TDG inhibitor compound and use thereof

Abstract

Provided in the present invention is a compound which inhibits TDG activity. Specifically, provided in the present invention is a compound having a novel structure, as shown in formula I. A small molecule inhibitor of the present invention has an excellent inhibitory effect on TDG.

Description

A TDG inhibitor compound and its use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a compound for inhibiting TDG activity, a preparation method and an application thereof. Background Art

[0002] Human thymine DNA glycosylase (TDG), a DNA glycosylase, mediates DNA repair through the DNA base-excision repair (BER) pathway. When a G·T or G·U mismatch occurs in the DNA duplex, TDG recognizes the mismatched base and hydrolyzes the N-glycosidic bond of the U or T, forming an apurinic / apyrimidinic site (AP site). TDG also promotes the binding of apurinic / apyrimidinic endonuclease 1 (APE1) to the AP site, cleaving the phosphodiester bond at the 5' end of the abasic deoxyribonucleoside. Other proteins and bases involved in the repair process then join in, ultimately repairing the DNA.

[0003] TDG is a key enzyme in the active DNA demethylation pathway, mediated by oxidation and the BER pathway. In the TET-TDG-mediated active DNA demethylation mechanism, 5-methylcytosine (5mC) is oxidized to 5-carboxycytosine (5caC) by a class of TET (ten-eleven-translocation protein) dioxygenases. The TDG enzyme specifically recognizes and removes 5caC, initiating the BER pathway to replace the original 5mC with cytosine, thereby achieving DNA demethylation. DNA methylation is an important epigenetic modification. TDG participates in epigenetic regulation by mediating active DNA demethylation, playing an important role in gene expression regulation, embryonic growth and development, and hematopoietic stem cell differentiation.

[0004] TDG can promote tumorigenesis and may be a potential target for cancer therapy. Studies have shown that TDG is overexpressed in some human colorectal carcinoma (CRC) patients. TDG acts as a positive regulator of WNT signaling by acting as an adaptor protein for the transcription factor TCF4 and recruiting CBP / p300. Stable transfection of TDG shRNA into several CRC cell lines inhibited cell growth. Importantly, stable knockdown of TDG expression reduced the ability of CRC cells to form tumors in xenograft experiments, indicating that TDG is essential for CRC cell proliferation in vivo. Furthermore, knockdown of TDG can inhibit tumor formation in melanoma cell lines in xenograft models, indicating that TDG activity is crucial for tumor induction and / or progression. Therefore, the development of specific small molecule inhibitors targeting TDG is very necessary and meaningful. Summary of the Invention

[0005] The purpose of the present invention is to provide a highly effective small molecule inhibitor targeting TDG.

[0006] The first aspect of the present invention provides a compound as shown in the following formula 1, or a deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0007] R1 is selected from the following groups: OH, H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl-C(O)-, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, -O(CH2) s R 10 , or -S(CH2) s R 10 ;s is 0, 1, 2 or 3; R 10 Selected from the group consisting of H, substituted or unsubstituted C 3-8 Carbocycle, substituted or unsubstituted 3-8 membered heterocycle, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring;

[0008] R2 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkyl;

[0009] R3 is selected from the following groups: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 12 Cycloalkyl, or (C1-C6 alkyl) C (O) R8, (C1-C6 alkyl) C (O) NHR8, (C1-C6 alkyl) C (O) N (substituted or unsubstituted C1-C6 alkyl) R8, (C1-C6 alkyl) C (O) OR8; wherein R8 is selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 Aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; The R9 is selected from the following group: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 a carbon ring, a substituted or unsubstituted 3-12-membered heterocyclic ring, or a substituted or unsubstituted 5-12-membered heteroaromatic ring; R 12 Selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 Selected from the group consisting of: substituted or unsubstituted C3-C 10 carbon ring;

[0010] m and n are each independently 0, 1, 2 or 3;

[0011] R4 is selected from the following groups: H, halogen, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 amino, substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-5-12 membered heteroaromatic ring,

[0012] Alternatively, R3 and R4 and the carbon atom to which they are attached together form a structure selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle;

[0013] R5 and R6 are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; or said R5 and R6 and the carbon atom to which they are attached together form a substituted or unsubstituted 3-12 membered carbocycle;

[0014] R6' is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl; or R6 and R6' together form =CH2

[0015] X is selected from O or S;

[0016] Z is selected from O, S or NR 14 ; Among them, R 14 is H or C1-C4 alkyl;

[0017] R7 is selected from the group consisting of H, substituted or unsubstituted C1-C 12 Alkyl, or C(O)R 11 、C(O)OR 11 、-CH2OC(O)OR 11 、-S(O)2NHR 11 ;

[0018] The R 11 Selected from the group consisting of H, substituted or unsubstituted C1-C 16 Alkyl, substituted or unsubstituted C6-C 10 Aryl, -(OCH2CH2) m - substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-8 membered heterocyclic group;

[0019] Unless otherwise specified, in the above formulas, the heteroaromatic ring, heteroaryl group, heterocycle or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aromatic ring, aryl group, heteroaromatic ring or heteroaryl group may be a monocyclic ring or a condensed ring; the carbocyclic ring, cycloalkyl group, heterocycle or heterocyclic group may be a monocyclic ring, a fused ring, a bridged ring or a spirocyclic ring; the carbocyclic ring, heterocycle or heterocyclic group may be saturated or partially unsaturated, but not aromatic.

[0020] The substitution refers to the substitution of hydrogen atoms on the corresponding group by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2-C 12 Alkoxycarbonyl, C1-C6 aldehyde, (C1-C6 alkyl) 3Si, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or substituted C1-C4 alkyl-OC(O)NH-, unsubstituted or halogenated C1-C4 alkyl-SO-, a 5-7 membered heterocycle which is unsubstituted or substituted by C1-C4 alkyl, or phenyl (which may have 1 to 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy).

[0021] In another preferred embodiment, the R1 is selected from the following groups: halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocyclic ring, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, or -O(CH2) s R 10 .

[0022] In another preferred embodiment, the compound of formula I has the structure shown in the following formula II:

[0023] Wherein, the A ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered aromatic heterocycle.

[0024] In another preferred embodiment, the compound has a structure shown in the following formula IV:

[0025] Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocycle, or a substituted or unsubstituted 3-8 membered heterocycle; wherein, the carbocycle or heterocycle may be saturated or partially unsaturated.

[0026] In another preferred embodiment, the compound has a structure shown in the following formula V:

[0027] Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbon ring, or a substituted or unsubstituted 3-10 membered heterocycle.

[0028] In another preferred embodiment, the compound has a structure shown in the following formula VI or VII:

[0029] Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the following group: CHR 15 NR 15 , O or S; t is 1 or 2; wherein the R 15 Selected from the group consisting of deuterium, halogen, hydroxy, carboxyl, mercapto, amino, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, and C1-C6 alkoxy.

[0030] In another preferred embodiment, R3 is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl.

[0031] In another preferred embodiment, R5 and R6 are independently selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl; or said R5 and R6 and the carbon atoms connected thereto together form a substituted or unsubstituted 3-6 membered carbocyclic ring.

[0032] In another preferred embodiment, R3 is selected from the following groups: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 12 Cycloalkyl, or (C1-C6 alkyl) C (O) R8, (C1-C6 alkyl) C (O) NHR8, (C1-C6 alkyl) C (O) N (substituted or unsubstituted C1-C6 alkyl) R8, (C1-C6 alkyl) C (O) OR8; wherein R8 is selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 Aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; The R9 is selected from the following group: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 a carbon ring, a substituted or unsubstituted 3-12-membered heterocyclic ring, or a substituted or unsubstituted 5-12-membered heteroaromatic ring; R 12 Selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 Selected from the group consisting of: substituted or unsubstituted C3-C 10 carbon ring;

[0033] m and n are each independently 0, 1, 2 or 3;

[0034] R4 is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -O-5-12 membered heteroaromatic ring;

[0035] Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aromatic ring, or a substituted or unsubstituted 5-10 membered aromatic heterocycle.

[0036] In another preferred embodiment, the compound has a structure shown in the following formula III:

[0037] Preferably, the compound has a structure as shown in the following formula III-A or III-B:

[0038] Preferably, the compound has any structure selected from the following groups:

[0039] In another preferred embodiment, the compound has a structure shown in the following formula IX:

[0040] Preferably, the compound has a structure as shown in the following formula IX-A or IX-B:

[0041] Preferably, the compound has any structure selected from the following groups:

[0042] In another preferred embodiment, the compound has a structure shown in the following formula X:

[0043] Preferably, the compound has a structure as shown in the following formula XA or XB:

[0044] Preferably, the compound has any structure selected from the following groups:

[0045] The second aspect of the present invention provides a pharmaceutical composition comprising (i) the compound according to the first aspect and (ii) a pharmaceutically acceptable carrier.

[0046] The third aspect of the present invention provides a compound as described in the first aspect, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt, or the use of the pharmaceutical composition as described in the second aspect, for preparing a drug for treating and / or preventing diseases associated with abnormal TDG expression.

[0047] In another preferred embodiment, the disease associated with abnormal TDG expression is tumor.

[0048] In another preferred embodiment, the tumor is selected from the following groups: lung cancer, acute leukemia, chronic leukemia, colorectal cancer, breast cancer, thyroid tumor, lymphoma, bile duct cancer, liver cancer, pancreatic cancer, bronchial cancer, esophageal cancer, skin cancer, oral cancer, gastric cancer, genitourinary tract tumors, central and peripheral nervous system tumors, or a combination thereof.

[0049] In another preferred embodiment, the tumor is selected from the following group: melanoma, acute myeloid leukemia, small cell lung cancer, and non-small cell lung cancer.

[0050] A fourth aspect of the present invention provides a method for inhibiting TDG activity, comprising the steps of:

[0051] The subject is contacted with an effective amount of the compound according to the first aspect, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, or its hydrate, or its crystal form, or its solvate, or the pharmaceutical composition according to the second aspect, thereby inhibiting TDG activity.

[0052] In another preferred embodiment, the method is in vitro non-therapeutic and non-diagnostic.

[0053] A fifth aspect of the present invention provides a method for treating and / or preventing a disease associated with overexpression of TDG, the method comprising the steps of:

[0054] An effective amount of the compound according to the first aspect, or a salt thereof, or an isomer thereof, or the pharmaceutical composition according to the second aspect is administered to a subject.

[0055] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 shows the IC inhibition of compound 14 on the proliferation of p53 mutant and wild-type tumor cell lines in vitro 50 . DETAILED DESCRIPTION

[0057] Through extensive and in-depth research, the present inventors unexpectedly discovered for the first time a class of compounds with TDG inhibitory activity, on the basis of which they completed the present invention.

[0058] the term

[0059] In the present invention, the halogen is F, Cl, Br or I.

[0060] In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, unless otherwise specified, all chemical formulae are intended to encompass any possible optical or geometric isomers (e.g., R-type, S-type or racemate, or cis-trans isomers of olefins, etc.).

[0061] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0062] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0063] In the present invention, the term C1-C6 amino refers to "C1-C6 alkyl-NH-" and "(C1-C6 alkyl)2N-", or similar structures thereof.

[0064] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0065] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0066] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The terms "C3-C8 cycloalkyl," "C3-C7 cycloalkyl," and "C3-C6 cycloalkyl" have similar meanings.

[0067] In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

[0068] In the present invention, the term "C1-C12 alkylaminocarbonyl" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.

[0069] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning. Preferably, "aryl group" is "C6-C12 aryl group" or "C6-C10 aryl group." The term "C6-C12 aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms and no heteroatoms in the ring, such as phenyl and naphthyl. The term "C6-C10 aryl group" has a similar meaning.

[0070] In the present invention, the terms "aromatic heterocycle," "heteroaromatic ring," or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0071] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, such as dioxolanyl. The term "3-7 membered heterocyclic group" has a similar meaning.

[0072] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, the two rings having a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc.

[0073] Compounds of formula (I) as TDG inhibitors

[0074] The present invention provides a class of compounds having TDG inhibitory activity:

[0075] wherein each group has the same definition as described above.

[0076] Pharmaceutical compositions and methods of administration

[0077] Since the compounds of the present invention have excellent biological activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate related diseases caused by abnormal activity or expression of TDG.

[0078] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0079] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0080] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0081] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0082] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0083] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0084] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0085] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0086] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0087] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0088] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can be administered together with other small molecule compounds to form PROTACs, or together with other macromolecular compounds such as monoclonal antibodies to form ADCs.

[0089] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0090] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0091] abbreviation:

[0092] The starting materials can be obtained from commercial sources or prepared by methods known or disclosed in the art.

[0093] The purification of intermediates and compounds is carried out by conventional chemical experimental operations such as normal phase or reverse phase chromatography or recrystallization. Normal phase chromatography is performed by pre-packed silica gel chromatography columns or preparative thin layer chromatography. Silica gel chromatography columns are mainly glass columns or flash column chromatography. The models of flash column chromatography are Or other brands. The mobile phase for normal phase chromatography is selected from petroleum ether / ethyl acetate, dichloromethane / methanol, or other suitable solvents and the proportions used for elution. Reverse-phase preparative liquid chromatography utilizes a C18 column, performed using a preparative liquid chromatograph or flash column chromatograph, with detection at 214 nM and 254 nM or using a preparative liquid chromatography-mass spectrometer. Gradient elution is performed using a mobile phase consisting of water / acetonitrile containing 0.1% hydrochloric acid, water / acetonitrile, water / acetonitrile containing 0.1% ammonium bicarbonate, water / acetonitrile containing 0.1% formic acid, water / acetonitrile containing 0.1% ammonia / acetonitrile, water / acetonitrile containing 0.1% trifluoroacetic acid, or other suitable solvent systems.

[0094] Prep HPLC was performed on a Gilson preparative HPLC system (GX-281). Representative prep HPLC conditions were as follows: ① FA method: Column: Boston Prime C18 150*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; ② FA method-A: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; ③ FA method-B: Phenomenex C18 80*30mm*5um; mobile phase: [water (0.225FA)-ACN].

[0095] The conventional post-processing described herein is as follows: combining the organic phases, drying them with anhydrous sulfuric acid or anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to remove the solvent. A second conventional post-processing procedure described herein is as follows: combining the organic phases, washing them with saturated brine (rarely with 30% lithium chloride solution), drying them with anhydrous sulfuric acid or anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to remove the solvent. Unless otherwise indicated, the reaction time indicated for a chemical reaction is the time at which LCMS, TLC, or other appropriate assays indicate completion of the reaction or complete disappearance of the starting material.

[0096] The structures of intermediates and compounds were characterized by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LCMS). The NMR spectrometer used was a Bruker Ascend TM-400 MHz or Bruker Ultrashield Plus 400 MHz or other models. The solvents used were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, or other deuterated solvents as noted. Spectral data were reported in the following format: chemical shift δ (peak splitting number, coupling constant J (Hz), number of hydrogen atoms). Tetramethylsilane was used as an internal standard for chemical shifts, and its chemical shift was set to zero (δ, 0 ppm). The meanings of some abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

[0097] Representative liquid chromatography-mass spectrometry (LCMS) methods for the structural characterization of intermediates and compounds are as follows:

[0098] LCMS was performed on an Agilent MSD mass spectrometer connected to an Agilent 1260 system with ultraviolet (UV, 254 or 220 nm) and mass spectrometry (MS, ESI + ) for testing.

[0099] Method 1: 5-95AB, column: Agilent Pursult 5 C18 20*2.0 mm, solvent A: 0.0375% TFA in water, solvent B: 0.1125% TFA in acetonitrile, 5% solvent B to 95% solvent B over 0.7 min, hold for 0.4 min, for a total of 1.5 min; flow rate: 1.5 mL / min; column temperature: 50°C.

[0100] Method 2: 5-95AB_3min_220&254_Agilent, column: Agilent Poroshell 120 EC-C18 2.7um 3.0*30mm, solvent A: 0.0375% TFA in water, solvent B: 0.1125% TFA in acetonitrile, 5% solvent B to 80% solvent B over 1.2 minutes, 80% solvent B to 95% solvent B over 1.3 minutes, hold for 0.5 minutes, for a total of 3 minutes; flow rate: 1.5 mL / min; column temperature: 50°C.

[0101] Method 3: 0-100AB_QC_220&254 column: ACQUITY UPLC BEH C18 50*2.1mm, 1.7um; Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in acetonitrile, 0% solvent B to 100% solvent B over 1 minute, hold for 0.2 minutes, for a total of 1.5 minutes; Flow rate: 1.0 mL / min; Column temperature: 40°C.

[0102] Method 4: 10-80AB_4min_220&254_Shimadzu, Column: Nano Chrom 120 C18 3.0*30mm, 3µm, Solvent A: 0.0375% TFA in water, Solvent B: 0.1125% TFA in acetonitrile, 10% to 80% solvent B over 3 minutes, hold for 0.5 minutes, for a total of 4 minutes; Flow rate: 0.8mL / min; Column temperature: 50°C.

[0103] Method 5: 5-95AB_1min_220&254_Agilent, column: Agilent Poroshell 120EC-C18 2.7um 3.0*30mm, solvent A: 0.0375% TFA in water, solvent B: 0.1125% TFA in acetonitrile, 5% solvent B to 95% solvent B over 0.4 minutes, hold for 0.3 minutes, for a total of 1 minute; flow rate: 2 mL / min; column temperature: 50°C.

[0104] Method 6: 0-95AB_1.5min_220&254_Agilent, Column: Waters, Xbridge C18 30*2.1mm, 3.5um, Solvent A: 0.0375% TFA in water, Solvent B: 0.1125% TFA in acetonitrile, 0% solvent B to 95% solvent B over 0.6 min, hold for 0.8 min, for a total of 1.5 min; Flow rate: 1.2 mL / min; Column temperature: 40°C.

[0105] Method 7: 10-80CD_3MIN_220&254_Shimadzu, column: XBridge C18 3.5um 2.1*30mm, solvent A: 0.025% aqueous ammonia, solvent B: acetonitrile, 10% solvent B to 80% solvent B over 2 minutes, hold for 0.48 minutes, for a total of 3 minutes; flow rate: 1 mL / min; column temperature: 50°C.

[0106] Method 8: 10-80AB_7min_220&254_Shimadzu column: Xtimate C18 2.1*30mm, 3um, solvent A: 0.0375% TFA in water, solvent B: 0.1125% TFA in acetonitrile, 10% solvent B to 80% solvent B over 6 minutes, hold for 0.5 minutes, for a total of 7 minutes; flow rate: 0.8 mL / min; column temperature: 50°C.

[0107] Representative catalytic hydrogenation procedures: Dissolve the compound in a suitable solvent, such as EA or THF, and add palladium on carbon (10% content, approximately 0.1 equivalent) or palladium hydroxide on carbon (20% content, approximately 0.1 equivalent). Thoroughly displace the hydrogen from the reaction mixture. Stir under a 15 psi hydrogen atmosphere at 25°C until LCMS indicates completion of the reaction. Filter the reaction mixture and concentrate to dryness under reduced pressure to obtain the purified product.

[0108] Example 1 Synthesis Method 1 of Compound 14

[0109] Step 1:

[0110] To a degassed and nitrogen-filled mixture of (S,S)-(+)-N,N'-bis(3,5-di-tert-butyl-o-hydroxybenzylidene)-1,2-cobalt diamino (CAS: 188264-84-8, 370 mg, 613.48 umol, 0.025 eq) and (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl-o-hydroxybenzylidene)-1,2-cyclohexanediaminocobalt (CAS: 176763-62-5, 370 mg, 613.48 umol, 0.025 eq) was added H2O (25 mL) ), ethyl diazoacetate (14-a-1) (3.50 g, 24.54 mmol, 80% purity, 1 eq) and phenyl vinyl sulfide (5.01 g, 36.81 mmol, 1.5 eq), and reacted at 40 ° C for 24 hours. TLC showed that the reaction was complete and two products were generated (PE: EA = 8: 1, Rf = 0.4, 0.5). Cooled to 25 ° C, degassed and flushed with oxygen several times, and then reacted at 25 ° C for 1 hour. Filtered with celite and rinsed with DCM (20 mL * 2), the aqueous phase was extracted with DCM (50 mL * 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was passed through a silica gel column chromatography ( 120g Purification by silica flash column (0-0.1, 2, 3% EA / PE, 80 mL / min) afforded 14-b-1 as a red oil (cis structure, 3.08 g, 13.85 mmol, 56.46% yield). 1 H NMR(400MHz,CDCl3)Shift 7.35-7.42(m,2H),7.26-7.30(m,2H),7.13-7.21(m,1H),4.07(q,J=7.11Hz,2H),2. 72(q,J=7.78Hz,1H),2.22-2.35(m,1H),1.45-1.53(m,2H),1.12(t,J=7.03Hz,3H).

[0111] Step 2:

[0112] Within one hour, m-CPBA (21.9 g, 101.96 mmol, 80% purity, 1.48 eq) was added in batches to a solution of compound (14-b-1) (15.3 g, 68.83 mmol, 1 eq) in DCM (400 mL) at 0°C and reacted at 25°C for 16 hours. After the reaction, a KOH (3 M, 500 mL) aqueous solution was added. The aqueous phase was extracted with DCM (300 mL*2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 220g Purification by silica flash column, 50-80% EA / PE, 100 mL / min) gave 14-c-1 as a brown oil (9.8 g, 41.12 mmol, 59.75% yield). (ESI) m / z = 238.9 [M+H] + . 1 H NMR(400MHz, CDCl3)δδ7.62-7.72(m,2H),7.50-7.55(m,3H),4.16-4.28(m,2H),2.62(dt,J=6.60,8.36Hz,1 H),2.14(dt,J=6.49,8.20Hz,1H),2.03-2.11(m,1H),1.64(dt,J=5.72,8.25Hz,1H),1.31(t,J=7.15Hz,3H).

[0113] Step 3:

[0114] To a solution of compound (14-a) (1.60 g, 5.53 mmol, 1 eq) and trimethylboroxane (4.17 g, 16.60 mmol, 4.64 mL, 50% purity, 3.0 eq) in DMF (40 mL) was added K2CO3 (2.29 g, 16.60 mmol, 3.0 eq) and the mixture was purged with nitrogen several times. Pd(dppf)Cl2 (202 mg, 276.70 umol, 0.05 eq) was added and the mixture was reacted at 100°C under nitrogen for 16 hours. After the reaction, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 24g Purification by silica flash column, 0-25% EA / PE, 35 mL / min) gave a yellow solid (14-b) (850 mg, 3.79 mmol, yield 68.49%). (ESI) m / z = 225.1 (M+1) + .

[0115] Step 4:

[0116] A solution of compound (14-b) (950 mg, 4.24 mmol, 1 eq) in DCM (10 mL) and TFA (2 mL) was reacted at 25°C for 2 hours. The reaction was concentrated under reduced pressure to afford a red oil, compound (14-c) (3.21 g, 13.47 mmol, 97.22% yield), which was used directly in the next step.

[0117] Step 5:

[0118] To a solution of compound (14-c) (722 mg, 4.34 mmol, 1 eq) and triisopropylsilyl chloride (1.26 g, 6.52 mmol, 1.39 mL, 1.5 eq) in THF (10 mL) were added imidazole (591 mg, 8.69 mmol, 2.0 eq) and DIEA (1.12 g, 8.69 mmol, 1.51 mL, 2.0 eq) and reacted at 25°C for 2 hours. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 24g Purification by silica flash column (0-10% EA / PE, 35 mL / min) gave a colorless oil (14-d) (1.23 g, 3.81 mmol, 87.78% yield). 1 H NMR(400MHz,CDCl3)Shift 10.29(s,1H),7.65(s,1H),6.40(s,1H),3.86(s,3H),2.19(s,3H),1.31-1.39(m,3H),1.08(s,18H).(ESI)m / z=323.3(M+1) + .

[0119] Step 6:

[0120] At -78 ° C, to a solution of compound (14-c-1) (635 mg, 2.67 mmol, 1 eq) in THF (25 mL), add isopropyl magnesium chloride solution (2M, 2.00 mL, 1.5 eq) and maintain stirring at -78 ° C for 15 minutes. Add a solution of compound (14-d) (860 mg, 2.67 mmol, 1.0 eq) in toluene (3 mL) and react at 0 ° C for 3 hours. After the reaction is completed, saturated NH4Cl aqueous solution (20 mL) is added to quench the reaction and extracted with EtOAc (20 mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography ( 24g The product was purified by silica flash column, 0-10% EA / PE, 35 mL / min) to obtain compound (14-e) (220 mg, 563.25 umol, 21.12% yield) as a colorless oil. 1 H NMR(400MHz, CDCl3)6.95-7.05(m,1H),6.37-6.45(m,1H),5.83(d,J=4.77Hz,0.3H),5.49(s,0.5H),4.60(s,0.3H),3.7 9-3.81(m,3H),2.63-2.68(m,0.3H),2.18-2.26(m,4.4H),1.25-1.38(m,4H),1.01-1.17(m,19H).(ESI)m / z=391.2(M+1) + .

[0121] Step 7:

[0122] To a solution of compound (14-e) (180 mg, 460.84 umol, 1 eq) in THF (5 mL) was added triethylamine trihydrofluoride (59.4 mg, 368.68 umol, 60.09 uL, 0.8 eq) and the mixture was reacted at 25°C for 3 hours. After the reaction was completed, a saturated aqueous solution of NaHCO3 (5 mL) was added to quench the reaction and the mixture was extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 12g The product was purified by silica flash column (0-30% EA / PE, 35 mL / min) to give compound 14 as a pink solid (70 mg, 283.89 μmol, 61.60% yield, 95% purity). (ESI) m / z = 235.0 (M+1) + .

[0123] Referring to the method of steps 5 to 7 in the synthesis method of compound 14, the starting materials listed in the following table were reacted to obtain the corresponding final compounds.

[0124] Example 2 Synthesis Method 2 of Compound 14

[0125] Step 1:

[0126] To a DMF (75 mL) solution of compound (14-c) (5.0 g, 30.09 mmol, 1 eq) was added K2CO3 (12.5 g, 90.27 mmol, 3.0 eq) and 3-bromo-1-propene (4.73 g, 39.12 mmol, 1.3 eq) and the mixture was reacted at 25°C for 3 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 80g The product was purified by silica flash column (0-10% EA / PE, 65 mL / min) to give compound (14-f) as a white solid (5.3 g, 25.70 mmol, 85.41% yield). 1 H NMR(400MHz,CDCl3)Shift 10.30(s,1H),7.64(d,J=0.61Hz,1H),6.40(s,1H),6.09m,1H),5.48(m,1 H),5.36(m,1H),4.65(td,J=1.53,5.01Hz,2H),3.91(s,3H),2.19(s,3H).

[0127] Step 2:

[0128] At -78 ° C, to a solution of compound (14-c-1) (8.09 g, 33.94 mmol, 1 eq) in THF (210 mL) was added isopropylmagnesium chloride solution (2M, 25.46 mL, 1.5 eq) and stirred at -78 ° C for 60 minutes. A solution of compound (14-f) (7.0 g, 33.94 mmol, 1.0 eq) in toluene (20 mL) was added and reacted at 0 ° C for 3 hours. After the reaction was completed, saturated NH4Cl aqueous solution (200 mL) was added to quench the reaction and extracted with EtOAc (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography ( 220g Purification was performed using a silica flash column (0-15% EA / PE, 30 mL / min) to obtain compound 14-g (4.8 g, 16.8 mmol, 49.49% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)Shift 6.96-7.08(m,1H),6.47(s,1H),6.00-6.18(m,1H),5.84(d,J=4.62Hz,0.24H),5 .51(s,0.7H),5.46(qd,J=1.65,17.28Hz,1H),5.27-5.36(m,1H),4.59(td,J=1.6 8,5.01Hz,2H),3.82-3.90(m,3H),2.61-2.72(m,0.2H),2.12-2.30(m,4.8H),1. 20-1.40(m,1H),0.96-1.10(m,1H),0.80-0.90(m,0.28H).(ESI)m / z=275.2(M+1) +

[0129] Step 3:

[0130] Pd(OAc)2(1.11g, 4.96mmol, 0.3eq) and PPh3(5.2g, 19.84mmol, 1.2eq) were added to a solution of compound (14-g) (4.53g, 16.53mmol, 1eq) in THF (100mL) and reacted at 25°C for 20 hours. After the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography ( 120g The product was purified by silica flash column (0-30% EA / PE, 60 mL / min) and then slurried with MTBE:PE (1:1, 10 mL) to obtain an off-white solid compound (14) (990 mg, 4.23 mmol, 25.64% yield). (ESI) m / z = 235.1 (M+1) + . 1HNMR(400MHz,DMSO-d6)Shift 9.19-9.67(m,1H),6.82-6.98(m,1H),6.44-6.54(m,1H),5.73(d,J=4.65Hz,0.2H),5.39(s,0.8H),3.64-3.79(m,3H),2.12 -2.28(m,2H),1.98-2.11(m,3H),1.29(dt,J=4.46,8.16Hz,0.8H),1.00-1.10(m,0.2H),0.96(q,J=4.28Hz,0.8H),0.71(br d,J=3.30Hz,0.2H)

[0131] Referring to the method of step 2 and step 3 in Example 2, the following starting materials were substituted for (14-c-1), and a two-step reaction was carried out with (14-f) to obtain the corresponding final compound.

[0132] The synthesis method of the starting material 44-A mentioned in the above table is:

[0133] Referring to the method of Step 2 in Example 1, 44-B (600 mg, 2.40 mmol) was reacted as the starting material to give a colorless oil 44-A (540 mg, yield 84.59%). 1 H NMR (400MHz, CDCl3) δ7.63-7.85(m,2H),7.38-7.61(m,3H),4.10-4.37(m,2H),2.38 -2.55(m,1H),1.90-2.15(m,1H),1.52-1.71(m,3H),1.22-1.42(m,4H),1.13(s,2H).

[0134] Referring to the method of Example 2, the following starting materials were used to carry out three-step reactions to obtain the corresponding final compounds.

[0135] The synthesis methods of the starting materials 284-A and 285-A mentioned in the above table are:

[0136] Step 1: A mixture of 2-methoxy-4-(prop-2-enyloxy)benzene-1-carbaldehyde (200 mg, 1.04 mmol, 1 eq) in N,N-dimethylaniline (2 mL) was stirred at 180°C for 4 hours under microwave conditions. The mixture was cooled to room temperature, diluted with EtOAc (15 mL), and washed with 1M HCl (3 mL x 3). The organic phase was subjected to standard post-processing to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE, EA ranging from 7 to 15%) to afford Compound 284-B (50 mg, 25% yield) as an off-white solid and Compound 285-B (82.5 mg, 41.3% yield) as a yellow solid.

[0137] Compound 284-B: 1 H NMR (400MHz, CDCl3) δ (ppm) 10.22 (s, 1H), 7.74 (d, J = 8.6Hz, 1H), 6.77 (d, J = 8.6Hz, 1H), 6.39 (br s,1H),6.06(ddt,J=5.9,10.5,16.8Hz,1H),5.09-5.25(m,2H),3.91(s,3H),3.47-3.60(m,2H).

[0138] Compound 285-B: 1 H NMR (400MHz, CDCl3) δ (ppm) 10.28 (s, 1H), 7.64 (s, 1H), 6.46 (s, 1H), 6.06-6.11 ( m,1H),5.92-6.06(m,1H),5.16-5.26(m,2H),3.88(s,3H),3.39(d,J=6.4Hz,2H)

[0139] Compound 284-A: Following the method for synthesizing compound 281-A from compound 281-B, 284-B (200 mg) was reacted to obtain compound 284-A (200 mg) as a yellow oil. The crude product was used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 195.2. 1 H NMR (400MHz, CDCl3) δ (ppm) 10.20 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 6.70 (d, J = 8.6Hz, 1H), 6.11 (br s,1H),3.92(s,3H),2.55-2.74(m,2H),1.52-1.65(m,2H),0.96-1.16(m,3H).

[0140] Compound 285-A: Following the method for synthesizing compound 281-A from compound 281-B, 285-B (330 mg) was reacted to obtain compound 285-A (330 mg) as an off-white solid. The crude product was used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 195.2. 1 H NMR(400MHz, CDCl3)δ(ppm)10.27(s,1H),7.64(s,1H),6.43(s,1H),6.06(s,1 H), 3.87 (s, 3H), 2.44-2.64 (m, 2H), 1.53-1.64 (m, 2H), 0.96 (t, J = 7.3Hz, 3H).

[0141] The synthesis methods of the starting materials 281-A and 281-B mentioned in the above table are:

[0142] Step 1: A mixture of compound 14-f (1.0 g, 4.85 mmol, 1 eq) and N,N-dimethylaniline (8 mL) was stirred at 180°C for 8 hours. TLC showed only a small amount of unreacted starting material. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), and washed with 1M HCl (10 mL x 3). The organic phase was subjected to conventional post-processing to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 7%) to obtain compound 281-B (640 mg, 3.10 mmol, yield 64%) as an off-white solid. LC-MS: (ESI) m / z [M+H] + 207.0.

[0143] Step 2: Dissolve compound 281-B (300 mg, 1.45 mmol) in EtOAc (30 mL) and add palladium / carbon (5% content, 60 mg). The reaction mixture is fully purged of hydrogen. Stir the reaction at 25°C under a 15 psi hydrogen atmosphere for 2 hours. Filter through celite and concentrate under reduced pressure to obtain an off-white solid compound 281-A (290 mg). The crude product is used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 209.1.

[0144] The synthesis method of the starting material 40-A mentioned in the above table is:

[0145] To a solution of compound 40-B (500 mg, 2.97 mmol) in DCM (10 mL) at -78°C was added a solution of dichloromethyl methyl ether (410 mg, 3.57 mmol) and titanium tetrachloride (1.41 g, 7.43 mmol) in DCM (5 mL). The mixture was stirred for 16 hours after warming to 25°C. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). Following standard post-processing, the product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 7%) to afford compound 40-A (440 mg, 75.44% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ10.20(s,1H),7.42(s,1H),6.42(s,1H),3.97(s,3H),3.97(s,3H),2.24(d,J=0.72Hz,3H).

[0146] The synthesis method of the starting material 116-A mentioned in the above table is:

[0147] Referring to the synthesis method of 40-A, 116-B (3.0 g, 14.27 mmol) was used for reaction to obtain a purple solid 116-A (2.2 g, yield 64.7%). 1 H NMR(400MHz,DMSO-d6)Shift 10.80(s,1H),10.11(s,1H),7.45(s,1H),6.54(s,1H),3.82(s,3H),3.57(s,3H),2.71-2.78(m,2H),2.53-2.60(m,2H).

[0148] The synthesis method of the starting material 48-A mentioned in the above table is:

[0149] Referring to the synthesis method of 40-A, 48-B (870 mg, 6.39 mmol) was used for the reaction to obtain a white solid 48-A (720 mg, yield 68.64%). 1 H NMR (400MHz, DMSO-d6) δ10.41(br s,1H),9.97(s,1H),7.56(s,1H),6.71(s,1H),2.90(q,J=7.46Hz,2H),2.12(s,3H),1.13(t,J=7.46Hz,3H).

[0150] The synthesis method of the starting material 62-A mentioned in the above table is:

[0151] Referring to the synthesis method of 40-A, 62-B (1.06 g, 5.14 mmol) was used to react to obtain a brown solid 62-A (432 mg, yield 19.3%, purity 73.3%). LCMS: (ESI) m / z = 235.0 (M+1) +

[0152] The synthesis method of the starting material 31-A mentioned in the above table is:

[0153] To a solution of compound 30-A (1.9 g, 12.33 mmol) and dimethylamine hydrochloride (3.02 g, 36.98 mmol) in DMF (50 mL) was added KCO (5.11 g, 36.98 mmol). The reaction was stirred at 110°C for 16 hours, then cooled to room temperature, and water (30 mL) was added. The product was extracted with EtOAc and THF (1:1, 50 mL x 3). After standard post-processing, the product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 20%) to afford compound 31-A (820 mg, 37.12% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ10.00(s,1H),7.59(s,1H),6.50(s,1H),2.85(s,6H),2.22(s,3H)

[0154] The synthesis method of the starting material 162-A mentioned in the above table is:

[0155] Step 1: Following the synthesis method of starting material 30-A, 162-C (1 g, 4.30 mmol) was reacted to give a yellow oil 162-B (0.95 g, yield 85.7%). LC-MS: (ESI) m / z. [M+H] + 258.1.

[0156] Step 2: Following the procedure of Step 4 in Example 1, 162-B (0.80 g) was reacted to obtain 162-A (0.62 g) as a yellow oil. The crude product was used directly in the next reaction. LC-MS: (ESI) m / z. [M+H] + 200.1.

[0157] The synthesis method of the starting material 32-A mentioned in the above table is:

[0158] Referring to the method of step 4 in Example 8-b, 15-A (500 mg, 2.33 mmol) was reacted with potassium ethylene trifluoroborate (934 mg, 6.98 mmol) to give an off-white solid compound 32-A (250 mg, yield 66.3%). 1 H NMR (CDCl3, 400MHz) δ10.13 (s, 1H), 7.66 (s, 1H), 7.52 (dd, J = 11.00, 17.36Hz, 1H), 6.9 7(s,1H),6.69(s,1H),5.65(d,J=17.36Hz,1H),5.46(d,J=11.00Hz,1H),2.31(s,3H).

[0159] The synthesis method of the starting material 35-A mentioned in the above table is:

[0160] To a mixture of compound 15-A (1 g, 4.65 mmol) in dioxane / water (20 mL, 9 / 1) was added 35-B (691 mg, 5.58 mmol) and K3PO4 (2.96 g, 13.95 mmol). After degassing and refilling with nitrogen three times, Pd(dppf)Cl2 (170 mg, 232.51 μmol) was added. The mixture was heated to 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated brine (50 mL), and extracted with EtOAc (20 mL*3) and THF (15 mL*3). Standard workup procedures gave the crude product, which was triturated in DCM (10 mL) and washed with DCM (2 mL*3) to afford compound 35-A as a white solid (767 mg, 77% yield). 1 H NMR(400MHz,DMSO-d6)δppm 2.23-2.28(m,3H)6.77-6.84(m,1H)7.72-7.86(m,1H)8.80-8.90(m,2H)9.19-9.28(m,1H)9.66-9.75(m,1H)10.82-10.94(m,1H).

[0161] The synthesis method of the starting material 41-A mentioned in the above table is:

[0162] Referring to the synthesis method of compound 35-A, 15-A (1 g, 4.65 mmol) was reacted with (E)-phenyleneboronic acid (413 mg, 2.79 mmol, 1.2 eq) to obtain a brown solid 41-A (302 mg, yield 54.51%). 1H NMR(400MHz,DMSO-d6)δppm 2.13-2.25(m,3H)7.14-7.21(m,1H)7.29-7.35(m,1H)7.37-7.47(m,2H)7.57-7.71(m,3H)8.03-8.20(m,1H)10.09-10.19(m,1H).

[0163] The synthesis method of the starting material 37-A mentioned in the above table is:

[0164] To a mixture of compound 15-A (500 mg, 2.33 mmol) in THF (10 mL) was added Pd(dppf)Cl2 (326 mg, 465 μmol). After degassing and refilling with nitrogen three times, TEA (1.18 g, 11.63 mmol), CuI (44.2 mg, 232.51 μmol), and 37-B (551 mg, 3.02 mmol) were added. The mixture was heated to 70°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and the organic phase was separated. After conventional workup, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to give compound 37-A (450 mg, yield 61.15%) as a yellow solid. 1 H NMR (CDCl3, 400MHz) δppm 10.44 (s, 1H) 7.76 (s, 1H) 6.98 (s, 1H) 5.77 (s, 1H) 2.30 (s, 3H) 1.09-1.23 (m, 22H).

[0165] The synthesis method of the starting material 61-A mentioned in the above table is:

[0166] To a mixture of compound 61-B (980 mg, 4.24 mmol) in toluene (50 mL) / water (5 mL) were added cyclopropylboronic acid (473 mg, 5.51 mmol) and K₃PO₄ (2.70 g, 12.7 mmol). The mixture was purged with nitrogen three times, and Pd(OAc)₂ (50 mg, 223 μmol) and tricyclohexylphosphine (490 mg, 1.75 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, diluted with 2 mL of saturated brine, and extracted with EA (5 mL x 2). Conventional post-processing procedures gave a residue, which was purified by silica gel column chromatography (THF:PE, THF ranging from 0 to 15%) to afford compound 61-A (330 mg, 40.48% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ (ppm) 10.26 (s, 1H), 7.64 (d, J = 0.7Hz, 1H), 6.50 (s, 1H), 3.89 (s, 3H), 1.61-1.75 (m, 1H), 0.92-1.03 (m, 2H), 0.61-0.67 (m, 2H).

[0167] The synthesis method of the starting material 64-A mentioned in the above table is:

[0168] Step 1: To a solution of 30-A (2.50 g, 16.2 mmol) in DMF (50 mL) was added NaSCH3 (4.16 g, 59.4 mmol). The mixture was reacted at 120°C until LC-MS indicated complete reaction. The mixture was cooled to room temperature, poured into water (50 mL), adjusted to pH 5 with 50% acetic acid, and extracted with EA (3 x 50 mL). Standard workup procedures yielded a residue, which was then purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 0 to 25%) to afford 47-A (1.5 g, 50.7% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.87(s,1H),7.62(s,1H),6.80(s,1H),2.38(s,3H),2.13(s,3H)

[0169] Step 2: To a solution of compound 64-C (1.0 g, 5.49 mmol) in DCM (20 mL) was added portionwise m-CPBA (2.79 g, 13.7 mmol, 85% purity) at 0°C and allowed to react at 25°C for 2 hours. The mixture was filtered and dried under vacuum to afford compound 64-A (3.2 g, 35% purity) as a white solid. The crude product was used directly in the next reaction.

[0170] The synthesis method of the starting material 278-A mentioned in the above table is:

[0171] Step 1: To a solution of 170-A (5.0 g, 32.9 mmol) in DMF (50 mL) were added K2CO3 (5.0 g, 36.2 mmol, 1.1 eq) and compound 278-B (4.24 g, 39.4 mmol, 1.2 eq). The mixture was reacted at 40°C for 3 hours. After cooling to room temperature, EA (100 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to afford compound 278-C (7 g, 95% yield) as a white solid. LC-MS: (ESI) m / z. [M+H] +224.21.

[0172] Step 2: To a solution of compound 278-C (2 g, 8.96 mmol) and compound 278-D (695 mg, 4.48 mmol) in 1,2-dichloroethane (40 mL) were added Pd(OAc)2 (201 mg, 896 μmol), silver trifluoroacetate (AgTFA) (198 mg, 896 μmol), and TFA (10.2 g, 89.6 mmol). After stirring at 25°C for 0.5 hour, NCS (1.80 g, 13.5 mmol) was added. The reaction was stirred at 60°C for 64.5 hours (LCMS indicated 15% starting material remaining). The reaction mixture was cooled to room temperature, saturated NaHCO3 solution (50 mL) was added, and the mixture was extracted with DCM (100 mL x 3). Conventional post-treatment procedures yielded a residue, which was then purified by silica gel column chromatography (EA:PE, EA from 0 to 21.5%) to afford compound 278-E (1.2 g, 4.66 mmol, 52% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 258.1.

[0173] Step 3: To a solution of 278-E (300 mg) in MeOH (5 mL) was added a solution of NaOH (70 mg) in water (2.5 mL). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, water (5 mL) was added, and the mixture was washed with MTBE (3 mL*2). The pH was adjusted to 2-3. The precipitated solid was filtered, and the filter cake was washed with water (5 mL*2) and dried under vacuum to obtain compound 278-A (200 mg, 90% yield) as a yellow solid. LCMS: (ESI) m / z. [M+H] + 187.1.

[0174] Referring to the method of step 2 and step 3 in Example 2, a two-step reaction was carried out starting from the following starting materials to obtain the corresponding final product compound.

[0175] The synthesis method of the starting material 283-A mentioned in the above table is:

[0176] Step 1: Dissolve compound 14-c (500 mg, 3.01 mmol, 1 eq) in an aqueous solution of hydrogen bromide (3 mL, 40% content). Add paraformaldehyde (130 mg) and a catalytic amount of concentrated sulfuric acid (92 mg, 938 μmol, 50 μL). Stir and react at 70°C for 16 hours. Cool to room temperature, dilute the reaction with water (10 mL), and extract with DCM (10 mL*3). The organic phase undergoes conventional post-processing to obtain the crude product. The crude product is crushed and slurried in a mixture of PE and DCM (5 / 1) at 25°C to obtain a brown solid (560 mg), a mixture of compounds 283-B and 283-C, which is used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 197.1.

[0177] Step 2: Dissolve the mixture of compounds 283-B and 283-C (560 mg) in MeOH (10 mL), add a methanol solution of sodium methoxide (5.4 M, 2.00 mL), and stir at 25°C for 16 hours. Concentrate under reduced pressure, adjust the pH to 4 with 1 M hydrochloric acid, extract with DCM (5 mL*3), and wash the organic phase with saturated NaHCO3 solution (5 mL). After conventional post-processing, a brown oil 283-D (430 mg) is obtained. The crude product is used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 211.2.

[0178] Step 3: To a solution of compound 283-D (430 mg) and K2CO3 (707 mg, 5.11 mmol) in DMF (5 mL) was added 3-bromo-1-propene (371 mg, 3.07 mmol). The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, saturated brine (5 mL) was added and the mixture was extracted with EtOAc (3 mL x 3). After standard post-processing, the crude product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 5.5%) to afford compound 283-A (482 mg, 64% yield over three steps) as a brown oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 10.29 (s, 1H), 7.71 (s, 1H), 6.12 (ddt, J = 5.3, 10.9, 16.7Hz, 1H), 5.46 (dd, J = 0.7, 1 7.2Hz, 1H), 5.31 (d, J = 10.4Hz, 1H), 4.50 (s, 2H), 4.48 (d, J = 5.7Hz, 2H), 3.98 (s, 3H), 3.47 (s, 3H), 2.30 (s, 3H).

[0179] The synthesis method of the starting material 42-A mentioned in the above table is:

[0180] Step 1: To a mixture of 42-B (3 g, 18 mmol) in ACN (30 mL) were added 3-bromopropene (2.2 g, 18 mmol) and NaCO (3.8 g, 36 mmol). The reaction was allowed to proceed at 70°C for 16 hours. After completion of the reaction, the solvent was evaporated to dryness, water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). Standard workup procedures were performed to obtain the crude product, which was purified by silica gel thin-layer chromatography (THF:PE, THF ranging from 0 to 20%) to afford 42-C (1.3 g, 35% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.92(br s,1H),9.98(s,1H),7.41-7.51(m,1H),6.50(s,1H),6.06(m,1H),5.27-5 .48(m,2H),4.59-4.74(m,2H),2.51-2.55(m,2H),1.12(t,J=7.5Hz,3H).

[0181] Step 2: To a mixture of 42-C (1.1 g, 5 mmol) in DMF (10 mL) were added iodomethane (1.1 g, 8.00 mmol) and K2CO3 (1.5 g, 10.6 mmol). The mixture was reacted at 20°C for 16 hours. Water (10 mL) was added and the mixture was extracted with EA (15 mL x 3). After conventional post-treatment, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 12%) to obtain a white solid 42-A (990 mg, yield 84%). LCMS: (ESI) m / z = 221.2 (M+1) + .

[0182] The synthesis method of the starting material 47-A mentioned in the above table is:

[0183] Step 1: Referring to the method of step 1 in Example 2, 30-A (268 mg, 1.74 mmol) was used as the starting material to give a white solid 47-B (260 mg, yield 77.00%). LCMS: (ESI) m / z = 195.1 (M+1) + .

[0184] Step 2: A mixture of 47-B (1 g, 5.15 mmol), 47-C (1.94 g, 10.3 mmol), and DIEA (2.00 g, 15.5 mmol) in dioxane (12 mL) was reacted at 120°C for 16 hours. LC-MS showed that ~32.3% of the starting material remained and ~48.0% of the desired product was produced. The solvent was evaporated to give the crude product, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to give 47-A (900 mg, 48.2% yield) as a brown oil. LCMS: (ESI) m / z = 363.5 (M+1) + .

[0185] Example 2-a Synthesis of Compound 46

[0186] Step 1: Following the procedure of step 2 in the synthesis of 47-A, 46-B (1.55 g, 15.45 mmol) and 47-B (1 g, 5.15 mmol) were reacted to completion, and post-treatment afforded a yellow solid 46-A (528 mg, 35.1% yield). LCMS: (ESI) m / z = 275.1 (M+1) + .

[0187] Steps 2 and 3: Following the procedures of Steps 2 and 3 in Example 2, a two-step reaction was performed starting with 46-A to obtain compound 46, a white solid, in a two-step yield of approximately 4.9%. LCMS: (ESI) m / z = 303.0 (M+1) + ;1H NMR(400MHz,DMSO-d6)δppm 0.75-0.88(m,1H)1.07(br s,1H)1.24-1.35(m,1H)2.04-2.11(m,3H)2.15-2.37(m,6H)2.55(br s,3H)2.70-2.80(m,2H)2.83-2.91(m,2H)5.58(s,1H)5.92(d,J=4.62Hz,1H)6.62-6.78(m,1H)7.06(s,1H)8.14(s,1H).

[0188] Referring to the synthesis method of Example 2-a, the following starting materials were reacted with compound 47-B in three steps to obtain the corresponding final compound.

[0189] Example 2-b Synthesis of Compound 55

[0190] Step 1: Referring to the synthesis method of 31-A, 55-B (1.13 g, 15.45 mmol) was reacted with 47-B (1 g, 5.15 mmol) to obtain 55-A (250 mg, yield 19.63%). 1 H NMR(CDCl3,400MHz)δppm 10.27(s,1H)7.63-7.75(m,1H)6.51-6.60(m,1H)6.01-6.18(m,1H)5.41-5.58(m,1H)5.35(dd,J =10.64,1.47Hz,1H)4.60-4.70(m,3H)3.17(q,J=7.09Hz,4H)2.23(s,3H)1.07(t,J=7.09Hz,6H).

[0191] Step 2 and Step 3: Following the procedures of Step 2 and Step 3 in Example 2, a two-step reaction was carried out starting with 55-A to obtain yellow solid compound 55. The two-step yield was approximately 5.3%. LCMS: (ESI) m / z = 276.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 9.21-9.54(m,1H)6.83-7.04(m,1H)6.64-6.76(m,1H)5.95(d,J=4.84Hz,0.201H)5.76(s,0.790H)2.80-2.97(m ,4H)2.28-2.36(m,1H)2.14-2.21(m,1H)2.04-2.13(m,3H)1.23-1.34(m,1H)0.98-1.07(m,1H)0.86-0.97(m,6H)

[0192] Referring to the synthesis method of Example 2-b, the following starting materials were reacted with compound 47-B in three steps to obtain the corresponding final compound.

[0193] Example 3-a Synthesis of Compounds 26, 27, 28 and 29

[0194] Note: The four compounds P1, P2, P3 and P4 obtained by chiral resolution in the synthesis route correspond to one of the following four structures respectively, and the absolute configuration has not yet been assigned.

[0195] Chiral resolution of compound 14-g

[0196] 500 mg of compound 14-g was separated using SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: 0.1% NH₃H₂O ETOH; B%: 10%-10%) to yield a colorless oily mixture containing four compounds (130 mg, 473.91 μmol, 26.00% yield) and a mixture containing P3 and P4. The P3 and P4 mixture was further separated using SFC (column: REGIS (S,S) WHELK-O1 (250 mm x 25 mm, 10 μm); mobile phase: 0.1% NH₃H₂O ETOH; B%: 30%-30% over 45 min) to yield compounds P3 and P4.

[0197] White solid compound (P3) (100 mg, 364.55 μmol, 20.00% yield). 1 H NMR(400MHz,CHLOROFORM-d)Shift 6.97-7.09(m,1H),6.47(s,1H),6.02-6.17(m,1H),5.84(d,J=4.77Hz,0.1H),5.41-5 .58(m,1.9H),5.32(dd,J=1.41,10.58Hz,1H),4.59(td,J=1.50,4.95Hz,2H),3.82-3. 93(m,3H),2.63-2.72(m,0.1H),2.15-2.29(m,5H),1.23-1.40(m,1.1H),0.98-1.11( m,1H),0.80-0.89(m,0.1H).(ESI)m / z=275.3(M+1)+,RT=0.94min.SFC:RT=3.227min.

[0198] White solid compound (P4) (100 mg, 364.55 μmol, 20.00% yield). 1H NMR(400MHz,CHLOROFORM-d)Shift 7.05(s,1H),6.47(s,1H),5.98-6.20(m,1H),, lq 5.84(d,J=4.65Hz,0.07H),5.51(s,0.93H),5.46(qd,J=1.61,17.29Hz,1H),5.27-5.38(m,1H),4.59(td,J=1.54,4.98Hz,2H ),3.85(s,3H),2.11-2.30(m,5H),1.22-1.40(m,1H),0.97-1.13(m,1H),0.78-0.91(m,0.11H).LCMS:(ESI)m / z=275.3(M+1) + ,RT=0.94min.SFC:RT=3.751min.

[0199] 130 mg of the colorless oily mixture containing the four compounds was re-separated using SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [CO₂-i-PrOH (0.1% NH₃H₂O)]; B%: 30%-30% per minute) to yield 100 mg of compound P1 and a mixture containing compounds P2, P3, and P4.

[0200] White solid compound (P1) (20 mg, 72.91 μmol, 4.0% yield). LCMS: (ESI) m / z = 275.3 (M+1) + ,RT=0.85min.SFC:RT=3.28min.

[0201] A 100 mg mixture containing three compounds P2, P3, and P4 was separated by a third SFC separation under the following conditions (column: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 25%-25%, 45 min) to obtain compound P2.

[0202] White solid compound (P2) (18 mg, 65.62 μmol, 3.6% yield). LCMS: (ESI) m / z = 275.3 (M+1) + ,RT=1.06min.SFC:RT=3.56min.

[0203] Note: The analytical conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral resolution of compound 14-g are: column: (S,S) Whelk-01 100×4.6mm ID, 5.0um; mobile phase: A:CO2B:Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL / min; column temperature: 40°C; ABPR: 100bar.

[0204] Synthesis of compound 28

[0205] Referring to the last step of the second synthesis method for compound 14, compound P3 (90 mg, 328.09 μmol) was reacted to obtain a pale yellow solid 28 (50 mg, 209.18 μmol, 63.76% yield). 1 H NMR(400MHz,DMSO-d6)Shift 9.28-9.63(m,1H),6.79-6.98(m,1H),6.45-6.55(m,1H),5.73(d,J=4.52Hz,0.2H),5.39(s,0.8H),3.66-3.80(m,3H),2 .12-2.29(m,1.8H),2.05(s,3H),1.21-1.36(m,1H),1.07(td,J=4.39,7.61Hz,0.2H),0.96(q,J=4.28Hz,0.8H),0.71(br d,J=3.42Hz,0.2H).LCMS:(ESI)m / z=235.2(M+1) + ,RT=0.76min.

[0206] Synthesis of compound 29

[0207] Referring to the last step of the second synthesis method of compound 14, compound P4 (90 mg, 328.09 μmol) was reacted to obtain a light yellow solid 29 (60 mg, 251.02 μmol, 76.51% yield). LCMS: (ESI) m / z = 235.2 (M+1) + ,RT=0.76min. 1H NMR(400MHz,DMSO-d6)Shift 9.26-9.66(m,1H),6.77-7.03(m,1H),6.45-6.62(m,1H),5.73(d,J=4.65Hz,0.2H),5.39(s,0.8H),3.62-3.83( m,3H),2.10-2.28(m,1.8H),2.05(s,3H),1.14-1.34(m,0.2H),0.96(q,J=4.24Hz,0.8H),0.65-0.76(m,0.2H).

[0208] Synthesis of compound 26

[0209] Referring to the last step of Method 2 for the synthesis of compound 14, compound P1 (18 mg, 65.62 μmol) was reacted and separated by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 23%-43%, 16 min) to afford 26 as a white solid (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m / z = 235.2 (M+1)+, RT = 0.890 min. 1 H NMR(400MHz,DMSO-d6)Shift 9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J=4.65Hz,1H),5.39(s,1H ),3.60-3.80(m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).

[0210] Synthesis of compound 27

[0211] Referring to the last step of the second synthesis method for compound 14, compound P2 (18 mg, 65.62 μmol) was reacted and separated by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase: [water(HCl)-ACN]; B%: 25%-45%, 16 min) to obtain a pale yellow solid 27 (5 mg, 19.64 μmol, 29.93% yield). LCMS: (ESI) m / z = 235.2 (M+1). + ,RT=0.838min. 1H NMR(400MHz,DMSO-d6)Shift 9.29-9.64(s,1H),6.78-7.00(s,1H),6.40-6.57(s,1H),5.73(d,J=4.52Hz,0.2H),5.39(s,0.8H),3.70-3.77(s,3H),2. 11-2.26(m,1.8H),2.05(s,3H),1.23-1.34(m,1.2H),1.07(dt,J=4.46,8.28Hz,0.2H),0.96(q,J=4.28Hz,0.8H),0.88(br d,J=5.14Hz,0.2H),0.68-0.74(m,0.2H).

[0212] Example 3-b Synthesis of Compounds 268 and 269

[0213] Note: The two compounds d1 and d2 obtained by chiral resolution in the synthesis route correspond to one of the following two structures respectively, and the absolute configuration has not yet been assigned.

[0214] Chiral resolution of compound 14-g

[0215] 10 g of compound 14-g was separated using SFC (column: REGIS (s, s) WHELK-O1 (250 mm × 50 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode; column temperature: 35°C; flow rate: 200 mL / min) to give an off-white solid compound d3 (0.9 g, 3.28 mmol, 9.00% yield) and an off-white solid compound d2 (1.1 g, 4.01 mmol, 11.00% yield).

[0216] Compound d3, (ESI) m / z = 275.1 (M+1) + , RT=1.426min. SFC: RT=3.217min, ~19.1% and RT=3.547min, ~80.9%. 1H NMR(400MHz, DMSO-d6)δ6.91(s,1H),6.66-6.73(m,1H),5.98-6.17(m,1H),5.77(d,J=4.65Hz,1H),5.37-5.55(m,1H),5.28(dd,J=1.41,10.58Hz ,1H),4.56-4.70(m,2H),3.79-3.89(m,3H),2.57(qd,J=4.92,7.50Hz,1H ),2.14-2.30(m,1H),2.10(s,3H),1.02-1.10(m,1H),0.65-1.01(m,1H).

[0217] Compound d2, (ESI) m / z = 275.1 (M+1) + , RT=1.423min. SFC: RT=3.264min, ~63.3% and RT=3.745min, ~36.7%. 1 H NMR(400MHz, DMSO-d6)δ6.87-7.04(m,1H),6.68(d,J=4.28Hz,1H),6.01-6.17( m,1H),5.76(d,J=4.52Hz,1H),5.37-5.52(m,2H),5.27(td,J=1.50,10.58Hz,1 H),4.48-4.77(m,2H),3.82(d,J=8.80Hz,3H),2.57(qd,J=4.89,7.60Hz,1H),2 .14-2.27(m,2H),2.10(d,J=2.20Hz,3H),1.03-1.31(m,1H),0.66-1.01(m,1H).

[0218] Note: The analytical conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral resolution of compound 14-g are: column: (S,S) Whelk-01 100×4.6mm ID, 5.0um; mobile phase: A:CO2B:Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL / min; column temperature: 40°C; ABPR: 100bar.

[0219] Synthesis of compound 268

[0220] Referring to the last step of the second synthesis method of compound 14, compound d3 (850 mg, 3.10 mmol) was reacted to give a white solid 268 (315 mg, 1.34 mmol, 43.4% yield). LCMS: (ESI) m / z = 235.0 (M+1) + , RT=1.062min. SFC: RT=3.790min, 74.64% and RT=4.125min, 25.28%. 1 H NMR (400MHz, DMSO-d6) δ9.25-9.73(m,1H),6.75-7.04(m,1H),6.33-6.61(m,1H),5.29-5.81(m,1H),3. 64-3.79(m,3H),2.12-2.26(m,2H),2.04(s,3H),1.28(dt,J=4.52,8.07Hz,1H),0.95(q,J=3.95Hz,1H).

[0221] Synthesis of compound 269

[0222] Referring to the last step of the second synthesis method of compound 14, compound d2 (18 mg, 52.5 μmol) was reacted to give a white solid 269 (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m / z = 235.2 (M+1) + ,RT=0.890min. 1 H NMR(400MHz, DMSO-d6)9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J=4.65Hz,1H),5.39(s,1H),3.60-3.80 (m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).SFC: RT=3.966min, 20.82% and RT=4.278min, 79.98%.

[0223] Note: The SFC analysis conditions for the RT results indicated in the synthesis of compounds 268 and 269 were: column: Chiralpak AD-3 150*4.6mm ID, 3um; mobile phase: A: CO2, B: iso-propanol (0.05% DEA); gradient: from 5% to 40% of B in 4 minutes and hold 40% for 2 minutes, then 5% of B for 2 minutes; flow rate: 2.5 mL / min; column temperature: 35°C; ABPR: 1500 psi

[0224] Example 4 Synthesis of Compound 2

[0225] Step 1: To a solution of compound 2-A (250 mg) in THF (10 mL) was added a solution of n-butyllithium in THF (0.71 mL, 2.4 mol / L, 0.85 mmol) at -78°C and stirred under nitrogen for 0.5 hours. Compound 2-B (172 mg, 1.48 mmol) was then added and the reaction was continued at -78°C with stirring for 3 hours. After completion of the reaction, the reaction was quenched with water (20 mL) and extracted with EA (25 mL x 3). After conventional post-processing, the crude product 2-C (90 mg) was obtained as a yellow oil. LC-MS: (ESI) m / z [M+H] + 343.1.

[0226] Step 2: To a solution of compound 2-C (90 mg, crude product) in THF (10 mL) was added tetrabutylammonium fluoride (244 mg, 0.93 mmol) at -78°C. The reaction was stirred at 25°C for 1 hour. After completion, the reaction was quenched with water (10 mL) and extracted with EA (20 mL x 3). After standard workup, the product was purified by silica gel column chromatography (EA:PE = 0 to 10%:90%) to afford compound 2 (60 mg) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ8.19–8.06(m,2H),7.56–7.43(m,3H),7.22–7.18(m,1H) ,6.89–6.87(m,1H),6.16–6.11(m,1H),3.30–3.27(m,4H).LC-MS:(ESI)m / z[M+H] + 229.7.

[0227] Example 4-a Synthesis of Compound 1

[0228] Step 1: Following the procedure of Step 1 in Example 4, compound 1-A (400 mg, 1.7 mmol) was reacted to obtain compound 1-B (160 mg, yield 36%). LC-MS: (ESI) m / z [M+H] + 262.

[0229] Step 2: A solution of compound 1-B (180 mg, 0.68 mmol) in TFA (1.02 mL) and DCM (15 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to afford compound 1-C (122 mg, 73% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 244.1.

[0230] Step 3: To a solution of compound 1-C (122 mg, 0.5 mmol) in DCM (10 mL) was added boron tribromide (2 M in DCM, 1.25 mL) at -10°C. The reaction was allowed to react for 2 hours. The reaction was diluted with EA (30 mL) and washed with saturated NaHCO₃ solution (15 mL x 2). After conventional post-processing, the product was purified by prep HPLC (column: YMC-Actus Triart C₁₈ 20*250 mm, 5 μm, phase A: H₂O (0.1% FA), phase B: ACN, 10%-95%) to afford compound 1 as a yellow solid (51.4 mg, 44% yield). LC-MS (ESI) m / z: 230.1 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 10.66 (s, 1H), 8.90 (dd, J=4.2, 1.8Hz, 1H), 8.55 (dd, J=8.4, 1.8Hz, 1H), 8.15 (s, 1H), 7.58 (d,J=8.0Hz,1H),7.55-7.49(m,1H),6.96(d,J=8.0Hz,1H),6.42(t,J=7.2Hz,1H),2.81-2.58(m,3H),2.26-2.14(m,1H).

[0231] Example 4-b Synthesis of Compound 287

[0232] Step 1: To a solution of compound 287-A (400 mg, 1.63 mmol) in THF (5 mL) was added a solution of n-butyllithium in THF (1.6 M in n-hexane, 1.53 mL, 2.45 mmol) at -78°C and stirred under nitrogen for 0.5 hours. Compound 2-B (1.96 mmol) was then added and the reaction continued to stir at -78°C for 3 hours. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with EA (15 mL x 3). After conventional post-processing, the product was purified by silica gel column chromatography (EA:PE, EA from 0 to 16%) to obtain compound 287-B (165 mg, 40.4% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 251.1.

[0233] Step 2: Following the method of Step 3 in Example 4-a, compound 287-B (160 mg) was reacted to obtain yellow solid compound 1 (7.1 mg, yield 4.7%). LC-MS: (ESI) m / z: 237 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 9.28 (s, 1H), 6.67 (d, J = 8.4Hz, 1H), 6.40 (d, J = 8.4Hz, 1H), 5.57 (t,J=7.5Hz,1H),4.29-4.20(m,4H),2.70-2.52(m,2H),2.48-2.41(m,1H),2.20-2.08(m,1H).

[0234] Example 5 Synthesis of Compounds 3, 112, and 107

[0235] Step 1: To a solution of compound 3-A (5.0 g, 23.78 mmol) in DCM (125 mL) at 20°C, aluminum chloride (6.98 g, 52.32 mmol) was added. After stirring for 10 minutes, compound 3-B (3.57 g, 35.68 mmol) was added all at once and stirred at 20°C for 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue was diluted with water (100 mL), the pH was adjusted to 1-2 with 1M HCl, and extracted with EA (100 mL x 3). After conventional post-processing, the product was purified by silica gel column chromatography (EA:PE = 0 to 70%:30%) to obtain a yellow solid compound 3-C (1.5 g, 4.59 mmol, yield 19.31%). LCMS: (ESI) m / z = 310.9 (M+1) +1.1H NMR(400MHz,DMSO-d6)Shift 12.02(br s,1H),10.42(s,1H),7.50(s,1H),6.54(s,1H),3.83(s,3H),3.57(s,3H),3.0 8(t,J=6.40Hz,2H),2.70-2.79(m,2H),2.52-2.55(m,2H),2.45-2.49(m,2H).

[0236] Step 2 (representative operation for constructing a five-membered lactone ring): To a mixture of compound 3-C (800 mg, 2.58 mmol) in water (30 mL) were added NaOH (309.38 mg, 7.73 mmol) and NaBH4 (292.60 mg, 7.73 mmol). The reaction was stirred at 20 ° C for 60 hours. The pH was adjusted to 1-2 with 2M HCl to precipitate a white solid, and the mixture was extracted with EA (100 mL × 3). After conventional post-treatment operations, the resulting residue was slurried with EA (10 mL), filtered, and washed with EA (3 mL × 2) to obtain a white solid compound 3 (520 mg, 1.76 mmol, yield 68.37%). LCMS: (ESI) m / z = 280.9 (M+1) + ; 1 HNMR(400MHz,DMSO-d6)Shift 12.04(br s,1H),9.61(br s,1H),7.00(s,1H),6.48(s,1H),5.59(t,J=7.53Hz,1H),3.72(s,3H),2.66-2.72(m, 2H), 2.62 (t, J = 9.41Hz, 1H), 2.53-2.59 (m, 1H), 2.40-2.46 (m, 3H), 2.03-2.15 (m, 1H).

[0237] Step 3: A solution of compound 3 (100 mg, 0.36 mmol) in DCM (3.0 mL) and TFA (0.5 mL) was stirred at 20°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE = 0 to 5%:95%) to afford compound 112 (77 mg, 0.28 mmol, 78.17% yield) as a white solid. LCMS: (ESI) m / z = 263.1 (M+1) + ,285.1(M+Na) + ; 1H NMR(400MHz,CHLOROFORM-d)Shift 7.17(s,1H),6.63(s,1H),5.73(t,J=7.03Hz,1H),3.85(s,3H),2.92-3.03(m,2 H),2.78-2.85(m,2H),2.68-2.77(m,1H),2.61-2.67(m,2H),2.04-2.17(m,1H).

[0238] Step 4: A solution of compound 112 (70 mg, 0.27 mmol) in MeOH (2 mL) was stirred at 50°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE = 0 to 35%:65%) to afford compound 107 (35 mg, 0.11 mmol, 42.33% yield) as a white solid. LCMS: (ESI) m / z = 294.9 (M+1) + ; 1 HNMR(400MHz,CHLOROFORM-d)Shift 7.90(s,1H),7.01(s,1H),6.52(s,1H),5.63-5.74(m,1H),3.80(s,3H),3.72(s, 3H),2.78-2.91(m,2H),2.70-2.77(m,2H),2.59-2.69(m,3H),2.06-2.19(m,1H).

[0239] A solution of compound 112 (70 mg, 0.27 mmol) in EtOH (2 mL) was stirred at 50°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE = 0 to 35%:65%) to afford compound 108 (25 mg, 0.077 mmol, 28.86% yield) as a white solid. LCMS: (ESI) m / z = 308.9 (M+1) + ,330.9(M+Na) + ; 1 H NMR(400MHz,CHLOROFORM-d)Shift 8.04(s,1H),7.01(s,1H),6.52(s,1H),5.65-5.72(m,1H),4.17(q,J=7.03Hz,2H),3.80(s,3H),2. 79-2.87(m,2H),2.69-2.74(m,2H),2.59-2.68(m,3H),2.06-2.19(m,1H),1.27(t,J=7.15Hz,3H).

[0240] Example 5-a Synthesis of Compound 109

[0241] To a solution of compound 112 (60 mg, 0.23 mmol) in DMF (2 mL) was added a 2M dimethylamine THF solution (114.39 uL), and the reaction was stirred at 20°C for 16 hours. LCMS showed that only a small amount of starting material (3%) remained unreacted. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 60%) to afford compound 109 (30 mg, 41% yield) as a white solid. LCMS: (ESI) m / z = 308.2 (M+1) + , 1 H NMR(400MHz,DMSO-d6)Shift 9.72(s,1H),7.00(s,1H),6.47(s,1H),5.59(t,J=7.65Hz,1H),3.72(s,3H),2.93(s,3H) ,2.81(s,3H),2.60-2.72(m,3H),2.52-2.59(m,2H),2.39-2.50(m,2H),2.02-2.19(m,1H)

[0242] Referring to the synthesis method of Example 5-a, the following starting materials were reacted with compound 112 to obtain the corresponding final compound.

[0243] Referring to the synthesis method of Example 5-a, the following starting materials were reacted to obtain the corresponding final compound.

[0244] Example 5-b Synthesis of Compound 130

[0245] Step 1: Compound 130-B (1.57 g, 7.69 mmol) in a 16 mL solution of NaHCO₃ (646 mg, 7.69 mmol) was added to compound 130-A (3.70 g, 23.1 mmol). NaHCO₃ (2.26 g, 26.9 mmol, 1.05 mL of aqueous solution) was periodically added to maintain the pH at 7.5. The mixture was stirred at 20°C for 16 hours. Phosphoric acid (5 mL) was added to adjust the pH to 4-5, and the mixture was extracted with EtOAc (15 mL x 3). The organic phase was cooled to 0°C to precipitate a solid, which was then filtered. The crude product was recrystallized from EtOAc (4 mL) to afford compound 130-C (2.1 g, 83% yield) as a white solid. 1H NMR (400MHz, DMSO-d6)Shift=12.50(br s,1H),7.88(br t,J=5.4Hz,1H),6.91(br d,J=8.0Hz,1H),4.08-3.94(m,1H),3.45-3.24(m,2H),2.00-1.86(m,2H),1.62(br d,J=10.0Hz,6H),1.38(s,8H),1.34(br s,1H),1.26-1.09(m,3H),0.97-0.77(m,2H).

[0246] Step 2: To a solution of compound 130-C (120 mg, 365 μmol) in DMF (2 mL) were added cyclohexylamine (43.5 mg, 438 μmol), DIEA (142 mg, 1.10 mmol), and HATU (166 mg, 438 μmol). The mixture was stirred at 20°C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). Standard workup procedures were performed to obtain the crude product. The crude product was crushed and slurried with EtOAc at 20°C for 3 h. Filtration afforded compound 130-D (100 mg, 66.82% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)Shift=7.84-7.71(m,1H),7.61(br d,J=7.8Hz,1H),6.65(br d,J=8.0Hz,1H),4.02-3.89(m,1H),3.49(br d,J=7.3Hz,1H),3.33-3.26(m,1H),3.24-3.13(m,1H),1.92(br d,J=6.8Hz,2H),1.63(br d,J=10.8Hz,10H),1.38(s,9H),1.30-1.03(m,9H),0.95-0.76(m,2H).

[0247] Step 3: Add HCl in dioxane (2M, 1 mL) to a mixture of compound 130-D (100 mg, 244 μmol) in dioxane (1 mL). Stir at 20°C for 3 hours. Concentrate under reduced pressure to obtain compound 130-E (90.0 mg, HCl salt) as a white solid. The crude product was used directly in the next reaction.

[0248] Step 4: To a solution of compound 130-E (50 mg, 0.134 mmol, HCl salt) in DMF (1 mL) were added TEA (40.8 mg, 0.4 mmol) and 112 (35.3 mg, 0.134 mmol). The reaction was stirred at 40°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by prep HPLC (FA method-B; B%: 35%-55%, 10 min) to afford compound 130 (25 mg, 29.32% yield) as a white solid. LCMS: (ESI) m / z = 572.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)Shift=9.61(br s,1H),7.85(dd,J=2.4,8.2Hz,1H),7.68(br d,J=6.8Hz,2H),6.99(d,J=2.5Hz,1H),6.48(s,1H),5.59(t,J=7.5Hz,1H),4.30(q,J=7.1Hz,1H),3.72(s,3 H),3.55-3.44(m,1H),3.29-3.17(m,2H),2.71-2.62(m,3H),2.38-2.31(m,2H),2.17-2.02(m,1H),1.91(br d,J=5.3Hz,2H),1.78-1.45(m,12H),1.32-0.99(m,9H),0.85(br d,J=10.0Hz,2H)

[0249] Referring to the methods of steps 2, 3, and 4 in the synthesis method of Example 5-b, the following starting materials were used in place of cyclohexylamine in step 2, and three steps of reaction were performed to obtain the corresponding final compound.

[0250] Example 6 Synthesis of Compound 111

[0251] To a solution of compound 3 (50 mg, 0.18 mmol) and isopropanol (10.72 mg, 0.18 mmol) in THF (2 mL) were added triphenylphosphine (93.58 mg, 356.80 μmol) and di-tert-butyl azodicarboxylate (DBAD, 61.62 mg, 0.27 mmol) at 20°C. The reaction was stirred at 20°C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE = 0 to 40%:60%) and then by preparative HPLC (FA method-A, B%: 33%-53%, 10 min) to give compound 111 (20 mg, 0.06 mmol, yield 33.74%) as a white solid. LCMS: (ESI) m / z = 322.9 (M+1) + ; 1 HNMR(400MHz,CHLOROFORM-d)Shift 8.17(s,1H),7.00(s,1H),6.52(s,1H),5.64-5.74(m,1H),5.04(quin,J=6.21Hz,1H),3.80(s ,3H),2.75-2.89(m,2H),2.59-2.72(m,5H),2.09-2.20(m,1H),1.24(dd,J=2.26,6.27Hz,6H).

[0252] Referring to the synthesis method of compound 111, the starting materials in the following table were reacted with compound 3 to obtain the corresponding final compound.

[0253] Example 7 Synthesis of Compound 4

[0254] Step 1: To a solution of compound 4-A (3.00 g, 11.8 mmol) in THF (60 mL) at 0°C, lithium aluminum hydride (360 mg, 9.49 mmol) was added. The reaction was stirred at 0°C for 1 hour. The reaction was quenched with 1 M hydrochloric acid solution and water (30 mL) was added. The mixture was extracted with EA. After standard workup, compound 4-B (2.55 g, 9.57 mmol, 82% yield) was obtained as a purple solid. 1 HNMR (400MHz, CDCl3) δ7.24(s,1H),6.51(s,1H),3.86(s,3H),3.68-3.66(t,J=4,2H),2.73-2.70(t,J=4,2H),1.89-1.83(m,2H).

[0255] Step 2: To a solution of compound 4-B (2.55 g, 9.77 mmol) in DCM (50 mL) were added DHP (2.05 g, 24.4 mmol) and pyridine p-toluenesulfonate (PPTS, 245 mg, 976 μmol). The reaction was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with DCM (20 mL x 3). After standard post-treatment, the product was purified by silica gel column chromatography (EA:PE, EA from 0 to 11.5%) to obtain a yellow oil 4-C (3.3 g, 6.15 mmol, 80% purity). LCMS: (ESI) m / z = 453.1 (M+Na). + .

[0256] Step 3: Ensure that the glassware used in this operation is dry and anhydrous. At -78°C, add n-butyllithium in THF (2.5M, 2.5mL) to a solution of compound 4-C (2.00g, purity 80%) in THF (50mL). After stirring for 1 hour, add succinic anhydride (932mg, 9.32mmol) and continue stirring for 2 hours. Add 10% citric acid solution (30mL) to quench the reaction, and the mixture is extracted with EA (30mL×3). After conventional post-treatment operation 2, purification by silica gel column chromatography (THF:PE, THF from 0 to 40%) gave a colorless oil 4-C (0.65g, 1.3mmol, LCMS purity 89.9%). LCMS: (ESI) m / z=473.2(M+Na) + . 1 HNMR showed that 2 molecules of succinic anhydride remained.

[0257] Step 4: To a mixture of compound 4-D (601 mg, 89.9% purity) in a NaOH (190 mg, 4.75 mmol) aqueous solution (5.5 mL) was added NaBH4 (75.70 mg, 2.00 mmol). The reaction was stirred at 25°C for 16 hours. 10% citric acid solution (30 mL) was carefully added to adjust the pH to 2. The mixture was extracted with EA (20 mL x 3). After conventional post-processing, 508 mg of a light yellow gum was obtained. LCMS showed that the product was 20.3% of compound 4-F [(ESI) m / z = 457.4 (M+Na) + ] and 54.8% of compound 4-E [(ESI) m / z=475.1(M+Na) + ] a mixture of.

[0258] Step 5: To a solution of a mixture of compounds 4-E and 4-F (190 mg) in THF (2 mL) and water (1 mL) was added p-toluenesulfonic acid monohydrate (40 mg, 210.28 μmol). The reaction was stirred at 25°C for 16 hours. Prep HPLC (FA method - A, B%: 15%-35%, 10 min) was used to isolate the off-white solid compound 4 (35 mg, 122.24 μmol). LCMS: (ESI) m / z = 267.1 (M+1) + ; 1 HNMR(400MHz,CHLOROFORM-d)Shift=7.02(s,1H),6.49(s,1H),5.74-5.67(m,1H),3.81(s,3H), 3.74-3.63(m,2H),2.81-2.70(m,2H),2.69-2.59(m,3H),2.22-2.11(m,1H),1.91-1.83(m,2H).

[0259] Example 8-a Synthesis of Compounds 5 and 6

[0260] Step 1: Under nitrogen, heat a suspension of sodium hydride (304 mg, 7.61 mmol, 60% purity) in DMSO (20 mL) at 65°C for one hour. Cool to room temperature, and add THF (20 mL) to the clear reaction mixture. Cool the reaction mixture to -15°C, and add a solution of trimethylsulfonium iodide (1.41 g, 6.92 mmol) in DMSO (20 mL) dropwise. After 3 minutes, add a solution of compound 6-A (2 g, 6.92 mmol) in THF (20 mL) dropwise. Stir the reaction at 25°C for 2 hours. Quench the reaction mixture with saturated NH4Cl (50 mL) at 0-10°C, dilute with 100 mL of water, and extract the mixture with EA (100 mL x 2). After standard workup, compound 6-B (2 g, crude) was obtained as a yellow gum, which was used directly in the next step.

[0261] Step 2: A yellow mixture of compound 6-B (2 g, crude product), (1-methoxy-2-methyl-prop-1-enyloxy)-trimethylsilane (5.75 g, 33 mmol), and tetrabutylammonium fluoride trihydrate (1.04 g, 3.30 mmol) was stirred at 60°C for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 3%) to afford compound 6-C (920 mg, 2.46 mmol, approximately 32% yield over two steps) as a yellow gum. 1H NMR (400MHz, CDCl3) δ (ppm) 7.53 (s, 1H), 6.82 (s, 1H), 5.61 (dd, J = 6.5, 9.5Hz, 1H), 5.29-5.34 (m, 2H), 3.85 (s, 3H), 3.78-3 .83(m,2H),2.52(dd,J=6.4,12.9Hz,1H),1.99(dd,J=9.8,12.8Hz,1H),1.38(s,3H),1.32(s,3H),1.26(t,J=7.03Hz,3H).

[0262] Step 3: Dissolve compound 6-C (760 mg, 2.04 mmol) and methyl prop-2-enoate (438 mg, 5.09 mmol) in 5 mL of anhydrous toluene. Add cesium carbonate (995 mg, 3.05 mmol), triphenylphosphine (427 mg, 1.63 mmol), and palladium acetate (183 mg, 814 mmol). The mixture is deoxygenated under reduced pressure, replaced with nitrogen, and stirred at 80°C for 12 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and diluted with 30 mL of water. The mixture is extracted with EA (30 mL x 2). Conventional post-processing procedures yield a residue, which is then purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 15%) to afford compound 6-D (560 mg, 1.48 mmol, 72.68% yield) as a white gel. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.95-8.01 (m, 1H), 7.55 (s, 1H), 6.81 (s, 1H), 6.39-6.47 (m, 1H), 5.63 (dd, J = 6.5, 9.5Hz, 1H), 5.33 (s, 2H), 3.89 (s, 3H) ),3.81(s,3H),3.78(d,J=7.03Hz,2H),2.53(dd,J=6.5,12.8Hz,1H),2.02(dd,J=9.8,12.8Hz,1H),1.39(s,3H),1.33(s,3H),1.23-1.27(m,3H).

[0263] Step 4: Following the representative catalytic hydrogenation procedure, compound 6-D (528 μmol) was used as the starting material to give yellow gum 6-E (342 μmol, 64.66% yield), which was purified by silica gel column chromatography (EA:PE, EA from 0 to 15%). 1H NMR (400MHz, CDCl3) δ (ppm) 7.13 (s, 1H), 6.77 (s, 1H), 5.64 (dd, J = 6.4, 9.6Hz, 1H), 5.27 (s, 2H), 3.83 (s, 3H), 3.72-3.81 (m, 2H), 3.69 (s, 3H),2.86-2.94(m,2H),2.55-2.62(m,2H),2.48(dd,J=6.5,12.8Hz,1H),1.99-2.05(m,1H),1.37(s,3H),1.32(s,3H),1.23-1.28(m,3H).

[0264] Step 5: A reaction mixture of 6-E (130 mg, 342 μmol) in DCM (1.5 mL) and TFA (0.1 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain a pink gum product, compound 6-F (130 mg, crude product), which was used directly in the next reaction. LC-MS: (ESI) m / z. [M+H] + 290.9.

[0265] Step 6: Dissolve 6-F (130 mg) in MeOH (1 mL), add aqueous NaOH solution (238 mg, 895 μmol), and stir the reaction mixture at 25°C for 30 minutes. The reaction mixture was adjusted to pH 3 with 1 M HCl solution and stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was diluted with 10 mL of water, and the mixture was extracted with EA (10 mL x 2). After conventional post-processing, the residue was purified by silica gel column chromatography to obtain compound 5 as a white solid (60 mg, 186 μmol, two-step yield 54.4%). LC-MS: (ESI) m / z. [M+H] + 323.1. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.65 (s, 1H), 7.02 (s, 1H), 6.48 (s, 1H), 5.58 (dd, J = 6.5, 9.8Hz, 1H), 3.72 (s, 3H), 3.57 (s,3H),3.34(s,2H),2.67-2.75(m,2H),2.30-2.37(m,1H),2.08(dd,J=10.0,12.5Hz,1H),1.25(s,3H),1.21(s,3H).

[0266] Step 7: Dissolve 5 (18 mg) in MeOH (10 mL) and add aqueous NaOH (1 M, 111 μL). The reaction mixture was stirred at 40°C for 60 hours. LCMS showed 18% of the starting material remaining, yielding 30% of the desired product. The reaction mixture was concentrated under reduced pressure, and EA and water (5 mL) were added. The pH was adjusted to 3 with 1 M HCl solution, and the mixture was extracted with EA (5 mL x 2). Conventional post-processing procedures gave a residue, which was purified by prep-HPLC (column: YMC Triart C18 150*25 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 10 min) to afford compound 6 (2 mg, 6.16 μmol, 11% yield) as a white solid. LCMS: ESI) m / z = 309.2 (M+H) + ;1HNMR(400MHz,DMSO-d6)Shift=12.03(br s,1H),9.62(br s,1H),7.03(s,1H),6.47(s,1H),5.57(dd,J=6.5,10.0Hz,1H),3.71(s,3H),2.68(t,J=7.7Hz,2H) ,2.42(t,J=7.7Hz,2H),2.31(dd,J=6.4,12.7Hz,1H),2.12-2.05(m,1H),1.24(s,3H),1.20(s,3H).

[0267] Example 8-b Synthesis of Compounds 7 and 8

[0268] Step 1 and Step 2: Referring to the methods of Step 1 and Step 2 of Example 5, compound 7-A was used as the starting material to obtain a white solid compound 7 in two steps. The yield of the two steps was about 2.4%. LCMS: (ESI) m / z = 288.6 (M+1) + ; 1 HNMR(400MHz,DMSO-d6)Shift 10.44(s,1H),7.36(s,1H),6.63(s,1H),5.59(t,J=7.65Hz,1H),3.76(s,3H),2.53-2.70(m,2H),2.41-2.50(m,1H),1.98-2.18(m,1H).

[0269] Step 3: To a solution of compound 7 (220 mg, 766.27 μmol) and chloromethyl ether (86.93 mg, 919.52 μmol) in acetone (8 mL) was added K2CO3 (317.72 mg, 2.30 mmol) and stirred at 20°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 35%) to obtain a colorless oil 8-A (250 mg, 706.14 μmol). (ESI) m / z = 346.9 (M+1) + . 1 H NMR(400MHz,CDCl3)Shift 7.48(s,1H),6.83(s,1H),5.61-5.77(m,1H),5.32(s,2H),3.86(s,3H),3.81( q,J=7.09Hz,2H),2.53-2.81(m,3H),2.02-2.28(m,1H),1.26(t,J=7.03Hz,3H)

[0270] Step 4 (Suzuki coupling reaction representative operation): To a mixture of compound 8-A (70 mg, 202.79 umol) and phenylboronic acid (74.18 mg, 608.37 umol) in THF / water (3 mL, 4 / 1) were added K3PO4 (129 mg, 608.37 umol) and XPhos Pd G3 (17.17 mg, 20.28 umol), degassed and refilled with nitrogen twice. It was heated to 60°C for 1 hour. The reaction solution was concentrated to dryness and diluted with ethyl acetate (3 mL). After conventional post-processing operations, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (PE:EA=1:1) to obtain compound 8-B (60 mg, yield 82.09%) as a yellow oil. LCMS: (ESI) m / z=343.2 (M+1) + ; 1 HNMR(400MHz,CHLOROFORM-d)Shift 7.44-7.52(m,2H),7.35-7.43(m,2H),7.27-7.33(m,2H),6.89(s,1H),5.67-5.82(m,1H),5.18(s,2H),3 .89(s,3H),3.66(dq,J=1.16,7.07Hz,2H),2.56-2.74(m,3H),2.13-2.28(m,1H),1.20(t,J=7.09Hz,3H).

[0271] Step 5: A solution of compound 8-B (80 mg, 0.23 mmol) in DCM (3.5 mL) and TFA (0.35 mL) was stirred at 20°C for 2 hours. The reaction was quenched with saturated NaHCO3 solution (2 mL), and the mixture was extracted with DCM (3 mL x 3). After conventional post-processing, the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a white solid compound 8 (35 mg, yield 50%). LCMS: (ESI) m / z = 284.9 (M+1) + . 1 H NMR(400MHz,DMSO-d6)Shift 9.81(s,1H),7.51(d,J=7.03Hz,2H),7.38(t,J=7.65Hz,2H),7.22-7.30(m,1H),7.19(s,1H),6.63(s ,1H),5.67(t,J=7.53Hz,1H),3.80(s,3H),2.54-2.73(m,2H),2.43-2.50(m,1H),2.12-2.25(m,1H).

[0272] Referring to the synthesis method of compound 8, the starting materials in the following table were reacted with compound 8-A to obtain the corresponding final compounds.

[0273] Example 9 Synthesis of Compound 11

[0274] Step 1: To a mixture of compound 8-A (100 mg, 0.29 mmol) in dioxane / water (4 mL, 1 / 1) were added potassium ferrocyanide (53.35 mg, 144.85 umol), potassium acetate (3.55 mg, 36.21 umol), t-Bu Xphos (2.46 mg, 5.79 umol, 0.02 eq), and t-Bu Xphos Pd G3 (2.30 mg, 2.90 umol). The mixture was degassed and filled with nitrogen. The reaction mixture was heated to 80°C for 2 hours. LCMS showed a small amount of starting material remaining, but the desired product had formed. The reaction mixture was cooled to room temperature and extracted with EA (5 mL x 3). After standard workup, the crude product was obtained. The crude product was purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 0 to 30%) to obtain compound 11-A (60 mg, 35.5% yield) as a colorless oil. LCMS: (ESI) m / z = 292.2 (M+1) + .

[0275] Step 2: A solution of compound 11-A (50 mg, 0.17 mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at 25°C for 1 hour. The reaction was quenched with saturated NaHCO3 solution (1 mL), and the mixture was extracted with EA (3 mL × 3). The aqueous phase was adjusted to pH 3-4 with 1 M HCl and extracted again with EA (5 mL × 3). After conventional post-processing operation 2, a residue was obtained, which was washed with DCM (1 mL) to obtain compound 11 (35 mg, 50% yield) as a white solid. LCMS: (ESI) m / z = 234.1 (M+1) + . 1 H NMR(400MHz,DMSO-d6)Shift 7.44(s,1H),6.54(s,1H),4.74(dd,J=4.39,7.40Hz,1H),3.80(s,3H),2.16-2.25(m,2H),1.77-1.90(m,1H),1.62-1.75(m,1H).

[0276] Example 10 Synthesis of Compound 12

[0277] Step 1: To a mixture of compound 12-A (5.76 g, 21.1 mmol) in acetonitrile (60 mL) were added NaHCO₃ (3.91 g, 46.50 mmol) and benzyl bromide (3.98 g, 23.25 mmol). The mixture was heated to 82°C and reacted for 16 hours. The reaction mixture was cooled to room temperature, water (80 mL) was added, and extraction was performed with EA (100 mL). After conventional post-processing, the crude product was obtained. The crude product was purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 29%) to obtain compound 12-B (4.6 g, yield 60.73%) as a yellow solid.

[0278] Step 2: To a mixture of compound 12-B (650 mg, 1.81 mmol) in acetonitrile (26 mL) was added 12-C (811 mg, 2.72 mmol) and cesium fluoride (826 mg, 5.44 mmol). The mixture was reacted at 20°C for 16 hours. Saturated brine (20 mL) was added and the mixture was extracted with EA (20 mL). Conventional post-processing was performed to obtain a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 20%) to afford 12-D (238 mg, 30.22% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δppm 1.10-1.14(m,3H)2.44-2.47(m,2H)2.95-3.02(m,2H)3.77-3.82(m,3H)3.97-4.0 1(m,2H)5.02-5.09(m,2H)6.07-6.12(m,1H)6.54-6.59(m,1H)7.11-7.38(m,10H)

[0279] Step 3: Following the representative catalytic hydrogenation procedure, compound 12-D (235 mg, 541 μmol) was reacted to give the yellow gum product 12-E (120 mg, 349 μmol). Purification: Silica gel column chromatography (EA:PE, EA from 0 to 15%). 1 H NMR (CDCl3, 400MHz) δ7.95 (d, J = 8.53Hz, 1H), 7.76 (s, 1H), 7.29-7.57 (m, 9H), 6.96 (d, J = 8.53Hz, 1H), 6.23 (br t,J=5.52Hz,1H),4.75(d,J=5.52Hz,2H),4.17-4.30(m,2H),3.89(s,3H),3.68(s,3H),2.76(t,J=7.53Hz,2H),2.41(t,J=7.53 Hz,2H),2.01(t,J=7.40Hz,2H),1.77-1.88(m,4H),1.63-1.77(m,3H),1.32-1.44(m,1H),1.15-1.29(m,3H),0.94-1.09(m,2H).

[0280] Step 4 (Representative ester hydrolysis procedure): To a mixture of compound 12-E (120 mg, 0.35 mmol) in THF (1 mL) and MeOH (1 mL) was added lithium hydroxide monohydrate (36.7 mg, 0.87 mmol, approximately 2.5 equivalents). The reaction was allowed to react at 65°C for 16 hours (LCMS indicated completion). The reaction solution was cooled to room temperature, the pH was adjusted to 1-2 with 2M HCl, and extracted with EA (4 mL x 3). Conventional workup procedures afforded a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 24% to 73%) to afford 12-F (65 mg, 58.82% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δppm 2.46-2.48(m,2H)2.95-3.03(m,2H)3.53-3.53(m,1H)3.71-3.78(m,3H)5.78-5.87(m,1H) 6.20-6.26(m,1H)6.97-7.03(m,2H)7.12-7.19(m,1H)7.34-7.44(m,2H)9.95-10.01(m,1H)

[0281] Step 5: Referring to the representative operation for constructing a five-membered lactone ring, compound 12-F (65 mg, 205 μmol) was reacted to obtain compound 12 (10 mg, yield 16.2%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm1.54-1.60(m,2H)2.06-2.11(m,2H)2.41-2.46(m,2H)3.65-3.72 (m,6H)5.98-6.07(m,2H)9.21-9.30(m,1H)11.78-11.91(m,1H).LCMS:(ESI)m / z=301.0(M+1) + .

[0282] Example 11 Synthesis of Compound 13

[0283] Step 1: To a mixture of methyltriphenylphosphonium bromide (Ph3PMeBr, 10.65 g, 29.82 mmol) in THF (80 mL) was added dropwise a solution of potassium tert-butoxide (1 M, 25.93 mL) in THF at 0°C under nitrogen and stirred at 0°C for 1 hour. Compound 13-A (4 g, 12.97 mmol) in THF (60 mL) was added to the reaction mixture at 0°C. The mixture was warmed to room temperature (20°C) and allowed to react for 16 hours. The reaction was quenched with saturated NH4Cl solution (5 mL) at 0-10°C, followed by addition of water (8 mL) and extraction with MTBE (4 mL x 3). Standard post-processing procedures were performed to obtain a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 0 to 4%) to afford Compound 13-B (2.03 g, 51% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm1.02-1.12(m,18H)1.21-1.30(m,3H)3.72-3.77(m,3H)5.0 7-5.14(m,1H)5.59-5.66(m,1H)6.39-6.48(m,2H)6.77-6.90(m,1H)7.34-7.39(m,1H).

[0284] Step 2: To a mixture of 13-B (1 g, 3.26 mmol, 1.2 eq) in DMF (10 mL) were added 13-C (584 mg, 2.72 mmol), H₂O (97.9 mg, 5.44 mmol), and nonacarbonyldiiron (cas: 15321-51-4, 49.4 mg, 135.94 umol). The reaction was incubated at 80°C for 16 hours. The mixture was cooled to room temperature, water (4 mL) was added, and extraction was performed with EA (12 mL). Conventional post-processing was performed to obtain a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 0 to 7% to 11.5%) to afford compound 13-D (157 mg, 13.11% yield) as a white solid. Its structure may be either cis or trans, but was not further characterized. 1 H NMR(400MHz,CHLOROFORM-d)δppm 1.11-1.14(m,18H)1.25-1.32(m,3H)2.66-2.85(m,2H)3.79-3.83(m,3H)3.91-3. 98(m,1H)5.78-5.87(m,1H)6.44-6.54(m,2H)7.12-7.22(m,1H)7.30-7.41(m,5H).

[0285] Step 3: To a mixture of 13-D (50 mg, 113.47 μmol) in THF (1 mL) was added TEA(HF)₃ (14.6 mg, 90.78 μmol). The reaction was allowed to react at 20°C for 2 hours. After completion, a saturated aqueous NaHCO₃ solution was added to adjust the pH to 7-8, and the product was extracted with EA (2 mL x 3). Standard workup procedures were performed to obtain the crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 62%) to afford Compound 13 (9 mg, 27.9% yield) as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δppm 2.40(m,0.6H),2.66-2.75(m,0.4H),2.76-2.87(m,0.4H),3.09(m,0.6H),3.95(m,0.4H),4.04(m,0.6H),5.00(br s,1H)5.73(dd,J=10.5,5.8Hz,0.6H),5.85(dd,J=7.8,4.8Hz,0.4H),6.38-6.57(m,2H),7.09-7.25(m,1H),7.31-7.60(m,5H)

[0286] Example 12 Synthesis of Compound 16

[0287] Step 1: To a mixture of 16-A (300 mg, 1.3 mmol) in DMF (6 mL) were added 3-bromopropene (235 mg, 1.95 mmol) and K2CO3 (358 mg, 2.60 mmol). The mixture was reacted at 25°C for 2 hours. Water (6 mL) was added and the mixture was extracted with EA (8 mL x 3). After conventional post-treatment, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow oil 16-B (220 mg, yield 62.5%). LCMS: (ESI) m / z = 273.0 (M+1) + .

[0288] Step 2: To a solution of 16-B (170 mg, 0.63 mmol) in DCM (4 mL) were added 16-C (655 mg, 3.76 mmol) and ZnI2 (360 mg, 1.13 mmol). The mixture was reacted at 25°C for 16 hours. Water (5 mL) was added, and the mixture was extracted with DCM (3 mL x 3). After conventional workup, a brown oil 16-D (280 mg) was obtained, which was used directly in the next reaction.

[0289] Step 3: To a solution of compound 16-D (280 mg) in DCM (4 mL) and TFA (0.4 mL) was added water (33.9 mg, 1.89 mmol) and the mixture was allowed to react at 25°C for 16 hours. After the reaction was completed, a saturated aqueous solution of NaHCO3 was added at 5°C to 10°C to adjust the pH to 7-8, and the mixture was extracted with DCM (2 mL x 3). After conventional post-processing, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow oil 16-E (17 mg, purity 74%). LCMS: (ESI) m / z = 327.0 [M+H] + .

[0290] Step 4: To a solution of compound 16-E (17 mg) in THF (0.5 mL) under nitrogen atmosphere were added Pd(PPh3)4 (6 mg, 5.2 μmol) and PPh3 (14.99 mg, 57.16 μmol) and reacted at 25°C for 16 hours. The reaction was concentrated under reduced pressure, and the residue was purified by prep-HPLC (FA method; B%: 23%-53%, 8 min) to afford compound 16 (1 mg, 3.36 μmol, approximately 5.3% yield for three steps) as a white solid. (ESI) m / z = 286.9 [M+H] + ). 1H NMR (400MHz, CHLOROFORM-d) δppm 6.70 (d, J = 2.32Hz, 1H) 6.43 (d, J = 2.32Hz, 1H) 6.12 (dd, J = 8.86, 6.91Hz, 1H) 5.90 (br s,1H)3.75(s,3H)2.65-2.82(m,2H)2.51-2.64(m,1H)2.35-2.46(m,1H).

[0291] Referring to the method of steps 2 to 4 in Example 12 (representative operation A for constructing a five-membered lactone ring), three steps of reaction were carried out using the starting materials in the following table to obtain the corresponding final compounds.

[0292] The synthesis method of the starting material 87-A mentioned in the above table is:

[0293] To a solution of compound 73-A (300 mg, 1.03 mmol) in DMF (5 mL) were added compound 87-B (395 mg, 2.06 mmol), potassium fluoride (59.8 mg, 1.03 mmol), and CuI (196 mg, 1.03 mmol). The mixture was heated to 80°C in the dark and allowed to react for 16 hours. The mixture was cooled to room temperature, filtered, and washed with EA. The filtrate was subjected to conventional post-processing to obtain a crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain compound 87-A (280 mg, 97% yield) as a gray solid. LCMS: (ESI) m / z = 280.9 (M+1) +

[0294] Example 12-a Synthesis of Compound 65

[0295] Step 1: A mixture of 47-B (3.6 g, 18.5 mmol), N-(2-methoxyethyl)methylamine (3.30 g, 37.1 mmol) and K2CO3 (5.12 g, 37.1 mmol, 2 eq) in dioxane (80 mL) was reacted at 120°C for 40 hours. LC-MS showed that ~32% of the starting material remained and ~65% of the desired product was produced. The reaction was diluted with EA (100 mL), filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 15%) to give 65-A (3.7 g, yield 75.8%) as a yellow oil. LCMS: (ESI) m / z = 264.3 (M+1) + .

[0296] Step 2 and Step 3: Following the procedures of Step 2 and Step 3 in Example 12, compound 65-A was reacted in two steps to obtain compound 65-B as an orange oil. The yield of the two steps was approximately 20%. LC-MS: (ESI) m / z. [M+H] + 320.3

[0297] Step 4: Following the procedure of Step 3 of Example 2, compound 65-A was reacted to obtain yellow oil 65 in a yield of 63%. LC-MS: (ESI) m / z. [M+H] + 280.3; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 7.05 (s, 1H), 6.66 (s, 1H), 5.87 (dd, J = 6.8, 9.0Hz, 1H), 3.37 (t, J = 5.9Hz, 2H ),3.22(s,3H),2.84-2.98(m,2H),2.63-2.75(m,1H),2.53-2.62(m,4H),2.44(m,1H),2.08-2.16(m,1H),2.07(s,3H).

[0298] Example 12-b Synthesis of Compound 66

[0299] Step 1: To a solution of compound 66-A (5 g, 29.4 mmol) in THF (50 mL) was added dropwise cyclopropylmagnesium bromide solution (0.5 M, 205 mL) at -78°C. The mixture was allowed to warm to 25°C and allowed to react for 16 hours. After completion of the reaction, saturated aqueous NH4Cl solution (200 mL) was added to quench the reaction and the mixture was extracted with EtOAc (200 mL x 3). After conventional post-processing, the crude product 66-B (7.6 g) was obtained as a yellow solid. LC-MS: (ESI) m / z. [M-OH] + 205.1.

[0300] Step 2: To a solution of 66-B (5 g) in DCM (100 mL) was added dropwise Et3SiH (5.23 g, 45 mmol) and TFA (10.2 g, 90.0 mmol) at -30°C. The reaction was maintained at -30°C to -20°C for 2 hours. After completion of the reaction, water (100 mL) was added, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The mixture was extracted with DCM (50 mL x 3). After standard workup, the crude product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 3%) to afford 66-C (5.14 g, approximately 83% yield over two steps) as a colorless oil. 1H NMR (400MHz, CDCl3) δ (ppm) 7.23 (dd, J=7.3, 8.4Hz, 1H), 6.64 (dt, J=2.6, 8.4Hz, 1H), 6.49 (dd, J=2.5, 10.6Hz, 1H), 1.95 (t, J= 8.6Hz,1H),1.03-1.12(m,2H),0.95-1.03(m,9H),0.73-0.82(m,6H),0.48-0.58(m,2H),0.22-0.34(m,4H),0.04-0.12(m,2H).

[0301] Step 3: To a solution of compound 66-C (5.14 g, 16 mmol) in ACN (60 mL) was added triethylamine trihydrofluoride (5.17 g, 32.1 mmol) and reacted at 25°C for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure and the product was dissolved in EtOAc (100 mL). After conventional post-processing, the crude product was obtained. Purification by silica gel column chromatography (EA:PE, EA from 0 to 3.5%) afforded 66-D (3.2 g, 88% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.19 (dd, J = 6.7, 8.50Hz, 1H), 6.63 (dt, J = 2.5, 8.4Hz, 1H), 6.53 (dd, J = 2.5, 10.0Hz, 1H), 5.22 (s, 1H), 1.9 7(t,J=8.0Hz,1H),1.12(tq,J=5.1,8.0Hz,2H),0.53-0.65(m,2H),0.36-0.46(m,2H),0.31(qd,J=4.8,9.4Hz,2H),0.06-0.19(m,2H).

[0302] Step 4: To a solution of compound 66-D (1 g, 4.85 mmol) in DCM (30 mL) was added NBS (949 mg, 5.33 mmol) and the mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 3%) to afford 66-E (610 mg, 44% yield), a colorless oil. 1H NMR (400MHz, CDCl3) δ (ppm) 7.38 (d, J = 7.8Hz, 1H), 6.61 (d, J = 9.4Hz, 1H), 5.24 (s, 1H), 1.92 (t, J = 8.1Hz, 1H), 1.0 9(tq,J=5.1,8.1Hz,2H),0.54-0.68(m,2H),0.38-0.50(m,2H),0.32(qd,J=4.8,9.57Hz,2H),0.08-0.19(m,2H).

[0303] Step 5 and Step 6: Referring to the method of Step 2 and Step 3 in Example 21, a two-step reaction was carried out using 66-E as the starting material to obtain a yellow oil 66-G (two-step yield of about 46.74%). 1 H NMR (400MHz, CDCl3) δ (ppm) 10.25 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 12 .5Hz,1H),6.04(tdd,J=5.1,10.5,17.3Hz,1H),5.43(qd,J=1.5,17.3Hz,1H),5 .35(qd,J=1.3,10.6Hz,1H),4.61(td,J=1.5,5.1Hz,2H),1.90(t,J=8.9Hz,1H ),1.06-1.23(m,2H),0.53-0.64(m,2H),0.26-0.37(m,4H),0.01-0.11(m,2H).

[0304] Step 7: Following the procedure of Step 1 in Example 12-a, 66-G (210 mg) was used as the starting material to give 66-H (200 mg, yield 76.07%) as a yellow oil. LC-MS: (ESI) m / z. [M+H] + 344.2

[0305] Step 8 and Step 9: Referring to the method of Step 2 and Step 3 in Example 2, a two-step reaction was carried out starting with 66-H to obtain an off-white solid compound 66. The two-step yield was about 51%. 1H NMR(400MHz,DMSO-d6)δ(ppm)9.15-9.43(m,1H),6.94-7.20(m,1H),6.60-6.80(m,1H),5.63-6.0 2(m,1H),3.42-3.45(m,2H),3.19-3.29(m,3H),2.89-3.04(m,2H),2.57-2.69(m,3H),2.28-2.36( m,1H),2.11-2.27(m,1H),1.67-1.79(m,1H),1.28(dt,J=4.7,8.35Hz,1H),1.03-1.15(m,2H),0.7 4-0.99(m,1H),0.41-0.54(m,2H),0.17-0.30(m,4H),-0.09-0.03(m,2H).LC-MS:(ESI)m / z.[M+H] + 372.4

[0306] Example 13 Synthesis of Compound 17

[0307] Step 1 refers to the method of step 1 in Example 2, step 2 refers to the method of step 2 in Example 2, and step 3 refers to the method of step 4 in Example 12. The starting materials in the following table are used for three-step reaction to obtain compound 17.

[0308] Referring to the method of steps 2 and 3 in Example 13, a two-step reaction was carried out using the starting materials in the following table to obtain the final compound.

[0309] Example 14 Synthesis of Compound 18

[0310] Step 1: Referring to the method of step 4 in Example 8-b, 15-A (2.0 g, 9.30 mmol) and 18-A (2.90 g, 13.95 mmol) were reacted to obtain an off-white solid compound 18-B (1.96 g, yield 84.17%). LCMS: (ESI) m / z = 217.0 (M+1) + .

[0311] Step 2 to Step 4: Referring to the method in Example 13, three steps of reaction were carried out using the starting materials in the following table to obtain the final compound.

[0312] The synthesis method of the starting material 82-A mentioned in the above table is:

[0313] Referring to the method of step 4 in Example 8-b, compound 67-A (750 mg, 2.99 mmol) was reacted with 18-A (932 mg, 1.5 eq) to give yellow solid compound 82-A (750 mg, yield 99%). LCMS: (ESI) m / z = 253.0 (M+1) +

[0314] Referring to the method of starting material 82-A, the starting materials in the following table were used instead of 18-A to react with compound 67-A to obtain the intermediate compound.

[0315] Example 15 Synthesis of Compound 19

[0316] Step 1: Referring to the method of Step 1 in Example 2, 19-B (1.6 g, 24.83% yield) was prepared from 19-A (5.1 g, 33.52 mmol) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 2.10(s,3H)

[0317] 4.64(d,J=5.00Hz,2H)5.30(dd,J=10.63,1.38Hz,1H)5.42(dd,J=17.26,1. 63Hz,1H)6.00-6.11(m,1H)6.50(s,1H)7.45(s,1H)9.96(s,1H)10.89(s,1H)

[0318] Step 2: To a solution of compound 19-B (400 mg, 2.08 mmol) in acetonitrile (8 mL) were added K2CO3 (575 mg, 4.16 mmol) and iodoethane (486 mg, 3.12 mmol), and the mixture was stirred at 25°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to afford 19-C (210 mg, 45.81%) as a white solid. (ESI) m / z = 245.2 (M+Na) + .

[0319] Step 3 and Step 4: Referring to the method of Step 2 and Step 3 in Example 2, 19-C (573 mg, 2.41 mmol) was used for two-step reaction to obtain yellow solid compound 19 (45 mg, two-step yield about 15.8%). 1H NMR(400MHz,CHLOROFORM-d)δppm 0.78-0.86(m,1H)0.95-1.07(m,1H)1.28-1.36(m,1H)1.38-1.44(m,3H)2.10-2.20(m,4H)2.21-2.28(m,1H)2.64-2.72(m,1H)3.90-4. 13(m,2H)4.75-5.10(m,1H)5.35-5.54(m,1H)5.83(d,J=4.63Hz,1H)6.33-6.46(m,1H)6.87-7.02(m,1H).LCMS:(ESI)m / z=249.1(M+1) +

[0320] Example 16 Synthesis of Compound 21

[0321] Following the method of Example 2, a three-step reaction was carried out starting with 19-B and benzyl bromide to obtain a white solid compound 21 (45 mg, three-step yield approximately 1.4%). LCMS: (ESI) m / z = 311.1 [M+H] + , 1 H NMR(400MHz,CHLOROFORM-d)δppm 7.32-7.48(m,5H)6.94-7.09(m,1H)6.46-6.56(m,1H)5.52-5.91(m,1H)5.02-5.16(m,2H)4.7 1-4.87(m,1H)2.23-2.70(m,1H)2.20(s,3H)2.00-2.17(m,1H)1.30(m,1H)0.97-1.07(m,1H).

[0322] Referring to the method in Example 16, the starting materials shown in the following table were used instead of benzyl bromide to carry out three-step reaction to obtain the final compound.

[0323] Example 17 Synthesis of Compound 20

[0324] Step 1: To a solution of potassium tert-butoxide (1 M in THF, 7.80 mL) in THF (20 mL) was added compound 19-B (1 g, 5.20 mmol) under ice-cooling conditions. The mixture was stirred at 0°C for 6 minutes before the addition of compound 20-A (CAS: 66003-76-7, 2.91 g, 6.76 mmol, 1.3 eq). The mixture was allowed to warm to room temperature (25°C) and reacted for 2 hours. The reaction mixture was added to ice water (20 mL) and extracted with EtOAc (15 mL x 3). Standard workup procedures afforded a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 0 to 3%) to afford 20-B as a yellow oil (290 mg, 21% yield). 1 H NMR(CDCl3,400MHz)δppm 10.31(s,1H)7.75(s,1H)7.35-7.48(m,2H)7.13-7.21(m,1H)7.00-7.10(m,2H)6.34(s,1H)

[0325] 5.91-6.03(m,1H)5.23-5.39(m,2H)4.41-4.53(m,2H)2.25(s,3H).

[0326] Step 2 and Step 3: Follow the procedures of Step 3 and Step 4 in Example 2 and perform two steps with 20-B to obtain white solid compound 20 (6 mg, two-step yield approximately 3.5%). LCMS: (ESI) m / z = 297.1 [M+H] + , 1 H NMR(CDCl3,400MHz)δppm 8.25-8.31(m,1H)8.09(d,J=8.56Hz,1H)7.58-7.67(m,1H)7.49-7.57(m,1H )6.88-6.93(m,1H)6.34(s,1H)2.51-2.61(m,1H)2.38-2.47(m,1H)1.63(br s,1H)1.32-1.37(m,1H).

[0327] Example 18 Synthesis of Compound 23

[0328] Step 1: To a solution of 19-B (500 mg, 2.60 mmol) in MeCN (10 mL) were added compound 23-A (664 mg, 2.86 mmol) and cesium carbonate (1.70 g, 5.20 mmol). The reaction was incubated at 80°C for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). Conventional workup procedures afforded a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 30%) to afford 23-B as a yellow solid (300 mg, 42% yield). 1 H NMR(CDCl3,400MHz)δppm 10.32(s,1H)7.70(s,1H)

[0329] 6.37(s,1H)6.00-6.18(m,1H)5.48(dd,J=17.17,1.32Hz,1H)5.38(dd,J=10.56,1.32Hz,1H)4.62-4.68(m,2H)4.47(q,J=8.00Hz,2H)2.23(s,3H)

[0330] Step 2 and Step 3: Follow the method of Step 3 and Step 4 in Example 2 and carry out two-step reaction with 23-B to obtain white solid compound 23 (10 mg, two-step yield approximately 2.5%). LCMS: (ESI) m / z = 303.1 [M+H] + , 1 HNMR(DMSO-d6,400MHz)δppm 9.29-10.19(m,1H)6.83-7.09(m,1H)6.48-6.61(m,1H)5.30-5.80(m,1H)4.61-4. 82(m,2H)2.15-2.28(m,2H)2.02-2.11(m,3H)1.03-1.36(m,1H)0.66-1.01(m,1H).

[0331] Example 19 Synthesis of Compound 33

[0332] Step 1: To a solution of compound 19-B (500 mg, 2.60 mmol) and compound 33-A (562 mg, 3.12 mmol) in DMF (10 mL) was added K2CO3 (1.08 g, 7.8 mmol) and reacted at 90°C for 15 hours. The mixture was cooled to room temperature, diluted with saturated brine (50 mL), and extracted with EtOAc (50 mL x 2). After conventional post-treatment, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to give compound 33-B (580 mg, yield 80.7%) as a yellow solid.

[0333] Step 2 and Step 3: Follow the methods of Step 2 and Step 3 in Example 2 to obtain a white solid 33 (two-step yield approximately 46%). LCMS: (ESI) m / z = 305.1 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)Shift 9.48(s,1H),6.94(s,1H),6.51-6.57(m,1H),5.36(s,1H),4.37-4.51(m,1H),3.86(td,J=4.22,11.32Hz,2H),3.39-3.5 5(m,2H),2.13-2.33(m,2H),2.04(s,3H),1.92-2.00(m,2H),1.50-1.71(m,2H),1.30(dt,J=4.38,8.13Hz,1H),0.90(br s,1H)

[0334] Referring to the method in Example 19, the starting materials shown in the following table were substituted for 33-A to carry out three-step reactions to obtain the final compound.

[0335] Example 20 Synthesis of Compound 38

[0336] To a solution of compound 37 (120 mg, 312.03 μmol) in THF (2 mL) was added tetrabutylammonium fluoride (122.37 mg, 468.04 μmol) at 20°C (room temperature). The reaction was stirred at 20°C for 3 hours. After completion, the reaction was quenched with water (3 mL) and extracted with EA (3 mL x 3). Following standard workup procedures, the product was purified by prep HPLC (FA method, B: 20%-50% over 8 min) to afford compound 2 (15 mg, 19.6% yield) as a white solid. 1 HNMR(400MHz, DMSO-d6)δ9.65-10.02(m,1H)6.96-7.10(m,1H)6.89-6.94(m,1H)5.86(d,J=4.84Hz,0.28H)5.53(s,0.81H)4.38-4.48 (m,1H)2.28(dd,J=8.36,3.74Hz,2H)2.10-2.18(m,3H)1.34(td,J=8.36,4.62Hz,1H)1.03-1.17(m,1H).LC-MS: (ESI)m / z=229.0[M+H] + .

[0337] Example 21 Synthesis of Compound 59

[0338] Step 1: Compound 59-A (6 g, 29 mmol) was reacted in tert-butyl alcohol (60 mL) and concentrated sulfuric acid (7.5 mL) at 40°C for 16 hours. The reaction was cooled to room temperature, quenched with water, and extracted with EtOAc (50 mL x 3). Standard workup procedures were performed to obtain the crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to afford Compound 59-B (2.2 g, 28.73% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.70 (s, 1H), 7.16 (s, 1H), 6.48-6.56 (m, 1H), 3.74 (s, 3H), 1.29 (s, 9H).

[0339] Step 2: Following the procedure of Step 1 in Example 12, compound 59-B (2.2 g) was reacted to obtain a white solid 59-C (2.2 g, yield 86%). LCMS: (ESI) m / z = 273.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.25 (s, 1H), 6.74 (s, 1H), 6.04-6.18 (m, 1H), 5.46 (dd, J = 1.8, 17. 39Hz, 1H), 5.30 (dd, J=1.7, 10.7Hz, 1H), 4.67 (d, J=5.1Hz, 2H), 3.83 (s, 3H), 1.28-1.34 (m, 9H).

[0340] Step 3: To a solution of compound 59-C (2.00 g, 6.7 mmol) in THF (20 mL) was added a 2.5 M solution of n-butyllithium in THF (3.2 mL) at -60°C. After stirring for 0.5 hours, DMF (977 mg, 13 mmol) was added, the temperature was raised to 25°C, and the reaction was continued with stirring for 3 hours. NH4Cl solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (30 mL x 3). After conventional post-processing operation II, the product was purified by silica gel column chromatography (THF:PE, THF from 0 to 30%) to give a white solid 59-D (0.61 g, yield 37%). LCMS: (ESI) m / z = 249.2 (M+H) + .

[0341] Step 4 and Step 5: Referring to the method of Step 2 and Step 3 in Example 2, 59-D (585 mg, 2.5 mmol) was used to carry out two-step reaction to obtain white solid compound 59. The two-step yield was about 4.5%. 1H NMR(400MHz,DMSO-d6)δ(ppm)9.48-9.66(m,1H),6.90-7.03(m,1H),6.43-6.56(m,1H),5.33-5.80(m,1H) ),3.69-3.78(m,3H),2.13-2.26(m,2H),1.07-1.37(m,10H),0.66-0.98(m,1H).LC-MS:(ESI)m / z.[M+H] + 277.3

[0342] Example 22 Synthesis of Compound 67

[0343] Step 1: To a solution of 16-A (2.1 g, 8.36 mmol) in DMF (40 mL) were added chloromethyl ether (1.58 g, 16.73 mmol) and K2CO3 (3.47 g, 25.09 mmol). The mixture was reacted at 25°C for 5 hours. Water (50 mL) was added and the mixture was extracted with EA (50 mL x 3). After conventional post-processing, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a white solid 67-B (2.3 g, yield 89%). LCMS: (ESI) m / z = 308.9 (M+1) + .

[0344] Steps 2 and 3: Following the procedures of Steps 2 and 3 in Example 12 (Representative Procedure B for the Construction of a Five-Membered Lactone Ring), a two-step reaction was performed using 67-B to obtain compound 67, a white solid, in a two-step yield of approximately 17.2%. LCMS: (ESI) m / z = 306.9 [M+H] + , 1 H NMR(400MHz, CDCl3)8.32(d,J=7.19Hz,1H),7.98(d,J=7.43Hz,1H),7.51-7.60(m,2H),7.32(s,1H),6.50(t,J=8.5 0Hz,1H),5.43-5.50(m,2H),3.82(q,J=7.00Hz,2H),2.83-2.94(m,2H),2.61-2.71(m,2H),1.28(t,J=7.07Hz,3H).

[0345] Referring to the method in Example 22 (Representative Operation C for Constructing a Five-membered Lactone Ring), a three-step reaction was carried out using the starting materials in the following table to obtain the final compound.

[0346] The synthesis method of the starting material 78-A mentioned in the above table is:

[0347] Referring to the synthesis method of intermediate 40-A, compound 78-B (440 mg, 2.46 mmol) was reacted to give yellow solid compound 78-A (400 mg, yield 78%). LCMS: (ESI) m / z = 207.0 (M+1) +

[0348] Referring to the method of steps 2 and 3 in Example 22 (representative operation B for constructing a five-membered lactone ring), the starting materials shown in the following table were reacted to obtain the final compound.

[0349] The synthesis method of the starting material 78-A mentioned in the above table is:

[0350] Following the method of Example 37, 78-A (60 mg) was used as the starting material to obtain yellow solid compound 144-A (50 mg, yield 69%). LCMS: (ESI) m / z = 248.9 [M+H] + .

[0351] Example 23 Synthesis of Compounds 71 ​​and 72

[0352] To a solution of compound 67 (45 mg, 146.51 μmol) in pyridine (1 mL) was added acetic anhydride (22.4 mg, 219.77 μmol). The mixture was reacted at 25°C for 16 hours. Water (3 mL) was added, and the mixture was extracted with EA (2 mL x 3). Conventional post-processing procedures gave a crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) and then chiral separation by SFC to afford compounds 71 ​​(5 mg) and 72 (5 mg) as white solids.

[0353] Chiral separation conditions were: column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: 0.1% NH₃H₂O IPA; B%: 15%-15%, flow rate: 100 mL / min.

[0354] The first compound LCMS: (ESI) m / z=349.0 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13-8.19 (m, 1H) 8.02-8.08 (m, 1H) 7.66-7.76 (m, 3H) 6.54 (dd, J = 10.38, 7.38 Hz, 1H) 2.90-3.03 (m, 1H) 2.78-2.88 (m, 1H) 2.62-2.68 (m, 1H) 2.54 (br d, J = 2.00 Hz, 1H) 2.48 (s, 3H). SFC chiral analysis: RT = 2.703 min

[0355] The second compound LCMS: (ESI) m / z=349.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.13-8.19 (m, 1H) 8.01-8.09 (m, 1H) 7.64-7.75 (m, 3H) 6.54 (dd, J = 10.32, 7.44 Hz, 1H) 2.90-3.03 (m, 1H) 2.78-2.89 (m, 1H) 2.62-2.68 (m, 1H) 2.54 (br s, 1H) 2.48 (s, 3H). SFC chiral analysis: RT = 2.974 min

[0356] Chiral analysis conditions are: Column: ChiralPak AS-3 150×4.6mm ID, 3um; Mobile phase: A:CO2 B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4.5min, then 5% of B for 1.5min; Flow rate: 2.5mL / min Column temp.: 40℃; Back pressure:100bar

[0357] Example 24 Synthesis of Compound 68

[0358] Step 1: Under nitrogen protection, Zn(CN)2 (68.8 mg, 0.59 mmol) and Pd(PPh3)4 (22.5 mg, 0.2 mmol) were added to a solution of compound 67-B (60 mg, 0.17 mmol) in NMP (1.2 mL). The mixture was heated to 120°C and reacted for 16 hours. The reaction solution was cooled to room temperature, water (5 mL) was added, and extracted with EA (5 mL*3). After conventional post-processing operation 2, the crude product was obtained. The crude product was purified by prep-HPLC (FA method; B%: 28%-48%, 13 min) to obtain a yellow solid 68-A (17 mg, yield 33%). LCMS: (ESI) m / z = 312.1 (M+1) + .

[0359] Step 2: Following the procedure of Step 3 in Example 12, 68-A (50 mg) was reacted to obtain white solid compound 68 (12 mg, yield 29.2%). LCMS: (ESI) m / z = 253.9 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)11.24(br s,1H),8.25-8.34(m,1H),8.18(br d,J=8.28Hz,1H),7.67-7.80(m,2H),7.06(s,1H),6.43-6.52(m,1H),2.83-2.98(m,1H),2.70-2.82(m,2H),2.28-2.42(m,1H)

[0360] Example 25 Synthesis of Compound 73

[0361] Step 1: To a solution of 67-A (2.7 g, 10.75 mmol) in DMF (54 mL) was added 3-bromopropylene (1.95 g, 16.13 mmol) and K2CO3 (4.46 g, 32.26 mmol). The mixture was reacted at 25°C for 16 hours. After filtration, the mixture was concentrated under reduced pressure. Water (60 mL) was added and the mixture was extracted with EA (60 mL x 3). After standard post-processing, the crude product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 4%) to afford 73-A as an off-white solid (yield 98%). 1H NMR (400MHz, CDCl3)10.68(s,1H),9.32(d,J=8.78Hz,1H),8.33(d,J=8.52Hz,1H),7.68-7.74(m,1H),7.58(t,J= 7.64Hz,1H),7.06(s,1H),6.19(ddt,1H),5.54-5.61(m,1H),5.45(dd,J=1.25,10.54Hz,1H),4.80-4.86(m,2H).

[0362] Step 2 to Step 3: Referring to the method of Step 2 to Step 3 in Example 12, compound 73-A was reacted in two steps to obtain compound 73 as a yellow oil (two-step yield is about 69%). 1 H NMR (400MHz, CDCl3)8.37(d,J=7.53Hz,1H),7.97(d,J=7.62Hz,1H),7.51-7.60(m,2H),6.99(s,1H),6.48(t,J=8.91Hz,1H),6.13-6.23 (m,1H),5.55(dd,J=1.25,17.32Hz,1H),5.41(dd,J=1.25,10.54Hz,1H),4.74(d,J=5.27Hz,2H),2.86-2.93(m,2H),2.64-2.70(m,2H).

[0363] Example 26 Synthesis of Compound 80

[0364] Following the procedure of step 4 in Example 8-b, 67 (70 mg, 227.91 μmol) was reacted with 80-A (1.2 eq) to obtain compound 80 (25 mg, 27% yield), a white solid. LCMS: (ESI) m / z = 371.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)10.57(s,1H),8.67(s,1H),8.27(d,J=8.03Hz,1H),7.89-7.98(m,4H),7.49-7.59(m,4H), 7.34-7.39(m,1H),6.85(s,1H),6.14(t,J=8.78Hz,1H),2.85-2.98(m,1H),2.72-2.80(m,1H),2.63-2.70(m,2H)

[0365] Referring to the method of Example 26, the starting materials shown in the following table were used in place of 80-A to carry out the reaction to obtain the corresponding final compounds.

[0366] The synthesis method of the starting material 103-A mentioned in the above table is:

[0367] Step 1: To a solution of 103-B (0.7 g, 3.57 mmol) in MeCN (14 mL) was added 4-tetrahydropyranyl methanesulfonate (4 eq) and cesium carbonate (6 eq). The reaction was incubated at 80°C for 24 hours. LCMS indicated that the reaction was incomplete, but the desired product was formed. The residue was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to afford 103-C (560 mg, 39% yield) as a yellow oil. LCMS: (ESI) m / z = 281.9 [M+1] +

[0368] Step 2: Under nitrogen protection, Pd(dppf)Cl2 (104 mg, 0.1 eq) was added to a mixture of compound 103-C (400 mg, 1.43 mmol), bis(pinacolato)diboron (2 eq), and potassium acetate (3 eq) in dioxane (8 mL). The reaction was allowed to proceed at 100°C under nitrogen protection for 16 hours. After completion of the reaction, the temperature was cooled to room temperature, water (10 mL) was added, and extraction was performed with EtOAc (10 mL x 3). After conventional post-processing, the crude product was obtained, which was then purified by silica gel column chromatography (EA:PE, EA from 0 to 14%) to obtain a yellow solid 103-A (420 mg, 84% yield). (ESI) m / z = 328.1 (M+1) + .

[0369] The synthesis method of the starting material 101-A mentioned in the above table is:

[0370] At 0°C, a solution of isopropylmagnesium chloride lithium chloride complex in THF (1.3M, 4.44 mL) was added dropwise to a solution of compound 101-B (1 g, 2.89 mmol) in THF (20 mL). After stirring for 1 hour, a solution of compound 98-C (1.07 g, 5.78 mmol) in THF (1.18 mL) was added dropwise. The temperature was raised to 25°C and the reaction was continued with stirring for 15 hours. Saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL × 2). After conventional post-treatment operation II, the product was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to obtain an off-white solid 101-A (600 mg, yield 56%). LCMS: (ESI) m / z = 347.1 (M+H) + .

[0371] The synthesis method of the starting material 98-A mentioned in the above table is:

[0372] To a solution of compound 98-B (500 mg, 2.14 mmol) in THF (20 mL) was added dropwise a 2.5 M solution of n-butyllithium in THF (1.71 mL) at -70°C. The mixture was stirred under nitrogen for 1 hour. Compound 98-C (794 mg, 4.27 mmol) was then added dropwise, and the temperature was raised to 0°C, followed by stirring for 3 hours. After completion, the reaction was quenched with saturated NH4Cl solution, concentrated under reduced pressure, and EtOAc (20 mL) was added. The filtrate was filtered, concentrated again under reduced pressure, and separated by silica gel column chromatography (EA:PE, EA ranging from 0 to 30%) to afford a yellow gum (220 mg, 51.76% yield). 1 H NMR (400MHz, DMSO-d6) Shift 8.72 (s, 1H), 8.67 (d, J = 5.06Hz, 1H), 7.39-7.51 (m, 6H), 1.17-1.25 (m, 12H).

[0373] Referring to the method of starting material 98-A, the starting materials in the following table were substituted for 98-B to obtain the corresponding borate ester starting materials.

[0374] Example 27 Synthesis of Compound 69

[0375] Step 1: Following the procedure of step 4 in Example 8-b, 67-B (100 mg) and 18-A (74 mg) were reacted to give a brown solid compound 69-A (50 mg, yield 47%). LCMS: ES19974-299-P1B1, (ESI) m / z = 367.5 [M+1] +

[0376] Step 2: Following the method of Step 3 in Example 12, compound 69-A (50 mg) was reacted to obtain white solid compound 69 (1.4 mg, yield 3.28%). LCMS: (ESI) m / z = 309.0 [M+1] + , 1H NMR(400MHz,DMSO-d6)Shift=10.50(br s,1H),8.23(d,J=8.0Hz,1H),7.91-7.84(m,2H),7.58-7.51(m,2H),7.51-7.45(m,1H),6. 76(s,1H),6.09(dd,J=7.8,10.0Hz,1H),3.93(s,3H),2.95-2.73(m,2H),2.70-2.57(m,2H)

[0377] Referring to the method in Example 27, the starting materials shown in the following table were substituted for 18-A to carry out the reaction to obtain the corresponding final compounds.

[0378] Example 28 Synthesis of Compound 84

[0379] Under nitrogen, K3PO4 (93.3 mg, 439 μmol) and Pd2(dba)3 (26.8 mg, 29.30 μmol) were added to a mixture of compound 67 (90 mg, 293 μmol) and 84-A (100 mg, 352 μmol) in THF / water (2.4 mL, 5 / 1). The mixture was heated to 60°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with EA (5 mL x 3). After standard workup, the crude product was purified by silica gel thin-layer chromatography (PE:EA, EA from 0 to 15%) and then by prep HPLC (FA method; B%: 35%-55%, 9 min) to afford compound 84 (18 mg, 16% yield) as a white solid. LCMS: (ESI) m / z = 385.1 [M+1] +

[0380] Example 28-a Synthesis of Compound 85

[0381] Under nitrogen protection, Pd2(dba)3 (23.8 mg, 26 μmol) was added to a mixture of compound 67 (80 mg, 0.26 mmol), 85-A (80 mg, 312 μmol), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (CAS: 1246888-90-3, 17.2 mg, 52.09 μmol), and CsF (59.3 mg, 390.70 μmol, 14.41 μL, 1.5 eq) in isopropanol (2 mL). The mixture was heated to 50°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with EA (5 mL x 3). After conventional post-processing, the crude product was obtained. The crude product was purified by silica gel thin-layer chromatography (PE:EA, EA from 0 to 25%) and then purified by prep HPLC (FA method, B%: 30%-50%, 9 min) to obtain a white solid compound 85 (10 mg, yield 10.6%). LCMS: (ESI) m / z = 356.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)10.77(br s,1H),8.89(s,1H),8.39(s,1H),8.32(d,J=7.48Hz,1H),8.11(dd,J=4.73,7.81Hz,2H),7.95(d,J =8.36Hz,1H),7.85(t,J=7.59Hz,1H),7.68-7.74(m,1H),7.55-7.66(m,2H),6.80(s,1H),5.80(br t,J=8.47Hz,1H),2.58-2.81(m,4H)

[0382] Example 29 Synthesis of Compound 74

[0383] Step 1: Under nitrogen, sodium methanesulfinate (29.3 mg, 287.50 μmol), K 3 PO 4 (81.4 mg, 383.33 μmol), CuI (1.83 mg, 9.58 μmol), and (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (2.25 mg, 9.58 μmol) were added to a solution of compound 67-B (70 mg, 0.19 mmol) in DMSO (1.4 mL). The mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EA, and water (5 mL) was added. The mixture was extracted with EA (10 mL x 3). Conventional workup procedures gave the crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to afford 74-A as a yellow gum (35 mg, 25% yield). LCMS: (ESI) m / z=365.0 (M+1) + .

[0384] Step 2: Following the method of Step 3 in Example 12, compound 74-A (30 mg) was reacted to obtain white solid compound 74 (10 mg, yield 40%). LCMS: (ESI) m / z = 307.0 [M+1] + , 1 H NMR(400MHz,DMSO-d6)11.23(br s,1H),8.29-8.35(m,1H),8.05-8.12(m,1H),7.67-7.73(m,2H),7.51(s,1H),6.74(dd,J=7.53,10.04Hz,1H),3.44(br s,3H),2.95(td,J=10.48,17.69Hz,1H),2.81(br dd,J=8.28,17.82Hz,1H),2.61(br d,J=10.54Hz,2H)

[0385] Example 30 Synthesis of Compound 75

[0386] Referring to the method of steps 1 to 3 in Example 12: 75-A was used as the starting material to react to obtain yellow solid compound 75-B, with a three-step yield of about 66.6%. 1 H NMR(400MHz,CHLOROFORM-d)Shift=7.21-7.12(m,2H),6.19(t,J=8.8Hz,1H),6.07-5. 91(m,1H),5.47-5.30(m,2H),4.54-4.52(m,2H),2.78-2.71(m,2H),2.59-2.54(m,2H).

[0387] Step 4: Under nitrogen, a mixture of compound 75-B (300 mg, 0.8 mmol), Pd(PPh3)4 (92.2 mg, 79.8 μmol), and morpholine (139.0 mg, 1.60 mmol) in THF (16 mL) was reacted at 20°C for 16 hours. Water (40 mL) was added, and the mixture was extracted with EA (30 mL x 3). After conventional post-processing, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to give compound 75 (125 mg, 47% yield) as a white solid. LCMS: (ESI) m / z = 336.8 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)Shift=10.58(s,1H),7.20-7.03(m,2H),6.09(t,J=8.8Hz, 1H),2.90-2.74(m,1H),2.70-2.59(m,1H),2.49-2.43(m,1H),2.42-2.25(m,1H).

[0388] Example 31 Synthesis of Compound 77

[0389] Step 1: To a solution of compound 77-A (1 g, 4.46 mmol) and NIS (1.14 g, 5.07 mmol) in DMSO / ACN (100 mL, 1:1) was added 77-E (65.6 mg, 223.16 μmol) and allowed to react at 25°C for 15 hours. Water (50 mL) was added and the mixture was extracted with EA (50 mL x 2). After conventional post-processing, 1 g of a gray solid was obtained, which was used directly in the next reaction. LCMS: (ESI) m / z = 351.8 (M+1) +

[0390] Step 2: Following the procedure of Step 1 in Example 22, 77-B (1 g crude product) was reacted to obtain yellow solid compound 77-C (1.1 g, purity 58.65%). LCMS: (ESI) m / z = 409.9 (M+1) +

[0391] Step 3: At -70 ° C, a solution of isopropylmagnesium chloride lithium chloride complex in THF (1.3M, 1.27 mL) was added dropwise to a solution of compound 77-C (560 mg) in THF (30 mL), the temperature was raised to 25 ° C, and the reaction was stirred for 1 hour. A solution of DMF (120 mg, 1.65 mmol) in THF (1 mL) was added at -70 ° C, the temperature was raised to 25 ° C, and the reaction was stirred for 0.5 hours. Water (10 mL) was added at 0 ° C to quench the reaction, and the mixture was extracted with EA (10 mL × 2). After conventional post-treatment operations, it was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to give a yellow solid 77-D (240 mg, purity 80.4%). LCMS: (ESI) m / z = 311.9 (M+H) + .

[0392] Step 4 and Step 5: Follow the procedures of Step 2 and Step 3 in Example 12 to carry out two steps of reaction with 77-D to obtain yellow solid compound 77. The yield of the five steps is 8.8%. LCMS: (ESI) m / z = 310.0 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)Shift 11.25(s,1H),8.91(d,J=4.49Hz,1H),8.54(d,J=8.56Hz,1H),7.56(dd,J=4.14,8.41Hz,1H ),7.11-7.14(m,1H),6.58(dd,J=7.53,8.78Hz,1H),2.71-2.91(m,2H),2.57-2.68(m,2H).

[0393] Example 32 Synthesis of Compound 86

[0394] Step 1: Referring to the method of step 4 in Example 8-b, 77-D (200 mg, 644.86 μmol) and 18-A (147 mg, 709.35 μmol) were reacted to obtain a yellow solid 86-A (130 mg, yield 64.75%). 1 H NMR (400MHz, CHLOROFORM-d) δ11.03(s,1H),9.02(dd,J=1.83,4.28Hz,1H),8.58(dd,J=1.83,8.44Hz,1H),7.87(s,1H),7.76( s,1H),7.44(dd,J=4.16,8.44Hz,1H),7.23(s,1H),5.52(s,2H),3.99(s,3H),3.82(q,J=7.09Hz,2H),1.26(t,J=7.09Hz,3H).

[0395] Step 2 and Step 3: Following the procedures of Step 2 and Step 3 in Example 12, 86-A (130 mg, 417.56 μmol) was used in two steps to obtain yellow solid compound 86 (4 mg). The yield for the two steps was approximately 2.7%. LCMS: (ESI) m / z = 309.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.85(dd,J=1.76,4.02Hz,1H),8.52(dd,J=1.76,8.28Hz,1H),7.92(s,1H),7.59(s,1 H),7.47(dd,J=4.27,8.28Hz,1H),6.84(s,1H),6.10(t,J=7.53Hz,1H),3.94(s,3H),2.85-2.98(m,1H),2.61-2.76(m,3H).

[0396] Example 33 Synthesis of Compounds 92, 93, and 94

[0397] Step 1: To a solution of compound 67-B (370 mg, 1.20 mmol) and DBU (273 mg, 1.80 mmol) in EtOH (10 mL) were added Pd(OAc)2 (26.8 mg, 119.68 μmol), molybdenum hexacarbonyl (Mo(CO)6, 173 mg, 658.25 μmol), and tri-tert-butylphosphine tetrafluoroborate (34.7 mg, 119.68 μmol) under nitrogen protection. The mixture was reacted at 90°C for 16 hours under nitrogen protection. The solvent was removed by filtration and distillation under reduced pressure. The product was purified by silica gel column chromatography (EA:PE, EA from 0 to 2%) to obtain compound 92-A (170 mg, 47% yield) as a yellow oil. LCMS: (ESI) m / z = 303.0 (M+1) + .

[0398] Step 2 and Step 3: Following the procedures of Step 2 and Step 3 in Example 12, 92-A (260 mg, 860 μmol) was used in two steps to obtain compound 92 (40 mg) as a white solid. The yield for the two steps was approximately 15.5%. LCMS: (ESI) m / z = 301.3 (M+1). + . 1H NMR (400MHz, CDCl3) δ8.35-8.50(m,1H),7.90-8.06(m,1H),7.59-7.77(m,2H),7.36(br s,1H),7.30(s,1H),5.90(dd,J=2.31,8.47Hz,1H),3.91-4.26(m,2H),2.77-2.93(m,1H),2.59-2. 73(m,1H),2.46(td,J=6.27,16.95Hz,1H),2.03(dt,J=6.71,14.36Hz,1H),1.25(t,J=7.15Hz,3H).

[0399] Step 4: Dissolve compound 92 (20 mg) in THF (0.3 mL) and add aqueous NaOH (10.7 mg, 266 μmol) (0.3 mL). Stir at 25°C for 2 hours. Adjust the pH of the reaction mixture to 2 with 1 M HCl solution, and extract the mixture with EA (1 mL x 3). Concentrate under reduced pressure to obtain the crude product. The crude product is ground and slurried with DCM (3 mL) for 10 minutes. Filter to obtain compound 93 (15 mg, 82.48% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.25(br s,1H),10.95(br s,1H),8.22-8.42(m,1H),7.99-8.16(m,1H),7.54-7.88(m,2H),7.04(s,1H),5.97(dd,J=2.53,8.25Hz,1H ),2.55-2.71(m,1H),2.33-2.47(m,1H),2.14-2.29(m,1H),1.83-1.98(m,1H).LCMS:(ESI)m / z=273.2(M+1) + .

[0400] Step 5: To a solution of compound 93 (40 mg, 146.92 μmol) and HOBT ammonium salt (CAS: 63307-62-0, 111.77 mg, 734.61 μmol) in DMF (1 mL) were added DIEA (56.96 mg, 440.77 μmol) and HATU (139.66 mg, 367.31 μmol). The mixture was stirred at 25°C for 2 h. The mixture was diluted with water (2 mL) and acetonitrile (1 mL) and filtered. The filtrate was concentrated and purified by prep HPLC (column: C18-1 150*30 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 5%-45%, 9 min) to afford compound 94 (20 mg, 50.18% yield) as a white solid.1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.25-8.40(m,1H),8.04-8.17(m,1H),7.64-7.83(m,2H),7.35(br s,1H),7.03(s,1H),6.82(br s,1H),5.95(dd,J=2.64,7.92Hz,1H),2.55-2.72(m,1H),2.18-2.33(m,1H),1.95-2.06(m,1H),1.80-1.95(m,1H).LCMS:(ESI)m / z=272.0(M+1) + .

[0401] Example 34 Synthesis of Compound 117

[0402] To a mixture of compound 116 (100 mg, 0.33 mmol) in THF (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, approximately 1.5 equivalents). The mixture was allowed to react at 25°C for 16 hours. The THF was removed by distillation under reduced pressure, and the pH was adjusted to 6-7 with AcOH. Prep HPLC separation (FA method, B: 18%-38%, 10 min) afforded a white solid (25 mg, 25.68% yield). 1 H NMR(400MHz,DMSO-d6)Shift 10.84(m,1H),9.38-12.31(m,1H),6.82-7.05(m,1H),6.42-6.56(m,1H),5.73(d,J=4.65Hz,0.24H),5.37(s,0.76H),3.67 -3.82(m,3H),2.64-2.75(m,2H),2.38-2.43(m,2H),2.21(dt,J=2.45,5.69Hz,2H),1.29(dt,J=4.46,8.16Hz,1H),1.05(br d,J=4.52Hz,1H),0.68-0.99(m,1H). LCMS: (ESI) m / z=293.3 (M+1) +

[0403] Example 35 Synthesis of Compounds 118 and 119

[0404] A solution of compound 117 (90 mg, 307.92 μmol) in TFA (0.2 mL) and DCM (2 mL) was stirred at 25°C for 1 hour. The reaction was quenched with saturated NaHCO3 solution (5 mL) and extracted with DCM (5 mL x 3). After conventional post-processing, a yellow oil 117-A (60 mg, yield 71.05%) was obtained. LCMS: (ESI) m / z = 275.3 (M+1). +

[0405] Compound 117-A (15 mg) was purified by prep HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 33%-53% B over 10 min) to give white solid compound 118 (8 mg, purity 80%) and white solid compound 119 (5 mg, purity 90%).

[0406] Compound 118: 1 H NMR(400MHz,DMSO-d6)Shift 7.15(s,1H),6.86(s,1H),5.48(s,1H),3.83(s,3H),2.89-2.98(m,2H),2. 75-2.83(m,2H),2.16-2.38(m,3H),1.30-1.37(m,1H),1.00-1.06(m,1H). LCMS:(ESI)m / z=275.3(M+1) +

[0407] Compound 119: 1 H NMR(400MHz,DMSO-d6)Shift 7.06(s,1H),6.77-6.86(m,1H),6.83(s,1H),5.80(d,J=4.52Hz,1H),3.84(s,3H),2.89-2.95(m,2H),2.73-2.81(m, 2H), 2.58-2.66 (m, 1H), 2.21 (ddd, J = 3.14, 5.58, 8.85Hz, 1H), 1.06 (dt, J = 4.89, 8.22Hz, 1H), 0.70 (q, J = 4.27Hz, 1H). LCMS:(ESI)m / z=275.3(M+1) +

[0408] Example 36 Synthesis of Compound 25

[0409] Step 1: Following the procedure of Step 6 of Example 1, (14-c-1) (1.5 g, 6.29 mmol) and Compound 25-A (860 mg, 2.67 mmol) were reacted to obtain Compound 25-B (70 mg, 2.9% yield) as a white solid. (ESI) m / z = 377.1 (M+1) + .

[0410] Step 2: To a solution of compound 25-B (60 mg, 159 μmol) in MeOH (2 mL) was added ammonium fluoride (11.8 mg, 318.67 μmol, 2 eq) and the mixture was allowed to react at 25°C for 2 hours. The reaction was concentrated under reduced pressure, and EtOAc (20 mL) was added. After conventional post-processing, the product was purified by silica gel column chromatography (EA / PE, EA from 0 to 50%) to afford compound 25 as a white solid (5 mg, yield 14.25%). (ESI) m / z = 221.0 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.11(d,J=8.03Hz,1H),6.46(d,J=2.26Hz,1H),6.39-6.44(m,1H),5 .50(s,1H),3.82(s,3H),2.25(m,1H),2.14-2.21(m,1H),1.33(m,1H),1.02-1.10(m,1H).

[0411] Example 37 Synthesis of Compound 134

[0412] To a solution of compound 134-A (20 mg, 96 μmol) in pyridine (0.5 mL) was added acetic anhydride (14.7 mg, 144.09 μmol). The reaction was allowed to react at room temperature (15°C) for 16 hours. The mixture was concentrated under reduced pressure, water (2 mL) was added, and extraction was performed with EA (1 mL x 2). Conventional post-processing procedures gave a crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to afford 134 as a yellow oil (15 mg, yield 60.28%). LCMS: ESI m / z = 251.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.34(d,J=8.44Hz,1H)6.73(dd,J=8.31,2.08Hz,1H)6.68(d,J=2.08Hz,1H)5.74(t,J=7. 03Hz,1H)3.85(s,3H)2.67-2.76(m,1H)2.60-2.66(m,2H)2.33(s,3H)2.09-2.20(m,1H).

[0413] Referring to the method in Example 37, the starting materials shown in the following table were substituted for 134-A to obtain the corresponding final compounds.

[0414] Referring to the method in Example 37, the starting materials listed in the following table were reacted to obtain the corresponding final compounds.

[0415] Example 38 Synthesis of Compound 138

[0416] To a solution of compound 67 (50 mg, 163 μmol) in DCM (2 mL) were added TEA (24.7 mg, 212 μmol) and benzoyl chloride (29.7 mg, 212 μmol), and the mixture was allowed to react at 25°C for 4 hours. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE, EA from 0 to 30%) to afford compound 138 (20 mg, 28.6% yield) as a white solid. LCMS: (ESI) m / z = 411.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=7.28Hz,2H),8.20(d,J=8.53Hz,1H),8.00(d,J=8.03Hz,1H),7.91(s,1H),7.81-7.8 7(m,1H),7.66-7.77(m,4H),6.58(dd,J=7.53,10.29Hz,1H),2.80-3.06(m,2H),2.64-2.75(m,1H),2.55-2.62(m,1H).

[0417] Referring to the method of Example 38, the starting materials shown in the following table were used to replace benzoyl chloride and react with compound 67 to obtain the corresponding final compound.

[0418] Example 39 Synthesis of Compound 140 and Compound 141

[0419] Step 1: To a solution of compound 67 (50 mg, 163 μmol) and compound 141-A (38.5 mg, 179 μmol, 1.1 eq) in DCM (2 mL) was added EDCI (40.5 mg, 211.63 μmol, 1.3 eq) and DMAP (1.99 mg, 16.28 μmol, 0.1 eq). The mixture was stirred at 25°C for 3 hours and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 30%) to afford compound 141 (70 mg, 82% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.09-7.95(m,2H),7.60-7.81(m,3H),6.54(br dd,J=7.64,9.96Hz,1H),4.52-4.77(m,1H),3.46-3.56(m,2H),2.62-3.06(m,3H),2.44(br d,J=5.14Hz,3H),1.90-2.16(m,2H),1.44(d,J=18.46Hz,9H).(ESI)m / z=403.9[M-Boc+H] +

[0420] Step 2 (representative method for removing the Boc protecting group): A solution of compound 141 (20 mg, 0.397 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The resulting residue was purified by prep HPLC (FA method; B%: 5%-35%, 8 min) to afford compound 140 (2 mg, 12% yield) as a white solid. LCMS: (ESI) m / z = 404.1 [M+H] + .1H NMR (400MHz, DMSO-d6) δ8.22(d,J=7.78Hz,1H),7.96(d,J=8.53Hz,1H),7.50-7.69(m,2H),7.11(s,1H),6.43(dd,J=7.53,10.29Hz,1H),3.67(br dd,J=6.02,8.53Hz,1H),2.74-3.07(m,4H),1.65-2.13(m,4H).

[0421] Referring to the method of step 1 in Example 39, the starting materials shown in the following table were substituted for 141-A and reacted with compound 67 to obtain the corresponding final compound.

[0422] Referring to the method of step 1 in Example 39, the starting materials shown in the following table were reacted to obtain the corresponding final compounds.

[0423] Example 40 Synthesis of Compound 161

[0424] Step 1: Using the method of Example 38, compound 76 (60 mg) and compound 161-A (5 eq) were reacted to obtain yellow solid compound 161-B (100 mg). The crude product was used directly in the next reaction.

[0425] Step 2: Following the procedure of Step 2 in Example 39, compound 161-B (100 mg) was reacted to obtain compound 161 (25 mg, approximately 29% yield for two steps) as a white solid. LCMS: (ESI) m / z = 398.1 (M+1) + , 1 H NMR(400MHz,DMSO-d6)Shift 8.46(br s,2H),8.30-8.36(m,1H),8.24(dd,J=2.87,7.03Hz,1H),8.16(d,J=8.44Hz,1H),7.52 -7.83(m,4H),6.41(s,0.86H),6.28(s,0.12H),2.54-2.70(m,2H),1.39-1.68(m,2H).

[0426] Example 41 Synthesis of Compound 143

[0427] To a solution of compound 142 (100 mg, 0.22 mmol) in DCM (2 mL) were added DIEA (84.9 mg, 657 μmol) and trichlorosilane (89.0 mg, 657 μmol). The reaction was stirred at 25°C for 2 hours. The reaction was quenched with saturated NaHCO₃ solution (10 mL), and the mixture was extracted with DCM (15 mL x 3). Conventional workup procedures were performed to obtain a residue, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 40%) to afford compound 143 (30 mg, 28% yield) as a white solid. LCMS: (ESI) m / z = 427.9 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.19(d,J=8.53Hz,1H),8.09-8.15(m,1H),7.93- 7.97(m,1H),7.81(s,1H),7.65-7.75(m,2H),7.39-7.45(m,1H),6.90(d,J =8.53Hz,1H),6.78-6.84(m,2H),6.69(t,J=7.53Hz,1H),6.57(dd,J=7.2 8,10.29Hz,1H),2.79-3.06(m,2H),2.65-2.74(m,1H),2.57-2.61(m,1H).

[0428] Example 42 Synthesis of Compound 149

[0429] To a solution of compound 149-A (36.7 mg, 146 μmol) and thionyl chloride (20.9 mg, 176 μmol) in DCM (0.2 mL) was added one drop of DMF and stirred at 40°C for 40 minutes. The temperature was lowered to 25°C, and the solvent was dried with nitrogen. A solution of compound 67 (30 mg, 97.68 μmol) in pyridine (2 mL) was added and stirred at 60°C for 1 hour. EtOAc (4 mL) was added, and standard post-processing procedures were performed to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE, EA ranging from 8% to 30%) to afford compound 149 (25 mg, 47% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 2.54-2.59(m,1H)2.68-2.74(m,1H)2.83-2.89(m,1H)2.92-3.00(m,1H)4.03(s,6H)6.57(dd,J=10.27,7.46Hz, 1H)7.15(s,1H)7.68(s,1H)7.74-7.81(m,2H)8.15-8.19(m,1H)8.20-8.26(m,1H).LCMS:(ESI)m / z=541.0(M+1) + .

[0430] Example 43 Synthesis of Compound 160

[0431] Compound 160-A (38 mg, 306 μmol) was added to a solution of compound 76 (65 mg, 204 μmol) and cesium carbonate (99.5 mg, 305.50 μmol) in DMF (2 mL) and allowed to react at 25°C for 16 hours. After completion of the reaction, saturated brine (10 mL) was added and the mixture was extracted with EtOAc (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, EA from 0 to 20%) and then by prep HPLC (FA method; B%: 43%-63%, 16 min) to afford compound 160 (10 mg, 12% yield) as a white solid. (ESI) m / z = 407.2 (M+1) + . 1 H NMR(400MHz, CDCl3), δ8.22-8.40(m,1H),8.09(d,J=8.58Hz,1H),7.48-7.69(m,2H),7.33(s,1H),6.33(s,1H),5.9 9(s,2H),3.87(s,3H),2.50-2.67(m,1H),2.42(dt,J=4.62,6.05Hz,1H),1.62-1.66(m,1H),1.37(q,J=4.03Hz,1H).

[0432] Example 44 Synthesis of Compound 163

[0433] Step 1:

[0434] Preparation of LDA solution: To a solution of diisopropylamine (402 mg, 3.98 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium in THF (2.5 M, 1.46 mL) at -78°C, and the mixture was stirred at 20°C for 0.5 h.

[0435] Compound 163-A (400 mg, 1.66 mmol) in THF (2 mL) was added to the above LDA solution at -20°C and stirred at 0°C for 1 hour. Tert-butyl bromoacetate (356 mg, 1.83 mmol) and 1,3-dimethyl-2-imidazolidinone (189 mg, 1.66 mmol) were then added and stirred at 0°C for 5 hours. The reaction was quenched with saturated NH4Cl solution (6 mL). After stirring at 20°C for 0.5 hours, the mixture was extracted with EtOAc (8 mL x 3). After standard workup, the crude product was obtained, which was then purified by silica gel column chromatography (EA / PE, EA from 8 to 32%) to afford 163-B (161 mg, 27.32% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δppm 1.36-1.40(m,9H)1.75-1.85(m,1H)2.00-2.06(m,1H)2.34-2.43(m,1H)2.54-2.57(m,1H)2 .81-2.92(m,2H)2.96-3.04(m,1H)6.66-6.70(m,1H)6.94-7.00(m,1H)10.63-10.70(m,1H).

[0436] Step 2: A solution of compound 163-B (140 mg, 394.12 μmol) in DCM (2 mL) and TFA (224 mg, 1.97 mmol, 150 μL, 5 eq) was reacted at 40°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 57%) to afford a yellow oil, 163-C (51 mg, 43% yield). LCMS: (ESI) m / z = 300.9 [M+H] + .

[0437] Step 3: Referring to the method of Step 2 of Example 5, compound 163-C (45 mg, 150.4 μmol) was reacted to obtain white solid compound 163 (12 mg, yield 28.2%). 1 H NMR (400MHz, CDCl3) δppm 1.86 (br dd,J=13.27,3.97Hz,1H)2.43(d,J=17.36Hz,1H)2.65-2.85(m,4H)2.97(dd,J=17.18,7.52H z,1H)5.03-5.22(m,1H)5.54(d,J=5.26Hz,1H)6.61(d,J=2.45Hz,1H)7.04(d,J=2.45Hz,1H). LCMS:(ESI)m / z=284.9(M+1) + .

[0438] Example 45 Synthesis of Compounds 164 and 165

[0439] Step 1: To a solution of compound 164-A (2.01 g, 16.22 mmol) in DCM (50 mL) was added aluminum chloride (3.24 g, 24.32 mmol). The mixture was stirred at 10°C for 10 minutes, followed by the dropwise addition of a solution of 164-B (2.5 g, 16.22 mmol) in DCM (5 mL). The mixture was stirred at 10°C for 10 minutes, and then refluxed for 3 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added, and the pH was adjusted to 1-2 with concentrated hydrochloric acid. The mixture was extracted with DCM (100 mL x 3). After standard workup, the crude product was obtained, which was then purified by silica gel column chromatography (EA / PE, EA ranging from 16 to 53%) to afford 164-C (180 mg, 4% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)11.95(br s,1H),10.18(s,1H),7.36(d,J=7.96Hz,1H),6.44(s,1H),6.40(dd,J=2.26,8.53Hz,1H),3.82(s,3H),3.67(br d,J=4.02Hz,1H),2.68(br s,1H),1.62-1.93(m,6H),1.49(br s,1H),1.34(br d,J=15.06Hz,4H)

[0440] Step 2: Referring to the method of Step 2 of Example 5, compound 164-C (100 mg, 359.3 μmol) was reacted (NaOH was 5 eq, NaBH4 was 40 eq) to obtain white solid compound 164 (18 mg, yield 19.1%) and white solid compound 165 (8 mg, yield 8.5%).

[0441] Compound 164: LCMS: (ESI) m / z=263.0 [M+1] + ; 1H NMR(400MHz, DMSO-d6)9.56(s,0.6H),9.47(s,0.3H),7.02(d,J=8.0Hz,0.3H),6.93(d,J=8.3Hz,0.6H),6.45(d,J=2.0Hz,0.6H),6.42 (d,J=2.0Hz,0.3H),6.36(dd,J=8.3,2.0Hz,1H),5.53(d,J=4.5Hz,0.3H),5.29(d,J=3.5Hz,0.6H),3.77(s,2H),3.75(s,1H),3.10(br t,J=5.6Hz,0.3H),2.65-2.72(m,1.2H),2.35-2.43(m,0.6H),1.98(br d,J=14.1Hz,0.4H),1.77-1.88(m,1.3H),1.42-1.63(m,3.2H),1.16-1.30(m,2H),0.83-1.05(m,1.2H),0.58-0.69(m,0.3H)

[0442] Compound 165: LCMS: (ESI) m / z=263.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)9.65(s,1H),7.15(d,J=8.5Hz,1H),6.44(s,1H),6.39(br d,J=8.3Hz,1H),5.33(d,J=10.3Hz,1H),3.74(s,3H),2.31-2.39(m,1H),1.92-2.04(m,2H),1.66-1.82(m,2H),1.61(br d,J=12.0Hz,1H),1.14-1.30(m,4H)

[0443] Example 46 Synthesis of Compound 166

[0444] Step 1: Following the representative catalytic hydrogenation procedure, compound 166-A (35 mg) was used as the starting material to obtain compound 166 (28 mg, 39% yield) as a white solid. Purification was performed by silica gel column chromatography (EA:PE, EA from 0 to 25%). LCMS: (ESI) m / z = 291.1 [M+1] + ; 1H NMR (400MHz, CDCl3)6.99(s,1H),6.58(s,1H),5.40(s,1H),3.92(s,1H),3.77(s,3H),2.84-2.93(m,2H),2.67-2.80(m,2H),1.60(s,3H).

[0445] Synthesis of Compound 168: To a solution of Compound 166 in DMF (0.5 mL) was added NaOH (0.5 M, 1.5 eq). The reaction was stirred at 25°C for 2 hours. LCMS indicated 20% starting material remaining and 35% desired product formed. The pH was adjusted to 6 with formic acid and the product was purified directly by prep HPLC (FA Method B; B%: 23%-43%, 10 min) to afford Compound 168 as a white solid (yield 54%). LCMS: (ESI) m / z = 309.0 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)9.67-11.99(m,1H),7.06(br s,1H),6.50(br s,1H),5.37(br s,1H),4.29(br s,1H),3.76(br s,1H),3.69(br s,3H),2.61-2.79(m,2H),2.44(br d,J=7.03Hz,2H),1.49-1.63(m,3H).

[0446] Synthesis of Compound 167: Following the synthesis method of Example 5-a, methylamine (33% in ethanol) was reacted with Compound 166 (reaction time: 2 hours, 44% of the starting material remained) to obtain Compound 167 as a white solid in a yield of 28.4%. LCMS: (ESI) m / z = 322.0 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)9.84(br s,1H),7.75(br s,1H),7.02(s,1H),6.49(s,1H),5.37(s,1H),4.29(s,1H),3.70(s,3H),2.63-2.71(m,2H),2.56(br d,J=4.28Hz,3H),2.24-2.32(m,2H),1.58(s,3H).

[0447] Example 47 Synthesis of Compound 169

[0448] To a mixture of compound 169-A (100 mg, 416 μmol) in THF (2 mL) and water (5 mL) were added NaOH (49.9 mg, 1.25 mmol) and NaBH4 (94.5 mg, 2.5 mmol). The reaction was stirred at 20°C for 3 hours. 1M HCl (5 mL) and EtOAc (5 mL) were added at 10°C, and the mixture was extracted with EA (5 mL x 2). The combined organic phases were dried with nitrogen (note: do not concentrate under reduced pressure) to obtain the crude product, which was purified by silica gel column chromatography (EA / PE, EA from 0 to 50%) to obtain white compound 169 (20 mg, yield 21%). LCMS: (ESI) m / z = 224.9 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.23(d,J=7.78Hz,1H),6.88(d,J=1.51Hz,1H),6.85(dd,J=1.51,7.78Hz,1H),5.03(br s,1H),4.79(dd,J=4.64,7.15Hz,1H),3.74(s,3H),2.15-2.23(m,2H),1.64-1.85(m,2H).

[0449] Example 48 Synthesis of Compound 171 and Compound 267

[0450] Step 1: Referring to the method of step 1 in Example 45, 164-A (9.5 g, 76.53 mmol) was reacted with 171-B (1 eq) to obtain a yellow solid 171-A (130 mg, yield 0.68%) and a yellow oil 267-A (14 g, 55.9 mmol, yield 73.1%).

[0451] Compound 171-A: 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H), 7.46 (s, 1H), 7.43-7.45 (m, 1H), 6.32-6.39 (m, 2H), 3.5 (s, 3H), 1.75 (s, 3H), 1.58 (s, 3H).

[0452] Synthesis of Compound 171: Compound 171-A (50 mg, 199 μmol) was dissolved in THF (5 mL), and palladium hydroxide on carbon (20% content, 100 mg) was added. The reaction mixture was thoroughly purged of hydrogen. The reaction mixture was stirred at 25°C under a 15 psi hydrogen atmosphere for 16 hours. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA / PE, EA ranging from 0 to 35%) to afford Compound 171 (15 mg, 32% yield) as a yellow solid.1 H NMR(400HMz,DMSO-d6)δ(ppm)9.59(s,1H),6.96-7.01(m,1H),6.35-6.44(m,2H),5.22-5.39(m,1H),3.75(s,3H),2.6 8-2.85(m,1H),2.49-2.55(m,1H),1.05-1.18(m,3H),0.94-1.03(m,2H),0.36-0.38(m,0.5H).LC-MS:(ESI)m / z.[M+H] + 237.0.

[0453] Synthesis of compound 267: Referring to the synthesis method of compound 171, compound 267-A (100 mg, 399 μmol, 1 eq) was reacted to obtain white solid compound 267 (30 mg, yield 30.5%). 1 H NMR (400HMz, DMSO-d6) δ (ppm) 9.72-9.92 (m, 1H), 6.97-7.13 (m, 1H), 6.42 (dt, J = 2.2, 4.7Hz, 2H), 5.20-5.69 (m,1H),3.70(s,3H),2.82-3.20(m,1H),2.56-2.80(m,1H),1.07(dd,J=7.4,15.7Hz,3H),0.36-0.98(m,3H). LC-MS:(ESI)m / z.[M+H] + 237.0.

[0454] Example 50 Synthesis of Compound 174

[0455] Step 1: Compound 174-A (100 mg, 485 μmol), morpholine (123 mg, 1.45 mmol, 3 eq), and glyoxylic acid (179 mg, 1.21 mmol, 135 μL, 2.5 eq) were stirred at 60°C for 16 hours. The mixture was cooled to room temperature, diluted with 5ACN (1 mL), and purified directly by prep HPLC (FA method, B: 15%-35% B over 38 min) to afford compound 174-B (38 mg, 22.4% yield) as a brown solid. 1H NMR (400MHz, CDCl3) δ (ppm) 7.87 (d, J = 8.6 Hz, 1H), 6.58 (dd, J = 2.4, 8.8 Hz, 1H), 6.48(d,J=2.2Hz,1H),6.03-6.20(m,1H),5.47(dd,J=1.3,17.4Hz,1H),5.38(d d,J=0.9,10.6Hz,1H),4.66(d,J=5.7Hz,2H),4.21(t,J=6.2Hz,1H),3.88(s,3H ),3.80-3.85(m,4H),3.65-3.74(m,1H),3.47-3.57(m,1H),2.81-2.88(m,4H).

[0456] Step 2: Following the procedure of Step 2 in Example 5 (representative operation for constructing a five-membered lactone ring), compound 174-B (310 mg, 887 μmol, 1 eq) was reacted to give a yellow oil 174-C (77 mg, 230 μmol, yield 26%). LC-MS: (ESI) m / z. [M+H] + 334.1.

[0457] Step 3: Referring to the method of Step 3 of Example 2, compound 174-C (77 mg, 230 μmol) was reacted to obtain a white solid compound (15 mg, 51 μmol, yield 22.1%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.68-10.17 (m, 1H), 7.05-7.22 (m, 1H), 6.42 (dd, J = 2.1, 4.5Hz, 2H), 5.61 (dd, J=5.0, 8.5Hz, 0.3H), 5.51 (dd, J=5.7, 10.8Hz, 0.7H), 3.91 (dd, J= 8.4,12.1Hz,0.7H),3.69-3.76(s,3H),3.67(dd,J=2.3,4.7Hz,0.3H),3.59(t,J=4.5Hz ,4H),2.76-2.91(m,2H),2.42-2.50(m,3H),2.18-2.39(m,1H).LC-MS:(ESI)m / z.[M+H] + 294.1.

[0458] Example 51 Synthesis of Compound 271 and Compound 272

[0459] Step 1: To a mixture of compound 271-A (500 mg, 3.49 mmol) and Na2CO3 (740 mg, 6.98 mmol) in THF / water (10 mL, 1:1) was added compound 271-B (500 mg, 3.94 mmol) at 0°C. The mixture was reacted at 0°C for 10 minutes. The solvent was removed under reduced pressure, and the crude product was isolated and purified by Prep HPLC (column: C18 150×40 mm; mobile phase: [water(FA)-ACN]; gradient: 1%-41% B over 9 min) to afford compound 271-C (520 mg, 64% yield) as a colorless oil. LCMS: (ESI) m / z = 234.0 (M+1) + .

[0460] Step 2:

[0461] Preparation of acid chloride: To a solution of compound 271-C (320 mg, 1.37 mmol) in DCM (5 mL) were added thionyl chloride (349 mg, 2.01 eq) and DMF (1.00 mg, 0.01 eq). The mixture was stirred at 25°C for 2 hours, concentrated under reduced pressure, and dissolved in THF (2 mL).

[0462] To a mixture of compound 271-D (140 mg, 687 μmol) in THF / water (10 mL, 1:1) was added Na₂CO₃ (218 mg, 2.06 mmol), and the temperature was cooled to 0°C. The acid chloride solution prepared above was added, and the mixture was stirred at 0°C for 10 minutes. The mixture was concentrated under reduced pressure, and the crude product was directly purified by prep HPLC (column: Boston Prime C₁₈ 150*30mm*5um; mobile phase: [Water(NH₃H₂O-NH₄HCO₃)-MeCN]; gradient: 10%-30% B over 10 min) to afford compound 271-E (110 mg, 38.29% yield) as a yellow solid. LC-MS: (ESI) m / z. [M+H] + 420.3.

[0463] Step 3: Following the procedure of Step 2 in Example 39 (representative method for removing the Boc protecting group), compound 271-E (110 mg) was reacted to obtain compound 271-F (80 mg, 184 μmol, 70.40% yield, TFA salt) as a white solid. LC-MS: (ESI) m / z. [M+H] + 320.0.

[0464] Step 4: To a solution of compound 271-F (70 mg, 161.36 μmol, 1 eq, TFA) in DMF (1 mL) were added DIEA (104 mg, 806 μmol, 5 eq) and compound 112 (42.3 mg, 161 μmol, 1.0 eq). The mixture was stirred at 50°C for 16 hours. The reaction solution was directly purified by prep HPLC (FA method, B: 18%-38% over 11 min) to afford compound 271 (15 mg, 26.4 μmol, 16.36% yield) and compound 272 (45 mg, 74.2 μmol, 46.00% yield) as a white solid.

[0465] Compound 271: 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.45-9.78 (m, 1H), 7.74-8.05 (m, 2H), 6.99 (d, J = 3.9Hz, 1H), 6.77 (br dd,J=10.7,16.3Hz,1H),6.48(s,1H),6.06(dd,J=2.3,16.8Hz,1H),5.48-5.73(m,2H),3.78-4.50(m,4H),3.72(s,3H),2.78-3 .13(m,3H),2.63-2.75(m,3H),2.40-2.46(m,1H),2.31-2.39(m,2H),1.89-2.24(m,4H),1.42-1.89(m,4H),1.04-1.38(m,2H). LC-MS:(ESI)m / z.[M+H] + 546.3

[0466] Compound 272: 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.35-9.86(m,1H),7.97-8.11(m,1H),7.80-7.96( m,1H),6.99(d,J=4.0Hz,1H),6.49(s,1H),5.59(t,J=7.5Hz,1H),4.72-4.81(m,1 H),4.00-4.39(m,2H),3.64-3.86(m,6H),2.61-3.06(m,8H),2.29-2.48(m,4H), 1.88-2.28(m,4H),1.42-1.87(m,4H),1.08-1.41(m,2H).LC-MS:(ESI)m / z.[M+H] + 582.5

[0467] Referring to the synthesis method of compound 271, the starting materials in the following table were used to carry out four-step reactions to obtain the corresponding final compounds.

[0468] Referring to the method of steps 3 and 4 in the synthesis of compound 271, the starting materials in the following table were used to carry out a two-step reaction to obtain the corresponding final compound.

[0469] The synthesis method of 292-A mentioned in the above table is

[0470] Following the procedure of step 2 in Example 5-b, 292-B (500 mg, 2.54 mmol) was reacted with 271-D (517.7 mg, 2.54 mmol) to obtain the white solid compound 292-A (70 mg, yield 7.2%). LC-MS (ESI) m / z: 384.4 (M+H) + .

[0471] Example 52 Synthesis of Compound 274

[0472] Step 1: To a solution of compound 274-A (5 g, 32.4 mmol) in toluene (50 mL) were added 274-B (6.04 g, 32.4 mmol) and paraformaldehyde (1.95 g, 64.8 mmol, 2 eq). The reaction was stirred at 50°C for 16 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to afford compound 274-C (9 g, 79% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 353.2.

[0473] Step 2: Add MnO2 (16 g, 184 mmol, 10 eq) to a solution of compound 274-C (6.5 g, 18.4 mmol) in DCM (60 mL) and stir at 25°C for 5 hours. Filter and concentrate under reduced pressure to obtain compound 274-D (2 g) as a white solid. The crude product was used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 351.1.

[0474] Step 3: Following the procedure of Step 1 in Example 2, compound 274-D (2 g) was reacted to obtain compound 274-E (2 g, two-step yield approximately 28%) as a yellow oil. LC-MS: (ESI) m / z [M+H] + 391.2.

[0475] Step 4: Following the procedure of Step 2 in Example 39 (representative method for removing the Boc protecting group), compound 274-E (2.5 g) was reacted to obtain compound 274-F (1.8 g) as a yellow oil. The crude product was used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 291.1.

[0476] Step 5: Following the procedure of Step 1 in Example 51, 274-E (500 mg, 1.24 mmol, TFA salt) was reacted to obtain a yellow oily compound 274-G (230 mg, approximately 34% yield over two steps). LC-MS: (ESI) m / z [M+H] + 381.1.

[0477] Step 6 and Step 7: Referring to the method of Step 2 and Step 3 in Example 2, 274-G (143 mg, 603 μmol) was used for two-step reaction to obtain white solid compound 274 (1 mg, two-step yield about 1.4%). 1 H NMR(400MHz,DMSO-d6)δ(ppm)6.89(s,1H),6.73-6.85(m,1H),6.46-6.53(m,1H),6.05-6.15(m,1H),5 .73-5.78(m,1H),5.63-5.71(m,1H),5.36-5.43(m,1H),3.73-3.80(m,3H),3.48-3.61(m,6H),2.41(br s,4H),2.12-2.26(m,2H),1.29(td,J=4.4,8.3Hz,1H),0.93-1.12(m,1H),0.63-0.70(m,1H).LC-MS:(ESI)m / z[M+H] + 373.3.

[0478] Example 53 Synthesis of Compound 276

[0479] To a solution of compound 14 (100 mg, 427 μmol) in DCM (5 mL) was added m-CPBA (4.33 mg, 21.3 μmol, 85% purity, 0.05 eq). After stirring at 25°C for 15 minutes, NBS (76 mg, 427 μmol) was added and the mixture was allowed to react at 40°C for 16 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and the product was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 6%) to afford Compound 276 (100 mg, 75% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.13-9.45 (m, 1H), 6.94-7.12 (m, 1H), 5.84 (d, J = 4.8Hz, 0.22H), 5.47 (s, 0.75H), 3.69-3.85 (m, 3H) ),2.56-2.63(m,0.27H),2.26-2.37(m,1.61H),2.17-2.21(m,3H),1.07-1.37(m,1H),0.78-1.06(m,1H).LC-MS:(ESI)m / z.[M+H] + 313.0.

[0480] Example 54 Synthesis of Compound 277

[0481] Step 1: To a mixture of compound 14-a (800 mg, 2.77 mmol) and 277-B (900 mg, 3.58 mmol) in toluene (15 mL) and H₂O (5 mL) was added cesium carbonate (2.7 g, 8.3 mmol). After thorough nitrogen displacement, RuPhos Pd G3 catalyst (CAS: 1445085-77-7, 231 mg, 276 μmol) was added and stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and extracted with EA (10 mL x 3). Conventional workup procedures gave a residue, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to afford compound 277-C (960 mg, 98% yield) as a white solid. LC-MS: Rt = 0.983 min, (ESI) m / z [M+H] + 354.2

[0482] Step 2: A solution of compound 277-C (870 mg, 2.46 mmol) in HCl in dioxane (2 M, 10 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to afford a green solid, compound 277-D (570 mg, HCl salt). The crude product was used directly in the next reaction. LC-MS: (ESI) m / z [M+H] + 196.1.

[0483] Step 3: Following the procedure of Step 2 in Example 5-b, 277-D (570 mg, HCl salt) was reacted with 1-adamantaneacetic acid (956 mg, 2 eq) to obtain a white solid compound 277-E (1.0 g, approximately 74% yield over two steps). LC-MS: (ESI) m / z [M+H] + 548.4.

[0484] Step 4: Following the procedure of Example 34, the reaction was carried out using 277-E (1.0 g) as the starting material. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH was adjusted to 1 with 1 M HCl. The precipitated solid was filtered to obtain compound 277-F (700 mg) as a white solid. The crude product was used directly in the next step. LC-MS: (ESI) m / z [M+H] + 372.2.

[0485] Step 5 to Step 7: Following the method of Example 2, 277-F (645 mg) was used as the starting material to carry out three steps of reaction to obtain white solid compound 277 (17 mg, four-step yield 12.6%). LC-MS: (ESI) m / z [M+H] + 440.2. 1 HNMR(400MHz,DMSO-d6)δ(ppm)9.48-9.88(m,1H),7.60-7.79(m,1H),6.78-6.98(m,1H),6.45-6. 56(m,1H),5.72(d,J=4.6Hz,0.2H),5.37(s,0.8H),3.64-3.81(m,3H),3.10-3.23(m,2H),2.58(br t,J=7.4Hz,2H),2.21(m,1.8H),1.89(br s,3H),1.73-1.83(m,2H),1.44-1.71(m,13H),1.24-1.35(m,1H),0.92-1.09(m,1H),0.71-0.78(m,0.2H)

[0486] The synthesis method of compound 14-a is:

[0487] Step 1: To a solution of 5-bromo-2,4-dihydroxybenzene-1-carbaldehyde (4.5 g, 20.74 mmol) in acetone (100 mL) were added chloromethyl ether (1.96 g, 20.74 mmol) and K2CO3 (8.60 g, 62.21 mmol). The mixture was reacted at 20°C for 16 hours. Saturated aqueous NH4Cl solution (50 mL) was added, and the mixture was extracted with EA (50 mL x 3). Standard workup procedures were performed to obtain a crude product, which was purified by silica gel column chromatography (EA:PE, EA ranging from 0 to 9%) to afford 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carbaldehyde (3.22 g, 56% yield) as a white solid.

[0488] Step 2: To a mixture of 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carbaldehyde (3.6 g, 13.09 mmol) in DMF (2 mL) were added iodomethane (2.23 g, 15.70 mmol) and KCO (3.62 g, 26.17 mmol). The mixture was reacted at 20°C for 16 hours. Water (50 mL) was added, and the mixture was extracted with EA (50 mL x 2). Standard workup procedures were performed to obtain a crude product, which was purified by silica gel thin-layer chromatography (EA:PE, EA ranging from 6 to 9%) to afford 14-a (3.58 g, 94% yield) as a white solid.

[0489] Example 55 Synthesis of Compound 129

[0490] Step 1: Wang Resin (400 mg, 0.544 mmol) was placed in a 40 mL reaction flask and suspended in 10 mL of DCM / DMF (1:9). In a separate vial, a solution of compound 129-A (440 mg, 1.07 mmol) and HOBt (146 mg, 1.08 mmol) in DMF (1 mL) was dissolved and added to the resin. DMAP (8 mg, 65.5 μmol) was added to the reaction flask, followed by DIC (145 mg, 1.15 mmol), and the reaction mixture was shaken at 25°C for 6 hours. Acetic anhydride (120 mg, 1.17 mmol) and pyridine (108 mg, 1.36 mmol) were added to the reaction flask and shaken at 25°C for an additional 30 minutes to cap any unreacted hydroxyl groups on the resin. The resin was filtered and washed twice with 20 mL of DMF and five times with 20 mL of DCM to obtain wet resin 129-B for the next step.

[0491] Step 2: Resin 129-B (0.544 mmol) was placed in a solid-phase synthesis reactor and 15 mL of DMF was added. The mixture was stirred for 30 seconds to dissolve, and then the solvent was removed by vacuum filtration. 15 mL of 20% piperidine / DMF was added, stirred for 15 minutes, and then the solvent was removed by vacuum filtration. 15 mL of 20% piperidine / DMF was added again, stirred for 15 minutes, and then the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF. 2-Cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (833 mg, 2.19 mmol), and HOAt (301 mg, 2.21 mmol) were dissolved in DMF (15 mL) and the solution was added to the resin and stirred for 30 seconds. DIPEA (643 mg, 4.98 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, after which the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF. The obtained resin 129-C was washed four times with 15 mL of DCM and then collected into a reaction flask for the next reaction.

[0492] Transfer some resin beads to a small glass tube, add 1 mL of 5% TFA in DCM and wait 3 hours. Remove the solvent and dilute with ACN / water (1:1, 1 mL). Filter and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m / z. [M+H] + 313.1.

[0493] Step 3: Resin 129-C (544 μmol) was placed in a reaction flask, and DCM (10 mL) and phenylsilane (482 mg, 4.46 mmol) were added. The mixture was gently stirred for 1 minute and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh3)4 (150 mg, 130 μmol) was added to the reaction suspension, which was vacuum degassed and purged with nitrogen five times. The reaction suspension was then shaken at 25°C under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed five times with 15 mL of DMF. A solution of 0.5% PIX (potassium isopropyl xanthate) and 0.5% DIEA in DMF (10 mL) was added, gently stirred for 5 minutes, and the solvent was removed by vacuum filtration. This was repeated twice, and the resin was washed five times with 15 mL of DMF. The resin was then washed five times with 15 mL of DCM to obtain the off-white resin 129-D, which was used for the next reaction.

[0494] Step 4: Resin 129-D (544 μmol) was placed in a reaction flask, 5% TFA / DCM solution (15 mL) was added to the resin, and the mixture was shaken at 25°C for 4 hours. The reaction suspension was filtered and the resin was washed three times with 15 mL of DCM. The filtrates were combined and concentrated under reduced pressure. The crude product was dissolved in 5 mL of deionized water and filtered to remove insoluble matter. This was repeated three times. The combined filtrate was freeze-dried to obtain a colorless syrupy product 129-E (156 mg, yield 83.77%, TFA salt), which was used directly in the next step. LC-MS: (ESI) m / z. [M+H] + 229.1;

[0495] Step 5: To a solution of 129-E (62 mg, 181 μmol, 1.2 eq., TFA salt) in DMF (1.5 mL) was added TEA (51 mg, 503 μmol), followed by compound 112 (40 mg, 153 μmol, 1.0 eq). The reaction mixture was stirred at 55°C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by prep HPLC (FA method-A; B%: 25%-45%, 10 min) to afford compound 129 (32 mg, 41.5% yield) as an off-white solid. LC-MS: (ESI) m / z. [M+H]+ 491.4; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.36-7.55 (m, 2H), 6.93 (s, 1H), 6.46 (s, 1H), 5.61-5.69 (m, 1H), 4.42 (br s,1H),3.74(s,3H),3.43-3.70(m,2H),2.66-2.90(m,2H),2.38-2.66(m,5H) ,1.97-2.22(m,3H),1.53-1.76(m,6H),0.99-1.28(m,3H),0.82-0.99(m,2H).

[0496] Referring to the method of Example 55, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five-step reaction to obtain the corresponding final compound.

[0497] Example 56 Synthesis of Compound 125

[0498] Step 1: Compound 125-A (780 mg, 1.95 mmol) was dissolved in DCM (15 mL), and DIPEA (964.57 mg, 7.46 mmol) was added to the molten solution. 2-Chlorotrityl chloride resin (CTC resin) (1.3 g, 1.0 mmol / g, 1.30 mmol) was added to the solution, and the mixture was shaken at 25°C for 2 hours. 2 mL of methanol was added to the solution, and the mixture was shaken at 25°C for 30 minutes. The mixture was filtered, and the resin was washed five times with 20 mL of DCM and dried under vacuum to obtain the desired yellow solid resin 125-B (1.78 g).

[0499] Step 2: Resin 125-B (1.54 g, 1.0 mmol) was placed in a solid-phase synthesis reactor. 20 mL of DCM was added and allowed to swell for 15 minutes. The solvent was then removed by vacuum filtration and washed once with 20 mL of DMF. 20 mL of 20% piperidine / DMF was added, stirred for 30 minutes, and the solvent was removed by vacuum filtration. 20 mL of 20% piperidine / DMF was added again, stirred for 30 minutes, and the solvent was removed by vacuum filtration. The resin was washed five times with 20 mL of DMF. Compound 129-A (827 mg, 2.02 mmol), HATU (768 mg, 2.02 mmol), and HOAt (275 mg, 2.02 mmol) were dissolved in DMF (10 mL). The solution was added to the resin and stirred for 30 seconds. DIPEA (890 mg, 6.89 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, after which the solvent was removed by vacuum filtration and the resin was washed five times with 15 mL of DMF. The resulting resin 125-C was washed five times with 15 mL of DCM and used in the next step.

[0500] Step 3: Resin 125-C (0.75 g, ~0.5 mmol) was placed in a solid-phase synthesis reactor. 15 mL of DCM was added and allowed to soak for 15 minutes to swell the resin. The solvent was then removed by vacuum filtration and washed once with 20 mL of DMF. 10 mL of 20% piperidine / DMF was added, stirred for 15 minutes, and then the solvent was removed by vacuum filtration. 20 mL of 20% piperidine / DMF was added again, stirred for 15 minutes, and then the solvent was removed by vacuum filtration and the resin was washed five times with 15 mL of DMF. 2-Cyclohexylacetic acid (285 mg, 2.00 mmol), HATU (760 mg, 2.00 mmol), and HOAt (273 mg, 2.01 mmol) were dissolved in DMF (10 mL) and the solution was added to the resin and stirred for 30 seconds. DIPEA (649 mg, 5.02 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, after which the solvent was removed by vacuum filtration and the resin was washed five times with 15 mL of DMF. The obtained resin 125-D was washed five times with 15 mL of DCM and then collected into a reaction flask for the next step.

[0501] Step 4: Referring to the method of step 3 of Example 55, resin 125-D (0.5 mmol, 1.0 eq.) was reacted to obtain yellow resin 125-E for the next reaction.

[0502] Transfer some resin beads to a small glass tube, add 1 mL of 2% TFA in DCM and wait 15 minutes. Remove the solvent and dilute with acetonitrile / water (1:1, 1 mL). Filter and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m / z. [M+H] + 388.2;

[0503] Step 5: Following the procedure of Step 4 in Example 55, the resin 125-E (0.5 mmol, 1.0 eq.) was reacted to obtain an off-white solid 125-F (232 mg, 92.52% yield, TFA salt). LC-MS: (ESI) m / z [M+H] + 388.3;

[0504] Step 6: Following the procedure of Step 5 of Example 55 (reaction temperature: 25°C), 125-F (71 mg, 183 μmol, TFA salt) was reacted to give Compound 125 (72 mg, 69.07% yield) as a white solid. LC-MS: (ESI) m / z. [M+H] + 650.6; 1H NMR (400MHz, CDCl3) δ (ppm) 7.03-7.21 (m, 3H), 6.89-7.01 (m, 1H), 6.47 (s, 1 H),5.62-5.69(m,1H),4.59-4.74(m,1H),3.77(s,3H),3.70-3.86(m,2H),3 .41-3.67(m,9H),3.23-3.39(m,1H),2.73-2.94(m,2H),2.48-2.70(m,7H), 1.98-2.22(m,3H),1.55-1.83(m,6H),1.05-1.33(m,3H),0.77-1.02(m,2H).

[0505] Referring to the method of Example 56, the starting materials in the following table were used to replace compounds 129-A and 125-B in the second step to carry out five-step reactions to obtain the corresponding final compounds.

[0506] Example 57 Synthesis of Compound 128

[0507] Step 1: Resin 129-B (0.544 mmol) was placed in a reaction flask, DCM (10 ml) and phenylsilane (482 mg, 4.46 mmol) were added, stirred gently for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh3)4 (140 mg, 121 umol) was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and then the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL of DCM five times, and then washed with 15 mL of DMF three times to obtain yellow resin 128-A for the next step.

[0508] Step 2: Resin 128-A (0.544 mmol) was placed in a solid-phase synthesis reactor and washed once with 20 mL of DMF. 2-Cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (834 mg, 2.19 mmol), and HOAt (302 mg, 2.22 mmol) were dissolved in DMF (10 mL) and added to the resin, stirring for 30 seconds. DIPEA (649 mg, 5.02 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, after which the solvent was removed by vacuum filtration and the resin was washed twice with 15 mL of DMF. A solution of 0.5% PIX and 0.5% DIPEA in DMF (10 mL) was added, stirred for 5 minutes, and then the solvent was removed by vacuum filtration. This was repeated twice, and the resin was washed three times with 15 mL of DMF. 15 mL of 20% piperidine in DMF was added, stirred for 30 minutes, and then the solvent was removed by vacuum filtration. Another 15 ml of 20% piperidine / DMF was added, stirred for 30 minutes, then the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF.

[0509] Step 3 and Step 4: Following the procedures of Step 4 and Step 5 of Example 55, a two-step reaction was carried out with 128-B to obtain compound 128 as a white solid in a 36% yield. LCMS: (ESI) m / z = 491.5 (M+1) + ; 1 H NMR (400MHz, CDCl3) δ7.51-7.68(m,1H),6.88-7.11(m,1H),6.96(s,1H),6.46(s,1H),5.61-5.72(m,1H),4.50(br s,1H),3.74(s,3H),3.42-3.68(m,2H),2.69-2.96(m,2H),2.41-2.69(m,5H),2.07-2. 24(m,1H),1.92-2.07(m,2H),1.53-1.76(m,6H),1.00-1.28(m,3H),0.77-0.97(m,2H).

[0510] Referring to the method of Example 57, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five-step reaction to obtain the corresponding final compound.

[0511] Example 58 Synthesis of Compound 126

[0512] Step 1: Resin 125-C (0.75 g, 0.5 mmol) was placed in a reaction flask. DCM (15 mL) and phenylsilane (438 mg, 4.05 mmol) were added. The mixture was gently stirred for 1 minute and allowed to swell for 15 minutes. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh3)4 (150 mg, 130 μmol) was added to the reaction suspension. The mixture was vacuum degassed and purged with nitrogen five times, and then shaken under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed five times with 15 mL of DMF. The resulting resin was placed in a solid-phase synthesis reactor. 2-Cyclohexylacetic acid (285 mg, 2.00 mmol), HATU (761 mg, 2.00 mmol), and HOAt (273 mg, 2.01 mmol) were dissolved in DMF (15 mL). The solution was added to the resin and stirred for 30 seconds. DIPEA (742 mg, 5.74 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, after which the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF. 15 mL of 20% piperidine in DMF was added, stirred for 15 minutes, and the solvent was removed by vacuum filtration. 15 mL of 20% piperidine in DMF was added again, stirred for 15 minutes, and the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF.

[0513] Step 2 and Step 3: Following the procedure of Step 4 and Step 5 of Example 55 (the reaction temperature in Step 5 was 25°C), a two-step reaction was carried out with 126-A to obtain compound 126 as a white solid in a 31% yield. LC-MS: (ESI) m / z [M+H] + 650.6; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.64-7.78 (m, 1H), 7.13-7.27 (m, 1H), 6.97 (s, 1H), 6.70-6.8 8(m,1H),6.47(s,1H),5.57-5.79(m,1H),4.60-4.72(m,1H),3.76(s,3H),3.70-3.84(m, 2H),3.43-3.67(m,10H),3.23-3.37(m,1H),3.23-3.37(m,1H),2.47-2.93(m,9H),2.09- 2.22(m,1H),1.90-2.09(m,2H),1.55-1.79(m,6H),1.04-1.31(m,3H),0.78-0.99(m,2H).

[0514] Example 59 Synthesis of Compound 122

[0515] Step 1: Following the procedure of Step 2 in Example 56, 122-B was substituted for compound 129-A and reacted with 125-B to obtain 122-A. Further, following the procedure of Example 58, 122-A was used as the starting material for three steps to obtain compound 122 as a white solid. LC-MS: (ESI) m / z. [M+H] + 650.4; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.57-7.79 (m, 1H), 7.10-7.27 (m, 1H), 6.97 (s, 1H), 6.60-6. 78(m,1H),6.47(s,1H),5.55-5.75(m,1H),4.62-4.73(m,1H),3.77(s,3H),3.69-3.87(m ,2H),3.38-3.69(m,9H),3.19-3.37(m,1H),2.72-2.97(m,2H),2.35-2.72(m,7H),2.08- 2.22(m,1H),1.88-2.08(m,2H),1.47-1.80(m,6H),1.04-1.33(m,3H),0.80-0.98(m,2H)

[0516] Example 60 Synthesis of Compound 286

[0517] Step 1: To a solution of compound 67-A (500 mg, 1.99 mmol) in pyridine (10 mL) was added acetic anhydride (2.03 g, 19.91 mmol). The reaction was incubated at 25°C for 16 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, and extraction was performed with EA (5 mL x 3). Conventional post-processing procedures gave a crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) to afford a yellow solid (560 mg, 95.94% yield). 1 H NMR(400MHz,DMSO-d6)δppm 10.60(s,1H)8.97(d,J=8.53Hz,1H)8.10(d,J=8.03Hz,1H)7.86(s,1H)7.79-7.84(m,1H)7.71-7.76(m,1H)2.49-2.50(m,3H).

[0518] Step 2 and Step 3: Following the procedures of Step 2 and Step 3 in Example 12, the product from the previous step (510 mg, 1.74 mmol) was used as the starting material for a two-step reaction to obtain Compound 286 as a yellow solid. The two-step yield was 73.6%. LCMS: m / z = 349.0 [M+H] + ; 1H NMR (400MHz, CDCl3) δppm 8.03-8.12(m,1H)7.90-7.98(m,1H)7.56-7.63(m,2H)7.52(s,1H)6.51(dd,J=10.57, 7.19Hz,1H)2.87-2.94(m,2H)2.67-2.77(m,1H)2.59-2.67(m,1H)2.47-2.51(m,3H).

[0519] Example 61 Chiral Resolution of Compound 172

[0520] Compound 172 (30 mg) was chirally separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₃H₂O)]; B%: 15%, isocratic elution mode) to afford compounds 293, 294, 295, and 296. Compound 293 (3 mg), white solid, SFC: Rt = 1.343 min. Compound 294 (10 mg), white solid, SFC: Rt = 1.497 min. Compound 295 (8 mg), white solid, SFC: Rt = 1.703 min. Compound 296 (3 mg), white solid, SFC: Rt = 1.775 min. The SFC analysis method was as follows: column: Chiralpak AD-3 100×4.6mm ID, 3μm; mobile phase: A:CO2 B:ethanol (0.05% DEA); gradient: B from 5% to 40% in 3 minutes, 40% B maintained for 0.5 minutes, and then 5% B maintained for 1.5 minutes; flow rate: 2.8mL / min; column temperature: 35°C; ABPR: 1500psi.

[0521] Biological activity test example 1

[0522] HTRF (homogeneous time-resolved fluorescence) technology was used to evaluate the inhibitory effect of the compounds on the binding of TDG to double-stranded DNA substrates.

[0523] Reagents and consumables

[0524] instrument

[0525] Microplate reader (manufacturer: Perkin Elmer, model: Envision multi-function microplate reader, equipped with HTRF function module) and Echo 550 (manufacturer: Labcyte, model: Echo 550)

[0526] Experimental methods

[0527] 1. Prepare a compound concentration gradient: Test compound starting at 250 μM, dilute three-fold, and assay in duplicate. Serially dilute the compound to 10 concentrations, each 40 times the final concentration, in a 384-well plate. Then, transfer 500 nl of the solution to a 384-well plate using an Echo550. Add 500 nl of 100% DMSO or non-biotinylated dsDNA substrate to each of the negative and positive control wells.

[0528] 2. Add 1.5 μl / well of Epigeneous Binding Domain diluent buffer to a 384-well plate and centrifuge at 1000 rpm for 1 min.

[0529] 3. Add 4 μl of His-tagged TDG protein (5 times the final concentration, 40 nM, diluted with Epigeneous Binding Domain diluent buffer) to a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 10 min.

[0530] 4. Add 4 μl of 5-fold final concentration of Biotin-labeled dsDNA substrate (final concentration 40 nM, diluted with Epigeneous Binding Domain diluent buffer) to a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

[0531] 5. Add 5 μl of 4-fold final concentration of Streptavidin-XL665 (final concentration 5 nM, diluted with Epigeneous Binding Domain Detection buffer) to a 384-well plate and centrifuge at 1000 rpm for 1 min.

[0532] 6. Add 5 μl of MAb Anti-6HIS-Eu cryptate Gold (final concentration 0.1 μg / ml, diluted with Epigeneous Binding Domain Detection buffer) at 4 times the final concentration to the 384-well plate and centrifuge at 1000 rpm for 1 min.

[0533] Incubate at 4°C overnight and read HTRF with a microplate reader.

[0534] Data Analysis

[0535] 1. Calculation of the Ratio value for each hole

[0536] Ratio=Signal 665nm / Signal 620nm×104

[0537] 2. Calculation of delta ratio value for each hole

[0538] delta Ratio=Ratio standard or sample-Ratio standard 0 (negative control)

[0539] 3. Using Four-Parameter Logistic (4PL) Curve Fitting IC 50

[0540] The biological test results are recorded in the table below. The results show that the exemplary compounds of the present invention have a strong inhibitory effect on the binding of TDG to double-stranded DNA substrates.

[0541] A:IC 50 ≤500nM;

[0542] B:500nM <IC 50 ≤5μM;

[0543] C:5μM <IC 50 ≤50μM;

[0544] D:>50μM

[0545] Using the above test method, the effects of the following compounds were obtained:

[0546] Biological Activity Test Example 2 Inhibition of Compound 14 on Proliferation of TP53 Mutant and Wild-Type Tumor Cells

[0547] IC of compound 14 against the proliferation of TP53 mutant and wild-type tumor cells 50 , the TP53 mutant and wild-type tumor cells used in this example are all human tumor cells.

[0548] Tumor cells were plated in 384-well plates and treated with DMSO or the indicated concentrations of compound 14 (0.04–30 μM). After 6 days of incubation, chemiluminescence intensity was measured using the CellTiter-Glo Luminescence Assay Kit (Promega). GraphPad Prism software was used to fit the curves and calculate the IC 50 value.

[0549] The results showed that compound 14 had a certain inhibitory effect on various tumor cell lines including lung cancer, liver cancer, skin cancer, bladder cancer, breast cancer, colon cancer and esophageal cancer, especially against p53 mutant tumor cell lines (including NCI-H446, Calu-1, NCI-H1299, RERF-LC-AI, NCI-H211, NCI-H2009, NCI-H23, VMRC-LCP, NCI-H441, PC9, NCI-H520, EBC-1, NCI-H1975, NCI-H2342, NCI-H647, HCC95, SK-LU-1, SW-900, SNU423, SNU449, HuCCT1, PLC / PRF / 5, SNU387, Hep3B, JHH-2, JHH7, The in vitro proliferation of the compounds of the present invention (SNU761, Huh7, CHL-1, RPMI-7951, SK-MEL-2, SK-MEL-28, MeWo, SK-MEL-3, 5637, UMUC3, RT112, HT1376, BT549, MDA-MB-468, MDA-MB-231, HS578T, EFM-19, MDA-MB-436, Colo320DM, Colo205, RKO_E6, NCI-H508, TE-15, TE-8, TE-1, TE-9, TE-10, TE-4, TE-6, TE-14, TT) was significantly inhibited ( Figure 1 ), indicating that each compound of the present invention, including compound 14, has excellent anti-tumor activity, especially anti-tumor activity against p53 mutant tumor cells.

[0550] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by the following formula 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt: R1 is selected from the group consisting of: OH, H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3- to 12-membered heterocycle, substituted or unsubstituted 5- to 12-membered heteroaryl, substituted or unsubstituted -O-3- to 12-membered heterocycle, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl-C(O)-, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, -O(CH2) s R 10 or -S(CH2) s R 10 ; s is 0, 1, 2 or 3; R 10 selected from the group consisting of: H, substituted or unsubstituted C 3-8 carbocyclic ring, substituted or unsubstituted 3- to 8-membered heterocyclic ring, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl ring; Each R2 is independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl; R3 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 12 cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)NHC(O)R8, (C1-C6 alkyl)C(O)OR8; R8 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, adamantane, or a substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 , -(CH2)CHR9NHC(O)(CH2) n R 13 , CHR9(CH2)NHC(O)(CH2) n R 13 ; R9 is selected from the group consisting of: H, -COOH, -CONHR 12 , -CONHCH2R 12 , -CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 carbocyclic ring, substituted or unsubstituted 3- to 12-membered heterocyclic ring, substituted or unsubstituted 5- to 12-membered heteroaryl ring; R 12 selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl ring; Said R 13 Selected from the group consisting of: substituted or unsubstituted C3-C 10 carbocyclic ring, substituted or unsubstituted 5- to 12-membered heterocyclic ring; Each of m and n is independently 0, 1, 2 or 3; R4 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 amino, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycle, substituted or unsubstituted 5- to 12-membered heteroaryl, substituted or unsubstituted -O-5- to 12-membered heteroaryl; Alternatively, R3 and R4 and the carbon atom to which they are attached together form a structure selected from the group consisting of: substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring, or substituted or unsubstituted 3-10 membered heterocyclic ring; Each of R5 and R6 is independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring, or substituted or unsubstituted 3-10 membered heterocyclic ring; or R5 and R6 and the carbon atom to which they are attached together form a substituted or unsubstituted 3-12 membered carbocyclic ring; R6' is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl; X is selected from O or S; Z is selected from O, S or NR 14 ; wherein, R 14 is H or a C1-C4 alkyl group; R7 is selected from the group consisting of: H, or C(O)R 11 , C(O)OR 11 , -CH2OC(O)OR 11 , -S(O)2NHR 11 ; The described R 11 Selected from the group consisting of: H, substituted or unsubstituted C1-C 16 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5- to 8-membered heterocyclic group; Unless otherwise specified, in the above formulas, the heteroaromatic ring, heteroaryl, heterocyclic ring or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aromatic ring, aryl, heteroaromatic ring or heteroaryl can be a monocyclic or fused ring; the carbocyclic ring, cycloalkyl, heterocyclic ring or heterocyclic group can be a monocyclic, spirocyclic, bridged or spiro ring; the carbocyclic ring, heterocyclic ring or heterocyclic group can be saturated or partially unsaturated, but not aromatic. The substitution mentioned above means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the following group: deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2-C 12 alkoxycarbonyl, C1-C6 aldehyde group, (C1-C6 alkyl)3Si, amino, C1-C6 amide group, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, adamantane, C1-C6 alkyl-amino, C1-C 12 alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-, C1-C4 alkyl-OC(O)NH- unsubstituted or substituted by C1-C4 alkyl, unsubstituted or halogenated C1-C4 alkyl-SO-, 5-7 membered heterocycle unsubstituted or substituted by C1-C4 alkyl, or phenyl (which may have 1-5 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy).

2. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, R1 is selected from the group consisting of: halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3- to 12-membered heterocyclic ring, substituted or unsubstituted 5- to 12-membered heteroaryl ring, substituted or unsubstituted -O-3- to 12-membered heterocyclic ring, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, or -O(CH2) s R 10 。 3. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The compound of formula I has the structure shown in formula II as follows: Wherein, the A ring is a substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring, or substituted or unsubstituted 3-10 membered heterocyclic ring; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaromatic ring.

4. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has the structure shown in Formula IV below: Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocyclic ring, or a substituted or unsubstituted 3-10 membered heterocyclic ring; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocyclic ring, or a substituted or unsubstituted 3-8 membered heterocyclic ring; wherein, the carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated.

5. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has the structure shown in Formula V below: Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring, or substituted or unsubstituted 3-10 membered heterocyclic ring.

6. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has a structure shown in Formula VI or VII as follows: Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the group consisting of: CHR 15 , NR 15 , O or S; t is 1 or 2; wherein R 15 is selected from the group consisting of: deuterium, halogen, hydroxyl, carboxyl, mercapto, amino, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

7. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, R3 is selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl.

8. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, Each of R5 and R6 is independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl; or R5 and R6 and the carbon atom to which they are attached together form a substituted or unsubstituted 3-6 membered carbocyclic ring.

9. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, R3 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 12 cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)C(O)OR8; wherein R8 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; wherein R9 is selected from the group consisting of: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 carbocyclic ring, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaryl ring; R 12 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl ring; the R 13 is selected from the group consisting of: substituted or unsubstituted C3-C 10 carbocyclic ring; Each of m and n is independently 0, 1, 2 or 3; R4 is selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -O-5-12 membered heteroaromatic ring; Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aromatic ring, or a substituted or unsubstituted 5-10 membered heteroaromatic ring.

10. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has the structure shown in Formula III below: Preferably, the compound has a structure shown in the following formula III-A or III-B: Preferably, the compound has any of the structures selected from the following group:

11. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has the structure shown in Formula IX as follows: Preferably, the compound has a structure shown in the following formula IX-A or IX-B: Preferably, the compound has any of the structures selected from the following group:

12. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound has the structure shown in Formula X below: Preferably, the compound has a structure represented by the following formula X-A or X-B: Preferably, the compound has any one of the structures selected from the following group:

13. The compound according to any one of claims 1-12, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt, characterized in that, The described compound is selected from the following group:

14. A pharmaceutical composition, characterized in that, Comprising (i) a compound as claimed in claim 1, or a deuterated product, stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

15. Use of a compound according to any one of claims 1-13, or a deuterated product, stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, For use in the preparation of a medicament for the treatment and / or prophylaxis of a disease associated with abnormal TDG expression; preferably, the disease is selected from the following group: In another preferred embodiment, the tumour is selected from the following group: lung cancer, acute leukaemia, chronic leukaemia, colorectal cancer, breast cancer, thyroid tumour, lymphoma, cholangiocarcinoma, liver cancer, pancreatic cancer, bronchial cancer, oesophageal cancer, skin cancer, bladder cancer, oral cancer, gastric cancer, urogenital tract tumours, central and peripheral nervous system tumours, or a combination thereof; more preferably, the tumour is selected from the following group: melanoma, acute myeloid leukaemia, small cell lung cancer, non-small cell lung cancer.

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