A pyrrolopyrimidine compound, a pharmaceutical composition containing the same and use thereof

Abstract

The application discloses a compound shown in formula I, an optical isomer of the compound or a pharmaceutically acceptable salt of the compound, and simultaneously provides a preparation method and application of the compound. The obtained compound shows certain Menin protein expression down-regulation effect, better cell proliferation inhibition activity and better PK effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a pyrrolopyrimidine compound having Menin expression downregulation activity. This invention also relates to pharmaceutical compositions in which the compound is an active ingredient and their applications. Background Technology

[0002] Menin, encoded by the MEN1 gene, is primarily located in the cell nucleus. As a scaffold protein, it plays multiple crucial roles in biological pathways such as cell growth regulation, cell cycle control, genome stability, bone development, and hematopoiesis. In the nucleus, it functionally crosstalks with different binding partners to regulate gene transcription and interacts with various signaling pathways, such as TGFβ (SMADs), NF-κB, Wnt (β-catenin), and other nuclear receptors (estrogen receptor ERα). In the cytoplasm, menin inhibits the activation of receptor tyrosine kinases AKT, SOS1, and ERK signaling through various mechanisms. When MLL is mutated, menin forms a complex with it to regulate the expression of downstream Hox family genes, leading to leukemia. If menin is absent, it cannot form a complex with mutated MLL, resulting in inhibited cell proliferation.

[0003] Studies have found that Menin inhibitors are effective against leukemia with KMT2A rearrangement (KMT2Ar) and NPM1 mutation (NPM1c). Therefore, the development of highly effective Menin inhibitors will bring hope for the treatment of patients with this subtype. In addition, Menin degradation also has good therapeutic effects in certain solid tumors, such as liver cancer, non-small cell lung cancer, and pancreatic cancer. Summary of the Invention

[0004] This invention provides a novel mechanism by which compounds exert antitumor effects through the degradation of menin proteins. These compounds can be used to treat and prevent diseases related to menin proteins.

[0005] This invention provides a class of compounds that act on a novel mechanism. These compounds inhibit tumor cell proliferation by downregulating the expression of Menin protein, and can be used to treat and prevent diseases related to Menin protein.

[0006] The present invention provides a composition and formulation comprising the above-mentioned pyrrolopyrimidine compounds.

[0007] This invention also provides an application of the above-described compounds, compositions, or formulations in the preparation of medicaments for the prevention or treatment of diseases caused by Menin pathway abnormalities. The compounds of this invention can serve as Menin protein downregulators for the treatment and prevention of Menin protein-related clinical applications, such as hematologic malignancies and solid tumors.

[0008] The present invention adopts the following technical solution:

[0009] This invention provides a compound having the general formula I, its optical isomer, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] The substituents and structures of the above compounds are further explained below:

[0012] A is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclic groups, and -NR. b R b’ -OR c The alkyl, heterocyclic, and cycloalkyl groups may be substituted by one or more halogens, hydroxyl groups, amino groups, oxo groups, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered alicyclic groups, C1-C3 alkylamine groups, and 4-6 membered heterocyclic groups.

[0013] R b R b’ R c Each is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclic group, wherein the alkyl, heterocyclic group, cycloalkyl group may be substituted by one or more halogens, hydroxyl groups, amino groups, oxo groups, C1-C3 alkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkyl groups, C1-C3 alkylamine groups, 4-12 membered heterocyclic groups.

[0014] As the preferred option, A is selected from... or -NR b R b’ ; n2 Ra are each independently selected from hydrogen, halogen, C1-C4 alkyl; G is selected from C, N, O, S; Re and Rf are each independently selected from unsubstituted, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups; Rg is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups; n1, n2, and j are each independently selected from 1, 2, 3, and 4; R b R b’ Each is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclic groups, wherein the alkyl, heterocyclic, and cycloalkyl groups may be substituted by halogen, hydroxyl, amino, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkylamine, or 4-12 membered heterocyclic groups; furthermore, R b R b’Each is independently selected from: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, wherein the alkyl, heterocyclic group, cycloalkyl group may be substituted by one or more halogens, hydroxyl groups, amino groups, oxo groups, C1-C3 alkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkyl groups, C1-C3 alkylamine groups, 4-6 membered heterocyclic groups.

[0015] As a further preferred option, A is selected from:

[0016]

[0017] R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino; as a preferred embodiment, R5 is selected from hydrogen, C1-C3 alkoxy, and C1-C3 alkylamino; as a further preferred embodiment, R5 is selected from hydrogen, methylamino, and dimethylamine.

[0018] L1 is selected from:

[0019]

[0020] Rh is selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; k is 0, 1, or 2; q is 0, 1, or 2; and d is 1 or 2.

[0021] As the preferred option, L1 is selected from:

[0022]

[0023] Z is selected from CH and N; as a preferred option, Z is selected from N.

[0024] Q is selected from NH, O, and S; as the preferred option, Q is selected from S.

[0025] X is selected from CH and N; as the preferred option, X is selected from N.

[0026] R1 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; as a preferred embodiment, R1 is selected from hydrogen, halogen, and C1-C4 alkyl; as a further preferred embodiment, R1 is selected from hydrogen and methyl.

[0027] R2 is selected from hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 alkylamino; as a preferred embodiment, R2 is selected from hydrogen, fluorine, chlorine, bromine, and methyl; as a further preferred embodiment, R2 is selected from hydrogen, fluorine, and methyl.

[0028] L2 is selected from

[0029] g is selected from 1, 2, and 3;

[0030] Cyc1 is selected from 4-12 membered heterocyclic groups;

[0031] R3 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 alkylamine.

[0032] R4 is either -Rj or -NH-Rj, where Rj is selected from... Or nitrile group;

[0033] R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, and halomethyl;

[0034] R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl,

[0035] c and t are each independently selected from 1, 2, and 3;

[0036] R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl group.

[0037] n is selected from 1, 2, 3, 4, and 5.

[0038] As a preferred option, Cy1 is selected from Where Rk is selected from hydrogen, C1-C4 alkyl, C1-C4 alkylamine, and C1-C4 haloalkyl; a is 0, 1, or 2; and b is 1, 2, 3, or 4.

[0039] R4 is selected from Or nitrile group;

[0040] R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, and halomethyl;

[0041] R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl,

[0042] c and t are each independently selected from 1, 2, and 3;

[0043] R j-4 R j-7 R j-8 Rj-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl group.

[0044] As a further preferred option, W is selected from Where Rk is selected from hydrogen and methyl; Rj is selected from... Or nitrile group; wherein R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, c and t are each independently selected from integers from 1 to 3; R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl; a is 1,2; b is 1,2,3.

[0045] The present invention is more preferably having a structure shown in general formula II, the optical isomer thereof or a pharmaceutically acceptable salt thereof:

[0046]

[0047] in:

[0048] A is selected from

[0049] Ra, Rb, Rc, and Rd are each independently selected from hydrogen, halogens, and C1-C4 alkyl groups;

[0050] G is selected from C, N, O, and S;

[0051] Re and Rf are each independently selected from non-existent, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamine, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups;

[0052] Rg is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups;

[0053] E is selected from NH, O, and S;

[0054] Ri and Rm are each independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0055] m is 0, 1, or 2;

[0056] n1 is 1 or 2;

[0057] j is 0, 1, or 2.

[0058] Preferably, the structure shown in formula (III) is used:

[0059] Where W is

[0060] As the preferred option, A is selected from...

[0061] R5 is selected from hydrogen, C1-C3 alkoxy, and C1-C3 alkylamino; in a further preferred embodiment, R5 is selected from hydrogen, methylamino, and dimethylamino.

[0062] L1 is selected from Where k is selected from 0 and 1;

[0063] q is selected from 0 and 1; d is selected from 1 and 2;

[0064] L1 is selected as the preferred choice

[0065] R1 is selected from hydrogen or methyl;

[0066] X is selected from CH and N; R2 is selected from hydrogen, fluorine, and methyl.

[0067] L2 is selected from

[0068] W selected Where Rk is selected from hydrogen and methyl; Rj is selected from... Or nitrile group; wherein R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, c and t are each independently selected from integers from 1 to 3; R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl; a is 1,2; b is 1,2,3;

[0069] As a further preferred option, Rj is preferably:

[0070] (X represents fluorine, chlorine, bromine, or iodine).

[0071] As a preferred option Selected from:

[0072] The present invention further prefers compounds with any of the following structures:

[0073]

[0074]

[0075]

[0076] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0077] The acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxyalkanic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphoric acids, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, octanoic acid, sebacic acid, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartaric acid, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, galacturonic acids, etc. Acid addition salts can be prepared by contacting a free base in a sufficient quantity of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base and then separated in a conventional manner.

[0078] The stereoisomers described in this invention include enantiomers, diastereomers, and geometric isomers. Some compounds of this invention have cycloalkyl groups that can be substituted at more than one carbon atom; in this case, all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of this invention.

[0079] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, or solvate thereof, and further comprising pharmaceutically acceptable excipients. The excipients are selected from: carriers, diluents, binders, lubricants, and wetting agents.

[0080] In some implementations, these pharmaceutical compositions may be used alone or in combination with other drugs to treat diseases, disorders, or conditions that benefit from the degradation of Menin protein.

[0081] The compounds of Formula I of the present invention can be formulated into pharmaceutical compositions in the following forms: syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, aqueous solutions, creams, ointments, lotions, gels, emulsions, etc.

[0082] The present invention also provides compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates or deuterated compounds thereof for the preparation of treatments, prevention and relief of diseases caused by Menin overactivation.

[0083] The present invention also provides the use of compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates or deuterated compounds thereof in the preparation of medicaments for the prevention and / or treatment of cancer. Detailed Implementation

[0084] The feasibility of the present invention will be illustrated below through examples. Those skilled in the art should understand that modifications or substitutions to the corresponding technical features based on the teachings of the prior art still fall within the scope of protection claimed by the present invention.

[0085] Synthesis of intermediate 1e in Example 1

[0086]

[0087] Step 1: 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine 1a (10 g, 35.7 mmol), morpholine (6.2 g, 71.5 mmol), and N,N-diisopropylethylamine (13.8 g, 107.3 mmol) were added sequentially to a reaction flask using n-butanol as the solvent. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 200 mL of water, and a solid precipitated. This solid was filtered and dried to obtain 1b, with a yield of 90%. LC-MS (ESI): m / z 331.2 [M+H] + .

[0088] Step 2: Under nitrogen protection, intermediate 1b (8 g, 24.2 mmol), 1-N-tert-butoxycarbonylpiperidin-4-borate pinacol ester (11.3 g, 36.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.7 g, 2.4 mmol), and potassium carbonate (10.1 g, 72.7 mmol) were added sequentially to a 500 mL three-necked flask containing 200 mL of 1,4-dioxane and 50 mL of water. The reaction system was stirred thoroughly overnight at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was poured into 200 mL of water. The mixture was extracted three times with ethyl acetate, and the organic layers were combined. The mixture was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 7.5 g of a pale yellow solid, intermediate 1c, with a yield of 79%. LC-MS (ESI): m / z 388.2 [M+H] + .

[0089] Step 3: Dissolve intermediate 1c (7g, 18.1mmol) in dichloromethane, add an equal volume of 4N ethyl hydrochloric acid solution, stir at room temperature for 3 hours. After the reaction is complete, evaporate the solvent directly to obtain a yellow solid intermediate 1d. LC-MS (ESI): m / z 288.1 [M+H] + .

[0090] Step 4: Intermediate 1d (5 g, 15.4 mmol), 2,4-dibromothiazole (7.5 g, 30.8 mmol), and triethylamine (7.8 g, 77.2 mmol) were added sequentially to a reaction flask using dimethyl sulfoxide as solvent. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 200 mL of water, and a solid precipitated. The solid was filtered and dried. The crude product was purified by silica gel column chromatography to give 5.5 g of a light yellow solid, intermediate 1e, with a yield of 79%. LC-MS (ESI): m / z 449.1 [M+H] + .

[0091] The structural formulas of intermediates 2a to 22a are as follows:

[0092]

[0093] Example 2 Synthesis of intermediate 2a

[0094] Following the synthetic method of intermediate 1e in Example 1, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 2a in 65% yield. LC-MS (ESI): m / z 447.1 [M+H] + .

[0095] Synthesis of intermediate 3a in Example 3

[0096] Following the synthetic method of intermediate 1e in Example 1, 1-N-tert-butoxycarbonylpiperidine-4-boronic acid pinacol ester was replaced with N-BOC-pyrrolidine-3-boronic acid pinacol ester, finally yielding intermediate 3a in 57% yield. LC-MS (ESI): m / z 435.1 [M+H] + .

[0097] Example 4 Synthesis of intermediate 4a

[0098] Following the synthetic method of intermediate 1e in Example 1, 1-N-tert-butoxycarbonylpiperidine-4-boronic acid pinacol ester was replaced with 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, finally yielding intermediate 4a in 65% yield. LC-MS (ESI): m / z 433.1 [M+H] + .

[0099] Synthesis of intermediate 5a in Example 5

[0100] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 3-(S)-3-methylmorpholine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 5a in 76% yield. LC-MS (ESI): m / z 461.1 [M+H] + .

[0101] Synthesis of intermediate 6a in Example 6

[0102] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 3-(R)-3-methylmorpholine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 6a in 64% yield. LC-MS (ESI): m / z 461.1 [M+H] + .

[0103] Synthesis of intermediate 7a in Example 7

[0104] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 3-(S)-3-methylmorpholine, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 7a in 71% yield. LC-MS (ESI): m / z 475.1 [M+H] + .

[0105] Synthesis of intermediate 8a in Example 8

[0106] Following the synthetic method of intermediate 1e in Example 1, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 8a in 70% yield. LC-MS (ESI): m / z 461.1 [M+H] + .

[0107] Synthesis of intermediate 9a in Example 9

[0108] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with cis-2,6-dimethylpiperazine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 9a in 65% yield. LC-MS (ESI): m / z 474.1 [M+H] + .

[0109] Synthesis of intermediate 10a in Example 10

[0110] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 2-piperazinone, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 10a in 69% yield. LC-MS (ESI): m / z 460.1 [M+H] + .

[0111] Synthesis of intermediate 11a in Example 11

[0112] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 1,1-thiomorpholine dioxide, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 11a in 56% yield. LC-MS (ESI): m / z 495.1 [M+H] + .

[0113] Synthesis of intermediate 12a in Example 12

[0114] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with N-methyltetrahydro-2H-pyran-4-amine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridin-4-boronic acid pinacol ester, finally yielding intermediate 12a in 66% yield, LC-MS (ESI): m / z 475.1 [M+H] + .

[0115] Synthesis of intermediate 13a in Example 13

[0116] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 4-aminotetrahydropyran, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridin-4-boronic acid pinacol ester, finally yielding intermediate 13a in 76% yield. LC-MS (ESI): m / z 461.1 [M+H] + .

[0117] Synthesis of intermediate 14a in Example 14

[0118] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with N-(2-methoxyethyl)methylamine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 14a in 66% yield. LC-MS (ESI): m / z 449.1 [M+H] + .

[0119] Synthesis of intermediate 15a in Example 15

[0120] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 2-methoxyethylamine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 15a in 75% yield. LC-MS (ESI): m / z 435.1 [M+H] + .

[0121] Synthesis of intermediate 16a in Example 16

[0122] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 4-methyl-4-hydroxypiperidine, and 1-N-tert-butoxycarbonylpiperidine-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 16a in 71% yield. LC-MS (ESI): m / z 475.1 [M+H] + .

[0123] Synthesis of intermediate 17a in Example 17

[0124] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 4-methyl-4-hydroxypiperidine, 1-N-tert-butoxycarbonylpiperidine-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 17a in 61% yield, LC-MS (ESI): m / z 489.1 [M+H] + .

[0125] Synthesis of intermediate 18a in Example 18

[0126] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with N-methylpiperazine, and 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 18a in 71% yield. LC-MS (ESI): m / z 460.1 [M+H] + .

[0127] Synthesis of intermediate 19a in Example 19

[0128] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with N-methylpiperazine, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 19a in 77% yield. LC-MS (ESI): m / z 474.1 [M+H] + .

[0129] Synthesis of intermediate 20a in Example 20

[0130] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 4-hydroxypiperidine, and 1-N-tert-butoxycarbonylpiperidine-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, finally yielding intermediate 20a in 71% yield. LC-MS (ESI): m / z 461.1 [M+H] + .

[0131] Example 21 Synthesis of intermediate 21a

[0132] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 3-(S)-3-methylmorpholine, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with 8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-en-3-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 21a with a yield of 67%. LC-MS (ESI): m / z 501.1 [M+H] + .

[0133] Synthesis of intermediate 22a in Example 22

[0134] Following the synthetic method of intermediate 1e in Example 1, morpholine was replaced with 3-oxa-8-azabicyclo[3.2.1]octane, 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester was replaced with 8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-en-3-boronic acid pinacol ester, and 2,4-dibromothiazole was replaced with 2,4-dibromo-5-methylthiazole, finally yielding intermediate 22a in 56% yield. LC-MS (ESI): m / z 513.1 [M+H] + .

[0135] Synthesis of intermediate 23e in Example 23

[0136]

[0137] Step 1: Under 0℃ conditions, 3-N-tert-butoxycarbonylaminocyclobutylamine (2.4 g, 14.1 mmol) and triethylamine (3.6 g, 35.2 mmol) were added sequentially to a reaction flask using dichloromethane as the solvent. Then, 3-bromobenzenesulfonyl chloride (3 g, 11.7 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was added to 200 mL of saturated sodium bicarbonate aqueous solution and extracted three times with dichloromethane. The combined organic layers were washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3.9 g of a white solid, intermediate 23b, with a yield of 83%. LC-MS (ESI): m / z 391.1 [M+H] + .

[0138] Step 2: Under nitrogen protection, intermediate 23b (2 g, 5.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 g, 0.5 mmol), pinacol diboronate (1.9 g, 7.7 mmol), and potassium acetate (1.5 g, 15.3 mmol) were sequentially added to a three-necked flask containing 100 mL of 1,4-dioxane. The reaction system was stirred thoroughly at 95 °C for 2 hours. After the reaction was completed and cooled to room temperature, the reaction solution was poured into 1 L of water and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product 23c was directly used for the next step of the reaction. LC-MS (ESI): m / z 439.2 [M+H] + .

[0139] Step 3: Under nitrogen protection, intermediate 1e (0.5 g, 1.1 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), intermediate 23c (0.9 g, 2.2 mmol), and potassium carbonate (0.5 g, 3.4 mmol) were sequentially added to a three-necked flask containing 90 mL of 1,4-dioxane and 30 mL of water. The reaction system was stirred thoroughly at 100 °C overnight. After the reaction was complete, the mixture was cooled to room temperature, poured into 100 mL of water, and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 0.5 g of a pale yellow solid, intermediate 23d, in 66% yield. LC-MS (ESI): m / z 681.2 [M+H] + .

[0140] Step 4: Dissolve intermediate 23d (0.5 g, 0.8 mmol) in dichloromethane, add an equal volume of 4N hydrochloric acid 1,4-dioxane solution, stir at room temperature for 2 hours. After the reaction is complete, evaporate the solvent directly to obtain a yellow solid intermediate 23e. LC-MS (ESI): m / z 581.2 [M+H] + .

[0141] The structural formulas of intermediates 24a to 63a are as follows:

[0142]

[0143]

[0144] Synthesis of intermediate 24a in Example 24

[0145] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with (R)-3-Boc-aminopiperidine, finally yielding intermediate 24a, LC-MS (ESI): m / z 609.2 [M+H] + .

[0146] Synthesis of intermediate 25a in Example 25

[0147] Referring to the synthesis method of intermediate 23e in Example 23, 1e was replaced with 2a, finally yielding intermediate 25a, LC-MS (ESI): m / z 579.2 [M+H] + .

[0148] Synthesis of intermediate 26a in Example 26

[0149] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with (S)-3-(Boc-amino)pyrrolidine, and 1e was replaced with 2a, finally yielding intermediate 26a. LC-MS (ESI): m / z 593.2 [M+H] + .

[0150] Synthesis of intermediate 27a in Example 27

[0151] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with (R)-3-(Boc-amino)pyrrolidine, and 1e was replaced with 2a, finally yielding intermediate 27a, LC-MS (ESI): m / z 593.2 [M+H] + .

[0152] Synthesis of intermediate 28a in Example 28

[0153] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with (R)-3-Boc-aminopiperidine, and 1e was replaced with 2a, finally yielding intermediate 28a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0154] Synthesis of intermediate 29a in Example 29

[0155] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with (S)-3-Boc-aminopiperidine, and 1e was replaced with 2a, finally yielding intermediate 29a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0156] Synthesis of intermediate 30a in Example 30

[0157] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 1-Boc-piperazine, and 1e was replaced with 2a, finally yielding intermediate 30a. LC-MS (ESI): m / z 593.2 [M+H] + .

[0158] Synthesis of intermediate 31a in Example 31

[0159] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 3-bromo-2-methylbenzenesulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 1-Boc-piperazine, and 1e was replaced with 2a, finally yielding intermediate 31a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0160] Synthesis of intermediate 32a in Example 32

[0161] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 3-bromo-4-methylbenzenesulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutylamine was replaced with 1-Boc-piperazine, and 1e was replaced with 2a, finally yielding intermediate 32a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0162] Synthesis of intermediate 33a in Example 33

[0163] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with (R)-1-N-Boc-2-methylpiperazine, and 1e was replaced with 2a, finally yielding intermediate 33a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0164] Synthesis of intermediate 34a in Example 34

[0165] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with (S)-1-N-Boc-2-methylpiperazine, and 1e was replaced with 2a, finally yielding intermediate 34a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0166] Synthesis of intermediate 35a in Example 35

[0167] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 1-Boc-piperazine, and 1e was replaced with 5a, finally yielding intermediate 35a. LC-MS (ESI): m / z 607.2 [M+H] + .

[0168] Synthesis of intermediate 36a in Example 36

[0169] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutylamine was replaced with 1-Boc-piperazine, and 1e was replaced with 6a, finally yielding intermediate 35a, LC-MS (ESI): m / z 607.2 [M+H] + .

[0170] Synthesis of intermediate 37a in Example 37

[0171] Following the synthetic method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 4-Boc-aminopiperidine, and 1e was replaced with 2a, finally yielding intermediate 37a, LC-MS (ESI): m / z 607.2 [M+H] + .

[0172] Synthesis of intermediate 38a in Example 38

[0173] Following the synthetic method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutylamine was replaced with 1-Boc-piperazine, and 1e was replaced with 2a, finally yielding intermediate 38a, LC-MS (ESI): m / z 594.2 [M+H] + .

[0174] Synthesis of intermediate 39a in Example 39

[0175] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 2a, finally yielding intermediate 39a, LC-MS (ESI): m / z 605.2 [M+H] + .

[0176] Synthesis of intermediate 40a in Example 40

[0177] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 3-bromo-2-fluorobenzenesulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 2a, finally yielding intermediate 40a, LC-MS (ESI): m / z 623.2 [M+H] + .

[0178] Synthesis of intermediate 41a in Example 40

[0179] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 5a, finally yielding intermediate 41a, LC-MS (ESI): m / z 619.2 [M+H] + .

[0180] Synthesis of intermediate 42a in Example 42

[0181] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 3-bromo-2-methylbenzenesulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 5a, finally yielding intermediate 42a. LC-MS (ESI): m / z 633.2 [M+H] + .

[0182] Synthesis of intermediate 43a in Example 43

[0183] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 7a, finally yielding intermediate 43a, LC-MS (ESI): m / z 634.2 [M+H] + .

[0184] Example 44 Synthesis of intermediate 44a

[0185] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 2a, finally yielding intermediate 44a. LC-MS (ESI): m / z 606.2 [M+H] +.

[0186] Synthesis of intermediate 45a in Example 45

[0187] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 8a, finally yielding intermediate 45a, LC-MS (ESI): m / z 620.2 [M+H] + .

[0188] Synthesis of intermediate 46a in Example 46

[0189] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 4a, finally yielding intermediate 46a. LC-MS (ESI): m / z 591.2 [M+H] + .

[0190] Example 47 Synthesis of Intermediate 47a

[0191] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 9a, finally yielding intermediate 47a, LC-MS (ESI): m / z 632.2 [M+H] + .

[0192] Synthesis of intermediate 48a in Example 48

[0193] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 10a, finally yielding intermediate 48a, LC-MS (ESI): m / z 618.2 [M+H] + .

[0194] Synthesis of intermediate 49a in Example 49

[0195] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 11a, finally yielding intermediate 49a, LC-MS (ESI): m / z 653.2 [M+H] + .

[0196] Synthesis of intermediate 50a in Example 50

[0197] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 12a, finally yielding intermediate 50a, LC-MS (ESI): m / z 633.2 [M+H] + .

[0198] Synthesis of intermediate 51a in Example 51

[0199] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 13a, finally yielding intermediate 51a, LC-MS (ESI): m / z 619.2 [M+H] + .

[0200] Synthesis of intermediate 52a in Example 52

[0201] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 14a, finally yielding intermediate 52a, LC-MS (ESI): m / z 607.2 [M+H] + .

[0202] Synthesis of intermediate 53a in Example 53

[0203] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 15a, finally yielding intermediate 53a, LC-MS (ESI): m / z 593.2 [M+H] + .

[0204] Synthesis of intermediate 54a in Example 54

[0205] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 16a, finally yielding intermediate 53a, LC-MS (ESI): m / z 633.2 [M+H] + .

[0206] Synthesis of intermediate 55a in Example 55

[0207] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 16a, finally yielding intermediate 55a, LC-MS (ESI): m / z 634.2 [M+H] + .

[0208] Synthesis of intermediate 56a in Example 56

[0209] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 17a, finally yielding intermediate 56a, LC-MS (ESI): m / z 648.2 [M+H] + .

[0210] Synthesis of intermediate 57a in Example 57

[0211] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 18a, finally yielding intermediate 57a, LC-MS (ESI): m / z 618.2 [M+H] + .

[0212] Synthesis of intermediate 58a in Example 58

[0213] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 18a, finally yielding intermediate 58a, LC-MS (ESI): m / z 619.2 [M+H] + .

[0214] Synthesis of intermediate 59a in Example 59

[0215] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 19a, finally yielding intermediate 59a, LC-MS (ESI): m / z 619.2 [M+H] + .

[0216] Synthesis of intermediate 60a in Example 60

[0217] Following the synthesis method of intermediate 23e in Example 23, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 20a, finally yielding intermediate 60a, LC-MS (ESI): m / z 619.2 [M+H] + .

[0218] Example 61 Synthesis of intermediate 61a

[0219] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutamine was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 20a, finally yielding intermediate 61a. LC-MS (ESI): m / z 620.2 [M+H] + .

[0220] Synthesis of intermediate 62a in Example 62

[0221] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 21a, finally yielding intermediate 62a, LC-MS (ESI): m / z 646.2 [M+H] + .

[0222] Synthesis of intermediate 63a in Example 63

[0223] Following the synthesis method of intermediate 23e in Example 23, 3-bromobenzenesulfonyl chloride was replaced with 5-bromopyridine-3-sulfonyl chloride, 3-N-tert-butoxycarbonylaminocyclobutane was replaced with 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester, and 1e was replaced with 22a, finally yielding intermediate 63a, LC-MS (ESI): m / z 672.2 [M+H]+ .

[0224] Synthesis of intermediate 64e in Example 64

[0225]

[0226] Step 1: 64a (3g, 10.2mmol), (R)-3-Boc-aminopiperidine (2.1g, 10.2mmol), and triethylamine (3.1g, 30.8mmol) were added sequentially to a reaction flask using acetonitrile as the solvent. The mixture was stirred at 60°C for 4 hours. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3.7g of a white solid, intermediate 64b, with a yield of 87%. LC-MS (ESI): m / z 411.1 [M+H] + .

[0227] Step 2: 64b (2 g, 4.8 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)thiobenzamide (1.3 g, 4.8 mmol) were added sequentially to a reaction flask using ethanol as solvent. The mixture was stirred at 60 °C for 2 hours. After the reaction was complete, a solid precipitated. The solid was filtered, and the crude product was purified by silica gel column chromatography to give 2.5 g of a yellow solid, intermediate 64c, with a yield of 89%. LC-MS (ESI): m / z 576.3 [M+H] + .

[0228] Step 3: Under nitrogen protection, intermediate 1b (0.5 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), intermediate 64c (1.3 g, 2.2 mmol), and potassium carbonate (0.6 g, 4.5 mmol) were sequentially added to a three-necked flask containing 90 mL of 1,4-dioxane and 30 mL of water. The reaction system was stirred thoroughly overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, poured into 100 mL of water, and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 0.5 g of a pale yellow solid, intermediate 64d, in 50% yield. LC-MS (ESI): m / z 652.3 [M+H] + .

[0229] Step 4: Dissolve intermediate 64d (0.5 g, 0.8 mmol) in dichloromethane, add an equal volume of 4N hydrochloric acid 1,4-dioxane solution, stir at room temperature for 2 hours. After the reaction is complete, evaporate the solvent directly to obtain a yellow solid intermediate 64e. LC-MS (ESI): m / z 552.3 [M+H]+ .

[0230] Synthesis of intermediate 65e in Example 65

[0231]

[0232] Step 1: 65a (3g, 12.0mmol), (R)-3-Boc-aminopiperidine (2.9g, 14.4mmol), and triethylamine (3.6g, 36.0mmol) were added sequentially to a reaction flask using acetonitrile as the solvent. The mixture was stirred at 60°C for 2 hours. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3.2g of a white solid, intermediate 65b, with a yield of 72%. LC-MS (ESI): m / z 369.1 [M+H] + .

[0233] Step 2: Under nitrogen protection, intermediate 65b (2 g, 5.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 g, 0.5 mmol), pinacol diboronate (2.1 g, 8.1 mmol), and potassium acetate (1.6 g, 16.3 mmol) were sequentially added to a three-necked flask containing 100 mL of 1,4-dioxane. The reaction system was stirred thoroughly at 95 °C for 2 hours. After the reaction was completed and cooled to room temperature, the reaction solution was poured into 1 L of water and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product 65c was directly used for the next step of the reaction. LC-MS (ESI): m / z 417.3 [M+H] + .

[0234] Step 3: Under nitrogen protection, intermediate 2a (0.5 g, 1.1 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), intermediate 65c (0.9 g, 2.2 mmol), and potassium carbonate (0.5 g, 3.3 mmol) were sequentially added to a three-necked flask containing 90 mL of 1,4-dioxane and 30 mL of water. The reaction system was stirred thoroughly overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, poured into 100 mL of water, and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 0.6 g of a pale yellow solid, intermediate 65d, with a yield of 81%. LC-MS (ESI): m / z 657.3 [M+H] + .

[0235] Step 4: Dissolve intermediate 65d (0.6 g, 0.9 mmol) in dichloromethane, add an equal volume of 4N hydrochloric acid 1,4-dioxane solution, stir at room temperature for 2 hours. After the reaction is complete, evaporate the solvent directly to obtain a yellow solid intermediate 65e. LC-MS (ESI): m / z 557.2 [M+H] + .

[0236] The structural formulas of intermediates 66a to 68a are as follows:

[0237]

[0238] Synthesis of intermediate 66a in Example 66

[0239] Following the synthesis method of intermediate 65e in Example 65, 2a was replaced with 1e, finally yielding intermediate 66a, LC-MS (ESI): m / z 559.3 [M+H] + .

[0240] Synthesis of intermediate 67a in Example 67

[0241] Following the synthesis method of intermediate 65e in Example 65, 2a was replaced with 3a, resulting in intermediate 66a. LC-MS (ESI): m / z 545.2 [M+H] + .

[0242] Synthesis of intermediate 68a in Example 68

[0243] Following the synthesis method of intermediate 65e in Example 65, 65a was replaced with 3-bromobenzoic acid, and triethylamine was replaced with HATU, finally yielding intermediate 68a. LC-MS (ESI): m / z 571.2 [M+H] + .

[0244] Synthesis of Example 69MJ-1

[0245]

[0246] Procedure: Intermediate 23e (400 mg, 0.6 mmol) was dissolved in 20 mL of dichloromethane, and then triethylamine (327.9 mg, 3.2 mmol) was added. Acryloyl chloride (76.2 mg, 0.8 mmol) was slowly added under ice bath conditions. After reacting at room temperature for 1 hour, saturated sodium bicarbonate aqueous solution was added, and the mixture was washed three times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 250 mg of compound MJ-1 as a yellow solid, with a yield of 60%. 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),8.28(t,J=1.8Hz,1H),8.14(s,2H),7.99–7.88(m,1H),7. 75–7.71(m,1H),7.63(d,J=7.8Hz,1H),7.44(d,J=2.4Hz,1H),6.43(d,J=2.1Hz,1H),6.10(s,1H) ,5.64–5.56(m,1H),4.15–4.03(m,4H),3.79(s,4H),3.71(dd,J=5.9,3.8Hz,4H),3.35(s,4H),3 .28–3.18(m,2H),2.97(s,1H),2.14–2.01(m,2H),1.80(dd,J=12.3,4.2Hz,2H),LC-MS(ESI):m / z 635.2[M+H] + .

[0247] Synthesis of Example 70MJ-2

[0248]

[0249] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 24a, resulting in MJ-2. 1 H NMR (400MHz, DMSO-d6) δ11.73(d,J=2.0Hz,1H),8.19(m,1H),8.15–8.12(m,2H),8.08(d,J=7.6Hz,1H),7.69–7.59(m,2H) ,7.54(s,1H),6.39(d,J=2.0Hz,1H),6.13–6.04(m,1H),5.59(dd,J=9.9,2.4Hz,1H),4.06(d,J=12.7Hz,2H),3.79(t,J=4. 7Hz,4H),3.70(dd,J=5.6,3.8Hz,4H),3.46(d,J=10.2Hz,1H),3.27–3.16(m,2H),2.94(d,J=11.8Hz,1H),2.26(t,J=10.0H z,1H),2.07(s,2H),1.79(d,J=11.3Hz,4H),1.72–1.66(m,2H),1.59–1.47(m,1H),1.24(d,J=6.3Hz,2H), LC-MS(ESI):m / z 663.2[M+H] + .

[0250] Example 71: Synthesis of MJ-3

[0251]

[0252] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 25a, resulting in MJ-3. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.66(d,J=6.7Hz,1H),8.25(d,J=2.6Hz,2H),8.17(s,1H),7.7 4(s,2H),7.58(s,1H),6.71(d,J=2.1Hz,1H),6.51(d,J=3.6Hz,1H),6.06(s,1H),5.58(dd,J=8.9,3. 4Hz,1H),4.41–4.34(m,1H),4.20(d,J=3.3Hz,2H),3.99(t,J=7.9Hz,2H),3.83(d,J=4.9Hz,4H),3.7 9(t,J=5.7Hz,2H),3.73(d,J=4.8Hz,4H),3.57(dd,J=8.2,6.4Hz,2H),2.70(s,2H),LC-MS(ESI):m / z 633.2[M+H] + .

[0253] Example 72 Synthesis of MJ-4

[0254]

[0255] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 26a, resulting in MJ-4. 1 H NMR (400MHz, DMSO-d6) δ12.02(d,J=2.0Hz,1H),8.31(d,J=6.3Hz,1H),8.22(s,1H),8.20–8.15(m,2H),7.73–7.68( m,1H),7.65(d,J=7.7Hz,1H),7.54(s,1H),6.71(d,J=2.0Hz,1H),6.52(s,1H),6.08–5.96(m,1H),5.53(dd,J=9.6,2 .7Hz,1H),4.21–4.17(m,2H),3.84(t,J=4.8Hz,4H),3.79(t,J=5.7Hz,2H),3.74–3.67(m,4H),3.07(d,J=3.6Hz,2H ),3.05(d,J=3.7Hz,2H),3.03(d,J=3.9Hz,2H),2.70(s,2H),2.01–1.89(m,1H),1.75–1.65(m,1H),LC-MS(ESI):m / z 647.2[M+H]+ .

[0256] Example 73: Synthesis of MJ-5

[0257]

[0258] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 27a, resulting in MJ-5. 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.97(s,1H),8.22(d,J=6.4Hz,1H),8.18(q,J=1.2Hz,1H),8.17–8.14(m ,1H),8.13(s,1H),7.66(dt,J=7.8,1.5Hz,1H),7.64–7.58(m,1H),7.51(s,1H),6.68(d,J=2.1Hz,1H),6.51–6 .40(m,1H),6.03–5.96(m,1H),5.50(dd,J=9.2,3.1Hz,1H),4.16(s,2H),4.09(q,J=5.8Hz,1H),3.84–3.78(m, 4H),3.76(t,J=5.7Hz,2H),3.69(dd,J=5.7,3.9Hz,4H),3.31(s,6H),2.67(s,2H),LC-MS(ESI):m / z647.2[M+H] + .

[0259] Example 74: Synthesis of MJ-6

[0260]

[0261] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 28a, resulting in MJ-6. 1H NMR (400MHz, DMSO-d6) δ12.00(d,J=2.0Hz,1H),8.17(s,2H),8.09(d,J=7.6Hz,1H),7.73–7.62(m,2H),7.55(s,1H),6.70(d,J=2.1 Hz,1H),6.50(s,1H),6.23(dd,J=17.1,10.0Hz,1H),6.11(dd,J=17.1,2.4Hz,1H),5.60(dd,J=9.9,2.4Hz,1H),4.26–4.13(m,2H), 3.91–3.82(m,4H),3.78(t,J=5.9Hz,2H),3.73(d,J=4.9Hz,4H),3.47(dd,J=11.1,4.0Hz,1H),3.32(d,J=7.4Hz,2H),3.17(d,J=5. 1Hz,1H),2.68(d,J=6.6Hz,2H),2.36–2.20(m,1H),1.74(m,2H),1.58–1.48(m,1H),1.23(dd,J=13.1,3.5Hz,1H), LC-MS(ESI):m / z 661.2[M+H] + .

[0262] Example 75: Synthesis of MJ-7

[0263]

[0264] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 29a, resulting in MJ-7. 1H NMR (400MHz, DMSO-d6) δ12.01(d,J=2.1Hz,1H),8.21(dt,J=6.8,2.0Hz,1H),8.17(s,2H),8.09(d,J=7.7Hz,1H),7.73–7.63(m,2H),7.57(s ,1H),6.71(d,J=2.1Hz,1H),6.54–6.46(m,1H),6.22(dd,J=17.1,9.9Hz,1H),6.11(dd,J=17.1,2.4Hz,1H),5.60(dd,J=9.9,2.4Hz,1H),4. 19(t,J=2.9Hz,2H),3.84(dd,J=5.8,3.9Hz,4H),3.79(t,J=5.7Hz,2H),3.73(dd,J=5.7,3.9Hz,4H),3.52–3.41(m,1H),3.34–3.28(m,2H), 2.70(s,2H),2.31–2.22(m,1H),1.85–1.63(m,2H),1.54(dd,J=10.0,3.9Hz,1H),1.23(dt,J=10.4,5.0Hz,2H), LC-MS(ESI):m / z661.2[M+H] + .

[0265] Example 76: Synthesis of MJ-8

[0266]

[0267] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 30a, resulting in MJ-8. 1 H NMR (400MHz, DMSO-d6) δ11.97(d,J=2.1Hz,1H),8.18(d,J=7.4Hz,1H),8.14(s,2H),7.68–7.58(m ,2H),7.52(s,1H),6.73–6.60(m,2H),6.47(s,1H),6.00(dd,J=16.7,2.3Hz,1H),5.59(dd,J=10. 5,2.3Hz,1H),4.16(d,J=2.8Hz,2H),3.80(dd,J=5.8,3.9Hz,4H),3.75(t,J=5.7Hz,2H),3.69(dd ,J=5.6,3.9Hz,4H),3.60(d,J=11.2Hz,4H),2.91(d,J=5.0Hz,4H),2.66(s,2H),LC-MS(ESI):m / z 647.2[M+H] + .

[0268] Example 77 Synthesis of MJ-9

[0269]

[0270] Procedure: Intermediate 30a (400 mg, 0.6 mmol) was dissolved in 5 mL of DMF, followed by the addition of N,N-diisopropylethylamine (246.5 mg, 1.9 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (408.3 mg, 0.8 mmol), and crotonic acid (0.31 g, 0.89 mmol). After reacting at room temperature for 3 hours, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 0.2 g of compound M-6 as a white solid, with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ12.15–11.79(m,1H),8.21(m,1H),8.17(d,J=3.1Hz,2H),7.68(t,J=7.6Hz,1H),7.65– 7.63(m,1H),7.55(s,1H),6.71(d,J=2.1Hz,1H),6.60(dd,J=14.9,6.9Hz,1H),6.50(d,J=3.7Hz,1H),6.40(dd ,J=15.0,1.7Hz,1H),4.25–4.11(m,2H),3.84(d,J=5.0Hz,4H),3.79(t,J=5.7Hz,2H),3.73(dd,J=5.7,3.8Hz, 4H), 3.61 (s, 4H), 2.91 (t, J=5.1Hz, 4H), 2.70 (s, 2H), 1.76 (dd, J=6.8, 1.6Hz, 3H), LC-MS (ESI): m / z661.2[M+H] + .

[0271] Example 78: Synthesis of MJ-10

[0272]

[0273] Referring to the synthesis method of MJ-9 in Example 77, crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-10. 1H NMR (400MHz, DMSO-d6) δ12.01(d,J=2.1Hz,1H),8.48(dd,J=4.3,1.4Hz,1H),8.31(dd,J=8.3,1.4Hz,1H),8.21(dt,J =7.4,1.6Hz,1H),8.17(s,1H),7.68(t,J=7.6Hz,1H),7.66–7.62(m,1H),7.55(s,1H),7.31(dd,J=8.4,4.3Hz,1H),6 .71(s,1H),6.54(d,J=3.4Hz,1H),4.20(d,J=3.4Hz,2H),3.84(t,J=4.8Hz,4H),3.79(t,J=5.7Hz,2H),3.73(dd,J=5 .7,3.8Hz,4H),3.61(s,4H),3.13(d,J=4.5Hz,2H),2.93(d,J=5.1Hz,4H),2.70(s,2H),2.22(s,6H),LC-MS(ESI):m / z 704.2[M+H] + .

[0274] Example 79: Synthesis of MJ-11

[0275]

[0276] Referring to the synthesis method of MJ-9 in Example 77, crotonic acid was replaced with 2-fluoroacrylic acid, finally yielding MJ-11. 1 HNMR (400MHz, DMSO-d6) δ12.32(s,1H),8.25(s,1H),8.22(dt,J=7.4,1.6Hz,1H),8.17(d,J=1.9Hz, 1H),7.69(t,J=7.6Hz,1H),7.67–7.63(m,1H),7.56(s,1H),6.82(s,1H),6.54(d,J=3.5Hz,1H),5.22 (t,J=4.4Hz,1H),5.09(d,J=4.0Hz,1H),4.21(d,J=3.5Hz,2H),3.91–3.85(m,4H),3.80(t,J=5.7Hz ,2H),3.77–3.73(m,4H),3.61(t,J=5.0Hz,4H),3.00(t,J=5.1Hz,4H),2.70(s,2H),LC-MS(ESI):m / z 665.2[M+H] + .

[0277] Example 80: Synthesis of MJ-12

[0278]

[0279] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 30a, and acryloyl chloride was replaced with sodium nitrile, finally yielding MJ-12. 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.25(m,1H),8.18(d,J=1.9Hz,1H),8.16(s,1H), 7.71(t,J=7.7Hz,1H),7.67–7.63(m,1H),7.59(s,1H),6.72(d,J=2.1Hz,1H),6.51(s,1 H),4.20(s,2H),3.83(t,J=4.8Hz,4H),3.78(t,J=5.7Hz,2H),3.72(t,J=4.8Hz,4H),3. 32(d,J=4.5Hz,4H),3.00(dd,J=6.2,4.1Hz,4H),2.71(d,J=8.3Hz,2H), LC-MS(ESI):m / z 618.2[M+H] + .

[0280] Example 81: Synthesis of MJ-13

[0281]

[0282] Referring to the synthesis method of MJ-9 in Example 77, crotonic acid was replaced with 4,4,4-trifluorobutenoic acid, finally yielding MJ-13. 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.22(d,J=7.4Hz,1H),8.19(s,1H),8.18(s,2H),7.69(t, J=7.6Hz,1H),7.66(d,J=1.7Hz,1H),7.55(s,1H),7.26(dd,J=15.5,2.2Hz,1H),6.74(d,J=2.1H z,1H),6.51(s,1H),4.20(d,J=3.0Hz,2H),3.85(t,J=4.8Hz,4H),3.79(t,J=5.8Hz,2H),3.73(d d,J=5.7,3.8Hz,4H),3.64(t,J=5.0Hz,4H),2.97(t,J=5.1Hz,4H),2.70(s,2H),LC-MS(ESI):m / z 715.2[M+H] + .

[0283] Example 82: Synthesis of MJ-14

[0284]

[0285] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 30a, and acryloyl chloride was replaced with chloroacetyl chloride, finally yielding MJ-14. 1 H NMR(400MHz,DMSO-d6)δ11.97(d,J=2.1Hz,1H),8.27–8.17(m,1H),8.14(s,2H),7.69 –7.57(m,2H),7.52(s,1H),6.68(d,J=2.1Hz,1H),6.47(t,J=3.4Hz,1H),4.30(s,2H) ,4.16(d,J=3.3Hz,2H),3.80(t,J=4.8Hz,4H),3.75(t,J=5.7Hz,2H),3.69(dd,J=5.6 ,3.8Hz,4H),3.58–3.45(m,4H),2.92(d,J=15.1Hz,4H),2.67(s,2H),LC-MS(ESI):m / z 669.2[M+H] + .

[0286] Example 83: Synthesis of MJ-15

[0287]

[0288] Referring to the synthesis method of MJ-9 in Example 77, crotonic acid was replaced with 2-butynic acid, finally yielding MJ-15. 1 HNMR (400MHz, DMSO-d6) δ12.02(s,1H),8.22(dd,J=7.5,1.6Hz,1H),8.17(d,J=2.9Hz,2H),7.68(t,J =7.6Hz,1H),7.64(dt,J=7.8,1.7Hz,1H),7.55(s,1H),6.72(d,J=2.1Hz,1H),6.51(s,1H),4.25–4.11 (m,2H),3.85–3.82(m,4H),3.79(t,J=5.7Hz,2H),3.73(q,J=6.3,4.5Hz,4H),3.56(t,J=5.0Hz,2H), 3.34(s,2H),2.98(t,J=5.1Hz,2H),2.92(t,J=5.2Hz,2H),2.70(s,2H),1.96(s,3H),LC-MS(ESI):m / z 659.2[M+H] + .

[0289] Example 84: Synthesis of MJ-16

[0290]

[0291] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 30a, and acryloyl chloride was replaced with vinylsulfonyl chloride, finally yielding MJ-16. 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),8.23(m,1H),8.18(d,J=2.5Hz,2H),7.70(t,J=7.6Hz,1H),7. 67–7.63(m,1H),7.56(s,1H),6.79(dd,J=16.5,10.0Hz,1H),6.71(d,J=2.1Hz,1H),6.51(d,J=3.4Hz ,1H),6.19–6.02(m,2H),4.20(d,J=3.4Hz,2H),3.84(t,J=4.8Hz,4H),3.79(t,J=5.7Hz,2H),3.73( dd,J=5.6,3.8Hz,4H),3.17–3.08(m,4H),3.05(dd,J=6.4,3.4Hz,4H),2.70(s,2H),LC-MS(ESI):m / z 683.2[M+H] + .

[0292] Example 85: Synthesis of MJ-17

[0293]

[0294] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 31a, resulting in MJ-17. 1 H NMR (400MHz, DMSO-d6) δ11.98(d,J=1.9Hz,1H),8.17(s,1H),7.86(dd,J=8.0,1.4Hz,1H),7.74(dd,J=7.8,1. 4Hz,1H),7.45(t,J=7.8Hz,1H),6.98(s,1H),6.84–6.73(m,1H),6.73–6.65(m,1H),6.49(d,J=3.4Hz,1H),6.1 1(dd,J=16.7,2.3Hz,1H),5.69(dd,J=10.5,2.3Hz,1H),4.14(d,J=3.2Hz,2H),3.83(t,J=4.7Hz,4H),3.73(s ,4H),3.72(s,2H),3.63(s,4H),3.16(d,J=4.8Hz,4H),2.67(s,2H),2.61(s,3H),LC-MS(ESI):m / z661.2[M+H] + .

[0295] Example 86: Synthesis of MJ-18

[0296]

[0297] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 32a, resulting in MJ-18. 1 H NMR (400MHz, DMSO-d6) δ11.99(d,J=2.0Hz,1H),8.17(s,1H),7.92(d,J=2.0Hz,1H),7.64–7. 50(m,2H),7.12(s,1H),6.77–6.64(m,2H),6.50(d,J=3.4Hz,1H),6.04(dd,J=16.7,2.3Hz,1H ),5.64(dd,J=10.5,2.3Hz,1H),4.16(s,2H),3.84(dd,J=5.8,3.8Hz,4H),3.75(s,2H),3.77 –3.69(m,4H),3.62(s,4H),2.91(d,J=5.0Hz,4H),2.69(s,2H),2.54(s,3H),LC-MS(ESI):m / z 661.2[M+H] + .

[0298] Example 87: Synthesis of MJ-19

[0299]

[0300] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 33a, resulting in MJ-19. 1H NMR (400MHz, DMSO-d6) δ11.98(d,J=2.1Hz,1H),8.19–8.15(m,1H),8.14(d,J=2.3Hz,2H),7.64(t,J=7.6Hz,1H),7.62 –7.57(m,1H),7.51(s,1H),6.68(d,J=2.2Hz,1H),6.65–6.60(m,1H),6.47(d,J=3.6Hz,1H),6.00(dd,J=16.7,2.3Hz,1 H),5.60(dd,J=10.5,2.3Hz,1H),4.22–4.09(m,2H),3.81(dd,J=5.8,3.8Hz,4H),3.75(t,J=5.7Hz,2H),3.72–3.66(m, 4H), 3.46 (d, J = 11.7Hz, 1H), 3.31 (s, 4H), 2.66 (s, 2H), 2.25 (d, J = 58.9Hz, 2H), 1.18 (d, J = 8.2Hz, 3H), LC-MS (ESI): m / z 661.2[M+H] + .

[0301] Example 88: Synthesis of MJ-20

[0302]

[0303] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 34a, resulting in MJ-20. 1 H NMR (400MHz, DMSO-d6) δ11.97(d,J=2.1Hz,1H),8.17(m,1H),8.14(d,J=1.8Hz,2H),7.64(t,J=7.6Hz,1H),7.60(m, 1H),7.51(s,1H),6.68(d,J=1.9Hz,1H),6.65–6.58(m,1H),6.47(d,J=3.7Hz,1H),6.00(dd,J=16.7,2.3Hz,1H),5. 60(dd,J=10.5,2.3Hz,1H),4.30–4.04(m,2H),3.81(t,J=4.8Hz,4H),3.75(t,J=5.7Hz,2H),3.69(dd,J=5.6,3.9Hz ,4H),3.46(d,J=11.8Hz,1H),3.31(s,4H),2.66(s,2H),2.36–2.09(m,2H),1.18(t,J=5.8Hz,3H), LC-MS(ESI):m / z 661.2[M+H] + .

[0304] Example 89: Synthesis of MJ-21

[0305]

[0306] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 35a, resulting in MJ-21. 1 H NMR (400MHz, DMSO-d6) δ11.98(d,J=2.0Hz,1H),8.21(dt,J=7.3,1.7Hz,1H),8.17(d,J=3.8Hz,2H),7.72–7.63(m,2H),7.54 (s,1H),6.74–6.65(m,2H),6.50(s,1H),6.03(dd,J=16.7,2.3Hz,1H),5.63(dd,J=10.5,2.3Hz,1H),4.77–4.70(m,1H),4.3 6(d,J=13.1Hz,1H),4.19(d,J=3.0Hz,2H),3.96(dd,J=11.2,3.6Hz,1H),3.79(t,J=6.0Hz,2H),3.72(t,J=13.8Hz,2H),3.6 4(d,J=9.4Hz,4H),3.51(td,J=12.0,3.0Hz,2H),2.94(t,J=5.1Hz,4H),2.69(s,2H),1.25(d,J=6.7Hz,3H), LC-MS(ESI):m / z 661.2[M+H] + .

[0307] Synthesis of Example 90MJ-22

[0308]

[0309] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 36a, resulting in MJ-22. 1H NMR (400MHz, DMSO-d6) δ11.95(d,J=2.0Hz,1H),8.17(dt,J=7.3,1.7Hz,1H),8.14(d,J=1.9Hz,1H),8.13(s,1H),7.69–7.58( m,2H),7.50(s,1H),6.70–6.60(m,2H),6.46(t,J=3.4Hz,1H),6.00(dd,J=16.7,2.3Hz,1H),5.59(dd,J=10.5,2.3Hz,1H),4.7 6–4.66(m,1H),4.32(d,J=13.8Hz,1H),4.16(d,J=3.3Hz,2H),3.92(dd,J=11.3,3.6Hz,1H),3.75(t,J=5.9Hz,2H),3.72–3.64 (m,2H),3.60(d,J=8.3Hz,4H),3.51–3.43(m,2H),2.90(t,J=5.0Hz,4H),2.66(s,2H),1.21(d,J=6.7Hz,3H), LC-MS(ESI):m / z 661.2[M+H] + .

[0310] Example 91: Synthesis of MJ-23

[0311]

[0312] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 37a, resulting in MJ-23. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.17(dt,J=7.0,1.8Hz,2H),8.14(d,J=4.9Hz,2H),7.69–7.60(m,1H),7.53(s ,1H),6.68(d,J=2.1Hz,1H),6.50(s,1H),6.16(dd,J=17.1,10.1Hz,1H),5.99(dd,J=17.1,2.4Hz,1H),5.50(dd,J=10 .1,2.3Hz,1H),4.15(d,J=3.3Hz,2H),3.79(d,J=4.9Hz,4H),3.77–3.73(m,2H),3.73–3.63(m,4H),3.51(d,J=12.1Hz ,2H),3.34(s,2H),2.66(s,2H),2.50(s,1H),1.79(d,J=12.6Hz,2H),1.52–1.37(m,2H),LC-MS(ESI):m / z661.2[M+H]+ .

[0313] Example 92: Synthesis of MJ-24

[0314]

[0315] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 38a, resulting in MJ-24. 1 H NMR (400MHz, DMSO-d6) δ12.02(d,J=2.1Hz,1H),9.40(d,J=2.0Hz,1H),8.79(d,J=2.2Hz,1H),8.44(t ,J=2.1Hz,1H),8.17(s,1H),7.78(s,1H),6.99–6.61(m,2H),6.52(d,J=3.5Hz,1H),6.03(dd,J=16.7 ,2.3Hz,1H),5.64(dd,J=10.5,2.3Hz,1H),4.21(d,J=3.1Hz,2H),3.84(dd,J=5.8,3.9Hz,4H),3.80( t,J=5.6Hz,2H),3.72(dd,J=5.7,3.8Hz,4H),3.64(s,4H),3.34(s,4H)2.70(s,2H),LC-MS(ESI):m / z 648.2[M+H] + .

[0316] Example 93: Synthesis of MJ-25

[0317]

[0318] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 39a, finally yielding MJ-25. 1H NMR(400MHz, DMSO-d6)δ12.00(d,J=2.1Hz,1H),8.28(q,J=2.0Hz,1H),8.24–8.18(m,1H),8.17(s,1H),7.77(dt,J=8.0,1.3Hz,1H) ,7.69–7.63(m,1H),7.58(d,J=2.9Hz,1H),6.71(d,J=2.1Hz,1H),6.51(s,1H),6.31(dd,J=16.8,10.2Hz,1H),6.13–6.07(m,1H),5 .65(m,1H),4.83–4.58(m,2H),4.20(d,J=3.3Hz,2H),3.84(t,J=4.8Hz,4H),3.79(t,J=5.7Hz,2H),3.73(dd,J=5.6,3.9Hz,4H),3. 59–3.47(m,1H),3.31–3.18(m,2H),2.70(s,2H),1.75–1.63(m,1H),1.24(d,J=6.9Hz,1H),1.04(d,J=10.3Hz,1H), LC-MS(ESI):m / z 659.2[M+H] + .

[0319] Example 94: Synthesis of MJ-26

[0320]

[0321] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with 2-methacrylic acid, finally yielding MJ-26. 1H NMR(400MHz, DMSO-d6)δ12.00(d,J=2.1Hz,1H),8.32–8.27(m,1H),8.21(d,J=7.9Hz,1H),8.17(s,1H),7.78(d, J=7.8Hz,1H),7.66(t,J=7.8Hz,1H),7.57(s,1H),6.71(d,J=2.1Hz,1H),6.51(d,J=3.5Hz,1H),5.29–4.97(m,2H ),4.55(dd,J=26.8,12.5Hz,2H),4.20(d,J=2.8Hz,2H),3.83(d,J=4.9Hz,4H),3.79(t,J=5.8Hz,2H),3.72(t,J =4.8Hz,4H),3.48–3.38(m,1H),3.25(d,J=22.9Hz,2H),2.70(s,2H),1.81(s,3H),1.21(s,1H),LC-MS(ESI):m / z 673.2[M+H] + .

[0322] Example 95: Synthesis of MJ-27

[0323]

[0324] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with 2-fluoroacrylic acid, finally yielding MJ-27. 1 H NMR (400MHz, DMSO-d6) δ12.00(d,J=2.0Hz,1H),8.28(d,J=1.9Hz,1H),8.21(dd,J=8.0,3.7Hz,1H),8.17(s,1H),7.78–7 .75(m,1H),7.67(m,1H),7.57(d,J=3.3Hz,1H),6.71(d,J=2.1Hz,1H),6.51(s,1H),5.47–5.29(m,1H),5.29–5.18(m,1H) ,4.63(d,J=37.3Hz,2H),4.20(d,J=3.0Hz,2H),3.83(d,J=4.9Hz,4H),3.79(t,J=5.8Hz,2H),3.72(dd,J=5.6,3.8Hz,4H ),3.31–3.22(m,2H),2.70(s,2H),1.75–1.63(m,1H),1.32–1.21(m,2H),1.08(dd,J=32.0,10.4Hz,1H),LC-MS(ESI):m / z 677.2[M+H] + .

[0325] Example 96: Synthesis of MJ-28

[0326]

[0327] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, resulting in MJ-28. 1 H NMR (400MHz, DMSO-d6) δ12.19–11.95(m,1H),8.28(d,J=1.9Hz,1H),8.21(dd,J=7.8,5.2Hz,1H),8.17(s,1H),7.80–7.74(m,1H), 7.70–7.63(m,1H),7.56(d,J=3.1Hz,1H),6.71(d,J=2.0Hz,1H),6.67–6.58(m,1H),6.51(d,J=3.5Hz,1H),5.94(dd,J=15.0,1.9Hz ,1H),4.79–4.51(m,2H),4.20(d,J=3.5Hz,2H),3.83(d,J=4.8Hz,4H),3.79(s,2H),3.73(d,J=4.9Hz,4H),3.54–3.45(m,1H),3.2 7–3.20(m,2H),2.70(s,2H),1.76(dd,J=6.9,1.7Hz,3H),1.71–1.53(m,1H),1.21(s,1H),1.09(d,J=11.4Hz,1H), LC-MS(ESI):m / z 673.2[M+H] + .

[0328] Example 97: Synthesis of MJ-29

[0329]

[0330] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-29. 1H NMR(400MHz, DMSO-d6)δ12.09–11.90(m,1H),8.28(s,1H),8.19(d,J=12.4Hz,2H),7.77(dd,J=7.9,1.5Hz,1H),7 .67(dd,J=7.8,6.0Hz,1H),7.57(d,J=3.4Hz,1H),6.71(d,J=1.9Hz,1H),6.51(s,2H),6.04(d,J=15.2Hz,1H),4.8 0–4.51(m,2H),4.20(d,J=3.3Hz,2H),3.85–3.81(m,4H),3.79(s,2H),3.73(d,J=4.8Hz,4H),3.25(s,2H),3.05–2 .92(m,2H),2.70(s,2H),2.15(s,3H),2.12(s,3H),1.77–1.61(m,1H),1.21(s,2H),1.09(m,1H),LC-MS(ESI):m / z 716.2[M+H] + .

[0331] Example 98: Synthesis of MJ-30

[0332]

[0333] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 39a, and acryloyl chloride was replaced with sodium nitrile, finally yielding MJ-30. 1 H NMR (400MHz, DMSO-d6) δ11.96(d,J=2.0Hz,1H),8.24(t,J=1.8Hz,1H),8.19(dt,J=7.8,1.4Hz,1H),8.13(s,1H),7.79–7.71(m ,1H),7.64(t,J=7.8Hz,1H),7.55(s,1H),6.67(d,J=2.0Hz,1H),6.47(d,J=1.6Hz,1H),4.53(d,J=2.4Hz,1H),4.27(s,1H),4. 16(q,J=2.8,2.3Hz,2H),3.88–3.75(m,4H),3.75(t,J=5.7Hz,2H),3.69(d,J=5.1Hz,4H),3.43(dd,J=9.4,2.2Hz,2H),3.31–3 .25(m,1H),3.17(dd,J=10.2,1.9Hz,1H),2.66(s,2H),1.65(d,J=10.5Hz,1H),1.04–0.96(m,1H),LC-MS(ESI):m / z630.2[M+H]+ .

[0334] Example 99: Synthesis of MJ-31

[0335]

[0336] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with 4,4,4-trifluorobutenoic acid, finally yielding MJ-31. 1 H NMR (400MHz, DMSO-d6) δ11.97(d,J=2.0Hz,1H),8.25(t,J=1.8Hz,1H),8.17(d,J=1.3Hz,1H),8.14(s,1H),7.81–7.71(m,1H),7.64(dd ,J=7.8,3.8Hz,1H),7.53(d,J=5.0Hz,1H),7.16(dd,J=15.3,2.2Hz,1H),6.86–6.69(m,1H),6.67(d,J=2.3Hz,1H),6.48(d,J=3.5Hz,1H ),4.87–4.47(m,2H),4.16(q,J=2.6Hz,2H),3.80(t,J=4.8Hz,4H),3.75(t,J=5.7Hz,2H),3.69(dd,J=5.7,3.9Hz,4H),3.59(d,J=1.9H z,1H),3.28–3.10(m,2H),2.66(d,J=6.1Hz,2H),1.66(dd,J=23.5,10.0Hz,1H),1.28–1.13(m,1H),1.07–0.98(m,1H),LC-MS(ESI):m / z 727.2[M+H] + .

[0337] Example 100: Synthesis of MJ-32

[0338]

[0339] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with (2E)-4-(1-piperidinyl)-2-butenoic acid, finally yielding MJ-32. 1H NMR (400MHz, DMSO-d6) δ12.00(d,J=2.0Hz,1H),8.27(d,J=1.8Hz,1H),8.17(s,2H),7.81–7.73(m,1H),7.71–7.62(m,1H) ,7.56(d,J=4.5Hz,1H),6.71(s,1H),6.51(s,2H),6.04–5.93(m,1H),4.76–4.49(m,2H),4.20(d,J=3.4Hz,2H),3.83(d,J= 4.8Hz,4H),3.79(s,2H),3.72(dd,J=5.5,3.8Hz,4H),3.36(s,2H),3.25(s,2H),3.06–2.89(m,2H),2.70(s,2H),2.27(d, J=18.6Hz,4H),1.76–1.61(m,1H),1.46(d,J=5.8Hz,4H),1.34(d,J=6.1Hz,2H),1.21(s,1H), LC-MS(ESI):m / z756.3[M+H] + .

[0340] Example 101 Synthesis of MJ-33

[0341]

[0342] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with propargyl acid, finally yielding MJ-33. 1 H NMR (400MHz, DMSO-d6) δ12.00(d,J=2.0Hz,1H),8.29(d,J=1.8Hz,1H),8.24–8.20(m,1H),8.17(s,1H),7.78(m, 1H),7.67(t,J=7.8Hz,1H),7.57(d,J=3.2Hz,1H),6.71(d,J=2.1Hz,1H),6.51(s,1H),4.79–4.56(m,2H),4.51( s,1H),4.24–4.14(m,2H),3.84(t,J=4.8Hz,4H),3.79(t,J=5.7Hz,2H),3.75–3.69(m,4H),3.60–3.46(m,1H),3 .32–3.22(m,2H),2.70(s,2H),1.82–1.67(m,1H),1.21(s,1H),1.13–1.01(m,1H),LC-MS(ESI):m / z657.2[M+H] + .

[0343] Example 102 Synthesis of MJ-34

[0344]

[0345] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 39a, and crotonic acid was replaced with 2-butynedic acid, finally yielding MJ-34. 1 H NMR (400MHz, DMSO-d6) δ12.00(d,J=2.0Hz,1H),8.28(d,J=2.1Hz,1H),8.22(dt,J=7.9,1.3Hz,1H),8.17(s,1H),7.78 –7.74(m,1H),7.67(t,J=7.8Hz,1H),7.57(d,J=1.9Hz,1H),6.71(d,J=2.1Hz,1H),6.51(d,J=3.5Hz,1H),4.73–4.51( m,2H),4.20(d,J=3.4Hz,2H),3.83(d,J=4.9Hz,4H),3.79(t,J=5.7Hz,2H),3.76–3.67(m,4H),3.46(d,J=1.6Hz,1H), 3.33–3.26(m,2H),3.24(s,1H),2.69(d,J=6.1Hz,2H),1.98(s,3H),1.76–1.68(m,1H),1.21(s,1H),LC-MS(ESI):m / z 671.2[M+H] + .

[0346] Example 103: Synthesis of MJ-35

[0347]

[0348] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 39a, and acryloyl chloride was replaced with chloroacetyl chloride, finally yielding MJ-35. 1H NMR (400MHz, DMSO-d6) δ12.01(d,J=2.1Hz,1H),8.28(s,1H),8.22(d,J=7.9Hz,1H),8.17(s,1H),7.77(t,J=5.0 Hz,1H),7.71–7.64(m,1H),7.57(s,1H),6.71(d,J=2.1Hz,1H),6.51(s,1H),4.65(s,2H),4.20(d,J=3.1Hz,2H), 3.83(d,J=4.9Hz,4H),3.79(s,2H),3.72(t,J=4.8Hz,4H),3.57–3.47(m,1H),3.35(s,2H),3.30–3.16(m,2H),2. 69(d,J=6.2Hz,2H),1.64(dd,J=40.6,10.0Hz,1H),1.21(s,1H),1.01(dd,J=47.3,10.2Hz,1H), LC-MS(ESI):m / z 681.2[M+H] + .

[0349] Example 104: Synthesis of MJ-36

[0350]

[0351] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 40a, finally yielding MJ-36. 1H NMR (400MHz, DMSO-d6) δ11.96(d,J=2.0Hz,1H),8.36(dtd,J=7.4,3.7,1.8Hz,1H),8.13(s,1H),7.86–7.68(m,1H),7.45(t,J=7.8H z,1H),7.31(d,J=2.8Hz,1H),6.67(d,J=1.9Hz,1H),6.47(d,J=3.5Hz,1H),6.31(dd,J=16.8,10.2Hz,1H),6.11(dd,J=4.7,2.2Hz, 1H),5.62(ddd,m,1H),4.91–4.43(m,2H),4.16(d,J=2.6Hz,2H),3.80(d,J=5.0Hz,4H),3.75(t,J=5.8Hz,2H),3.72–3.66(m,4H),3 .61–3.47(m,2H),3.13(d,J=4.9Hz,1H),2.66(s,2H),1.81(dd,J=27.6,9.8Hz,2H),1.45(dd,J=32.0,10.4Hz,1H), LC-MS(ESI):m / z 677.2[M+H] + .

[0352] Example 105: Synthesis of MJ-37

[0353]

[0354] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 41a, finally yielding MJ-37. 1H NMR (400MHz, DMSO-d6) δ11.98(d,J=2.0Hz,1H),8.28(d,J=2.0Hz,1H),8.23–8.18(m,1H),8.17(s,1H),7.77(dt,J=7.8,1.5Hz,1H),7.67(dd, J=7.8,2.7Hz,1H),7.57(d,J=2.8Hz,1H),6.67(d,J=2.1Hz,1H),6.50(t,J=3.4Hz,1H),6.31(dd,J=16.8,10.2Hz,1H),6.11(m,1H),5.65(m,1 H),4.83–4.69(m,2H),4.70–4.54(m,2H),4.36(d,J=13.1Hz,1H),4.29–4.18(m,2H),3.96(dd,J=11.3,3.5Hz,1H),3.79(t,J=5.8Hz,2H),3.7 6–3.64(m,2H),3.56–3.45(m,2H),3.34(s,2H),3.30–3.14(m,2H),2.70(d,J=6.0Hz,2H),1.55(m,1H),1.25(d,J=6.7Hz,3H), LC-MS(ESI):m / z 673.2[M+H] + .

[0355] Example 106: Synthesis of MJ-38

[0356]

[0357] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 42a, finally yielding MJ-38. 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),8.16(s,1H),7.92(dd,J=8.0,1.4Hz,1H),7.75(d,J=7.6Hz,1H),7.45(t,J=7.8Hz,1H),6.98 (s,1H),6.67(t,J=2.2Hz,1H),6.48(s,2H),6.23–6.12(m,1H),5.73–5.65(m,1H),5.00–4.68(m,2H),4.41(dd,J=42.1,15.9Hz,2H ),4.14(d,J=2.9Hz,2H),3.95(dd,J=11.2,3.5Hz,1H),3.80–3.69(m,3H),3.69–3.57(m,2H),3.54–3.44(m,2H),3.31(d,J=2.2Hz, 2H),3.22(d,J=9.0Hz,1H),2.68(s,2H),2.64–2.58(m,3H),1.99–1.78(m,2H),1.25(d,J=6.7Hz,3H), LC-MS(ESI):m / z687.2[M+H] + .

[0358] Example 107: Synthesis of MJ-39

[0359]

[0360] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 43a, finally yielding MJ-39. 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.14(t,J=2.4Hz,1H),8.96(d,J=2.1Hz,1H),8.34(d,J=2.3Hz,1H),8.15(s,1H),6.66(d, J=2.2Hz,1H),6.49(s,1H),6.32(dd,J=16.8,10.2Hz,1H),6.10(m,1H),5.65(m,1H),4.82–4.65(m,2H),4.35(d,J=13.2Hz,1H),4 .13(d,J=3.5Hz,2H),3.95(dd,J=11.5,3.6Hz,1H),3.72(s,2H),3.69–3.65(m,2H),3.58(dd,J=10.0,2.3Hz,2H),3.49(dd,J=11 .8,3.2Hz,2H),3.35(s,3H),3.33(s,2H),3.32–3.28(m,2H),2.67(s,2H),2.48–2.47(m,3H),1.86–1.65(m,1H),LC-MS(ESI):m / z 688.2[M+H] + .

[0361] Example 108: Synthesis of MJ-40

[0362]

[0363] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 44a, resulting in MJ-40. 1 H NMR (400MHz, DMSO-d6) δ12.02(d,J=2.0Hz,1H),10.51(s,1H),9.39(dd,J=3.9,2.0Hz,1H),8.93(t,J=2.2Hz,1H ),8.56(t,J=2.0Hz,1H),8.17(s,1H),7.79(d,J=2.4Hz,1H),6.71(d,J=2.0Hz,1H),6.52(s,1H),6.14–6.03(m,1 H),5.65(m,1H),4.84–4.60(m,2H),4.21(d,J=2.8Hz,2H),3.83(d,J=5.0Hz,4H),3.80(d,J=5.5Hz,2H),3.72(dd ,J=5.6,3.8Hz,4H),3.57(dd,J=10.6,8.7Hz,1H),3.36(s,4H),2.70(s,2H),1.87–1.66(m,1H),LC-MS(ESI):m / z 660.2[M+H]+ .

[0364] Example 109: Synthesis of MJ-41

[0365]

[0366] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 44a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-41. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),9.51–9.13(m,1H),8.93(d,J=2.2Hz,1H),8.57(t,J=1.9Hz,1H),8.49–8.40( m,1H),8.17(s,1H),7.79(d,J=1.5Hz,1H),7.25(dd,J=8.4,4.3Hz,1H),6.71(d,J=1.7Hz,1H),6.51(s,1H),4.81–4 .65(m,2H),4.21(s,2H),3.83(d,J=4.9Hz,4H),3.80(s,2H),3.76–3.67(m,4H),3.57–3.44(m,2H),3.35–3.29(m,2 H),3.25(d,J=5.9Hz,1H),3.16(s,2H),2.69(s,2H),2.30(s,3H),2.25(s,3H),1.95–1.65(m,1H),LC-MS(ESI):m / z 717.2[M+H] + .

[0367] Example 110: Synthesis of MJ-42

[0368]

[0369] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 45a, resulting in MJ-42. 1H NMR (400MHz, DMSO-d6) δ11.99(d,J=2.0Hz,1H),9.15(d,J=2.5Hz,1H),8.97(d,J=2.1Hz,1H),8.34(t,J=2 .2Hz,1H),8.17(s,1H),7.70–7.38(m,1H),6.70(d,J=2.0Hz,1H),6.49(s,1H),6.11(m,1H),5.65(m,1H), 4.87–4.61(m,2H),4.13(d,J=2.9Hz,2H),3.83(t,J=4.7Hz,4H),3.76–3.70(m,4H),3.69(s,2H),3.59–3. 51(m,1H),3.34(s,2H),3.32–3.27(m,2H),2.67(s,2H),2.48(s,3H),1.83–1.65(m,1H),LC-MS(ESI):m / z 674.2[M+H] + .

[0370] Example 111 Synthesis of MJ-43

[0371]

[0372] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 46a, resulting in MJ-43. 1 H NMR (400MHz, DMSO-d6) δ12.25(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.24–8.20(m,1H),8.19(s,1H),7.78(m ,1H),7.68(m,1H),7.52(d,J=1.7Hz,1H),6.89–6.79(m,1H),6.59–6.54(m,1H),6.32(dd,J=16.8,10.2Hz,1H) ,6.10(m,1H),5.65(m,1H),4.65(t,J=13.3Hz,4H),4.46(s,2H),3.86(t,J=4.8Hz,4H),3.74(t,J=4.8Hz,4H), 3.61–3.51(m,1H),3.35(s,2H),3.32–3.17(m,2H),1.70(dd,J=23.3,10.1Hz,1H),LC-MS(ESI):m / z645.2[M+H] + .

[0373] Example 112 Synthesis of MJ-44

[0374]

[0375] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 47a, resulting in MJ-44. 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.28(d,J=2.0Hz,1H),8.23–8.18(m,2H),7.77(m,1H),7.68(dd,J=7.8,2.6Hz,1H),7. 58(d,J=2.7Hz,1H),6.70(d,J=1.9Hz,1H),6.53(s,1H),6.31(dd,J=16.8,10.2Hz,1H),6.10(m,1H),5.65(m,1H),4.68(s,2H) ,4.63–4.51(m,2H),4.27–4.16(m,2H),3.80(t,J=5.7Hz,2H),3.55–3.48(m,1H),3.37–3.32(m,1H),3.29–3.19(m,2H),3.10 (s,2H),2.97(d,J=7.3Hz,2H),2.73(s,2H),1.78–1.60(m,1H),1.25(s,3H),1.24(s,3H),1.05–0.99(m,1H),LC-MS(ESI):m / z 686.2[M+H] + .

[0376] Example 113 Synthesis of MJ-45

[0377]

[0378] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 48a, resulting in MJ-45. 1H NMR (400MHz, DMSO-d6) δ12.06(d,J=2.1Hz,1H),10.59(s,1H),8.28(d,J=1.9Hz,1H),8.21(d,J=2.8Hz,2H),8.18(s ,1H),7.80–7.74(m,1H),7.68(dd,J=7.8,2.7Hz,1H),7.58(d,J=2.5Hz,1H),6.70(d,J=2.1Hz,1H),6.53(s,1H),6. 10(m,1H),5.64(m,1H),4.86–4.53(m,2H),4.36(s,2H),4.26–4.16(m,2H),4.08–3.95(m,2H),3.79(t,J=5.7Hz,2H ),3.59–3.49(m,1H),3.36(s,4H),3.30–3.17(m,2H),2.71(s,2H),1.91–1.60(m,1H),LC-MS(ESI):m / z672.2[M+H] + .

[0379] Example 114 Synthesis of MJ-46

[0380]

[0381] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 49a, finally yielding MJ-46. 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.54(s,1H),8.27(d,J=2.1Hz,1H),8.23(s,1H),8.21(s,1H),7 .77(d,J=8.0Hz,1H),7.68(dd,J=7.9,2.9Hz,1H),7.59(d,J=2.7Hz,1H),6.71(d,J=2.1Hz,1H),6.56(s, 1H),6.10(m,1H),5.65(m,1H),4.29(d,J=5.7Hz,4H),4.26–4.17(m,2H),3.80(s,2H),3.55(d,J=2.6Hz ,2H),3.35(s,4H),3.23(d,J=3.5Hz,4H),2.71(s,2H),1.69(m,1H),1.45–1.28(m,1H),LC-MS(ESI):m / z 707.2[M+H] + .

[0382] Example 115: Synthesis of MJ-47

[0383]

[0384] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 50a, resulting in MJ-47. 1 H NMR (400MHz, DMSO-d6) δ12.01–11.79(m,1H),8.28(d,J=2.2Hz,1H),8.24–8.19(m,1H),8.12(s,1H),7.77(d,J =7.8Hz,1H),7.67(dd,J=7.8,2.6Hz,1H),7.57(d,J=2.7Hz,1H),6.67–6.59(m,2H),6.47(s,1H),6.11(m,1H), 5.65(m,1H),4.99(s,1H),4.84–4.46(m,2H),4.19(s,2H),4.01–3.91(m,2H),3.79(s,2H),3.62–3.45(m,4H), 3.29–3.23(m,2H),3.20(s,3H),2.69(s,3H),1.86(dd,J=12.3,4.3Hz,2H),1.60–1.47(m,3H),LC-MS(ESI):m / z 687.2[M+H] + .

[0385] Example 116: Synthesis of MJ-48

[0386]

[0387] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 51a, finally yielding MJ-48. 1H NMR(400MHz, DMSO-d6)δ11.82(s,1H),10.55(s,1H),8.28(d,J=1.9Hz,1H),8.23–8.19(m,1H),8.10(s,1H),7.77(dt,J=7.8,1.4Hz,1H),7 .67(td,J=7.8,2.8Hz,1H),7.58(d,J=2.6Hz,1H),7.44(s,1H),6.69(d,J=2.1Hz,1H),6.47(s,1H),6.20–6.03(m,1H),5.65(m,1H),4.87–4 .52(m,2H),4.18(d,J=3.4Hz,2H),3.95–3.87(m,2H),3.81(t,J=5.7Hz,2H),3.56–3.50(m,1H),3.47–3.39(m,2H),3.33(s,2H),3.28–3.1 9(m,2H),2.65(s,2H),1.94–1.81(m,2H),1.76–1.63(m,1H),1.56(dd,J=11.8,4.2Hz,2H),1.06–0.98(m,1H),LC-MS(ESI):m / z673.2[M+H] + .

[0388] Example 117: Synthesis of MJ-49

[0389]

[0390] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 52a, finally yielding MJ-49. 1H NMR (400MHz, DMSO-d6) δ11.90(d,J=2.1Hz,1H),8.28(d,J=2.0Hz,1H),8.21(m,1H),8.10(s,1H),7.77(m,1H),7.66(m,1H) ,7.57(d,J=2.7Hz,1H),6.61(d,J=2.7Hz,1H),6.47(d,J=3.5Hz,1H),6.36–6.27(m,1H),6.11(m,1H),5.68–5.63(m,1H),4. 86–4.53(m,2H),4.36–4.14(m,2H),3.89(t,J=5.8Hz,2H),3.79(t,J=5.7Hz,2H),3.58(t,J=5.7Hz,2H),3.55–3.52(m,1H), 3.35(s,3H),3.30(s,2H),3.26(s,3H),3.22(d,J=2.4Hz,2H),2.68(s,2H),1.68(dd,J=22.6,10.1Hz,1H), LC-MS(ESI):m / z 661.2[M+H] + .

[0391] Example 118: Synthesis of MJ-50

[0392]

[0393] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 53a, resulting in MJ-50. 1H NMR (400MHz, DMSO-d6) δ11.82(s,1H),10.40(s,1H),8.28(d,J=1.9Hz,1H),8.22(s,1H),8.11(s,1H),7.82–7.74(m,1H),7.7 0–7.66(m,2H),7.58(d,J=2.6Hz,1H),6.66(d,J=2.1Hz,1H),6.47(s,1H),6.10(ddd,J=16.8,7.0,2.3Hz,1H),5.65(m,1H),4 .83–4.52(m,2H),4.18(d,J=2.8Hz,2H),3.81(t,J=5.7Hz,2H),3.61(d,J=5.5Hz,2H),3.51(t,J=5.7Hz,2H),3.39–3.32(m,2 H),3.27(s,3H),3.23(dd,J=7.0,2.2Hz,2H),2.64(s,2H),1.68(dd,J=22.2,10.1Hz,1H),1.06–0.98(m,1H),LC-MS(ESI):m / z 647.2[M+H] + .

[0394] Example 119: Synthesis of MJ-51

[0395]

[0396] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 54a, resulting in MJ-51. 1H NMR (400MHz, DMSO-d6) δ11.92(d,J=2.0Hz,1H),8.28(d,J=5.9Hz,1H),8.21(ddt,J=6.4,2.8,1.5Hz,1H),8.12(s,1H),7.77(dt,J=8.0,1. 4Hz,1H),7.66(td,J=7.8,2.8Hz,1H),7.57(d,J=2.7Hz,1H),6.64(d,J=1.9Hz,1H),6.49(d,J=3.7Hz,1H),6.31(dd,J=16.8,10.2Hz,1H), 6.10(m,1H),5.69–5.60(m,1H),4.83–4.53(m,2H),4.46(s,1H),4.30–4.20(m,2H),4.21–4.16(m,2H),3.78(t,J=5.8Hz,2H),3.63–3.50( m,4H),3.36(s,3H),3.30–3.21(m,2H),2.70(s,2H),1.74–1.62(m,1H),1.62–1.54(m,2H),1.52(dd,J=10.0,3.9Hz,2H),LC-MS(ESI):m / z 687.2[M+H] + .

[0397] Example 120MJ-52 Synthesis

[0398]

[0399] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 55a, resulting in MJ-52. 1H NMR (400MHz, DMSO-d6) δ12.06–11.77(m,1H),10.32(s,1H),9.39(dd,J=4.0,2.0Hz,1H),8.93(t,J=2.1Hz,1H), 8.56(q,J=2.0Hz,1H),8.12(s,1H),7.78(d,J=2.5Hz,1H),6.63(d,J=2.0Hz,1H),6.49(s,1H),6.16–6.07(m,1H) ,5.65(m,1H),4.86–4.61(m,2H),4.46(s,1H),4.32–4.14(m,4H),3.79(t,J=5.7Hz,2H),3.63–3.48(m,4H),3.3 6(s,3H),3.30(d,J=1.5Hz,2H),2.70(s,2H),1.81–1.68(m,1H),1.62–1.46(m,4H),LC-MS(ESI):m / z688.2[M+H] + .

[0400] Example 121 Synthesis of MJ-53

[0401]

[0402] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 55a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-53. 1H NMR (400MHz, DMSO-d6) δ12.03–11.85(m,1H),9.39(dd,J=7.5,2.1Hz,1H),8.92(d,J=2.2Hz,1H),8.57(d,J=2.2Hz,1H),8.37(dd ,J=4.3,1.4Hz,1H),8.12(s,1H),7.78(d,J=1.4Hz,1H),6.65–6.61(m,1H),6.49(s,1H),4.69(d,J=15.9Hz,2H),4.34–4.18(m,4H ),3.79(d,J=5.8Hz,2H),3.65–3.53(m,4H),3.40–3.28(m,2H),3.08–2.93(m,2H),2.89(d,J=7.2Hz,2H),2.70(s,3H),2.14(s,3 H),2.10(s,3H),1.75(dd,J=22.4,10.0Hz,1H),1.56(d,J=3.9Hz,2H),1.54–1.46(m,2H),1.22(d,J=9.3Hz,1H), LC-MS(ESI):m / z 745.2[M+H] + .

[0403] Example 122 Synthesis of MJ-54

[0404]

[0405] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 56a, resulting in MJ-54. 1H NMR (400MHz, DMSO-d6) δ12.02–11.86(m,1H),10.30(s,1H),9.14(t,J=2.5Hz,1H),8.96(t,J=2.1Hz,1H),8.35(t,J=2.2Hz, 1H),8.11(s,1H),6.62(d,J=2.1Hz,1H),6.47(s,1H),6.11(m,1H),5.65(m,1H),4.86–4.62(m,2H),4.45(s,1H),4.24(d,J=1 3.2Hz,2H),4.16–4.10(m,2H),3.70(t,J=5.7Hz,2H),3.62–3.50(m,4H),3.35(s,3H),3.31(dd,J=5.8,3.6Hz,2H),2.67(s, 2H),2.48(d,J=1.1Hz,3H),1.83–1.71(m,1H),1.56(d,J=3.8Hz,2H),1.52–1.43(m,2H),1.33–1.24(m,1H),LC-MS(ESI):m / z 702.2[M+H] + .

[0406] Example 123 Synthesis of MJ-55

[0407]

[0408] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 56a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-55. 1H NMR (400MHz, DMSO-d6) δ11.89(d,J=2.1Hz,1H),9.14(dd,J=5.1,2.0Hz,1H),8.96(d,J=2.2Hz,1H),8.51–8.20(m,1H),8.11(s,1H),6.62(d, J=2.1Hz,1H),6.48–6.44(m,1H),6.06(d,J=15.2Hz,1H),5.76(s,1H),4.84–4.64(m,2H),4.44(s,1H),4.24(d,J=13.2Hz,2H),4.14(d,J=3. 6Hz,2H),3.71(t,J=5.8Hz,2H),3.58–3.53(m,2H),3.52–3.43(m,2H),3.32(s,2H),3.03–2.91(m,2H),2.68(s,2H),2.48(d,J=1.3Hz,3H),2 .13(s,3H),2.09(s,3H),1.84–1.69(m,1H),1.55(q,J=5.3,4.5Hz,2H),1.53–1.41(m,2H),1.29–1.21(m,1H),1.15(s,3H),LC-MS(ESI):m / z 759.3[M+H] + .

[0409] Example 124: Synthesis of MJ-56

[0410]

[0411] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 57a, resulting in MJ-56. 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.28(d,J=2.0Hz,1H),8.23–8.18(m,1H),8.15(s,1H),7.80–7.75(m,1H),7.66(td,J=7.8,2.7H z,1H),7.57(d,J=2.7Hz,1H),6.68(d,J=2.0Hz,1H),6.51(d,J=1.7Hz,1H),6.38–6.25(m,1H),6.11(m,1H),5.65(m,1H),4.86–4.52(m ,2H),4.20(d,J=2.9Hz,2H),3.93–3.84(m,4H),3.78(d,J=5.7Hz,2H),3.59–3.49(m,1H),3.37–3.29(m,2H),3.29–3.21(m,2H),3.02( d,J=7.3Hz,1H),2.70(s,2H),2.26(s,3H),1.84–1.60(m,1H),1.21(s,1H),1.17(t,J=7.3Hz,2H),1.08–0.98(m,1H),LC-MS(ESI):m / z 672.2[M+H] + .

[0412] Example 125: Synthesis of MJ-57

[0413]

[0414] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 58a, resulting in MJ-57. 1H NMR (400MHz, DMSO-d6) δ11.99(d,J=2.0Hz,1H),9.39(dd,J=3.9,2.0Hz,1H),8.93(d,J=2.2Hz,1H),8.56(d,J= 2.1Hz,1H),8.15(s,1H),7.78(d,J=2.5Hz,1H),6.68(d,J=2.0Hz,1H),6.50(s,1H),6.32(s,1H),6.16–6.07(m, 1H),5.65(m,1H),4.82–4.65(m,2H),4.21(d,J=3.0Hz,2H),3.88(s,4H),3.80(s,2H),3.64–3.52(m,3H),3.39– 3.33(m,2H),3.30(s,2H),3.02(d,J=7.3Hz,2H),2.70(s,2H),2.26(s,3H),1.93–1.60(m,1H),LC-MS(ESI):m / z 673.2[M+H] + .

[0415] Example 126: Synthesis of MJ-58

[0416]

[0417] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 58a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-58. 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),9.39(dd,J=7.4,2.1Hz,1H),8.93(d,J=2.2Hz,1H),8.57(d,J=2.1Hz,1H),8.15(s,1H),7.78 (d,J=1.5Hz,1H),6.68(d,J=1.9Hz,1H),6.56(d,J=6.2Hz,1H),6.50(s,1H),6.06(d,J=15.2Hz,1H),4.69(d,J=16.1Hz,2H),4.21(d ,J=3.5Hz,2H),3.86(t,J=4.9Hz,4H),3.80(t,J=5.7Hz,2H),3.58–3.43(m,2H),3.33(s,2H),3.04(dd,J=6.2,1.4Hz,1H),2.97(dd ,J=6.7,1.7Hz,2H),2.70(s,2H),2.43(t,J=5.1Hz,4H),2.23(s,3H),2.15(s,3H),2.12(s,3H),1.87–1.69(m,1H),LC-MS(ESI):m / z 730.2[M+H] + .

[0418] Example 127: Synthesis of MJ-59

[0419]

[0420] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 59a, finally yielding MJ-59. 1H NMR (400MHz, DMSO-d6) δ12.06–11.88(m,1H),9.14(t,J=2.4Hz,1H),8.97(d,J=2.2Hz,1H),8.35(d,J=2.2Hz,1H),8 .14(s,1H),6.67(d,J=1.9Hz,1H),6.48(s,1H),6.36–6.27(m,1H),6.15–6.06(m,1H),5.65(ddd,J=10.2,4.2,2.3H z,1H),4.80–4.65(m,2H),4.25–4.07(m,2H),3.96–3.82(m,4H),3.70(t,J=5.7Hz,2H),3.44–3.27(m,4H),2.99(d, J=7.3Hz,2H),2.67(s,2H),2.47(s,3H),2.45(s,2H),2.24(s,3H),1.85–1.66(m,1H),1.25(s,1H),LC-MS(ESI):m / z 687.2[M+H] + .

[0421] Example 128: Synthesis of MJ-60

[0422]

[0423] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 59a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-60. 1H NMR (400MHz, DMSO-d6) δ12.10–11.93(m,1H),9.14(s,1H),8.96(d,J=2.2Hz,1H),8.35(t,J=2.4Hz,1H),8.14(s,1H),6.66(d,J= 1.8Hz,1H),6.60–6.56(m,1H),6.48(s,1H),6.10–6.02(m,1H),4.83–4.64(m,2H),4.17–4.05(m,2H),3.85(t,J=4.9Hz,4H),3.7 0(t,J=5.8Hz,2H),3.56–3.43(m,2H),3.32(d,J=3.4Hz,4H),2.99(ddd,J=23.0,5.3,1.7Hz,2H),2.89(s,2H),2.67(s,2H),2.48 (d,J=1.1Hz,3H),2.42(s,2H),2.22(s,3H),2.14(s,3H),2.11(s,3H),1.73(d,J=9.9Hz,1H),1.35–1.17(m,1H),LC-MS(ESI):m / z 744.3[M+H] + .

[0424] Example 129: Synthesis of MJ-61

[0425]

[0426] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 60a, resulting in MJ-61. 1H NMR (400MHz, DMSO-d6) δ11.94(d,J=1.9Hz,1H),8.28(d,J=1.9Hz,1H),8.21(ddt, J=6.3,4.8,1.4Hz,1H),8.13(s,1H),7.77(dt,J=7.9,1.4Hz,1H),7.67(td,J=7.8 ,2.8Hz,1H),7.57(d,J=2.7Hz,1H),6.64(d,J=2.0Hz,1H),6.50(d,J=3.2Hz,1H), 6.31(dd,J=16.8,10.2Hz,1H),6.10(ddd,J=16.8,7.2,2.3Hz,1H),5.65(ddd,J=10 .3,5.7,2.3Hz,1H),4.79(d,J=4.2Hz,1H),4.71–4.55(m,2H),4.33(dt,J=13.2,4 .8Hz,2H),4.26–4.14(m,2H),3.79(t,J=5.0Hz,2H),3.65–3.50(m,1H),3.40(d,J =3.5Hz,2H),3.33(s,2H),3.29–3.19(m,2H),2.69(d,J=6.2Hz,2H),2.06–1.78(m ,2H),1.68(dd,J=22.6,10.2Hz,1H),1.39(dd,J=8.9,4.1Hz,2H),LC-MS(ESI):m / z 673.2[M+H] + .

[0427] Example 130MJ-62 Synthesis

[0428]

[0429] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 60a, and crotonic acid was replaced with trans-4-dimethylaminocrotonic acid, finally yielding MJ-62. 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),8.40(dd,J=4.3,1.4Hz,1H),8.28(s,1H),8.19(dd,J=8.5,1.4Hz,1H),8.13(s,1H),7.77(dd,J=7.9,1.6Hz,1H), 7.67(dd,J=7.8,6.3Hz,1H),7.57(d,J=3.6Hz,1H),6.64(d,J=1.9Hz,1H),6 .49(s,1H),6.05(dd,J=15.2,1.6Hz,1H),4.76(s,1H),4.70–4.54(m,2H),4. 33(dt,J=13.6,4.5Hz,2H),4.19(d,J=3.6Hz,2H),3.79(d,J=5.8Hz,2H),3. 77(s,2H),3.53–3.45(m,2H),3.44–3.37(m,2H),3.25(s,2H),3.09–3.03(m, 1H),2.70(s,2H),2.17(s,3H),2.14(s,3H),1.88–1.78(m,2H),1.68(td,J= 11.1,10.6,5.7Hz,1H),1.40(m,2H),1.23(d,J=9.9Hz,1H),LC-MS(ESI):m / z 730.2[M+H] + .

[0430] Example 131 Synthesis of MJ-63

[0431]

[0432] Referring to the synthesis method of MJ-9 in Example 77, 30a was replaced with 60a, and crotonic acid was replaced with 4,4,4-trifluorobutenoic acid, finally yielding MJ-63. 1H NMR (400MHz, DMSO-d6) δ11.94(s,1H),8.29(d,J=1.8Hz,1H),8.22(d,J=7.2Hz,1H),8.13(s,1H),7.78(m,1H),7.69–7.66(m,1H),7 .57(d,J=4.8Hz,1H),7.19(dd,J=15.3,2.2Hz,1H),6.86–6.77(m,1H),6.64(d,J=2.0Hz,1H),6.49(s,1H),4.90(s,1H),4.76(d,J=4 .3Hz,1H),4.72–4.54(m,2H),4.32(dd,J=11.9,6.3Hz,2H),4.25–4.18(m,2H),3.78(d,J=6.0Hz,2H),3.67–3.57(m,1H),3.43–3.38 (m,2H),3.27–3.15(m,2H),2.70(s,2H),1.88–1.81(m,2H),1.75–1.66(m,1H),1.40(d,J=9.4Hz,2H),1.21(s,2H),LC-MS(ESI):m / z 741.2[M+H] + .

[0433] Example 132: Synthesis of MJ-64

[0434]

[0435] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 61a, resulting in MJ-64. 1H NMR (400MHz, DMSO-d6) δ11.95(d,J=1.9Hz,1H),9.39(dd,J=3.9,2.0Hz,1H),8.93(t,J=2.1Hz,1H),8.57(t,J=2.0Hz,1H),8.13(s,1H),7 .78(d,J=2.5Hz,1H),6.63(d,J=2.0Hz,1H),6.50(d,J=3.4Hz,1H),6.33(dd,J=16.7,10.2Hz,1H),6.10(m,1H),5.65(m,1H),4.87–4.77(m ,2H),4.75–4.61(m,2H),4.32(m,2H),4.21(q,J=2.6Hz,2H),3.79(d,J=6.0Hz,1H),3.76(d,J=4.3Hz,1H),3.63–3.52(m,1H),3.40(s,2H) ,3.36(s,2H),3.30(d,J=1.5Hz,2H),2.71(d,J=6.1Hz,2H),1.84(dd,J=9.0,4.5Hz,2H),1.79–1.69(m,1H),1.40(m,2H),LC-MS(ESI):m / z 674.2[M+H] + .

[0436] Example 133: Synthesis of MJ-65

[0437]

[0438] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 62a, finally yielding MJ-65. 1H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 9.10 (t, J = 2.2Hz, 1H), 9.04–8.81 (m, 1H),8.30(t,J=2.1Hz,1H),8.20–7.99(m,1H),6.83(d,J=5.1Hz,1H),6.54( s,1H),6.29(dd,J=10.3,3.5Hz,1H),6.14–5.99(m,1H),5.66–5.37(m,1H), 4.80(s,1H),4.76–4.63(m,2H),4.56–4.40(m,2H),4.30(t,J=11.1Hz,1H),3 .92(dd,J=11.2,3.6Hz,1H),3.66(dd,J=17.3,4.0Hz,2H),3.60–3.41(m,2H ),3.35(s,3H),3.32(d,J=2.0Hz,2H),3.30–3.27(m,2H),3.19(d,J=9.3Hz,2 H),2.43(s,3H),2.31(dd,J=14.7,6.6Hz,2H),2.14(t,J=5.9Hz,1H),2.00( dd,J=11.8,8.8Hz,1H),1.78(d,J=12.1Hz,2H), LC-MS(ESI):m / z714.2[M+H] + .

[0439] Example 134: Synthesis of MJ-66

[0440]

[0441] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 63a, finally yielding MJ-66. 1H NMR (400MHz, DMSO-d6) δ11.84(s,1H),9.13(s,1H),8.96(s,1H),8.39–8.24(m,1H),8.13(s,1H),7.57(s,1H),6.83(d,J=5. 2Hz,1H),6.55(s,1H),6.12(s,1H),5.64(dd,J=10.1,2.3Hz,1H),4.80(s,2H),4.69(d,J=11.8Hz,2H),4.53–4.40(m,1H),4. 24(s,2H),3.60(s,1H),3.57(s,2H),3.32(s,2H),3.29(d,J=2.0Hz,2H),3.22(s,2H),2.43(d,J=1.1Hz,1H),2.32(d,J=16. 7Hz,3H),2.04–1.95(m,2H),1.90(d,J=5.3Hz,2H),1.79(s,2H),1.70(d,J=10.8Hz,1H),1.41–1.30(m,1H),LC-MS(ESI):m / z 726.2[M+H] + .

[0442] Example 135MJ-67 Synthesis

[0443]

[0444] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 64e, resulting in MJ-67. 1 H NMR(400MHz,DMSO-d6)δ12.42(d,J=2.1Hz,1H),8.21(d,J=2.4Hz,2H),8.09(s,5H),7 .98(s,1H),7.45(s,1H),7.35(d,J=1.8Hz,2H),6.23(d,J=1.9Hz,1H),6.07(s,1H),5 .58–5.51(m,1H),3.92(dd,J=5.8,3.9Hz,4H),3.76(dd,J=5.6,3.9Hz,4H),3.63–3.5 4(m,2H),3.35(s,4H),2.87–2.72(m,2H),1.75(s,2H),1.54(s,1H),LC-MS(ESI):m / z 606.2[M+H] + .

[0445] Example 136: Synthesis of MJ-68

[0446]

[0447] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 65e, resulting in MJ-68. 1 H NMR (400MHz, DMSO-d6) δ12.01(d,J=2.0Hz,1H),8.17(s,1H),8.06(s,1H),7.80(s,2H),7.36(s,1H),7.29 (s,1H),6.71(d,J=2.0Hz,1H),6.52(s,1H),6.24(dd,J=17.0,10.2Hz,1H),6.05(d,J=16.9Hz,1H),5.61–5 .50(m,1H),4.25–4.13(m,2H),3.84(t,J=4.8Hz,4H),3.78(t,J=5.7Hz,2H),3.72(dd,J=5.6,3.9Hz,4H), 3.52(s,2H),3.36(s,2H),2.69(s,4H),1.94(d,J=23.8Hz,1H),1.74(s,2H),1.52(s,1H),LC-MS(ESI):m / z 611.2[M+H] + .

[0448] Example 137: Synthesis of MJ-69

[0449]

[0450] Referring to the synthesis method of Example 69MJ-1, 23e was replaced with 66a, finally yielding MJ-69. 1H NMR (400MHz, DMSO-d6) δ11.72(d,J=2.0Hz,1H),8.12(s,1H),7.96(d,J=8.0Hz,1H),7.83–7.70(m,2H),7.33(t,J=7.6Hz,1H),7.24(d, J=9.4Hz,2H),6.39(d,J=2.0Hz,1H),6.21(dd,J=17.1,10.1Hz,1H),6.04(dd,J=17.1,2.3Hz,1H),5.54(dd,J=9.9,2.3Hz,1H),4.07(d, J=13.0Hz,2H),3.79(dd,J=5.7,3.8Hz,4H),3.70(dd,J=5.6,3.7Hz,4H),3.50(s,2H),3.20(dd,J=13.1,10.5Hz,2H),3.02–2.88(m,1H) ,2.80–2.60(m,2H),2.17–2.01(m,2H),1.98(d,J=6.7Hz,1H),1.79(m,4H),1.49(d,J=12.2Hz,2H),1.26–1.12(m,2H),LC-MS(ESI):m / z 613.2[M+H] + .

[0451] Example 138MJ-70 Synthesis

[0452]

[0453] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 67a, resulting in MJ-70. 1H NMR (400MHz, DMSO-d6) δ11.82(d,J=2.0Hz,1H),8.22(s,1H),7.14(d,J=8.0Hz,1H),7.93–7.80(m,2H),7.43(t,J=7.6Hz,1H),7.34( d,J=9.4Hz,2H),6.49(d,J=2.0Hz,1H),6.41(dd,J=17.1,10.1Hz,1H),6.14(dd,J=17.1,2.3Hz,1H),5.64(dd,J=9.9,2.3Hz,1H),4. 17(d,J=13.0Hz,2H),3.89(dd,J=5.7,3.8Hz,4H),3.80(dd,J=5.6,3.7Hz,4H),3.30(dd,J=13.1,10.5Hz,2H),3.12–2.98(m,1H),2. 90–2.70(m,2H),2.27–2.11(m,2H),1.95(d,J=6.7Hz,1H),1.89(m,4H),1.59(d,J=12.2Hz,2H),1.36–1.22(m,2H),LC-MS(ESI):m / z 599.2[M+H] + .

[0454] Example 139: Synthesis of MJ-71

[0455]

[0456] Referring to the synthesis method of MJ-1 in Example 69, 23e was replaced with 68a, resulting in MJ-71. 1H NMR (400MHz, DMSO-d6) δ12.02(d,J=2.0Hz,1H),8.27(s,2H),8.19(d,J=7.6Hz,1H),7.83–7.72(m,2H),7.65(s,1H),6.71(d,J=2.1 Hz,1H),6.50(s,1H),6.33(dd,J=17.1,10.0Hz,1H),6.21(dd,J=17.1,2.4Hz,1H),5.50(dd,J=9.9,2.4Hz,1H),4.16–4.13(m,2H), 3.91–3.82(m,4H),3.88(t,J=5.9Hz,2H),3.63(d,J=4.9Hz,4H),3.57(dd,J=11.1,4.0Hz,1H),3.42(d,J=7.4Hz,2H),3.27(d,J=5. 1Hz,1H),2.58(d,J=6.6Hz,2H),2.46–2.40(m,1H),1.72(m,2H),1.57–1.47(m,1H),1.21(dd,J=13.0,3.4Hz,1H), LC-MS(ESI):m / z 625.3[M+H] + .

[0457] Example 140MJ-72 Synthesis

[0458]

[0459]

[0460] Step 1: Under 0℃ conditions, 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid-1,1-dimethyl ethyl ester (1.8 g, 9.3 mmol) and triethylamine (2.4 g, 23.4 mmol) were added sequentially to a reaction flask using dichloromethane as the solvent. Then, 5-bromopyridine-3-sulfonyl chloride (2.0 g, 7.8 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was added to 200 mL of saturated sodium bicarbonate aqueous solution and extracted three times with dichloromethane. The combined organic layers were washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.4 g of a white solid, intermediate B, with a yield of 91%. LC-MS (ESI): m / z 418.1 [M+H] + .

[0461] Step 2: Under nitrogen protection, intermediate B (2 g, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 g, 0.5 mmol), pinacol diborate (1.8 g, 7.2 mmol), and potassium acetate (1.4 g, 14.1 mmol) were sequentially added to a three-necked flask containing 100 mL of 1,4-dioxane. The reaction system was stirred thoroughly at 95 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into 1 L of water, extracted three times with ethyl acetate, and the organic layers were combined. After washing twice with saturated sodium chloride, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product C was directly used for the next step of the reaction. LC-MS (ESI): m / z 466.2 [M+H] + .

[0462] Step 3: 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine 1a (2.0 g, 7.2 mmol), N,N,N'-trimethylethylenediamine (1.5 g, 14.3 mmol), and N,N-diisopropylethylamine (2.8 g, 21.5 mmol) were added sequentially to a reaction flask using n-butanol as the solvent. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 50 mL of water, and a solid precipitated. This solid was filtered and dried to obtain intermediate D, with a yield of 89%. LC-MS (ESI): m / z 346.1 [M+H] + .

[0463] Step 4: Under nitrogen protection, intermediate D (2.0 g, 5.7 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.7 g, 8.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.4 g, 0.5 mmol), and potassium carbonate (2.4 g, 17.4 mmol) were added sequentially to a 250 mL three-necked flask containing 90 mL of 1,4-dioxane and 30 mL of water. The reaction system was stirred thoroughly at 100 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was poured into 200 mL of water. The mixture was extracted three times with ethyl acetate, and the organic layers were combined. The mixture was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2 g of light yellow solid intermediate E, yield 86%. LC-MS (ESI): m / z 401.2 [M+H] + .

[0464] Step 5: Dissolve intermediate E (2 g, 5.7 mmol) in dichloromethane, add an equal volume of 4N ethyl hydrochloric acid solution, stir at room temperature for 3 hours. After the reaction is complete, evaporate the solvent directly to obtain a yellow solid intermediate F. LC-MS (ESI): m / z 301.2 [M+H] + .

[0465] Step Six: Intermediate F (2.0 g, 5.9 mmol), 2,4-dibromothiazole (1.7 g, 7.1 mmol), and N,N-diisopropylethylamine (2.3 g, 17.2 mmol) were added sequentially to a reaction flask using dimethyl sulfoxide as the solvent. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 200 mL of water, and a solid precipitated. The solid was filtered and dried. The crude product was purified by silica gel column chromatography to obtain 2 g of a light yellow solid, intermediate G, with a yield of 72%. LC-MS (ESI): m / z 462.1 [M+H] + .

[0466] Step 7: Under nitrogen protection, intermediate G (2.0 g, 4.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.3 g, 0.4 mmol), intermediate B (4.0 g, 8.6 mmol), and potassium carbonate (1.8 g, 12.9 mmol) were sequentially added to a three-necked flask containing 30 mL of 1,4-dioxane and 10 mL of water. The reaction system was stirred thoroughly at 100 °C overnight. After the reaction was complete, the mixture was cooled to room temperature, poured into 100 mL of water, and extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2.7 g of a pale yellow solid, intermediate H, with a yield of 86%. LC-MS (ESI): m / z 721.3 [M+H] + .

[0467] Step 8: Dissolve intermediate H (2.7 g, 4.4 mmol) in dichloromethane, add an equal volume of 4N hydrochloric acid 1,4-dioxane solution, stir at room temperature for 2 hours. After the reaction is complete, evaporate the solvent directly to obtain yellow solid intermediate I. LC-MS (ESI): m / z 621.2 [M+H] + .

[0468] Step 9: Dissolve intermediate I (500 mg, 0.7 mmol) in 20 mL of dichloromethane, then add triethylamine (230.9 mg, 2.2 mmol), and slowly add acryloyl chloride (82.2 mg, 0.9 mmol) under ice bath conditions. After reacting at room temperature for 1 hour, add saturated sodium bicarbonate aqueous solution, wash and extract three times with dichloromethane, combine the organic layers, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 200 mg of yellow solid compound MJ-72, with a yield of 38%. 1H NMR(400MHz, DMSO-d6)δ11.91(d,J=2.2Hz,1H),8.31–8.26(m,1H),8.24–8.19(m,1H),8.10(s,1H),7.83–7.74(m,1H),7. 67(dd,J=7.8,2.9Hz,1H),7.57(d,J=2.6Hz,1H),6.63(s,2H),6.48(s,1H),6.17–6.05(m,1H),5.65(ddd,J=10.3,5.3,2.3 Hz,1H),4.68(s,2H),4.20–4.12(m,2H),3.88–3.83(m,2H),3.78(d,J=5.4Hz,2H),3.60–3.50(m,2H),3.43(d,J=2.4Hz,2H ),3.15(s,3H),2.68(s,2H),2.62(d,J=7.1Hz,2H),2.29(d,J=3.1Hz,6H),1.68(dd,J=22.0,10.0Hz,1H), LC-MS(ESI):m / z 675.2[M+H] + .

[0469] Example 141 Synthesis of MJ-73

[0470]

[0471] Following the synthesis method of Example 140MJ-72, N,N,N'-trimethylethylenediamine was replaced with morpholine, and 1a was replaced with 4-chloro-6-iodo-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-amino, finally yielding MJ-73, LC-MS (ESI): m / z 689.2 [M+H] + .

[0472] Example 142MV4-11 Cell Proliferation Inhibition Experiment

[0473] MV4-11 cells were cultured and collected using IMDM supplemented with 10% fetal bovine serum (FBS). Cell concentrations were diluted according to a 7-day treatment time, and 180 μL of cell suspension was added to each well of a 96-well cell culture plate to achieve a cell count of 2000. A control group was also included, containing only IMDM supplemented with 10% FBS. 10 μL of DMSO (final concentration 0.2%) was added to the control cell wells. The test compound was serially diluted 3-fold from a 10 mM stock solution, and 10 μL of each solution was added to the compound cell wells (DMSO final concentration 0.2%). Cells were incubated at 37°C in a 5% CO2 incubator for 7 days. The reaction solution was prepared according to the MTS kit, and 20 μL was added to each well. Cells were incubated at 37°C in a 5% CO2 incubator for 3-4 hours. The absorbance (OD) at 490 nm was read using a microplate.490 ), and absorbs light at 690nm (OD). 690 ) as background value, with OD 490 Subtract OD 690 Obtain OD DMSO or OD 化合物 The formula for calculating the inhibition rate of a compound is: Inhibition rate = (OD) / (OD + OD) DMSO -OD 化合物 ) / (OD DMSO -OD 空白 ()×100%. The proliferation inhibition IC50 of the compound. 50 The results were fitted using GraphPad Prism 5.0. The experiment was repeated three times, with three parallel experiments per experiment to calculate the mean and standard deviation. The results are shown in Table 1. The positive control was BMF-219.

[0474] Table 1. Inhibitory activity of compounds against MV4-11 cell proliferation

[0475]

[0476]

[0477] a: 0-200nM; b: 200-500nM; c: 500-1000nM

[0478] As shown in Table 1, the compound of Formula I described in this invention exhibits excellent inhibitory effects on the growth of human myeloid monocytic leukemia MV-4-11 cells. It has the potential to be used in the preparation of drugs for the treatment and prevention of leukemia.

[0479] Example 143: Menin protein expression downregulation test

[0480] After cell resuscitation, cells were cultured to the logarithmic growth phase and seeded into 24-well plates. A 1 μM drug solution was prepared and used to treat cells for 24 hours, after which the cells were collected and washed. Cells were lysed using total protein extract, and protein concentration was determined using a BCA kit. Protein samples were boiled in loading buffer in preparation for electrophoresis. After electrophoresis, proteins were transferred to PVDF membranes and blocked for 1 hour. The membranes were washed with TBST and then incubated with primary antibody (1:1000) and secondary antibody (1:5000), with washing after each incubation step. Finally, the cells were developed using ECL and the results were recorded using a gel imaging system. Data analysis was performed using GraphPad Prism 9 and ImageJ software.

[0481] Table 2. Downregulation rate of compound Menin protein @1μM

[0482]

[0483] a: 0-20; b: 20-50; c: 50-100.

[0484] Example 144: Plasma stability (mouse) test of compound 144

[0485] After thawing the plasma, centrifuge at 3220×g for 5 minutes. Add 98 μL of plasma to each well of a 96-well plate (blank, T0, T10, T30, T60, and T120, respectively). Add 2 μL of the compound solution to each well of the 96-well plate. Incubate the reaction plate in a 37°C water bath and start the timer. After incubation, add 500 μL of stop solution (acetonitrile containing tolbutamide and labetalol as internal standards) to the reaction plate and mix thoroughly. Centrifuge each plate at 3220×g for 20 minutes. Transfer 150 μL of supernatant from each reaction plate to the corresponding bioanalytical plate. Seal the analytical plates and store them at 2–8°C until LC-MS / MS analysis.

[0486] Table 3. Stability of compounds in mouse plasma

[0487] Compound ID <![CDATA[T 1 / 2 (min)]]> Compound ID <![CDATA[T 1 / 2 (min)]]> BMF-219 1.3 MJ-1 >289.1 MJ-3 >289.1 MJ-25 >289.1 MJ-29 >289.1 MJ-68 >289.1

[0488] Experimental results:

[0489] As shown in the table above, our compound exhibits significantly greater plasma stability compared to the positive control, demonstrating better drug-like properties.

[0490] Example 145: Detection of exposure levels in animals

[0491] Experimental objective:

[0492] IG: The exposure level of MJ-25 in SD Rat plasma was tested at a dose of 20 mg / kg.

[0493] Experimental methods:

[0494] Preparation and processing of standard curves and quality control samples: Dilute 1 mg of the compound with 1 mL of DMSO, and then dilute with blank acetonitrile to prepare standard working solutions containing compound concentrations of 200, 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.1, and 0.05 μg / mL, respectively. Take 2.5 μL of standard working solution, add 47.5 μL of blank acetonitrile, and then add 200 μL of 5 ng / mL loratadine acetonitrile solution to prepare the standard. Vortex for 2-3 min, then centrifuge at 13500 rpm and 4℃ for 10 min, and collect the supernatant.

[0495] Unknown sample preparation and processing: Take 50 μL of plasma sample, add 200 μL of 5 ng / mL loratadine acetonitrile solution, vortex for 2-3 min, centrifuge at 13500 rcf, 4℃ for 10 min, and take the supernatant for LC-MS / MS analysis.

[0496]

[0497] Experimental results:

[0498] The data in the table above show that our compound has a certain level of exposure in vivo, and can be developed for oral administration.

Claims

1. A pyrrolopyrimidine compound, characterized in that, Compounds of formula I, their optical isomers, or pharmaceutically acceptable salts thereof: in: A is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclic groups, and -NR. b R b’ -OR c The alkyl, heterocyclic, and cycloalkyl groups may be substituted by one or more halogens, hydroxyl groups, amino groups, oxo groups, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered alicyclic groups, C1-C3 alkylamine groups, and 4-6 membered heterocyclic groups. R b R b’ R c Each is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclic group, wherein the alkyl, heterocyclic group, cycloalkyl group may be substituted by one or more halogens, hydroxyl groups, amino groups, oxo groups, C1-C3 alkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkyl groups, C1-C3 alkylamine groups, 4-12 membered heterocyclic groups; R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamine. L1 is selected from Rh is selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. k is 0, 1, or 2; q is 0, 1, or 2; d is 1 or 2; Z is selected from CH and N; Q is selected from NH, O, and S; R1 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. X is selected from CH and N; R2 is selected from hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 alkylamino. L2 is selected from g is selected from 1, 2, and 3; Cyc1 is selected from 4-12 membered heterocyclic groups; R3 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 alkylamine. R4 is either -Rj or -NH-Rj, where Rj is selected from... Nitrile group; R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, and halomethyl; R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, c and t are each independently selected from 1, 2, and 3; R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl group; n is selected from 1, 2, 3, 4, and 5.

2. The pyrrolopyrimidine compound according to claim 1, characterized in that, Cy1(-R4) is selected from Where Rk is selected from hydrogen, C1-C4 alkyl, C1-C4 alkylamine, and C1-C4 haloalkyl; a is 0, 1, or 2; and b is 1, 2, 3, or 4.

3. The pyrrolopyrimidine compound according to claim 1, characterized in that, A is selected from or -NR b R b’ ; Each of the two Ra atoms is independently selected from hydrogen, halogen, or C1-C4 alkyl groups; G is selected from C, N, O, and S; Re and Rf are each independently selected from unsubstituted, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups; Rg is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups; n1 and j are each independently selected from 1, 2, 3, and 4; R b R b’ Each is independently selected from: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, wherein the alkyl, heterocyclic group, and cycloalkyl group may be arbitrarily substituted with halogen, hydroxyl, amino, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkylamine, 4-6 membered heterocyclic group.

4. The pyrrolopyrimidine compound according to claim 1, characterized in that, R5 is selected from hydrogen, C1-C3 alkoxy, and C1-C3 alkylamine groups; R1 is selected from hydrogen, halogens, and C1-C4 alkyl groups; R2 is selected from hydrogen, hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

5. The pyrrolopyrimidine compound according to claim 1, characterized in that, The compound has the structure shown in general formula II, its optical isomer, or a pharmaceutically acceptable salt thereof: in: A is selected from Ra, Rb, Rc, and Rd are each independently selected from hydrogen, halogens, and C1-C4 alkyl groups; G is selected from C, N, O, and S; Re and Rf are each independently selected from non-existent, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamine, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups; Rg is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups; E is selected from NH, O, and S; Ri and Rm are each independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl; m is 0, 1, or 2; n1 is 1 or 2; j is 0, 1, or 2; R5 is selected from hydrogen, C1-C3 alkoxy, and C1-C3 alkylamine groups; L1 is selected from Where k is selected from 0 and 1; q is selected from 0 and 1; d is selected from 1 and 2; R1 is selected from hydrogen and C1-C4 alkyl groups; X is selected from CH and N; R2 is selected from hydrogen, fluorine, chlorine, bromine, and methyl; L2 is selected from W selected Where Rk is selected from hydrogen and methyl; Rj is selected from... Or nitrile group; wherein R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, c, t Each is independently selected from 1, 2, and 3; R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl groups; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl; a is selected from 1, 2; b is selected from 1, 2, 3.

6. The pyrrolopyrimidine compound according to claim 5, characterized in that, W selected Where Rk is selected from hydrogen and methyl; Rj is selected from... Or nitrile group; wherein R j-1 R j-2 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, R j-3 Selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, halomethyl, c and t are each independently selected from integers from 1 to 3; R j-4 R j-7 R j-8 R j-9 Each is independently selected from hydrogen or C1-C4 alkyl; R j-5 It is a halomethyl group; R j-6 It is a vinyl or halomethyl; a is 1, 2; b is 1, 2, 3.

7. The pyrrolopyrimidine compound according to claim 6, characterized in that, It has the structure shown in equation (III): Where W is 8. The pyrrolopyrimidine compound according to any one of claims 1 to 7, characterized in that, L1 is selected from R1 is selected from hydrogen or methyl; X is selected from CH and N; R2 is selected from hydrogen, fluorine, and methyl; L2 is selected from A is selected from R5 is selected from hydrogen, methylamino, and dimethylamino groups; Selected from:

9. The pyrrolopyrimidine compound according to claim 1, characterized in that, The compound is selected from the following compounds:

10. A pharmaceutical composition, characterized in that, Includes the compound according to any one of claims 1-9.

11. A pharmaceutical preparation, characterized in that, The pharmaceutical composition comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from the compounds of any one of claims 1-9, their optical isomers, or their pharmaceutically acceptable salts.

12. The use of any compound according to any one of claims 1-9 in the preparation of a medicament for treating diseases by downregulating Menin protein expression, either alone or in combination with other drugs.

13. The application according to claim 12, characterized in that, The drug is used to treat one or more diseases, such as hematologic malignancies like leukemia, liver cancer, colon cancer, pancreatic cancer, solid tumors like non-small cell lung cancer, and diabetes.

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