HQY-18-26.

[0495] LC-MS (m / z): 547 (M+H) + .

[0496] 1 H NMR (400MHz, DMSO) δ9.80-9.51(m,1H),8.82-8.52(m,1H),8.25(d,J=5.1Hz,1H),8.19( s,1H),7.84(d,J=8.0Hz,1H),7.80-7.71(m,1H),7.41-7.30(m,1H),6.87(s,1H),6.74( d,J=9.6Hz,1H),6.46(d,J=11.2Hz,1H),4.39-4.32(m,3H),3.49-3.43(m,1H),2.54(s, 2H),2.10-1.99(m,2H),1.88(t,J=6.7Hz,2H),1.59-1.51(m,2H),1.17(d,J=6.6Hz,6H).

[0497] Example 106 Synthesis of Compound HZL-1-2

[0498] The raw material benzoic acid was replaced with 5-azaindole-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HZL-1-2.

[0499] LC-MS (m / z): 554 (M+H) + .

[0500] 1 H NMR (400MHz, DMSO) δ13.27 (s, 1H), 9.48 (s, 1H), 9.39-9.19 (m, 1H), 8.79 (d, J = 6.0Hz, 1H), 8. 48(d,J=5.9Hz,1H),8.23(s,1H),8.07(s,1H),7.82(d,J=8.1Hz,1H),7.81-7.71(m,1H),7.4 1-7.32(m,1H),4.55-4.37(m,2H),3.88-3.68(m,3H),3.57-3.31(m,2H),3.00(s,1H),2.12- 1.99(m,1H),1.93-1.81(m,1H),1.78-1.63(m,1H),1.61-1.53(m,1H),1.16(d,J=6.0Hz,6H).

[0501] Example 107 Synthesis of Compound HZL-1-4

[0502] The raw material benzoic acid was replaced with 2,3-dihydro-1H-indene-1-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HZL-1-4.

[0503] LC-MS (m / z): 554 (M+H) + .

[0504] 1 H NMR (400MHz, DMSO) δ9.82-9.42(m,1H),8.92-8.37(m,1H),8.18(s,1H),7.83(d,J=7.7Hz,1H), 7.83-7.73(m,1H),7.71-7.42(m,1H),7.39-7.29(m,1H),7.30-7.20(m,1H),7.21-7.15(m,1H), 7.15-7.10(m,1H),7.11-6.94(m,1H),4.23-4.07(m,2H),4.06-3.60(m,2H),3.56-3.08(m,2H), 3.11-2.66(m,2H),2.39-2.14(m,2H),2.15-1.74(m,3H),1.71-1.36(m,2H),1.20-0.90(m,6H).

[0505] Example 108 Synthesis of Compound HZL-1-6

[0506] The raw material benzyl bromide was replaced with 2-chloro-1H-imidazo[4,5-B]pyridine, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-6.

[0507] LC-MS (m / z): 527 (M+H) + .

[0508] 1 H NMR(400MHz,DMSO)δ9.56(s,1H),9.07-8.59(m,1H),8.19(s,1H),8.16-7.8 8(m,1H),7.94-7.62(m,2H),7.58-7.24(m,1H),7.22(d,J=12.8Hz,1H),4.30 -3.99(m,3H),3.93-3.82(m,2H),3.50-3.45(m,2H),3.44-3.25(m,3H),2.08 -1.97(m,1H),2.00-1.88(m,1H),1.68-1.63(m,1H),1.20(t,J=12.9Hz,6H).

[0509] Example 109 Synthesis of Compound HZL-1-10

[0510] The raw material benzyl bromide was replaced with 2-chloro-7-nitro-1H-benzo[d]imidazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-10.

[0511] LC-MS (m / z): 541 (M+H) + .

[0512] 1 H NMR (400MHz, DMSO) δ12.63(s,1H),9.62-9.42(m,1H),8.78-8.50(m,1H),8.20(s,1H),7.75(s,2H),7.55-7.08(m,2H),6.97(t,J= 7.9Hz,1H),6.61-6.48(m,2H),3.85-3.74(m,2H),3.51-3.13(m,4H),2.03-1.91(m,2H),1.74-1.58(m,2H),1.18(d,J=6.7Hz,6H).

[0513] Example 110 Synthesis of Compound HZL-1-19

[0514] The raw material benzyl bromide was replaced with 3-chloro-1,2-benzisoxazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-19.

[0515] LC-MS (m / z): 527 (M+H) + .

[0516] 1 H NMR (400MHz, DMSO) δ9.74-9.46(m,1H),8.82-8.43(m,1H),8.21(s,1H),8.02-7.63(m,3H),7.56(s,2H),7.44 -7.06(m,3H),3.49-3.25(m,3H),3.15-2.86(m,3H),2.03-1.86(m,2H),1.76-1.56(m,2H),1.26-1.15(m,6H).

[0517] Example 111 Synthesis of Compound HZL-1-22

[0518] The raw material benzoic acid was replaced with benzofuran-3-carboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HZL-1-22.

[0519] LC-MS (m / z): 554 (M+H) + .

[0520] 1 H NMR (400MHz, DMSO) δ9.78-9.35(m,1H),8.78-8.33(m,1H),8.21-7.96(m,1H),7.82(d,J=7.5Hz,1H),7.76-7.51(m,4H),7.42-7.23(m,4H),3.7 1-3.62(m,2H),3.43(s,2H),3.20-3.10(m,1H),2.02-1.96(m,1H),1.90 -1.78(m,1H),1.71-1.62(m,1H),1.57-1.50(m,1H),1.23-1.14(m,7H).

[0521] Example 112 Synthesis of Compound HZL-1-31

[0522] The raw material benzyl bromide was replaced with 2,5-dichlorobenzoxazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-31.

[0523] LC-MS (m / z): 561 (M+H) + .

[0524] 1 H NMR(400MHz,DMSO)δ9.78-9.46(m,1H),8.82-8.45(m,1H),8.21(s,1H),7.87-7.65(m,2 H),7.54-7.37(m,1H),7.37-7.27(m,2H),7.27-7.12(m,1H),7.01(dd,J=8.4,2.1Hz,1H ),3.96-3.90(m,2H),3.83-3.72(m,1H),3.50-3.41(m,1H),3.35-3.24(m,1H),3.23-3. 15(m,1H),2.03-1.93(m,1H),1.92-1.83(m,1H),1.69-1.53(m,2H),1.21-1.09(m,6H).

[0525] Example 113 Synthesis of Compound HZL-1-32

[0526] The raw material benzyl bromide was replaced with 2,6-dichlorobenzoxazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-32.

[0527] LC-MS (m / z): 561 (M+H) + .

[0528] 1 H NMR(400MHz,DMSO)δ9.79-9.50(m,1H),8.77-8.45(m,1H),8.22(s,1H),7.95-7.68(m,2H) ,7.58-7.44(m,1H),7.43-7.31(m,1H),7.28-7.21(m,1H),7.18(dd,J=8.3,1.7Hz,1H),4. 14-4.09(m,2H),3.98-3.88(m,2H),3.53-3.41(m,1H),3.30-3.22(m,1H),3.20-3.12(m,1 H),2.01-1.93(m,1H),1.92-1.83(m,1H),1.70-1.55(m,2H),1.17(dd,J=6.5,3.8Hz,6H).

[0529] Example 114 Synthesis of Compound HZL-1-34

[0530] The raw material benzyl bromide was replaced with 2-chloro-7-fluoro-1H-benzo[d]imidazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-34.

[0531] LC-MS (m / z): 544 (M+H) + .

[0532] 1 H NMR(400MHz,DMSO)δ12.95(s,1H),9.54(s,1H),8.66(s,1H),8.19(s,1H),7.74(s,2H),7.48-7.19(m,4H),7 .10(t,J=9.5Hz,2H),2.89(s,1H),2.73(s,2H),2.04-1.91(m,3H),1.80-1.58(m,3H),1.17(d,J=5.3Hz,6H).

[0533] Example 115 Synthesis of Compound HZL-1-35

[0534] The raw material benzyl bromide was replaced with 2-chlorobenzoxazole, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-35.

[0535] LC-MS (m / z): 527 (M+H) + .

[0536] 1 H NMR(400MHz,DMSO)δ9.86-9.40(m,1H),8.77-8.44(m,1H),8.22(s,1H),7.89-7.69(m,2 H),7.54-7.37(m,1H),7.41-7.23(m,3H),7.14(t,J=7.6Hz,1H),7.00(t,J=7.7Hz,1H), 4.13(d,J=11.8Hz,1H),3.93(d,J=10.8Hz,1H),3.79(s,1H),3.48-3.41(m,1H),3.27-3 .13(m,2H),2.01-1.94(m,1H),1.93-1.86(m,1H),1.67-1.56(m,2H),1.22-1.11(m,6H).

[0537] Example 116 Synthesis of Compound HZL-1-70

[0538] The raw material benzoic acid was replaced with 3-indolecarboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound HZL-1-70.

[0539] LC-MS (m / z): 539 (M+H) + .

[0540] 1 H NMR (400MHz, DMSO) δ11.59(s,1H),9.54(s,1H),8.75(s,1H),8.19(s,1H),8.04(s,1H),7.93-7.66(m,4H),7.42(d,J=8.1Hz,1H),7.15(t,J=7 .5Hz,1H),7.08(t,J=7.4Hz,1H),4.40-4.16(m,2H),3.74-3.68(m,2H) ,3.63-3.44(m,3H),2.23-2.14(m,1H),2.04-1.97(m,1H),1.15(s,6H).

[0541] Example 117 Synthesis of Compound HZL-1-76

[0542] The raw material 3-indolecarboxaldehyde was replaced with 5-fluoroindole-3-carboxaldehyde, and the other reaction steps were the same as in Example 5 to obtain compound HZL-1-76.

[0543] LC-MS (m / z): 557 (M+H) + .

[0544] 1 H NMR (400MHz, DMSO) δ11.62(s,1H),9.50(s,1H),8.72(s,1H),8.14(s,1H),7.85-7.56(m,4H),7.51-7.20 (m,3H),7.01(s,1H),4.49(s,2H),2.86-2.64(m,2H),2.05-1.89(m,2H),1.78-1.67(m,1H),1.16(s,6H).

[0545] Example 118 Synthesis of Compound HZL-1-77

[0546] The raw material 3-indolecarboxaldehyde was replaced by 3-formyl indazole, and the other reaction steps were the same as in Example 5 to obtain compound HZL-1-77.

[0547] LC-MS (m / z): 540 (M+H) + .

[0548] 1 H NMR(400MHz,DMSO)δ13.57(s,1H),10.20(s,1H),9.50(s,1H),8.13(s,1H) ,7.99(d,J=8.2Hz,1H),7.83(d,J=7.9Hz,1H),7.76-7.57(m,2H),7.43(t, J=7.6Hz,2H),7.33(s,1H),7.24(t,J=7.7Hz,1H),4.94-4.65(m,2H),3.09 -2.90(m,2H),2.18-1.88(m,2H),1.86-1.32(m,3H),1.16(d,J=6.7Hz,6H).

[0549] Example 119 Synthesis of Compound HZL-1-104

[0550] The raw material benzyl bromide was replaced with 2-chloro-7H-pyrrolo-2,3-d-pyrimidine, and the other reaction steps were the same as in Example 3 to obtain compound HZL-1-104.

[0551] LC-MS (m / z): 513 (M+H) + .

[0552] 1H NMR (400MHz, DMSO) δ12.20(s,1H),9.53(s,1H),8.73(s,2H),8.21(d,J=7.2Hz,1H),7.90-7.65(m,3H),7.43(d,J=3.9Hz,1H),7.34(t,J =7.7Hz,1H),6.53(d,J=3.7Hz,1H),3.70-3.56(m,4H),3.53-3.40(m,2H),2.34-2.27(m,1H),2.19-2.11(m,1H),1.18(d,J=6.4Hz,6H).

[0553] Example 120 Synthesis of Compound BFT-1-34

[0554] The raw material benzoic acid was replaced with 3,3-difluorocyclohexanecarboxylic acid, and the other reaction steps were the same as in Example 1 to obtain compound BFT-1-34.

[0555] LC-MS (m / z): 556 (M+H) + .

[0556] 1 H NMR (400MHz, DMSO) δ9.78-9.40(m,1H),8.93-8.47(m,1H),8.29-8.00(m,1H),7.83-7.72(m,1H),7.59-7.16(m,2H),4.37(d,J=12.6Hz,1H),3 .47-3.38(m,2H),3.02(s,2H),2.85(s,1H),2.33(s,1H),2.12-1.86(m ,3H),1.78(s,3H),1.66-1.46(m,2H),1.37(s,2H),1.29-1.10(m,6H).

[0557] Example 121 Synthesis of Compound BFT-1-54

[0558] The raw material benzyl bromide was replaced with 3-(bromomethyl)-1,1-difluorocyclohexane, and the other reaction steps were the same as in Example 3 to obtain compound BFT-1-54.

[0559] LC-MS (m / z): 542 (M+H) + .

[0560] 1H NMR (400MHz, DMSO) δ9.53 (s, 1H), 9.29 (s, 1H), 8.83-8.53 (m, 1H), 8.18 (d, J = 1.6Hz, 1H),7.94-7.69(m,2H),7.62-7.30(m,2H),5.40-5.06(m,1H),3.57(s,2H),3.45(p,J =6.8Hz,2H),3.36-3.19(m,1H),3.07(s,2H),2.92-2.61(m,2H),2.14(s,1H),2.09- 1.84(m,4H),1.81-1.60(m,4H),1.46(d,J=10.5Hz,2H),1.18(dd,J=6.8,3.9Hz,6H).

[0561] Example 122 Synthesis of Compound BFT-1-61

[0562] The raw material benzoic acid was replaced with 2-hydroxy-2-phenylpropionic acid, and the other reaction steps were the same as in Example 1 to obtain compound BFT-1-61.

[0563] LC-MS (m / z): 558 (M+H) + .

[0564] 1 H NMR (400MHz, DMSO) δ9.73-9.47(m,1H),8.80-8.51(m,1H),8.18(s,1H),8.00-7.64(m,2H),7.59-6.97(m,5H),6.25(s,1H), 4.44(s,2H),3.45(dd,J=13.8,7.1Hz,2H),3.02-2.64(m,2H),2.33(s,1H),1.99(s,1H),1.52(s,3H),1.18(t,J=7.0Hz,6H).

[0565] Example 123 Synthesis of Compound BFT-1-65

[0566] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (3S,4S)-tert-butyl-3-amino-4-fluoropyrrolidine-1-carboxyl, and the raw material benzoic acid was replaced with 5-fluoroindole-3-carboxylic acid. The other reaction steps were the same as in Example 1 to obtain compound BFT-1-65.

[0567] LC-MS (m / z): 575 (M+H) + .

[0568] 1H NMR (400MHz, DMSO) δ11.80(s,1H),9.56(s,1H),8.23(s,1H),7.98(s,1H),7.86-7.66(m,3H),7.43(d,J=4.4Hz,1 H),7.03(td,J=9.2,2.8Hz,1H),5.58-5.00(m,2H),4.53-4.12(m,3H),3.49-3.39(m,1H),1.16(d,J=6.7Hz,6H).

[0569] Example 124 Synthesis of Compound BFT-1-66

[0570] The raw material (R)-1-Boc-3-aminopiperidine was replaced with (3S,4S)-tert-butyl-3-amino-4-fluoropyrrolidine-1-carboxyl, and the raw material 3-indolecarboxaldehyde was replaced with 5-fluoroindole-3-carboxaldehyde. The other reaction steps were the same as in Example 5 to obtain compound BFT-1-66.

[0571] LC-MS (m / z): 561 (M+H) + .

[0572] 1 H NMR (400MHz, DMSO) δ11.59 (s, 1H), 9.50 (s, 1H), 8.55 (s, 1H), 8.22 (d, J = 12.5Hz, 1H), 7.93-7.54 (m, 4H), 7.51-7. 26(m,2H),7.02(t,J=9.4Hz,1H),5.66-5.02(m,2H),4.81-4.44(m,3H),3.54-3.21(m,3H),1.16(t,J=6.5Hz,6H).

[0573] Example 125 Synthesis of Compound BFT-1-89

[0574] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclohexyl)carbamate, and the benzyl bromide was replaced with methyl 2-bromomethyl-5-fluoro-2-nitrobenzoate. The other reaction steps were the same as in Example 3 to obtain compound BFT-1-89.

[0575] LC-MS (m / z): 573 (M+H) + .

[0576] 1H NMR(400MHz,DMSO)δ9.55(s,1H),8.84-8.59(m,1H),8.14(s,1H),8.10-7.72(m,2H),7.53(s,1H),6.73-6.49(m,2H), 4.26-4.15(m,2H),3.89-3.74(m,2H),3.73-3.68(m,1H),2.17-1.71(m,4H),1.68-1.29(m,4H),1.17(t,J=6.4Hz,6H).

[0577] Example 126 Synthesis of Compound BFT-1-91

[0578] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-bromomethyl-5-fluoro-2-nitrobenzoate. The other reaction steps were the same as in Example 3 to obtain compound BFT-1-91.

[0579] LC-MS (m / z): 559 (M+H) + .

[0580] 1 H NMR (400MHz, DMSO) δ9.64(q,J=10.8Hz,1H),8.89-8.51(m,1H),8.19(d,J=4.2Hz,1H),7.94-7.75(m,2H),7.61-7.04(m,1H),6.8 1-6.46(m,2H),5.00-4.59(m,2H),4.26-4.17(m,2H),3.46(s,1H),2.24-1.79(m,4H),1.82-1.52(m,2H),1.16(d,J=6.6Hz,6H).

[0581] Example 127 Synthesis of Compound BFT-2-13

[0582] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-bromomethylbenzoate. The other reaction steps were the same as in Example 3 to obtain compound BFT-2-13.

[0583] LC-MS (m / z): 526 (M+H) + .

[0584] 1H NMR (400MHz, DMSO) δ9.53(s,1H),8.86-8.60(m,1H),8.57-8.27(m,1H),8.17(s,1H),7.88-7.76(m,2H),7.73-7.66(m,1H),7.61(s,2H),7.52-7. 32(m,1H),5.78(s,1H),4.82(s,1H),4.54-4.46(m,2H),4.27-4.17(m,2H ),2.24-1.95(m,3H),1.97-1.83(m,1H),1.86-1.51(m,2H),1.17(s,6H).

[0585] Example 128 Synthesis of Compound BFT-2-37

[0586] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1S,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-bromomethyl-5-fluoro-2-nitrobenzoate. The other reaction steps were the same as in Example 3 to obtain compound BFT-2-37.

[0587] LC-MS (m / z): 559 (M+H) + .

[0588] 1 H NMR (400MHz, DMSO) δ9.69 (s, 2H), 8.71 (s, 1H), 8.60 (s, 1H), 8.21 (s, 2H), 7.86 (d, J = 7.9Hz, 2H), 7.41 (s, 1H), 6.54 (t, J=9.9Hz,2H),4.54(t,J=8.4Hz,2H),4.24(s,2H),2.32(s,2H),1.90(s,2H),1.75-1.65(m,2H),1.17(d,J=6.6Hz,6H).

[0589] Example 129 Synthesis of Compound HZL-2-66

[0590] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-(bromomethyl)nicotinate. The other reaction steps were the same as in Example 3 to obtain compound HZL-2-66.

[0591] LC-MS (m / z): 527 (M+H) + .

[0592] 1H NMR(400MHz,DMSO)δ9.65(s,1H),8.77(s,1H),8.74-8.39(m,1H),8.20(s,1H),8 .07(d,J=5.4Hz,1H),7.84(d,J=4.2Hz,3H),7.62-7.49(m,1H),7.45-7.29(m,1H) ,4.91-4.83(m,1H),4.62-4.52(m,2H),3.98-3.88(m,1H),3.45(s,1H),2.25-1. 98(m,3H),1.96-1.84(m,1H),1.84-1.70(m,1H),1.73-1.60(m,1H),1.17(s,6H).

[0593] Example 130 Synthesis of Compound HZL-2-82

[0594] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-bromomethyl-5-fluorobenzoate. The other reaction steps were the same as in Example 3 to obtain compound HZL-2-82.

[0595] LC-MS (m / z): 544 (M+H) + .

[0596] 1 H NMR (400MHz, DMSO) δ9.78-9.53(m,1H),9.18-8.42(m,1H),8.20(s,1H),7.84(d,J=8.0Hz,1H), 7.79(t,J=7.5Hz,1H),7.65(dd,J=7.8,4.6Hz,1H),7.45(d,J=8.3Hz,2H),7.37(t,J=7.6Hz,1H) ,4.79(s,1H),4.53-4.45(m,1H),4.44-4.08(m,2H),3.47-3.40(m,2H),2.24-2.09(m,1H),2.0 9-1.99(m,2H),1.94-1.86(m,1H),1.81-1.70(m,1H),1.70-1.60(m,1H),1.16(d,J=6.4Hz,6H).

[0597] Example 131 Synthesis of Compound HZL-2-87

[0598] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with methyl 2-(bromomethyl)-3-cyanobenzoate. The other reaction steps were the same as in Example 3 to obtain compound HZL-2-87.

[0599] LC-MS (m / z): 551 (M+H) + .

[0600] 1 H NMR (400MHz, DMSO) δ9.62(s,1H),9.05-8.53(m,1H),8.20(s,1H),8.10(d,J=7.5Hz,1H),8.00(d,J=7 .6Hz,1H),7.84(d,J=7.9Hz,1H),7.83-7.77(m,1H),7.71(t,J=7.7Hz,1H),7.34(s,1H),4.85-4.78( m,1H),4.77-4.72(m,1H),4.71-4.60(m,1H),4.40-4.27(m,2H),3.50-3.40(m,1H),2.22-2.07(m,2H ),2.06-1.98(m,1H),1.95-1.87(m,1H),1.86-1.76(m,1H),1.71-1.59(m,1H),1.17(d,J=6.5Hz,6H).

[0601] Example 132 Synthesis of Compound BFT-2-51

[0602] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with 3-aminophthalic anhydride. The other reaction steps were the same as in Example 3 to obtain compound BFT-2-51.

[0603] LC-MS (m / z): 555 (M+H) + .

[0604] 1H NMR(400MHz,DMSO)δ9.82-9.46(m,1H),8.94-8.53(m,1H),8.19(s,1H),7.88-7.79( m,2H),7.47-7.40(m,1H),7.38-7.31(m,1H),6.97(d,J=7.8Hz,2H),4.73-4.65(m,1H ),4.53-4.39(m,1H),3.48-3.43(m,1H),2.36-2.24(m,1H),2.24-2.16(m,1H),2.07 -1.97(m,J=7.0Hz,2H),1.91-1.81(m,1H),1.71-1.57(m,1H),1.17(d,J=5.8Hz,6H).

[0605] Example 133 Synthesis of Compound HQY-18-18

[0606] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with 4-fluorophthalic anhydride. The other reaction steps were the same as in Example 3 to obtain compound HQY-18-18.

[0607] LC-MS (m / z): 558 (M+H) + .

[0608] 1 H NMR (400MHz, DMSO) δ9.76-9.54(m,1H),8.84-8.61(m,1H),8.20(s,1H),7.97-7.92(m,1H),7.8 6(d,J=1.0Hz,1H),7.84(d,J=1.2Hz,1H),7.79-7.75(m,1H),7.69-7.64(m,1H),7.37(t,J=7.7 Hz,1H),4.81-4.69(m,1H),4.54-4.39(m,1H),3.49-3.40(m,2H),2.37-2.31(m,1H),2.24-2.1 7(m,1H),2.07-1.99(m,2H),1.93-1.88(m,1H),1.70-1.61(m,1H),1.17(dd,J=6.7,2.0Hz,6H).

[0609] Example 134 Synthesis of Compound HQY-18-34

[0610] The raw material (R)-1-Boc-3-aminopiperidine was replaced with tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate, and benzyl bromide was replaced with 5-fluoro-3-aminophthalic anhydride. The other reaction steps were the same as in Example 3 to obtain compound HQY-18-34.

[0611] LC-MS (m / z): 573 (M+H) + .

[0612] 1 H NMR(400MHz,DMSO)δ9.82-9.54(m,1H),8.78-8.52(m,1H),8.19(s,1H),7.86 -7.75(m,3H),7.67(t,J=8.9Hz,1H),7.37(t,J=7.7Hz,1H),4.71-4.60(m,1H) ,4.41-4.32(m,1H),3.48-3.41(m,2H),2.36-2.28(m,1H),2.25-2.17(m,1H) ,2.08-1.99(m,2H),1.93-1.88(m,1H),1.71-1.61(m,1H),1.20-1.13(m,6H).

[0613] Biological test example 1: Cancer cell growth inhibition activity test

[0614] To verify the inhibitory effect of the compounds of the present invention on cancer cell growth at the cellular level, Jurkat cells (hematological cancer, suspension type) and PA-1, SK-OV-3, and COV362 cells (solid tumor, adherent type) were selected, and the absorbance at 490 nm was detected using a microplate reader to calculate the number of viable cells. The biological activity of the compounds in inhibiting cancer cell growth was obtained and compared with the reported cyclin K degraders CR8 and SR4835.

[0615] Cell lines: Jurkat acute lymphoblastic leukemia cell line, PA-1 human ovarian teratoma cell line, SK-OV-3 human ovarian cancer cell line, COV362 human endometrioid ovarian cancer cell line

[0616] Methods: Using the TTPLabtech automated micropipettor platform, Mosquito, 50 nL of compounds at different concentrations were added to a 384-well plate. Cells in the logarithmic growth phase were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cell concentration was adjusted to 2 × 10 5 / mL(Jurkat), 3×10 4 / mL (PA-1 / SK-OV-3 / COV362), cells were seeded into drug well plates, 50μl per well. After culturing in a cell culture incubator (37°C, 5% CO2) for 72h, 10μl CellTiter Aqueous MTS solution was incubated at room temperature for 60 minutes, and chemical absorbance was measured to measure cell number. The unstimulated DMSO control well was set as 100% cell viability. Compound IC was calculated using Prism Graphpad statistical software. 50 value.

[0617] Table 1 Test results of molecular glue's growth inhibitory activity on different ovarian cancer cell lines

[0618] The above results show that compounds ZSQ-25-3 and HQY-10-35 exhibited good cell inhibitory activity on four human blood disease and solid tumor cells, which are better than the reported Cyclin K degraders CR8 and SR483.

[0619] Biological Test Example 2 Evaluation of Cell Cyclin Levels

[0620] Molecular glues, as the name suggests, are small molecules that promote the interaction between two proteins. In the study of undruggable targets, drug development has shifted from inhibiting function to reducing the expression level of the target protein. Normal protein degradation pathways within cells are mainly divided into two major categories: one is through the ubiquitin-proteasome system, and the other is the autophagy-lysosome system. The previously reported cell cycle kinase inhibitor CR8 selectively induces the degradation of Cyclin k and its related protein CDK12. To compare the degradation ability of the new molecular glue on cell cycle proteins, ovarian cancer cell lines were treated with drugs and lysed with detergents, and then intracellular protein levels were measured using Western blot technology.

[0621] Experimental conditions and process: SK-OV-3 and COV362 cells were cultured in vitro and grown to the logarithmic growth phase. The cells were digested and collected, centrifuged at 1000 rpm for 5 min, and the supernatant was discarded. The cell concentration was adjusted to 1.5 × 10 5In a 6-well cell culture plate, 2 ml of cells were added to each well, along with 2 μL of a 1 μM drug stock solution, along with THZ531, CR8, SR4835, or a DMSO control. After incubation in a cell culture incubator (37°C, 5% CO2) for 2 / 6 hours, the cells were washed twice with pre-chilled PBS, the solution aspirated, and 200 μL of 1% SDS cell lysis buffer, protease inhibitors, and phosphatase inhibitors were added to the wells. The cells were transferred to sample tubes and lysed on a shaker at 4°C for 30 minutes. The cells were then heated at 95°C for 10 minutes in a metal bath and centrifuged at 15,000 rpm for 15 minutes at room temperature. The supernatant of the cell lysate was collected. Protein content in each group was determined using a BCA protein quantification kit, and the protein content was adjusted with SDS lysis buffer to a final volume of 100 μL. Samples were analyzed by Western blot.

[0622] Western-blot: Add 25 μL of 5X protein loading buffer to 100 μL of cell lysate and heat at 95°C for 10 minutes. After the sample cools down, use SDS-PAGE (8%) gel for electrophoresis at 60V. After 30 minutes, switch to 120V until the leading band is electrophoresed to the bottom of the gel. Use a turbo semi-dry transfer system with a constant current of 0.3A for 120 minutes to transfer the proteins in the gel to a NC membrane with a pore size of 0.2 μm. The transferred NC membrane is placed in 5% skim milk powder (TBST solution) for blocking at room temperature for 1 hour and incubated with the corresponding primary antibody at 4°C overnight. Wash with TBST 3 times, 10 minutes each time. Incubate with the corresponding secondary antibody at room temperature for 2 hours. Wash with TBST three times, 10 minutes each time. Incubate with ECL luminescent solution and detect the luminescent signal.

[0623] The experimental results showed that ZSQ25-3 and the positive compound CR8 / SR4835 could effectively promote the degradation of Cyclin K at a concentration of 1 μM, and promote the degradation of CDK12 / 13 protein after 6 hours; under the same action time and concentration conditions, the compound ZSQ-25-3 had a better effect on protein degradation than the control compound CR8 / SR4835; the protein inhibitor THZ531 and ZSQ-25-49 (structure ) failed to promote the degradation of related proteins. However, some active compounds, HQY-14-28, HQY-17-26, HQY-17-83, and BFT-1-91, effectively promoted the degradation of Cylin K after treating cells for 4 hours at a minimum concentration of 30 nM (Figure 2). These results demonstrate that the compounds of the present invention can function as molecular glues, a property not observed in all tumor suppressors, suggesting that the compounds of the present invention possess properties distinct from those of other similar tumor suppressor drugs.

[0624] Biological Test Example 3 Growth Inhibitory Activity Test of Various Ovarian Cancer Cell Lines

[0625] To verify the growth inhibitory effects of some representative compounds of this invention on ovarian and lung cancer cell lines at the cellular level, various ovarian cancer cells were selected to compare the growth inhibitory activities of ZSQ-25-3 and ZSQ-25-49. Simultaneously, THZ531-resistant SKOV3 and COV362 cells were cultured to test the growth inhibitory activity of compound ZSQ-25-3. Furthermore, the number of cell clones was assessed by crystal violet staining in SKOV3 and COV362 ovarian cancer cells and A549 and H460 lung cancer cells, respectively (Figure 3).

[0626] Methods: Various ovarian cancer and non-small cell lung cancer cells were cultured in vitro and grown to the logarithmic growth phase. The cells were then digested and collected, centrifuged at 1000 rpm for 5 min, and the supernatant was discarded. The cell concentration was adjusted to 1.5 × 10 5 / mL, cells were seeded into 12-well plates, 1ml per well. 5μL of compound or DMSO at various concentrations was added to the corresponding wells. After incubation in a cell culture incubator (37°C, 5% CO2) for one week (medium change during this period), each well was fixed with 4% PFA solution for 20 minutes, then stained with 0.1% crystal violet solution for 20 minutes. The cells were washed twice with PBS and scanned for imaging. The unstimulated DMSO control well was defined as 100% cell viability.

[0627] Experimental results showed that the representative compound ZSQ-25-3 had a significantly better growth inhibitory effect on ovarian cancer cells than the reported CDK12 inhibitors or CCNK molecular glues, as well as the control compound ZSQ-25-49 that could not effectively degrade CCNK. Other compounds, such as HQY-17-83, could completely inhibit the growth of four cancer cells at a concentration of 0.01nM.

[0628] Biological Test Example 4: SKOV3 xenograft mouse ovarian cancer tumor growth inhibitory activity test

[0629] To verify the inhibitory effect of the representative compound HQY-14-28 on ovarian cancer cells in vivo in mice, a xenograft tumor model with SKOV3 ovarian cancer cells was established to test the tumor growth inhibitory activity of HQY-14-28. By comparing the tumor growth size between the experimental and control groups, the bioactivity of HQY-14-28 in inhibiting ovarian cancer cell growth in vivo was determined (Figure 4).

[0630] Methods: 5- to 6-week-old female nude mice were intraperitoneally inoculated with SKOV3 cells to establish a xenograft tumor model. After successful model establishment, the mice were treated with HQY-14-28: one group received oral administration of 5 and 10 mg / kg of the drug, respectively; the other group received intraperitoneal administration of 3 and 5 mg / kg of the drug at a concentration of 1 mg / mL. Dosing was continued once daily for 21 days. After treatment, the total weight of the peritoneal tumor lesions was measured and calculated.

[0631] The experimental results showed that the mice did not lose weight after drug treatment, proving that HQY-14-28 has a certain safety in the body. At the same time, compared with the blank control group, HQY-14-28 exhibited significant tumor growth inhibitory activity.

[0632] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by the following formula (I), or its optical isomer, or its pharmaceutically acceptable salt, In the formula: L is selected from the group consisting of: a chemical bond, a C1-C4 alkylene group, or L1; wherein L1 is hydroxy-substituted or unsubstituted X1 is selected from: CH, N; Y is selected from the group consisting of: a chemical bond, a C1-C4 alkylene group, wherein X2 is selected from the group consisting of: a chemical bond, a substituted or unsubstituted methylene group, an oxygen atom, NH, NCH3; wherein X3 is selected from the group consisting of: a chemical bond, a substituted or unsubstituted C1-C4 alkylene group; m is 0, 1, 2, 3 or 4; Ring A is a C4-C14 cycloalkyl group, a 4-14 membered heterocyclic group having 1-3 heteroatoms selected from N, O or S, a C6-C14 aryl group, a 5-14 membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S; wherein the ring can be a monocyclic, bicyclic or tricyclic ring; Each R1 is independently selected from an oxo group (C=O), a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a cyano group, a halogen, a hydroxyl group, a nitro group, -NR a R b , a substituted or unsubstituted S(O)2, a substituted or unsubstituted 5- to 10-membered heteroaryl; R a and R b are each independently selected from hydrogen, a C1-C4 alkyl group, and an acetyl group; n is 0, 1, 2, 3, 4 or 5; The substitution in the substituted or unsubstituted means that the group is substituted by 1 to 3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, cyano, halogen, hydroxy, nitro; The halogen is F, Cl, Br or I.

2. The compound of formula I or its optical isomers, or pharmaceutically acceptable salts thereof according to claim 1, characterized in that, The compound of formula I has the structure shown in formula I-1, I-2, I-3 or I-4 as follows: wherein, p is selected from 1, 2, 3 or 4; The definitions of Ring A, R1, X1, Y, n, m are as described in claim 1.

3. The compound of formula I or its optical isomers, or pharmaceutically acceptable salts thereof according to claim 1, characterized in that, The aforementioned L1 is selected from the following group which may be substituted or unsubstituted: Wherein substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl.

4. The compound of formula I or its optical isomers, or pharmaceutically acceptable salts thereof according to claim 1, characterized in that, The A ring described above is selected from the following group which may be substituted or unsubstituted: Wherein substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the following group: halogen, hydroxyl, oxo group (C=O), C1-C4 alkyl, cyano group, -NR a R b ; R a and R b are each independently selected from hydrogen, C1-C4 alkyl, and acetyl group.

5. The compound of formula I or its optical isomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that, The R1 is selected from the group consisting of: F, Cl, oxo group (C=O), amino, methyl-substituted amino, carbomethoxy-substituted amino, cyano, nitro, hydroxy, methoxy, methyl-substituted S(O)2.

6. The compound of formula I or its optical isomers, or its pharmaceutically acceptable salts as claimed in claim 1, wherein the compound of formula I is selected from the following group:

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises (1) a compound as described in claim 1 or its optical isomer, or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically acceptable carrier.

8. Use of the compound or its optical isomer as claimed in claim 1, or its pharmaceutically acceptable salt, or the pharmaceutical composition as claimed in claim 7, characterized in that, For preparing a pharmaceutical composition for treating cancer and other diseases related to cell cycle kinase activity as a cell cycle-dependent kinase degrader; or for preparing a PROTAC as a molecular glue.

9. The use according to claim 8, characterized in that, The cell cycle-dependent kinases are selected from the group consisting of: CDK 7, CDK 9, CDK 12, CDK 13, Cyclin K.

10. The use according to claim 8, characterized in that, The cancer and other diseases related to cell cycle kinase activity are selected from the group consisting of: T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), neuroblastoma, non-small cell lung cancer (NSCLC), colon cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), multiple myeloma, ovarian cancer, Ewing's sarcoma, skin cancer, prostate cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, brain tumor, squamous cell carcinoma, peritoneal cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.

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