Heterocyclic derivatives, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are a class of heterocyclic compounds represented by formula (I) or formula (IIa) or stereoisomers and pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing formula (I) or formula (IIa). The compounds of the present invention have significant anti-HSV virus activity and physicochemical properties of long-acting compounds, and can be used for preparing a drug of a viral HSV inhibitor, a pharmaceutical composition containing the drug, or the like.

Description

Heterocyclic derivatives and their pharmaceutical compositions and applications Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts and pharmaceutical compositions containing formula (I) or formulas (IIa-IIb), and their use as antiviral drugs, particularly as helicase-primase inhibitors in the preparation of drugs for the prevention and / or treatment of HSV virus infection. Background Technology

[0002] Herpesviruses are enveloped, double-stranded linear DNA viruses containing approximately 70–200 protein-coding genes, the exact number depending on the virus type. Herpesvirus particles (infectious particles) are approximately 200 nm in diameter and mainly consist of four components: core, nucleocapsid, envelope, and periapsis.

[0003] Based on biological and genetic differences, human herpesviruses (HHV) can be divided into three subfamilies: α, β, and γ-herpesviruses. To date, eight human herpesviruses have been identified: herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpesviruses 6-8 (HHV6-8). After initial infection, these herpesviruses can establish lifelong infection in the human body, existing in asymptomatic latent states and acute reactivation states. Herpesvirus infection is a widespread and socially harmful disease, with an overall incidence rate as high as 20%. In people with healthy immune systems, herpes virus infection usually does not cause life-threatening diseases, only causing oral and genital herpes, varicella-zoster, infantile rashes, and infectious mononucleosis. However, when the immune system is compromised (such as after HIV infection or organ transplantation), herpes virus may cause developmental disorders, vision and hearing loss, and life-threatening diseases such as cancer, pneumonia, and encephalitis.

[0004] Herpes simplex virus (HSV) is a DNA virus widely found in humans. There are two main types of HSV: HSV-1 and HSV-2. The HSV genome is double-stranded linear DNA, existing in both circular and linear forms within the virus. According to WHO statistics on HSV infection in 2016, approximately 3.7 billion people (67%) under the age of 50 worldwide are infected with HSV-1, primarily causing oral herpes; among people aged 15-49 worldwide, approximately 491 million (13%) are infected with HSV-2, primarily causing genital herpes. After infection, the virus can enter neurons and remain latent in ganglia, potentially recurring and causing symptoms at any time. HSV is characterized by its long-term latency, recurrent attacks, and affinity for nerve tissue.

[0005] Currently, the most widely used anti-HSV drugs in clinical practice are nucleoside analogs such as acyclovir (ACV) and its derivatives. These drugs have problems such as high dosage, significant side effects, high frequency of use, and easy development of drug resistance. Although existing drugs can reduce the recurrence frequency of HSV and alleviate clinical symptoms to some extent, they still cannot achieve the ultimate goal of preventing recurrence and curing the disease.

[0006] With in-depth research into the biological characteristics and pathogenic mechanisms of herpesviruses and the rapid development of new drug design and screening technologies, more new targets and compounds against herpesviruses have been discovered and have shown potential in preclinical and clinical trials.

[0007] Helicase-primase is a unique target of HSV, with no homology to human cells and tissues, and plays a crucial role in viral DNA unwinding and the initiation of genetic material synthesis. This invention develops a novel, highly active, long-acting antiviral compound targeting this new target, overcoming current clinical problems of drug resistance and high-frequency drug use, and ultimately achieving the goal of inhibiting viral recurrence and achieving clinical cure. Summary of the Invention

[0008] The purpose of this invention is to provide heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts, and pharmaceutical compositions containing formula (I) or formulas (IIa-IIb). These compounds, as helicase-primase inhibitors with a novel mechanism, exhibit potent anti-HSV-1 and HSV-2 activity. Through repeated trial and error and structural optimization, we found that the spirocyclic compounds of formula (I) exhibit higher anti-HSV-2 activity than Pritelivir, and possess a long half-life and good permeability, making them suitable for long-acting oral formulations. Furthermore, due to the compounds' low solubility, subcutaneous or intramuscular injection formulations may achieve the clinical effect of once-every-months injection, greatly improving patient compliance and reducing the chance of relapse. The long-acting and high-activity properties of these compounds further inhibit the possibility of drug resistance. During extensive experimental research, a class of compounds of formula (IIa) was also discovered, in which fluorinated compounds showed excellent anti-HSV activity. The electron-withdrawing groups such as fluorine and carbonyl groups reduced the possibility of benzyl oxidation, improving the physicochemical properties of the original compounds. Both of these compounds exhibit characteristics of long-acting compounds and have very low carbonic anhydrase toxicity. More importantly, these compounds resist resistance to existing nucleoside analogues, providing more options for drug-resistant patients and opening up possibilities for combination therapies.

[0009] Furthermore, through understanding the structure-activity relationship of compounds, this invention provides CNS compounds with good activity. Herpes simplex virus encephalitis can recur and is extremely painful. The efficacy of nucleoside analogues is extremely limited. This invention provides drugs that can cure or alleviate herpes simplex virus encephalitis. The compounds of this invention have lower toxicity and higher lipid solubility, and may have good clinical therapeutic effects on herpes simplex virus encephalitis caused by HSV infection.

[0010] There is also a broad market for antiviral drugs in prevention. Our developed long-acting oral or injectable drugs can suppress HSV viral replication for a longer period, making complete eradication of the HSV virus possible. In addition, for organ transplant patients and patients with weakened immune systems, long-acting injectable drugs can suppress viral activation or infection, and can be used alone or in combination to effectively treat or prevent HSV infection.

[0011] To achieve the above objectives, the present invention adopts the following technical solution: a heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt, wherein the heterocyclic derivative has the structure shown in formula (I) or formulas (IIa-IIb):

[0012] in:

[0013] (1) Each R1 is independently selected from halogens (such as F, Cl, Br, I, etc.), cyano, hydroxyl, C 1-6 Alkyl, deuterated C1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-12 Aromatic compounds, R1′ is selected from H, CN, OH, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl or C 3-6 The cycloalkyl group, or R1′, is selected from the prodrug group that yields the parent compound in vivo via chemical hydrolysis or enzymatic degradation, and R1″ is selected from C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 3-6 Cycloalkyl; n is 1, 2, 3 or 4;

[0014] (2) R2 is selected from H, halogen, cyano, hydroxyl, -SO2NH2, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0015] (3) R3 is selected from the following groups, either unsubstituted or substituted: saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, aromatic carbocyclic group, wherein the substituent used for substitution is selected from one or more of the following groups: halogen (such as F, Cl, Br, I, etc.), cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, oxo, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne group, unsubstituted or substituted 5-10 membered aliphatic heterocyclic group or 5-10 membered heteroaromatic group;

[0016] (4) R4 is selected from H, D, halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, amino, C 2-6 Alkyne group; or R4 is absent;

[0017] (5) Each R5 is independently selected from H, D, hydroxyl, halogen, cyano, amide, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C2-6 Alkyne group, where m is 0, 1, 2, 3 or 4; or, m is 2, and two R5 groups are attached to one or two carbon atoms to form a first ring, which is a monocyclic, bridged, spirocyclic, fused or polycyclic ring;

[0018] (6) A is selected from saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, and aromatic carbocyclic group;

[0019] (7) B does not exist, or B is selected from C. 1-3 Alkylene, O, S or NR6′, where NR6′ is selected from H or C 1-6 alkyl;

[0020] (8) T and V are independently CH or N;

[0021] (9) X and Y are independently selected from one bond, O, and O-(CR2′R3′). t S, NCH3, (CR2′R3′) t Or a broken key; R2′ and R3′ are independently selected from H, D, and C. 1-3 Alkyl, halogen, or R2′ and R3′ connected to the same carbon atom (e.g., R2′ and R3′ can be connected together) and form a spirocycle with the ring containing X and Y, or R2′ and R3′ connected to different carbon atoms and form a fused ring with the ring containing X and Y, or one of R2′ and R3′ is H or D, and the other is connected to W to form a ring; t is 0, 1, 2, or 3;

[0022] (10) In equation (I), M is C or N, and satisfies: when M is N, Y is a broken bond and X is a bond;

[0023] Q is CH2, O, or S;

[0024] (11) P is selected from a bond or (CR4′R5′). a R4′ and R5′ are independently selected from H, D, and deuterated C. 1-3 Alkyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, F, or R4′ and R5′ are attached to the same carbon atom and form a spiro ring with the ring containing P; a is 1, 2 or 3;

[0025] (12) R6 and R7 are independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl groups, or atoms connected to R6 and R7 and connected to each other together to form a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is substituted by 0, 1, 2 or more R5s;

[0026] (13) In equation (IIa), W is C, CH or N, and satisfies: when W is N, R4 does not exist; when W is C and R4 does not exist, there is a double bond between W and X or a double bond between W and Y.

[0027] E is either CH or N;

[0028] (14) The heteroatoms in the saturated heterocyclic group, unsaturated heterocyclic group, aliphatic heterocyclic group, and heteroaromatic group are independently selected from one or more of O, S, N and oxo.

[0029] In some embodiments of the present invention, both T and V are CH; or, one of T and V is CH and the other is N.

[0030] In some embodiments of the present invention, Q is CH2 or O, B is absent, and M is C.

[0031] In some embodiments of the present invention, the prodrug group is selected from...

[0032] In some embodiments of the present invention, the heterocyclic derivative has the structure shown in formula (IA):

[0033] The definitions of R1, R2, R3, R5, P, m, n, X, Y, and A are the same as before.

[0034] Furthermore, X, Y, and the carbon atoms and M connected to them together form a 4-8 membered ring, and this 4-8 membered ring contains 0 or 1 heteroatom. Even further, X, Y, and the carbon atoms and M connected to them together form a 5-6 membered carbon ring, a 5-6 membered oxygen heterocycle, or a 5-6 membered sulfur heterocycle.

[0035] In some embodiments of the present invention, P is a single bond, methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, or fluoroethyl; and / or, the first ring is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... In some embodiments of the present invention Selected from the following groups:

[0036] In some embodiments of the present invention Selected from the following groups:

[0037] In some embodiments of the present invention, in formula (IIa), W is N and E is CH; or, in formula (IIa), W is N and E is N, and R6 and R7 are connected together with the atoms connected to them to form a 5-8 membered nitrogen heterocycle; or, in formula (IIa), W is CH, one of X and Y is a broken bond and the other is a bond.

[0038] In some embodiments of the present invention, in formula (IIa), one of X and Y is O and S, and the other is (CR2′R3′). t W is C or CH, E is N, and R6 and R7 are connected together with the atoms connected to them to form a 5-8 membered nitrogen heterocycle. The substituent on the 5-8 nitrogen heterocycle is R5, and t is 0, 1, 2, or 3.

[0039] In some embodiments of the present invention, in formula (IIa), for The definitions of R1, R5, m, and n are the same as before.

[0040] In some embodiments of the present invention, the heterocyclic derivative has the structure shown in formula (IIa-A):

[0041] The definitions of R1, R2, R3, R4, R5, m, n, X, and Y are the same as before.

[0042] Furthermore, both X and Y are (CR2′R3′). t R4 is selected from halogen, cyano, methyl, ethyl, propyl, hydroxy, amino, methoxy or ethoxy, and t is 0 or 1;

[0043] Alternatively, X and Y can be independently selected from O, S, or (CR2′R3′). t And not both of them are (CR2′R3′). t R4 is selected from H, D, halogen, cyano, methyl, ethyl, propyl, hydroxy, amino, methoxy, or ethoxy, and t is 1.

[0044] In some embodiments of the present invention, one of R2′ and R3′ is H or D, and the other is connected to W to form a 3-5 membered ring, for example, a 3-membered carbon ring, a 4-membered carbon ring or a 5-membered carbon ring.

[0045] In some embodiments of the present invention, one of X and Y is selected from a key, and the other is a broken key. Further, in some cases, in formula (IIa) or formula (IIa-A), X is selected from a key, and Y is a broken key.

[0046] In some embodiments of the present invention Selected from the following groups:

[0047] In some embodiments of the present invention Selected from the following groups:

[0048] Another technical solution provided by the present invention: a heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt, wherein the heterocyclic derivative has the structures shown in formulas (IIb-1) and (IIb-2):

[0049] in:

[0050] (1) Each R1 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 alkyl, R1′ is selected from H, CN, OH, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl or cyclopropyl, R1″ is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl group; n is 1, 2, 3 or 4;

[0051] (2) R2 is selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0052] (3) R3 is selected from unsubstituted or substituted groups of the following: saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, aromatic carbocyclic group, wherein the substituent used for substitution is selected from one or more of the following groups: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, oxo, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne group, unsubstituted or substituted 5-10 membered alicyclic or heterocyclic groups;

[0053] (4) A is selected from heteroaryl and aromatic carbocyclic groups;

[0054] (5) Z is selected from CH or N;

[0055] (6) The heteroatoms in saturated heterocyclic groups, unsaturated heterocyclic groups, aliphatic heterocyclic groups, and heteroaromatic groups are independently selected from one or more of O, S, N, and oxo.

[0056] In some embodiments of the present invention Selected from the following groups:

[0057] In some embodiments of the present invention, R2 is selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, methyl, ethyl, halomethyl or haloethyl.

[0058] In some embodiments of the present invention, R3 is selected from unsubstituted or substituted aromatic carbocyclic groups, or from unsubstituted or substituted 5-10 membered heterocyclic groups. Further, according to some specific aspects of the present invention, R3 is selected from unsubstituted or substituted groups such as: benzene ring, pyrrole, dolin, imidazole, pyrazole, furan, oxazole, isoxazole, thiophene, thiazole, pyridine, quinoline, pyrimidine, indazole, and benzothiazole.

[0059] In some embodiments of the present invention, R3 is selected from unsubstituted or substituted benzene rings, unsubstituted or substituted furans, unsubstituted or substituted pyridines, unsubstituted or substituted imidazoles, unsubstituted or substituted thiazoles, unsubstituted or substituted thiophenes, or other five- or six-membered heteroaromatic rings.

[0060] In some embodiments of the present invention, R3 is selected from...

[0061] In some embodiments of the present invention, the heterocyclic derivative is the racemic form, R configuration, or S configuration of the corresponding compound.

[0062] In some embodiments, the substituted groups are independently selected from H, deuterium, halogens (F, Cl, Br, I), cyano, hydroxyl, amide, carboxyl, oxo, alkynyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkoxy, halogenated C 3-6 Cycloalkoxy, C 2-6 Heterocyclic alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-10 heteroaryl, C 1-6 Alkyl sulfone group, C 1-6 Alkyl mercapto; heteroatoms are selected from oxygen, nitrogen, sulfur, oxo, and -SO2-.

[0063] In some embodiments, the alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc., C 1-6 Alkyl groups are those with 1 to 6 carbon atoms.

[0064] In some implementations, halogenated C 1-6 Alkyl groups can be obtained by substituting one or more hydrogens from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc., using F, Cl, Br, or I.

[0065] In some implementations, deuterated C 1-6 Alkyl groups can be formed by substituting one, two, three, or more deuterium atoms into the C atom. 1-6 Hydrogen in the alkyl group is obtained. Hydroxyl-substituted C 1-6 Alkyl groups can be formed by substituting one, two, three, or more hydroxyl groups for the C group. 1-6 Hydrogen is obtained from alkyl groups.

[0066] In some implementations, C 6-12 Aromatic groups include, but are not limited to, benzene rings and naphthalene.

[0067] In some implementations, C 2-6 The alkynyl group includes, but is not limited to, ethynyl, propynyl, butynyl, penynyl, etc.

[0068] In some embodiments, the alkoxy group includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, isohexyloxy, etc., C 1-6 Alkoxy groups refer to alkoxy groups with 1 to 6 carbon atoms.

[0069] In some embodiments, the haloalkoxy group includes, but is not limited to, the hydrogen that can be obtained by substituting one or more of the following: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, isohexyloxy, etc.

[0070] In some embodiments, the heterocyclic group includes alicyclic heterocyclic groups containing heteroatoms and heteroaromatic cyclic groups containing heteroatoms, etc., for example, it can be a saturated heterocyclic group or an unsaturated heterocyclic group, and there can be one, two or more heteroatoms, and it can be monocyclic, bicyclic or polycyclic, wherein the heteroatoms are nitrogen, oxygen, sulfur, oxo, etc. The carbocyclic group is a pure carbon ring without heteroatoms, and it can be monocyclic, bicyclic or polycyclic, and can contain double bonds or not, for example, it can be a saturated carbocyclic group or an unsaturated carbocyclic group.

[0071] Furthermore, the saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, and unsaturated carbocyclic group can be, but are not limited to, 3-20 membered rings, such as 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, 12-membered rings, 13-membered rings, 14-membered rings, 15-membered rings, 16-membered rings, 17-membered rings, 18-membered rings, 19-membered rings, 20-membered rings, etc.

[0072] The heterocyclic and aromatic carbonyl groups can be, but are not limited to, 5-20 membered rings, 5-15 membered rings, 5-10 membered rings, or 5-8 membered rings, for example, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, 12-membered rings, 13-membered rings, 14-membered rings, 15-membered rings, 16-membered rings, 17-membered rings, 18-membered rings, 19-membered rings, 20-membered rings, etc.

[0073] In some embodiments, the substituents in "substituted 5-10 membered alicyclic or 5-10 membered heterocyclic" include, but are not limited to, halogens (F, Cl, Br, I), cyano groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, oxo, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne groups, etc.

[0074] In some embodiments, the alkylene group can be, for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH(CH3)-, -C(CH3)2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2-, etc.

[0075] In some implementations, C 3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0076] In some embodiments, the first ring may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. wait.

[0077] In some embodiments of the present invention, the heterocyclic derivatives are selected from the following structures:

[0078] Another technical solution provided by the present invention is a pharmaceutical composition containing heterocyclic derivatives or their stereoisomers as described above, and pharmaceutically acceptable salts.

[0079] Furthermore, the pharmaceutical composition is an antiviral pharmaceutical composition, which further comprises one or more therapeutic agents selected from the following categories: nucleoside analogues, protease inhibitors, non-nucleoside inhibitors, neutralizing antibodies, etc.

[0080] In some embodiments, the pharmaceutical composition of the present invention may be composed of the following proportions:

[0081] Another technical solution provided by the present invention is the use of the above-mentioned heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts, or pharmaceutical compositions in the preparation of drugs for the prevention and / or treatment of viral infectious diseases.

[0082] Another technical solution provided by the present invention is the use of the above-mentioned heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of drugs for the prevention and / or treatment of HSV viral infections.

[0083] Furthermore, the aforementioned heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions are used as helicase-primase inhibitors in drugs for the prevention and / or treatment of HSV viral infections.

[0084] Furthermore, the HSV virus in the HSV viral infection is HSV-1 or HSV-2; the HSV viral infection includes herpes simplex keratitis, genital herpes, cold sores, herpes simplex encephalitis, disseminated herpes simplex virus, and other diseases or complications caused by HSV viral infection (including Alzheimer's disease and dementia directly related to HSV infection) or complications.

[0085] Another technical solution provided by the present invention is the application of the above-mentioned heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts as long-acting compounds for the prevention and / or treatment of viral infectious diseases in the preparation of pharmaceutical compositions for the prevention and / or treatment of viral infectious diseases, wherein the pharmaceutical compositions have a long-acting effect.

[0086] Furthermore, the pharmaceutical composition may be in the form of an oral formulation, an injectable formulation, or a topical formulation.

[0087] The present invention also provides the use of the aforementioned heterocyclic derivatives or stereoisomers thereof, pharmaceutically acceptable salts, or pharmaceutical compositions as helicase-primase inhibitors for the prevention and / or treatment of HSV viral infections.

[0088] The pharmaceutical composition according to the present invention, wherein the compound of the present invention is preferably present in a therapeutically effective amount.

[0089] The above-mentioned pharmaceutical compositions also include pharmaceutically acceptable carriers, such as pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavorings, sweeteners, etc.

[0090] The pharmaceutical products prepared using the compounds of this invention as active ingredients can take various forms, such as tablets, powders, capsules, granules, oral liquids, and injectable formulations. The preferred dosage form of the pharmaceutical composition is tablets, capsules, or injections.

[0091] All of the above-mentioned dosage forms of drugs can be prepared using conventional methods in the pharmaceutical field.

[0092] The present invention further provides a method for preparing a heterocyclic derivative or its stereoisomer with the structure shown in formula (I), comprising the following steps:

[0093] Intermediate A, intermediate B, sodium tert-butoxide, Pd₂(dba)₃, and Xantphos were sequentially added to toluene. After nitrogen purging, the reaction was heated (the reaction temperature could be, but was not limited to, 70-120°C, and the reaction time could be, but was not limited to, 1-10 h). After the reaction was complete, the reaction solution was quenched in water, extracted with ethyl acetate, and purified twice by silica gel column chromatography (DCM / MeOH = 100 / 1) and preparative plate purification (DCM / MeOH = 20 / 1) to obtain solid product (I). The leaving groups of intermediate B, in addition to chlorine, include F, Br, I, or OTf. The reaction time and temperature fluctuate within a reasonable range depending on the properties of the compound. Pd₂(dba)₃ can also be replaced by various commercially available Pd(Ph₃P)₄, Pd(dppf)Cl₂, Pd(CH₃CN)₂Cl₂, PdCl₂, or Pd(Ph₃P)₂Cl₂. Furthermore, the substitution reaction between A and B can also be carried out with the participation of CuI or CuBr.

[0094] The present invention further provides a method for preparing the heterocyclic derivative represented by formula (IIa-A), comprising the following steps:

[0095] In some implementation examples, the preparation process of compounds of formula (IIa-A) can be as follows:

[0096] Synthesis of compound C:

[0097] Add A, B, and 50% T3P / EA sequentially to dry DMF. After purging with nitrogen three times, stir overnight at room temperature. Quench with saturated sodium bicarbonate solution, extract with ethyl acetate, wash the organic phase sequentially with semi-saturated and saturated brine, dry with anhydrous sodium sulfate, and purify by preparative HPLC to obtain a white solid compound C. There are many options for the condensation reaction of amides, such as DCC / HOBT, HATU, HBTU, COMU, etc.

[0098] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0099] This invention provides a class of heterocyclic derivatives with high activity, low toxicity, low solubility, and very low clearance, which can be used to develop long-acting oral or injectable anti-HSV drugs. We synthesized a class of spirocyclic compounds whose conformationally restricted stereochemical features significantly improved their pharmacokinetic parameters. Compared with non-spirocyclic compounds, the drug exposure represented by AUC was significantly increased, and they exhibited excellent half-life. This class of compounds demonstrates clear inventiveness. Introducing an F-substituent at the α-position of the amide significantly reduced the metabolic rate and prolonged the half-life due to its electronic and steric hindrance effects. We also synthesized and compared other substituents, finding that the introduction of the F atom, in particular, retained high activity while improving the stability of the compound and extending its metabolic time. The PK advantage brought by the introduction of the F atom at this site was an unexpected result, thus demonstrating significant inventiveness. Furthermore, the thiolated compounds at the indene ring are completely different from those at the oxygen atom position; in in vitro tests, the thiolated compounds showed superior anti-HSV activity.

[0100] This invention also provides a class of heterocyclic compounds that permeate the BBB, exhibiting excellent anti-HSV activity and structural specificity, along with low carbonic anhydrase toxicity and long-acting physicochemical properties, making them promising candidates for clinical application.

[0101] Terminology Definition

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0103] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. This includes cis-trans isomers, enantiomers, and conformational isomers. All stereoisomers are within the scope of this invention. The compounds of this invention can be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.

[0104] The term "salt" refers to a pharmaceutically acceptable salt formed by the compound of the present invention with an acid, which may be an organic or inorganic acid, specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or analogs thereof.

[0105] The term "solvent" refers to the form of the compounds of this invention that form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvate in which coordination with water occurs. Within the scope of this invention, hydrates are preferred solvates.

[0106] The term "crystallization" refers to the various solid forms formed by the compounds described in this invention, including crystalline and amorphous forms.

[0107] The term "hydrocarbon group" refers to saturated alkyl, alkenylalkyl, and alkynylalkyl groups.

[0108] The term "saturated alkyl" refers to a straight-chain, branched, or cyclic saturated or unsaturated substituent mainly composed of carbon and hydrogen. Preferably, it has 1-20 carbon atoms, more preferably 1-12 carbon atoms. The term "alkyl" refers to a straight-chain, branched, or cyclic saturated hydrocarbon group. Alkyl groups specifically include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2-methylbutyl and 2,3-dimethylbutyl, 16-alkyl, and 18-alkyl. The term "C 1-20 Alkyl refers to a straight-chain, branched, or cyclic saturated hydrocarbon group containing 1-20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When an alkyl group is substituted, the substituent can be substituted at any usable connection point, and the substituent can be monosubstituted or polysubstituted. Substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In naming, the substituent is usually placed before the alkyl group, for example, C10. 1-3 Alkoxy C 3-8 cycloalkyl C 1-6 Alkyl refers to C 1-6 Alkyl groups, which are C 3-8 Cycloalkyl substitution, and the C 3-8Cycloalkyl groups are also C 1-3 Alkoxy substitution, for example: the structural formula of methoxycyclobutylmethyl is:

[0109] The terms "alkenyl" and "alkynyl" refer to straight-chain, branched, or cyclic unsaturated hydrocarbon groups containing double and triple bonds, respectively, preferably with 2-20 carbon atoms, more preferably 2-12 carbon atoms. Alkenyl and alkynyl groups include substituted and unsubstituted alkenyl and alkynyl groups. When substituted, the substituent can be substituted at any usable linker, and the substituent can be monosubstituted or polysubstituted. The substituent is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In nomenclature, the substituent is usually placed before the alkenyl or alkynyl group.

[0110] The term "ring" refers to both carbon rings and heterocycles. "Carbocyclic group" or "carbon ring" refers to a carbon cyclic group having 3-20 carbon atoms, preferably 3-16, and more preferably 4-12, including cycloalkyl, cycloalkenyl, aryl, bicyclic carbon rings, and polycyclic carbon cyclic groups. "Heterocyclic group" or "heterocycle" includes heteroaryl, non-aromatic heterocyclic, bicyclic, and polycyclic heterocyclic groups having one or more identical or different heteroatoms chosen arbitrarily from O, S, and N within the ring. The term "ring" includes monocyclic, bridged, spirocyclic, fused, and polycyclic rings.

[0111] The term "cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic cycloalkyl group. A monocyclic group may include 3-10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups include unsubstituted and substituted groups. Substituents are selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester, amino, amide, hydroxy, cyano, nitro, aryl, and heteroaryl groups.

[0112] The term "aryl" refers to both aromatic carbocyclic groups and heterocyclic groups.

[0113] The term "aromatic carbocyclic group" refers to an aromatic group consisting of a 6-10 member, all-carbon monocyclic or polycyclic aromatic ring, including phenyl, naphthalene, biphenyl, etc. Aryl groups can be substituted or unsubstituted. Substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0114] The term "heterocyclic cyclic group" refers to a group in a heteroaromatic system containing 1-10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, etc. Monocyclic cyclic groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, etc. Fused heterocyclic cyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromone, fluorenone, quinoxaline, 3,4-dihydronaphthone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc. Heterocyclic groups can be substituted or unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0115] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0116] The term "deuterium" is an isotope of hydrogen, with an atomic mass twice that of hydrogen and a stronger bond to carbon. "Deuteration" and "deuterium" indicate that hydrogen is replaced with deuterium at a specified position. A "deuterated substituent" is a substituent in which at least one hydrogen atom is replaced by deuterium enriched in a specified percentage.

[0117] The term "halogenated alkyl" refers to an alkyl group that is substituted by at least one halogen atom.

[0118] The term "heterocyclic group" refers to a cyclic group containing at least one heteroatom, such as nitrogen, oxygen, sulfur, or thiocyanate. Heterocyclic groups include monocyclic and polycyclic groups.

[0119] If the connecting portion of the described structure is a bond, then the left-hand side of the described structure is directly bonded to the right-hand side of the described structure. For example, if the chemical structure is described as XLY, and L is selected from a single bond, then the chemical structure will be XY. If the connecting portion of the described structure is a broken bond, then the left-hand side of the described structure is directly broken to the right-hand side of the described structure. Detailed Implementation

[0120] The following examples are intended to provide a more comprehensive understanding of the invention by those skilled in the art, but do not limit the invention in any way. The structures of all compounds have been determined... 1 Determined by HNMR or MS.

[0121] The abbreviations used in the examples are as follows:

[0122] The present invention will be further described below with reference to specific embodiments:

[0123] Synthesis of intermediates

[0124] Example 1: Synthesis of intermediates IM1a and IM1b

[0125] The reaction route is shown below:

[0126] Synthesis of intermediate 2:

[0127] At 0°C, dimethyl carbonate (60 mL, 0.71 mol) was added to a suspension of sodium hydride (38 g, 0.95 mol) in tetrahydrofuran (1 L). After stirring for 10 minutes, intermediate 1 (100 g, 0.47 mol) was added in portions. After nitrogen purging, the mixture was stirred at 0°C until no gas was generated. Then, the temperature was raised to 50°C and the reaction was carried out for 2 hours. After the reaction was completed, the reaction solution was poured into 5 L of saturated ammonium chloride aqueous solution for quenching. Methyl tert-butyl ether (2 L) was added, filtered, and dried to obtain a white solid intermediate 2 (110 g, 87%). 1 HNMR (400MHz, CDCl3): δ7.69(s,1H),7.64(s,0.35H),7.62(s,1H),7.55-7.51(m,1.6H),3.86 (s,1H),3.80(s,3H),3.76-3.73(m,1H),3.59-3.54(m,1H),3.50(s,0.6H),3.39-3.33(m,1H).

[0128] Synthesis of intermediates 3-1 and 3-2:

[0129] At 0°C, triethylsilane (382 mL, 1.67 mol) was added dropwise to a trifluoroacetic acid (450 mL) solution of intermediate 2 (90 g, 0.33 mol). After the addition was complete, the mixture was stirred overnight at 30°C. The solvent was removed by concentration, and the residue was diluted with ethyl acetate (500 mL). The residue was washed successively with sodium bicarbonate solution (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and purified with petroleum ether solution containing 1% ethyl acetate to obtain the crude product. The crude product was slurried in petroleum ether (200 mL) at -20°C, and filtered to obtain a yellow solid, which was a mixture of intermediates 3-1 and 3-2 (70 g, 85%). Intermediate 3-1: 1HNMR (400MHz, CDCl3): δ7.34 (s, 1H), 7.28-7.26 (m, 1H), 7.07 (d, J = 8.0Hz, 1H), 3.72 (s, 3H), 3.39-3.11 (m, 5H).

[0130] Synthesis of intermediate 4:

[0131] A mixture of intermediates 3-1 and 3-2 (36.7 g, 0.15 mol) was refluxed with a DMF solution (295 mL) of benzenesulfonyl hydrazine (50 g, 0.29 mol) for 6 hours. The mixture was then quenched in a saturated ammonium chloride aqueous solution (1 L), extracted with ethyl acetate (800 mL), and the organic layer was washed twice with semi-saturated brine (500 mL) and once with saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (1.6-2.5% ethyl acetate in petroleum ether solution) to obtain a deep yellow liquid intermediate 4 (26 g, 70%). 1 HNMR (400MHz, CDCl3): δ7.34 (s, 1H), 7.28-7.26 (m, 1H), 7.07 (d, J = 8.0Hz, 1H), 3.72 (s, 3H), 3.39-3.11 (m, 5H).

[0132] Synthesis of intermediate 5:

[0133] Under nitrogen protection, a THF (300 mL) solution of intermediate 4 (20 g, 0.08 mol) was added dropwise to a THF (200 mL) solution of LiHMDS (1 M, 156 mL, 0.16 mol). After stirring for 1 h, a THF (500 mL) solution of NFSI (74 g, 0.24 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 16 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (1.2% ethyl acetate in petroleum ether solution) to obtain 12 g of a yellow oil. 6 g of this oil was used to prepare intermediate 5 (2.8 g, 26%) by reverse reaction. 1 HNMR (400MHz, CDCl3): δ7.37-7.30(m,1H),7.13-7.07(m,2H),3.87(s,3H),3.65-3.45(m,2H),3.38-3.25(m,3H).

[0134] Synthesis of intermediate 6:

[0135] Intermediate 5 (2.8 g, 0.01 mol), pyridine-2-tri-n-butyltin (3.94 mL, 0.01 mol), and tetra-triphenylphosphine palladium (1.18 g, 1.03 mmol) were added to 1,4-dioxane (70 mL), purged with nitrogen three times, heated to 90 °C, and stirred for 6 hours. The reaction mixture was poured into a saturated potassium fluoride solution (100 mL), stirred for half an hour, filtered through diatomaceous earth, and extracted with ethyl acetate (100 mL). The organic phase was washed twice with water (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (7-10% ethyl acetate in petroleum ether solution) to obtain a chromophore-like solid intermediate 6 (1.5 g, 54%). MS: [MH] + 272.35; 1 HNMR (400MHz, CDCl3): δ8.69-8.67(m,1H),7.92(s,1H),7.84(d,J=8.0,1.6Hz,1H),7.77-7.69(m, 2H),7.35(d,J=8.0Hz,1H),7.24-7.21(m,1H),3.88(s,3H),3.74-3.61(m,2H),3.52-3.38(m,2H).

[0136] Synthesis of intermediate 7:

[0137] At 0°C, LiOH (718 mg, 17.10 mmol) was added to a mixture of tetrahydrofuran (8 mL), methanol (4 mL), and water (4 mL) containing intermediate 6 (1.16 g, 4.28 mmol), and stirred at room temperature for 2 hours. Dilute hydrochloric acid (4 N, 4.3 mL) was added to the reaction mixture at 0°C, and the mixture was concentrated to dryness. A mixture of dichloromethane and methanol (10:1, 100 mL) was added, and the mixture was filtered. The filtrate was concentrated to dryness and purified by silica gel column chromatography (3-5% methanol in dichloromethane solution) to obtain a chromophore-like solid intermediate 7 (1.05 g, 95%). MS: [MH] + 258.05; 1 HNMR (400MHz, DMSO-d6): δ8.64-8.62(m,1H),7.93-7.82(m,4H),7.33-7.29(m,2H),3.63-3.49(m,2H),3.15-3.01(m,2H).

[0138] Synthesis of intermediates IM1a and IM1b:

[0139] Intermediate 7 (1.14 g, 4.43 mmol) was chirally resolved by SFC (CHIRALPAKAD-H, 75% CO2, 25% MeOH (0.1% DEA)) to give a white solid IM1a (520 mg, 45%), MS: [MH]. + 258.05; CHAIRL HPLC: 6.60min.IM1b (500mg, 44%), MS: [MH] + 258.05; CHAIRL HPLC: 8.47 min.

[0140] Example 2: Synthesis of intermediates IM2S and IM2R

[0141] The reaction route is shown below:

[0142] Synthesis of intermediate 9:

[0143] Intermediate 8 (99 g, 0.52 mol), allyltributyltin (207 g, 0.62 mol), and bis(triphenylphosphine)palladium dichloride (18.27 g, 0.03 mol) were added to N,N-dimethylformamide (1 L). The mixture was purged with nitrogen three times and heated to 80 °C for 6 hours. The reaction solution was poured into 1 L of saturated potassium fluoride aqueous solution and stirred for half an hour. The solution was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (500 mL × 2). The organic phase was washed successively with semi-saturated brine (1 L × 2) and saturated brine (1 L), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (5-10% ethyl acetate in petroleum ether solution) to obtain a brown liquid intermediate 9 (65 g, 81%). MS: [MH] + 151.90; 1 HNMR (400MHz, CDCl3): δ6.80-6.75(m,2H),6.63-6.59(m,1H),5.98-5.88(m,1H),5.17-5.07(m,2H),3.53(s,2H),3.27(d,J=6.0Hz,2H).

[0144] Synthesis of intermediate 10:

[0145] At room temperature, acetic anhydride (116 mL, 1.24 mol) was added dropwise to a dichloromethane (1 L) solution of intermediate 9 (62.5 g, 0.41 mol); the mixture was stirred overnight at room temperature; the reaction solution was quenched with water (1 L); the organic phase was washed successively with sodium bicarbonate solution (500 mL), saturated brine (500 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (50% ethyl acetate in petroleum ether solution) to give a white solid intermediate 10 (66 g, 83%). MS: [MH]+ 193.95; 1 HNMR (400MHz, CDCl3): δ7.68-7.65(m,1H),7.15(s,1H),6.96-6.88(m,2H) ,5.98-5.88(m,1H),5.21-5.06(m,2H),3.34(d,J=4.0Hz,2H),2.14(s,3H).

[0146] Synthesis of intermediate 11:

[0147] Palladium dichloride dichloride (11.25 g, 0.04 mol) and copper nitrate trihydrate (10.48 g, 0.04 mol) were added to a mixed solution of intermediate 10 (83.78 g, 0.43 mol) in acetic acid (1250 mL) and acetic anhydride (170 mL). The reaction solution was heated to 30 °C and stirred for 16 hours under an oxygen atmosphere. The reaction solution was concentrated, and ethyl acetate (500 mL) and water (500 mL) were added. The organic phase was washed successively with sodium bicarbonate solution (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (30% ethyl acetate in petroleum ether solution) to obtain a brown solid intermediate 11 (56.5 g, 52%). MS: [MH] + 252.50; 1 HNMR (400MHz, CDCl3): δ8.08-8.04(m,1H),6.92-6.87(m,2H),4.66-4.41(m,1H),4.23-4.19(m ,1H),3.98-3.93(m,1H),3.40-3.34(m,1H),2.86(d,J=16.0Hz,1H),2.35(s,3H),2.04(s,3H).

[0148] Synthesis of intermediate 12:

[0149] At 0°C, lithium hydroxide aqueous solution (1M, 256 mL, 0.26 mol) was added dropwise to a methanol (650 mL) solution of intermediate 11 (64.4 g, 0.31 mol). After the addition was complete, the mixture was reacted at this temperature for 1 hour. The mixture was then cooled to 0°C, and the pH was adjusted to 6-7 with 2N dilute hydrochloric acid solution. Dichloromethane / methanol (10:1, 400 mL) and water (500 mL) were added. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (30% ethyl acetate in petroleum ether solution) to obtain intermediate 12 as a brown solid (32.2 g, 60%). MS: [MH] + 210.00; 1HNMR (400MHz, CDCl3): δ8.05(s,0.5H),7.05(s,0.5H),6.93-6.89(m,2H),5.00-4.33(m,1H),3.7 3-3.57(m,2.5H),3.37-3.30(m,1H),2.89-2.65(m,1H),2.39(d,J=34.80Hz,3H),2.10(s,0.5H).

[0150] Synthesis of intermediate 13:

[0151] At 0°C, methanesulfonyl chloride (3.70 mL, 0.05 mol) was added dropwise to a solution of intermediate 12 (5 g, 0.02 mol) and N,N-diisopropylethylamine (16.65 mL, 0.10 mol) in dichloromethane (70 mL). After the addition was complete, the mixture was stirred at room temperature for 2 hours, then quenched with water (100 mL). The organic phase was washed successively with sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude brown solid intermediate 13. MS: [MH] + 288.55.

[0152] Synthesis of intermediate 14:

[0153] Intermediate 13 (0.02 mol) was dissolved in tetrabutylammonium fluoride (100 mL, 0.1 mol), purged with nitrogen, and reacted at 70 °C for 16 hours. The reaction solution was concentrated to dryness, and dichloromethane (50 mL) and water (70 mL) were added. The organic phase was washed successively with sodium bicarbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (50% ethyl acetate in petroleum ether solution) yielded a brown solid intermediate 14 (2.5 g, two steps: 50%). MS: [MH] + 212.00; 1 HNMR (400MHz, DMSO-d6): δ7.94 (s, 1H), 7.12 (d, J = 8.0Hz, 1H), 6.70-6.95 (m, 1H), 4.93- 4.84(m,1H),4.60-4.33(m,2H),3.41-3.36(m,1H),2.83(d,J=16.0Hz,1H),2.23(s,3H).

[0154] Synthesis of intermediate 15:

[0155] Intermediate 14 (2.5 g, 0.01 mol) was added in portions to chlorosulfonic acid (28 mL) at 0 °C; the reaction mixture was then heated to 50 °C and reacted for 5 hours; the reaction solution was quenched in ice water, extracted with dichloromethane (50 mL), and the organic phase was dried over saturated brine (50 mL) and anhydrous sodium sulfate; the mixture was concentrated to give intermediate 15 (2.73 g, 75%) as a brown solid. MS: [MH] + 309.90; 1 HNMR (400MHz, DMSO-d6): δ8.27(d,J=4.0Hz,1H),7.02(d,J=8.0Hz,1H),4.90-4.83 (m,1H),4.58-4.34(m,2H),3.38-3.32(m,1H),2.80(d,J=16.0Hz,1H),2.23(s,3H).

[0156] Synthesis of intermediate 16:

[0157] Ammonia solution (15 mL) was added to a tetrahydrofuran solution (55 mL) containing intermediate 15 (2.73 g, 8.81 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under vacuum to obtain a brown solid intermediate 16 (2.5 g, 98%). MS: [MH] + 291.30; 1 HNMR (400MHz, DMSO-d6): δ8.39(d,J=4.0Hz,1H),7.34(d,J=12.0Hz,3H),4.98-4.90 (m,1H),4.65-4.36(m,2H),3.48-3.41(m,1H),2.92(d,J=16.0Hz,1H),2.25(s,3H).

[0158] Synthesis of intermediate 17:

[0159] Concentrated hydrochloric acid (5 mL) was added to an ethanol (40 mL) solution of intermediate 16 (2.5 g, 8.61 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was concentrated to dryness, diluted with water (75 mL), alkalized with ammonia (37.5 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to give a brown solid intermediate 17 (1.8 g, 85%). MS: [MH] + 248.90; 1HNMR (400MHz, CDCl3): δ7.04(d,J=6.0Hz,1H),6.94(d,J=9.6Hz,1H),4.97(s,2H),4.49-4.25(m,3H),3.25-3.19(m,1H),2.82-2.76(m,1H).

[0160] Synthesis of intermediates IM2R and IM2S:

[0161] Intermediate 17 (500 mg, 2.01 mmol) was chirally resolved by SFC (CHIRALPAKAD-H, 70% CO2, 30% IPA) to obtain a brown solid IM2R (160 mg, 32%), MS: [MH]. + 240.25; CHAIRL HPLC: 10.34min. IM2S (190mg, 38%), MS: [MH] + 240.25; CHAIRLHPLC: 8.17 min.

[0162] Example 3: Synthesis of intermediate IM3

[0163] Synthesis of intermediate 19:

[0164] Intermediate 18 (1.0 g, 7.407 mmol) was dissolved in acetic acid (10 mL), and NaBH3CN (1.4 g, 22.22 mmol) was added in portions under nitrogen protection. The mixture was stirred overnight at room temperature. After dilution with water, the pH was adjusted to 6-7 with saturated NaHCO3. The mixture was extracted three times with DCM (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (2%–5% ethyl acetate in petroleum ether solution) to obtain a pale yellow oil intermediate 19 (680 mg, 67%). MS: [MH] + 138.00; 1 HNMR (400MHz, CDCl3): δ6.90-6.80(m,1H),6.78-6.73(m,1H),6.60-6.57(m,1H),3.61(t,J=8Hz,2H),3.06(t,J=8Hz,2H).

[0165] Synthesis of intermediate 20:

[0166] Intermediate 19 (680 mg, 4.964 mmol) was dissolved in 8 mL of H₂SO₄. Ag₂SO₄ (820 mg, 2.63 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 0.5 h after the addition was complete. Br₂ (818 mg, 5.112 mmol) was added dropwise at -5 °C, and the reaction was continued at this temperature for 0.5 h after the addition was complete. The temperature was then raised to room temperature for 1 h. The reaction mixture was quenched in ice water, filtered, and the filtrate was adjusted to pH 6-7 with NaOH. The mixture was extracted three times with EA (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate to obtain a brown solid intermediate 20 (800 mg, 75%). MS: [MH] + 217.80; 1 HNMR (400MHz, CDCl3): δ6.94-6.91 (m, 1H), 6.80-6.79 (m, 1H), 3.63 (t, J = 8Hz, 2H), 3.03 (t, J = 8Hz, 2H).

[0167] Synthesis of intermediate 21:

[0168] Intermediate 20 (803 mg, 3.718 mmol) was dissolved in DCM (8 mL), and (Boc)₂O (1.22 g, 5.576 mmol) and DIPEA (834 mg, 6.468 mmol) were added. The mixture was stirred overnight under nitrogen protection. The reaction solution was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (1.6%–3.2% ethyl acetate in petroleum ether solution) to give a white solid intermediate 21 (800 mg, 68%). 1 HNMR (400MHz, CDCl3): δ8.11-7.65(m,1H),6.94(d,J=8Hz,1H),4.04(t,J=8Hz,2H),3.08(t,J=8Hz,2H),1.61-1.60(m,9H).

[0169] Synthesis of intermediate 22:

[0170] Intermediate 21 (2.66 g, 8.418 mmol) was dissolved in 1,4-dioxane (27 mL), and 4-tert-butylbenzyl mercaptan (1.82 g, 10.101 mmol), Xantphos (487 mg, 0.842 mmol), DIPEA (3.26 g, 25.253 mmol), and Pd2(dba)3 (771 mg, 0.842 mmol) were added. The mixture was heated to 105 °C and stirred for 6 hours under nitrogen protection. The mixture was quenched with water, extracted three times with EA (30 mL), and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 1.2%–2.4% ethyl acetate) to obtain a yellow solid intermediate 22 (3.1 g, 89%). 1HNMR (400MHz, DMSO-d6): δ7.76-7.46(m,1H),7.35-7.33(m,2H),7.27(d,J=8Hz,2H),7.14(d ,J=8Hz,1H),4.14(s,2H),3.93(t,J=8Hz,2H),3.06(t,J=8Hz,2H),1.51(s,9H),1.28(s,9H).

[0171] Synthesis of intermediate 24:

[0172] NCS (4.0 g, 29.879 mmol) and 2N HCl (3 mL) were added to ACN (60 mL), and the mixture was cooled to 0 °C and intermediate 22 (3.1 g, 7.469 mmol) was added. The mixture was reacted at 0 °C for 1 hour, and then extracted twice with water and EA (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product 23. The crude product was dissolved in THF (48 mL), cooled to 0 °C, and then ammonia (9 mL) was added. The mixture was reacted at 0 °C for 30 min. Water was added, and the mixture was extracted twice with EA (30 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 14%–33% ethyl acetate) to obtain yellow solid intermediate 24 (2.2 g, 93%). 1 HNMR (400MHz, DMSO-d6): δ7.55(s,2H),7.40-7.15(m,2H),3.95(t,J=8Hz,2H),3.14(t,J=8Hz,2H),1.51(s,9H).

[0173] Synthesis of IM3:

[0174] Intermediate 24 (1.1 g, 3.481 mmol) was dissolved in DCM (5 mL), and HCl / 1,4-dioxane (5 mL) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and replaced three times with DCM to give a pale yellow solid IM3 (700 mg, 93%). 1 HNMR (400MHz, DMSO-d6): δ7.67(s,2H),7.43-7.18(m,2H),3.67(t,J=8Hz,2H),3.16(t,J=8Hz,2H).

[0175] Example 4: Synthesis of intermediate IM4

[0176] Synthesis of intermediate 27:

[0177] Under nitrogen protection at 0℃, a DMF (175 mL) solution of intermediate 25 (50 g, 0.15 mol) was added dropwise to a DMF (1750 mL) suspension of activated zinc powder (29.8 g, 0.46 mol), and the reaction was allowed to proceed for 1 h after the addition was complete. Intermediate 26 (30 mL, 0.23 mol), Pd2(dba)3 (13.91 g, 0.02 mol), and POT (18.5 g, 0.06 mol) were added to DMF (75 mL). The supernatant of intermediate 25 was slowly added dropwise to intermediate 26, and the mixture was stirred overnight at room temperature after the addition was complete. The reaction mixture was quenched with a semi-saturated saline solution, extracted with EA (1 L × 2), and the organic phase was washed successively with semi-saturated brine and saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 5% ethyl acetate) to obtain a brown solid intermediate 27 (25 g, purity: 60%). 1 HNMR (400MHz, DMSO-d6): δ7.64-7.61(m,1H),7.38(d,J=8.0Hz,1H),7.28-7.22(m,1H),7.10-7 .05(m,1H),4.34-4.28(m,1H),3.65(s,3H),3.21-3.16(m,1H),2.94-2.88(m,1H),1.30(s,9H).

[0178] Synthesis of intermediate 28:

[0179] Intermediate 27 (25 g, purity: 60%) and HCl / 1,4-dioxane (200 mL) were added to dichloromethane (200 mL), and the reaction was carried out at room temperature for 3 h. The reaction mixture was concentrated to dryness, and water (1 L) and EA (500 mL) were added. The pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate solution, and extracted with DCM (500 mL × 2). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid intermediate 28 (8 g, 20%). MS: [MH] + 275.85, 277.70; 1 HNMR (400MHz, DMSO-d6): δ7.62-7.59(m,1H),7.26-7.23(m,1H),7.08-7.0 3(m,1H),3.60(s,3H),3.05-3.30(m,1H),2.84-2.78(m,1H),1.87(s,2H).

[0180] Synthesis of intermediate 29:

[0181] Intermediate 28 (6.5 g, 0.03 mol) and TEA (8.18 mL, 0.06 mol) were dissolved in DCM (130 mL), cooled to 0 °C, and acetyl chloride (2 mL, 0.03 mol) was added dropwise. The reaction mixture was allowed to react for 4 h after the addition was complete. The reaction solution was washed successively with sodium bicarbonate solution (200 mL), saturated brine (200 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether solution containing 30% ethyl acetate) yielded a white solid intermediate 29 (5.9 g, 78%). MS: [MH] + 318.00, 319.80; 1 HNMR (400MHz, DMSO-d6): δ8.41 (d, J=8.0Hz, 1H), 7.65-7.61 (m, 1H), 7.23-7.20 (m, 1H), 7.11-7 .06(m,1H),4.59-4.53(m,1H),3.62(s,3H),3.21-3.16(m,1H),2.98-2.92(m,1H),1.78(s,3H).

[0182] Synthesis of intermediate 30:

[0183] At 0°C, LiBH4 (608 mg, 0.03 mol) was added in portions to intermediate 29 (5.9 g, 0.02 mol) in 100 mL of THF solution, and the reaction was allowed to proceed for 4 hours after the addition was complete. The reaction was quenched at 0°C with 1 N NaOH solution. The solid was filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (using ethyl acetate solution containing 30% petroleum ether) to obtain a white solid intermediate 30 (5.0 g, 93%). MS: [MH] + 289.95, 291.80; 1 HNMR (400MHz, DMSO-d6): δ7.73(d,J=8.0Hz,1H),7.61-7.57(m,1H),7.21-7.17(m,1H),7.06-7.01(m,1H),4. 87(t,J=6.0Hz,1H),4.06-4.00(m,1H),3.42-3.32(m,2H),3.02-2.97(m,1H),2.69-2.63(m,1H),1.72(s,3H).

[0184] Synthesis of intermediate 31:

[0185] Intermediate 30 (5 g, 0.02 mol), CuI (3.28 g, 0.02 mol), cesium carbonate (16.85 g, 0.05 mol), and N,N'-dimethyl-1,2-cyclohexanediamine (4.08 mL, 0.03 mol) were sequentially added to NMP (50 mL). The mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. The reaction solution was quenched with semi-saturated brine (500 mL), extracted with ethyl acetate (200 mL × 2), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate solution containing 50% petroleum ether) to give intermediate 31 (2 g, 55%) as a brown solid. MS: [MH] + 210.15; 1 HNMR (400MHz, DMSO-d6): δ7.95-7.92(m,1H),7.10-7.05(m,1H),6.97-6.91(m,1H),5.09(m,1H),4.52(d,J =8.0Hz,1H),3.47-3.42(m,1H),3.30-3.28(m,1H),3.26-3.22(m,1H),2.85(d,J=16.0Hz,1H),2.24(s,3H).

[0186] Synthesis of intermediate 32:

[0187] Intermediate 31 (1.8 g, 8.6 mmol) and triphenylphosphine (4.97 g, 12.05 mmol) were dissolved in DCM (90 mL). After purging with nitrogen, the solution was cooled to 0 °C. A DCM solution of carbon tetrabromide (3.0 g, 9.03 mmol) in 9 mL was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was reacted at room temperature for 16 hours. The reaction mixture was washed with water (70 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (petroleum ether solution containing 30% ethyl acetate) to give intermediate 32 (1.3 g, 55%) as a brown solid. MS: [MH] + 271.95, 273.80; 1 HNMR (400MHz, DMSO-d6): δ7.91(t,J=8.0Hz,1H),7.14(d,J=8.0Hz,1H),6.99-6.74(m,1H),4.88-4.83 (m,1H),3.79-3.75(m,1H),3.57-3.50(m,1H),3.46-3.39(m,1H),2.98(d,J=16.0Hz,1H),2.26(s,3H).

[0188] Synthesis of intermediate 33:

[0189] Intermediate 32 (1.1 g, 4.04 mmol), AIBN (398 mg, 2.43 mmol), and Bu3SnH (3.26 mL, 12.13 mmol) were dissolved sequentially in toluene (22 mL). After purging with nitrogen three times, the reaction solution was heated to 110 °C and reacted for 2 hours. The reaction solution was poured into a saturated potassium fluoride aqueous solution and stirred for 0.5 h. The solid was filtered off, and the filtrate was extracted with EA (100 mL × 2) and water (100 mL). The organic phase was washed sequentially with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether solution containing 30% ethyl acetate) yielded a brown solid intermediate 33 (0.68 g, 87%). MS: [MH] + 194.15; 1 HNMR (400MHz, DMSO-d6): δ7.99-7.95(m,1H),7.11(d,J=8.0Hz,1H),6.99-6.94(m,1H),4.61(t ,J=8.0Hz,1H),3.40-3.34(m,1H),2.65(d,J=16.0Hz,1H),2.20(s,3H),1.21(d,J=4.0Hz,3H).

[0190] Synthesis of intermediate 35:

[0191] Intermediate 33 (680 mg, 3.52 mmol) was added in portions to chlorosulfonic acid (14 mL) at 0 °C, and the mixture was heated to 50 °C and reacted for 5 hours. The reaction solution was poured into ice water, extracted with dichloromethane (50 mL), and the organic phase was washed successively with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate was used to obtain a brown solid intermediate 34 (1.1 g, 100%). MS: [MH] + 291.95.

[0192] Ammonia solution (5 mL) was added to a tetrahydrofuran solution (30 mL) containing intermediate 34 (1.1 g, crude), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether solution containing 50% ethyl acetate) to obtain a brown solid intermediate 35 (700 mg, 96%). MS: [MH] + 273.0; 1 HNMR (400MHz, DMSO-d6): δ8.43(d,J=8.0Hz,1H),7.57(s,2H),7.34(d,J=8.0Hz,1H),4.70- 4.65(m,1H),3.46-3.39(m,1H),2.73(d,J=16.0Hz,1H),2.23(s,3H),1.22(d,J=8.0Hz,3H).

[0193] IM4 synthesis:

[0194] Concentrated hydrochloric acid (1.5 mL) was added to a solution of intermediate 35 (700 mg, 2.51 mmol) in ethanol (5 mL), and the mixture was stirred at 80 °C for 4 hours. The reaction solution was concentrated to dryness, and water (20 mL) and ammonia (3 mL) were added. The mixture was extracted with ethyl acetate (30 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated to give a brown solid IM4 (560 mg, 85%). MS: [MH] + 231.00; 1 HNMR (400MHz, DMSO-d6): δ7.37(s,2H),7.03(d,J=12.0Hz,1H),6.75(d,J=4.0Hz,1H),5.8 4(s,1H),3.93-3.87(m,1H),3.12-3.06(m,1H),2.56-2.52(m,1H),1.16(d,J=8.0Hz,3H).

[0195] Example 5: Synthesis of intermediate IM5

[0196] Synthesis of intermediate 37:

[0197] Intermediate 36 (17.02 g, 0.13 mol) was added to thionyl chloride (37 mL), followed by dropwise addition of chlorosulfonic acid (43 mL). After the addition was complete, the temperature was raised to 100 °C and the reaction was allowed to proceed for 16 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate (50 mL). The organic phase was washed successively with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate yielded a brown oily intermediate 37 (30.17 g), which was used directly in the next step without purification.

[0198] IM5 synthesis:

[0199] Intermediate 37 (30.17 g, 0.13 mol) was added to THF (150 mL), cooled to 0 °C, and ammonia solution (38 mL) was added dropwise. After the addition was complete, the temperature was raised to 0 °C and the reaction was allowed to proceed for 4 hours. The reaction was quenched with water, extracted with ethyl acetate (250 mL), and the organic phase was washed successively with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated to dryness, slurried with petroleum ether (50 mL), and filtered to give a brown solid IM5 (12.5 g). MS: [MH] + 213.30; 1 HNMR (400MHz, CDCl3): δ5.18(s,2H),2.62(s,3H).

[0200] Example 6: Synthesis of intermediate IM6

[0201] Synthesis of IM6:

[0202] Deuterated methylamine hydrochloride (6.37 g, 90.28 mmol) was added to THF (72 mL), cooled to 0 °C, and an aqueous solution of IM5 (2.40 g, 11.29 mmol, 14 mL) was added dropwise. After the addition was complete, the mixture was heated to 55 °C and reacted for 15 hours. The solution was concentrated to dryness, and methanol was added to remove water. The solution was purified by silica gel column chromatography (using a dichloromethane solution containing 2% methanol) to give a brown solid IM6 (3.5 g). MS: [MH] + 213.30; 1 HNMR (400MHz, DMSO-d6): δ7.96(s,1H),7.33(s,2H),2.29(s,3H).

[0203] Example 7: Synthesis of intermediate IM7

[0204] Synthesis of intermediate 59:

[0205] Intermediate 38 (5.0 g, 19.68 mmol) was dissolved in 1,4-dioxane / H₂O (60 mL / 15 mL), and 2,5-difluorophenylboronic acid (3.73 g, 23.61 mmol), potassium phosphate (8.34 g, 39.36 mmol), and Pd(dppf)Cl₂ (1.44 g, 1.97 mmol) were added. The mixture was heated to 80 °C and stirred overnight under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether solution containing 10%–20% ethyl acetate) to give intermediate 39 (4.6 g, 82%) as a pink solid. MS: [MH] + 288.35; 1 HNMR (400MHz, DMSO-d6): δ12.09(s,1H),7.88(s,1H),7.55(d,J=8.0Hz,1H),7.50-7.45(m,1H),7.44-7.32(m,2H),7.25-7.17(m,2H),3.89(s,3H).

[0206] Synthesis of intermediate 40:

[0207] Intermediate 39 (5.0 g, 17.41 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to 0 °C, and lithium aluminum hydride (858.7 mg, 22.63 mmol) was added in portions. After the addition was complete, the mixture was slowly heated to room temperature and stirred overnight. The reaction solution was cooled to 0 °C, and water (0.9 mL), 15% sodium hydroxide aqueous solution (0.9 mL), and water (2.7 mL) were added dropwise to quench the reaction. The mixture was filtered, and the solid was washed with ethyl acetate (50 mL). The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (using a petroleum ether solution containing 25%–33% ethyl acetate) to give a yellow solid intermediate 40 (4.3 g, 95%). MS: [MH] + 260.35; 1 HNMR (400MHz, DMSO-d6): δ11.16(s,1H),7.67(s,1H),7.42(d,J=12.0Hz,1H),7.39-7.28(m,2H), 7.26-7.22(m,1H),7.20-7.13(m,1H),6.34(br,1H),5.29(t,J=8.0Hz,1H),4.62(d,J=4.0Hz,2H).

[0208] Synthesis of intermediate 41:

[0209] Intermediate 40 (3.0 g, 11.57 mmol) was dissolved in DCM (45 mL), cooled to 0 °C, and Dess-Martin (9.8 g, 23.14 mmol) was added in three portions at room temperature. The mixture was stirred for 20 minutes under nitrogen protection. The mixture was filtered, and the filter cake was washed with dichloromethane and ethyl acetate (1 / 1). The filtrate was washed successively with saturated sodium bicarbonate aqueous solution (40 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 15%–50% ethyl acetate) yielded a black solid intermediate 41 (2.8 g, 94%). 1 HNMR (400MHz, DMSO-d6): δ12.12(s,1H),9.89(s,1H),8.00-7.95(m,2H),7.52-7.34(m,3H),7.26-7.18(m,2H).

[0210] Synthesis of intermediate 42:

[0211] Intermediate 41 (4.0 g, 16.18 mmol) was dissolved in nitromethane (40 mL), and ammonium acetate (486.3 mg, 6.31 mmol) was added. The mixture was heated to 100 °C and stirred for 4 hours. After cooling to room temperature, the crude product was concentrated and purified by silica gel column chromatography (using a petroleum ether solution containing 10%–20% ethyl acetate) to give intermediate 42 (1.6 g, 34%) as a yellow solid. MS: [MH]+ 301.00; 1 HNMR (400MHz, DMSO-d6): δ11.93(s,1H),8.19(d,J=12Hz,1H),8.07(d,J=12.0Hz,1H) ,7.86(s,1H),7.56-7.48(m,2H),7.45-7.33(m,2H),7.31(s,1H),7.26-7.19(m,1H).

[0212] Synthesis of intermediate 43:

[0213] Intermediate 42 (1.6 g, 5.33 mmol) was dissolved in tetrahydrofuran (25 mL), cooled to 0 °C, and lithium aluminum hydride (1.21 g, 32.0 mmol) was added in portions. The mixture was slowly heated to room temperature and stirred for 4 hours. The reaction solution was cooled to 0 °C, and water (1.2 mL), 15% sodium hydroxide aqueous solution (1.2 mL), and water (3.6 mL) were added dropwise to quench the reaction. The mixture was filtered, washed with ethyl acetate (50 mL), and the filtrate was collected. The filtrate was purified by silica gel column chromatography (petroleum ether solution containing 33% ethyl acetate) to give intermediate 43 (940 mg, 64%) as a yellow solid. MS: [MH] + 273.15; 1 HNMR (400MHz, DMSO-d6): δ11.12(br,1H),7.64(s,1H),7.39(d,J=8.0Hz,1H),7.37-7.29(m,2H), 7.25-7.20(m,1H),7.20-7.13(m,1H),6.29(s,1H),3.03(t,J=8.0Hz,2H),2.91(d,J=8.0Hz,2H).

[0214] The synthesis of IM7:

[0215] Intermediate 43 (940 mg, 3.45 mmol) and CDI (615.7 mg, 3.80 mmol) were dissolved in 1,4-dioxane (10 mL) and refluxed overnight under nitrogen protection. The reaction solution was cooled to room temperature and concentrated to give the crude product, which was purified by silica gel column chromatography (using a petroleum ether solution containing 20%–33% ethyl acetate) to give a brown solid IM7 (160 mg, 15.5%). MS: [MH] + 299.00; 1HNMR (400MHz, CDCl3): δ8.38(d,J=8.0Hz,1H),7.67(br,1H),7.46-7.40(m,1H),7.22-7.16(m,1H),7.1 4-7.06(m,1H),7.01-6.92(m,1H),6.39(s,1H),5.48(br,1H),3.61-3.54(m,2H),3.15(t,J=8.0Hz,2H).

[0216] Example 8: Synthesis of intermediates IM8a and IM8b

[0217] Synthesis of intermediate 46:

[0218] Boc-β-alanine (10.12 g, 53.46 mmol) and N-methylmorpholine (5.41 g, 53.46 mmol) were added to DMF (90 mL), and the mixture was cooled to -20 °C under nitrogen protection. Isobutyl chloroformate (7.30 g, 53.46 mmol) was added, and the reaction was continued at the above temperature for 10 minutes. Then, a solution of 4-bromophenyl-1,2-diamine (10 g, 53.46 mmol) in DMF (10 mL) was added dropwise, and the mixture was allowed to react at room temperature for 3 hours after the addition was complete. The reaction solution was diluted with ethyl acetate (300 mL), washed successively with water (100 mL × 3), and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, a black solid intermediate 46 (18 g). MS: [MH] + 359.2.

[0219] Synthesis of intermediate 47:

[0220] Intermediate 46 (18 g, crude) was dissolved in acetic acid (100 mL) and reacted at 80 °C for 2 hours. The solution was concentrated, and acetic acid was removed by displacement with ethyl acetate (100 mL). The crude product was purified by silica gel column chromatography (using a petroleum ether solution containing 16-50% ethyl acetate) to give intermediate 47 (6.8 g, two steps, 37%) as a pink solid. MS: [MH] + 341.2; 1 HNMR (400MHz, CDCl3): δ7.69(s,1H),7.41-7.39(m,1H),7.33-7.30(m,1H),5.22(s,1H),3.68-3.64(m,2H),3.16-3.13(m,2H),1.42(s,9H).

[0221] Synthesis of intermediate 48:

[0222] Intermediate 47 (6.8 g, 19.99 mmol) was dissolved in DCM (150 mL), and HCl / 1,4-dioxane (130 mL) was added. The mixture was reacted at room temperature for 3 hours. The solution was concentrated to dryness, and dichloromethane (100 mL) was added three times to displace the solution, giving a white solid intermediate 48 (5.2 g, 94%). MS: [MH] + 241.15; 1 HNMR (400MHz, DMSO-d6): δ8.30(br,2H),7.97(s,1H),7.72-7.69(m,1H),7.61-7.58(m,1H),5.32(s,1H),3.39-3.20(m,4H).

[0223] Synthesis of intermediates 49 and 50:

[0224] Intermediate 48 (3.0 g, 12.49 mmol) was dissolved in 1,4-dioxane (60 mL), and CDI (2.33 g, 14.37 mmol) was added. The mixture was refluxed for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed successively with water (50 mL × 3), saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solution was concentrated to give a mixture of intermediates 49 and 50 (2.3 g, 69%), which were off-white solids. MS: [MH] + 265.9, 267.7; 1 HNMR (400MHz, CDCl3): δ8.34-8.32(m,0.5H),8.02-8.00(m,0.5H),7.86-7.83(m,0.5H),7.57 -7.55(m,0.5H),7.48-7.45(m,1H),5.74-5.70(m,1H),3.73-3.69(m,2H),3.33-3.28(m,2H).

[0225] Synthesis of IM8a and IM8b:

[0226] A mixture of intermediates 49 and 50 (1.6 g, 6.01 mmol), 2,5-difluorophenylboronic acid (1.23 g, 7.82 mmol), Pd(dppf)Cl2 (439.5 mg, 0.60 mmol), and potassium carbonate (2.49 g, 18.04 mmol) were added to 1,4-dioxane / H2O (26 mL / 6 mL). After purging with nitrogen three times, the mixture was heated to 100 °C for 4 hours. The reaction solution was filtered, washed with ethyl acetate (200 mL), and the filtrate was washed successively with water (150 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using a solution of 25% ethyl acetate in petroleum ether and 5% methanol in dichloromethane) to give a mixture of orange solids IM8a and IM8b (1.0 g, 55%). MS: [MH] + 299.95; 1 HNMR (400MHz, CDCl3): δ8.32-8.19(m,1H),7.87-7.75(m,1H),7.54-7.52(m,1H),7.22-7.18(m ,1H),7.15-7.09(m,1H),7.06-6.97(m,1H),5.73(s,1H),3.76-3.70(m,2H),3.38-3.29(m,2H).

[0227] Example 9: Synthesis of intermediate IM9

[0228] Synthesis of intermediate 52:

[0229] Intermediate 51 (10 g, 0.041 mol), 2-tributyltin pyridine (15.9 g, 0.043 mol), and Pd(PPh3)4 (2.38 g, 0.002 mol) were added to 1,4-dioxane (100 mL), purged three times with nitrogen, and heated to 90 °C with stirring overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography (using a petroleum ether solution containing 5%–33% ethyl acetate) to obtain a white solid intermediate 52 (8.1 g, 82%). MS: [MH] + 242.35; 1 HNMR (400MHz, CDCl3): δ8.75-8.76(m,1H),8.02-7.99(m,2H),7.82-7.75(m,2H),7.4 6-7.44(m,2H),7.29-7.26(m,1H),4.25-4.19(m,2H),3.72(s,2H),1.33-1.31(m,3H).

[0230] Synthesis of IM9:

[0231] Intermediate 52 (8.1 g, 0.034 mol) and lithium hydroxide monohydrate (5.65 g, 0.134 mol) were added to THF / MeOH / H2O (40 mL / 20 mL / 20 mL), and reacted at room temperature for 2 hours. The reaction solution was concentrated to remove the organic solvent, and the pH was adjusted to 6-7 with HCl (2N). The mixture was filtered and dried to obtain the crude product. Purification by silica gel column chromatography (using a dichloromethane solution containing 3%-14% methanol) yielded a pale pink solid IM9 (6.3 g, 88%). MS: [MH] + 214.25; 1 HNMR (400MHz, DMSO-d6): δ8.68-8.66(m,1H),8.05-8.02(m,2H),7.97-7.95(m,1H),7.91-7.87(m,1H),7.40-7.34(m,3H),3.63(s,2H).

[0232] Example 10: Synthesis of intermediate IM10

[0233] Synthesis of intermediate 54:

[0234] Intermediate 53 (10.0 g, 54.6 mmol) was dissolved in DMF (100 mL), and an aqueous solution of sodium methanethiol (4.6 g, 65.5 mmol) (20 mL) was added dropwise. The mixture was stirred at room temperature for 20 minutes after the addition was complete. The solution was filtered, the solid was washed with water, and dried under vacuum to give intermediate 54 (7.1 g, 61%), a brown solid. MS: [MH] + 211.90; 1 HNMR (400MHz, DMSO-d6): δ11.00(br,1H),7.37(d,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),2.58(s,3H).

[0235] Synthesis of intermediate 55:

[0236] Lithium aluminum hydride (1.8 g, 47.35 mmol) was suspended in THF (60 mL) and cooled to 0 °C. Intermediate 54 (5.0 g, 23.67 mmol) was added in portions, and the mixture was slowly brought to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C, and water (1.8 mL), 15% sodium hydroxide aqueous solution (1.8 mL), and water (5.4 mL) were added dropwise to quench the reaction. The mixture was filtered, and the solid was washed with ethyl acetate (50 mL). The filtrate was collected and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using petroleum ether solution containing 11% ethyl acetate) to obtain a dark green oily intermediate 55 (1.08 g, 25%). MS: [MH] + 181.90;1 HNMR (400MHz, CDCl3): δ8.16(br,1H),7.36(d,J=8.0Hz,1H),7.29(d,J=12.0Hz,1H),7.22(t,J=4.0Hz,1H),6.52-6.47(m,1H),2.49(s,3H).

[0237] Synthesis of intermediate 56:

[0238] Intermediate 55 (4.5 g, 24.83 mmol) was dissolved in glacial acetic acid (25 mL), cooled to 10 °C, and sodium cyanoborohydride (4.7 g, 74.49 mmol) was added in portions. After addition, the mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (25 mL × 2). The aqueous phase was neutralized to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (25 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (using petroleum ether solution containing 20% ​​ethyl acetate) to obtain the green oily intermediate 56 (1.88 g, 41%). MS: [MH] + 184.00; 1 HNMR (400MHz, CDCl3): δ6.82(d,J=12.0Hz,1H), 6.56(d,J=4.0Hz,1H), 3.56(t,J=8.0Hz,2H), 2.99(t,J=10.0Hz,2H), 2.41(s,3H).

[0239] Synthesis of intermediate 57:

[0240] Intermediate 56 (1.88 g, 10.26 mmol) was dissolved in tetrahydrofuran (25 mL), and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (5.32 g, 20.52 mmol) and DMAP (1.25 g, 10.26 mmol) were added. The mixture was stirred overnight at room temperature. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed successively with water (15 mL × 3) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (using petroleum ether solution containing 5% ethyl acetate) to give a pale yellow oil intermediate 57 (2.6 g, 77%). MS: [MH] + 328.05; 1HNMR (400MHz, CDCl3): δ7.84 (br, 1H), 6.84 (d, J = 12.0Hz, 1H), 4.40-4.22 (m, 2H), 4.02 (t,J=8.0Hz,2H),3.07(t,J=8.0Hz,2H),2.47(s,3H),1.15-1.03(m,2H),0.07(s,9H).

[0241] Synthesis of intermediate 58:

[0242] Intermediate 57 (2.65 g, 8.09 mmol) was dissolved in DCM (35 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (1.54 g, 8.90 mmol) was added in portions. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated sodium sulfite aqueous solution (25 mL × 2) and saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 20%–50% ethyl acetate) yielded a white solid intermediate 58 (2.6 g, 93%). MS: [MH] + 687.80; 1 HNMR (400MHz, CDCl3): δ8.38-7.86(m,1H),6.92(d,J=12.0Hz,1H),4.43-4.25(m,2H),4. 08(d,J=8.0Hz,2H),3.15(t,J=8.0Hz,2H),2.80(s,3H),1.22-1.04(m,2H),0.06(s,9H).

[0243] Synthesis of intermediate 59:

[0244] Intermediate 58 (2.6 g, 7.57 mmol), MgO (1.53 g, 15.14 mmol), Rh(OAc)₂ (3.66 g, 11.36 mmol), BocNH₂ (1.77 g, 15.14 mmol), and diacetyliodobenzene (167.3 mg, 0.38 mmol) were added to DCM (60 mL) and stirred overnight at 40 °C under nitrogen protection. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (50 mL), and the filtrate was concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 20%–33% ethyl acetate) yielded yellow oil intermediate 59 (2.18 g, 62%). MS: [MH] + 458.95; 1HNMR (400MHz, CDCl3): δ8.50-8.02(m,1H),7.03(d,J=8.0Hz,1H),4.43-4.24(m,2H),4.12-4. 04(m,2H),3.32(s,3H),3.19(t,J=10.0Hz,2H),1.40(s,9H),1.20-1.01(m,2H),0.07(s,9H).

[0245] Synthesis of IM10:

[0246] Intermediate 59 (2.18 g, 4.75 mmol) and TBAF (1 M, THF, 5.7 mL, 5.70 mmol) were added to THF (25 mL) and stirred at room temperature for 1 hour. The mixture was quenched with water (25 mL), extracted with ethyl acetate (25 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether solution containing 50% ethyl acetate) yielded a yellow oil IM10 (1.4 g, 93%). MS: [MH] + 314.95; 1 HNMR (400MHz, CDCl3): δ7.12(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),3.91(br ,1H),3.64(t,J=8.0Hz,2H),3.31(s,3H),3.09(t,J=10.0Hz,2H),1.40(s,9H).

[0247] Example 11: Synthesis of intermediate IM11

[0248] Synthesis of intermediate 60:

[0249] Intermediate 61 (500 mg, 2.058 mmol) was dissolved in 1,4-dioxane / H₂O (60 mL / 15 mL), and 2,5-difluorophenylboronic acid (423 mg, 2.675 mmol), potassium phosphate (872 mg, 4.114 mmol), and Pd(dppf)Cl₂ (151 mg, 0.206 mmol) were added. The mixture was heated to 80 °C and stirred overnight under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether solution containing 1%–9% ethyl acetate) to give intermediate 60 (470 mg, 83%) as a pink solid. MS: [MH] + 276.90; 1HNMR (400MHz, CDCl3): δ7.52-7.48(m,2H),7.40-7.36(m,2H),7.16-7.07(m,2H ),7.02-6.96(m,1H),4.20-4.17(m,2H),3.68-3.66(m,2H),1.26-1.24(m,3H).

[0250] Synthesis of IM12:

[0251] Intermediate 60 (200 mg, 0.725 mmol) and lithium hydroxide monohydrate (122 mg, 2.898 mmol) were added to THF / MeOH / H2O (1 mL / 0.5 mL / 0.5 mL), and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to remove the organic solvent, and HCl (2N) was added to adjust the pH to 6-7. A solid precipitated out, which was filtered to obtain the solid. After drying, a white solid IM12 (165 mg, 92%) was obtained. 1 HNMR (400MHz, CDCl3): δ7.51(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.15-7.07(m,2H),7.02-6.96(m,1H),3.71(s,2H).

[0252] Example 12: Synthesis of intermediate IM12

[0253] Synthesis of intermediate 62:

[0254] At 0 °C, thionyl chloride (1.53 g, 12.87 mmol) was added dropwise to a 10 mL ethanol solution of intermediate 61 (2.0 g, 8.58 mmol). After the addition was complete, the mixture was heated to reflux and stirred for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and replaced three times with ethanol and dichloromethane to give a white solid intermediate 62 (2.0 g, 89%). MS: [MH] + 260.95; 1 HNMR (400MHz, CDCl3): δ7.27-7.26(m,1H),7.25-7.24(m,1H),7.17-7.13(m,1H),4.17(q,J=8.0Hz,2H),3.61(s,2H),1.26(t,J=8.0Hz,3H).

[0255] Synthesis of intermediate 63:

[0256] Intermediate 62 (1.0 g, 3.83 mmol), 2,5-difluorophenylboronic acid (786.3 mg, 4.98 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (280.0 mg, 0.38 mmol), and potassium carbonate (1.59 g, 11.49 mmol) were added to 1,4-dioxane / H₂O (15 mL / 5 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and stirred overnight. The mixture was filtered, and the filtrate was diluted with ethyl acetate (60 mL), then washed successively with water (40 mL) and saturated brine (30 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 9% ethyl acetate) yielded a yellow oily intermediate 63 (1.0 g, 88%). MS: [MH] + 295.10; 1 HNMR (400MHz, CDCl3): δ7.37-7.33(m,1H),7.30-7.27(m,2H),7.15-7.09(m,2H ),7.04-6.98(m,1H),4.20(q,J=8.0Hz,2H),3.71(s,2H),1.28(t,J=8.0Hz,3H).

[0257] Synthesis of IM12:

[0258] Intermediate 63 (1.0 g, 2.40 mmol) and lithium hydroxide monohydrate (285.5 mg, 6.80 mmol) were added to THF / MeOH / H2O (5 mL / 2.5 mL / 2.5 mL), and stirred overnight at room temperature. The reaction solution was concentrated at 25 °C to remove THF / MeOH, adjusted to pH 4 with 2N hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give an off-white solid IM12 (900 mg, 95%). 1 HNMR (400MHz, CDCl3): δ7.38-7.34(m,1H),7.31-7.27(m,2H),7.15-7.09(m,2H),7.05-6.99(m,1H),3.77(s,2H).

[0259] Example 13: Synthesis of intermediate IM13

[0260] Synthesis of intermediate 65:

[0261] At 0 °C, di-tert-butyl dicarbonate (4.41 mL, 0.02 mol) was added dropwise to a solution of intermediate 64 (4.5 g, 0.02 mol) and triethylamine (3.20 mL, 0.02 mol) in dichloromethane (45 mL). After the addition was complete, the mixture was brought to room temperature and stirred for 2 h. The reaction solution was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a gray oily liquid intermediate 65 (5.5 g, 96%). MS: [MH] + 241.80, 282.85; 1 HNMR (400MHz, CDCl3): δ7.42-7.36 (m, 2H), 7.15-7.08 (m, 1H), 4.63 (t, J = 8.4Hz, 4H), 1.51 (s, 9H).

[0262] Synthesis of intermediate 66:

[0263] Intermediate 65 (5.96 g, 0.02 mol), pyridine-2-tri-n-butyltin (6.72 mL, 0.02 mol), and tetra-triphenylphosphine palladium (1.15 g, 1.0 mmol) were added to 1,4-dioxane (60 mL), purged with nitrogen three times, and stirred at 90 °C for 6 hours. The reaction mixture was poured into a saturated potassium fluoride solution (100 mL), stirred for half an hour, filtered, and extracted with ethyl acetate (150 mL). The organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 7-10% ethyl acetate) to obtain a chromophore-like solid intermediate 66 (3.6 g, 60%). MS: [MH] + 297.05; 1 HNMR (400MHz, CDCl3): δ8.68 (d, J = 4.8Hz, 1H), 7.93-7.86 (m, 2H), 7.78-7.70 ( m,2H),7.38-7.31(m,1H),7.25-7.22(m,1H),4.76-4.71(m,4H),1.53(s,9H).

[0264] Synthesis of IM13:

[0265] Intermediate 66 (0.5 g, 1.66 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (2.5 mL) was added. The reaction was carried out at room temperature for 2 h. The solution was concentrated to give a white solid, IM13 (0.5 g, 100%). MS: [MH] + 196.95.

[0266] Example 14: Synthesis of intermediate IM14

[0267] Synthesis of intermediate 68:

[0268] Intermediate 67 (4.0 g, 17.62 mmol), (2,5-difluoro)phenylboronic acid (4.17 g, 26.42 mmol), bis(triphenylphosphine)palladium dichloride (615 mg, 0.88 mmol), and potassium phosphate (7.48 g, 35.24 mmol) were added to Tol / EtOH / H2O (60 mL / 24 mL / 12 mL), purged three times with nitrogen, and then heated to 70 °C and stirred for 6 hours. The mixture was filtered, and the filtrate was diluted with ethyl acetate (60 mL), then washed successively with water (40 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then slurried with 50 mL of ethyl acetate and filtered to obtain a gray solid intermediate 68 (2.58 g, 56%). MS: [MH] + 261.25.

[0269] Synthesis of IM14:

[0270] Intermediate 68 (1.50 g, 5.76 mmol) was dissolved in THF (30 mL), cooled to 0 °C, and sodium borohydride (1.09 g, 28.82 mmol) was added. Boron trifluoride diethyl ether (12.31 g, 40.32 mmol) was added dropwise. The mixture was brought to room temperature and stirred overnight. The reaction solution was quenched with 1 N hydrochloric acid, the pH was adjusted to 8 with saturated sodium bicarbonate, extracted with ethyl acetate (50 mL), the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was used directly in the next step as a pale yellow solid, IM14 (1.35 g, 95%). MS: [MH] + 247.25.

[0271] Example 15: Synthesis of intermediate IM15

[0272] Synthesis of intermediate 70:

[0273] At 0 °C, trimethylsilyl cyanide (5.46 mL, 0.04 mol) was added dropwise to a mixed solution of intermediate 69 (20 g, 0.09 mol) and aluminum trichloride (582 mg, 4.37 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a deep yellow solid intermediate 70 (20.8 g, 73%). 1HNMR (400MHz, CDCl3): δ7.67(d,J=4.0Hz,1H),7.02(d,J=8.0Hz,1H),3.07-2.91(m,2H),2.79-2.72(m,1H),2.47-2.40(m,1H),0.24(s,9H).

[0274] Synthesis of intermediate 71:

[0275] Intermediate 70 (20 g, 0.02 mol) and stannous chloride (60 g, 0.32 mol) were added to a mixed solution of acetic acid (230 mL) and concentrated hydrochloric acid (23 mL). The reaction solution was heated to 120 °C and stirred for 16 h. The reaction solution was concentrated to dryness, and EA (300 mL) and a saturated sodium bicarbonate solution (300 mL) were added. The organic phase was separated, and the aqueous phase was adjusted to pH 2-3 with 2N dilute hydrochloric acid and extracted with ethyl acetate (200 mL). The ethyl acetate solution was washed successively with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid intermediate 71 (12 g, 58%). 1 HNMR (400MHz, DMSO-d6): δ12.58(s,1H),7.58-7.56(m,1H),7.28(d,J=12.0Hz,1H),4.02-3.98(m,1H),2.97-2.79(m,2H),2.37-2.22(m,2H).

[0276] Synthesis of intermediate 72:

[0277] At 0°C, intermediate 71 (2 g, 7.72 mmol), methyl iodide (1.44 mL, 23.16 mmol), and potassium carbonate (2.13 g, 15.44 mmol) were added to DMF (20 mL), and the mixture was stirred at room temperature for 16 h after the addition was complete. EA (200 mL × 2) and semi-saturated brine (200 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (7% ethyl acetate in petroleum ether solution) yielded a yellow oily liquid intermediate 72 (1.3 g, 65%). 1 HNMR (400MHz, CDCl3): δ7.53(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),4.00(t,J=8 .0Hz,1H),3.75(s,3H),3.08-3.00(m,1H),2.90-2.82(m,1H),2.51-2.32(m,2H).

[0278] Synthesis of intermediate 73:

[0279] Intermediate 72 (1 g, 3.66 mmol), p-tert-butylbenzyl mercaptan (0.82 mL, 4.39 mmol), Xantphos (212 mg, 0.37 mmol), DIPEA (1.91 mL, 10.98 mmol), and Pd2(dba)3 (335 mg, 0.37 mmol) were added to 1,4-dioxane (20 mL), and the mixture was heated to 105 °C and stirred for 16 hours under nitrogen protection. The mixture was quenched with water, extracted three times with EA (30 mL), washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 1.2%–2.4% ethyl acetate) yielded a yellow solid intermediate 73 (1.2 g, 88%). 1 HNMR (400MHz, CDCl3): δ7.32-7.29(m,3H),7.23-7.20(m,2H),6.93(d,J=8.0Hz,1H),4.09-4.02(m,2H),3 .95(t,J=4.0Hz,1H),3.70(s,3H),3.10-3.01(m,1H),2.91-2.83(m,1H),2.49-2.29(m,2H),1.29(s,9H).

[0280] Synthesis of intermediate 74:

[0281] NCS (1.58 g, 11.81 mmol), 2N hydrochloric acid (0.8 mL), and intermediate 73 (1.1 g, 2.95 mmol) were added to ACN (18 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with water, extracted with EA (25 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in THF (25 mL), cooled to 0 °C, and ammonia water (3.5 mL) was added. The reaction was carried out at 0 °C for 30 min. The reaction solution was quenched with water, extracted twice with EA (30 mL), washed once with saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (petroleum ether solution containing 10%–33% ethyl acetate) to obtain a yellow solid intermediate 74 (0.65 g, 81%). 1 HNMR(400MHz, CDCl3): δ7.88(d,J=8.0Hz,1H),7.09(d,J=6.0Hz,1H),5.07(s,2H),4.05 (t,J=8.0Hz,1H),3.75(s,3H),3.19-3.11(m,1H),3.01-2.93(m,1H),2.56-2.37(m,2H).

[0282] Synthesis of IM15:

[0283] Intermediate 74 (0.65 g, 2.38 mmol) was dissolved in THF / MeOH / H2O (8 mL, 4 mL, 4 mL), and lithium hydroxide monohydrate (400 mg, 9.51 mmol) was added. The reaction was carried out at room temperature for 3 hours, and EA (100 mL) and water (100 mL) were added. The pH of the aqueous phase was adjusted to 2-3 with 2N dilute hydrochloric acid, and then EA (50 × 2 mL) was added for extraction. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid IM15 (400 mg, 65%). 1 HNMR (400MHz, DMSO-d6): δ12.63(s,1H),7.75(d,J=8.0Hz,1H),7.57(s,2H),7.3 1(d,J=8.0Hz,1H),4.04(t,J=6.0Hz,1H),3.06-2.87(m,2H),2.35-2.28(m,2H).

[0284] Example 16: Synthesis of intermediate IM16

[0285] Synthesis of intermediate 77:

[0286] Intermediate 75 (25.0 g, 0.28 mol) and intermediate 76 (25.7 g, 0.28 mol) were added to ethanol (250 mL) and stirred at room temperature for 16 h. EA (250 mL) was added to the reaction mixture, and the pH was adjusted to 7 with saturated sodium bicarbonate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was then slurried with petroleum ether at 0 °C to obtain a brown solid intermediate 77 (27.0 g, 76%).

[0287] Synthesis of intermediate 78:

[0288] Intermediate 77 (4.5 g, 35 mmol) was dissolved in DCM (75 mL), cooled to -5 to 5 °C, and NBS (6.3 g, 43 mmol) was added in portions. The mixture was stirred at -5 to 5 °C for 2 h. The solution was concentrated to dryness, ethanol (25 mL) was added, and the mixture was stirred and filtered to remove the solid. The filtrate was concentrated to dryness, EA (50 mL) was added, and the solution was washed successively with water and saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated to give a brown solid intermediate 78 (1.51 g, 21%). MS: [MH] + 207.30; 1 HNMR (400MHz, CDCl3): δ2.89(s,3H),2.19(s,3H).

[0289] Synthesis of IM16:

[0290] Intermediate 78 (1.1 g, 5.31 mmol) was dissolved in THF (dry, 10 mL), and sodium methanethiol (0.74 g, 10.62 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with EA (50 mL), and the organic layer was washed successively with water and saturated brine. The solution was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (containing 2% methanol in DCM solution) to give a brown solid IM16 (0.70 g, 76%). MS: [MH] + 175.00; 1 HNMR (400MHz, CDCl3): δ2.93(s,3H),2.28(s,3H),2.26(s,3H).

[0291] Example 17: Synthesis of intermediate IM17

[0292] Synthesis of IM17:

[0293] Intermediate 79 (1.00 g, 4.29 mmol), 2-hydroxy-5-fluorophenylboronic acid (0.80 g, 5.15 mmol), Pd(dppf)Cl2 (0.15 mg, 0.22 mmol), and potassium phosphate (1.82 g, 8.58 mmol) were added to Tol / EtOH / H2O (20 mL / 8 mL / 4 mL), purged three times with nitrogen, and heated to 70 °C for 6 hours. The mixture was then quenched with water (50 mL), and the pH was adjusted to 5–6 with dilute hydrochloric acid (1 N). Extraction was performed with ethyl acetate (50 mL), and the organic layer was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using DCM solution containing 5% methanol) to obtain a yellow solid IM17 (0.36 g, 31.8%). MS: [2 M-H] - 526.95; 1 HNMR (400MHz, CDCl3): δ7.68-7.62(m,1H),7.48-7.44(m,1H),7.36-7.32(m ,1H),7.19-7.16(m,1H),7.01-6.90(m,3H),7.48-7.44(m,1H),3.71(s,2H).

[0294] Example 18: Synthesis of intermediate IM18

[0295] Synthesis of intermediate 80:

[0296] Intermediate 4 (1.00 g, 3.92 mmol), 2-methoxy-5-fluorophenylboronic acid (1.00 g, 5.88 mmol), Pd(dppf)Cl2 (0.28 mg, 0.39 mmol), and potassium phosphate (1.67 g, 7.84 mmol) were added to Tol / EtOH / H2O (15 mL / 6 mL / 2 mL), purged three times with nitrogen, and heated to 70 °C for 6 hours. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (PE solution containing 2.5% EA) to give intermediate 80 (1.20 g, 100%), a white solid.

[0297] Synthesis of IM18:

[0298] Intermediate 80 (1.1 g, 3.66 mmol) was dissolved in THF / EtOH / H2O (20 mL, 2 mL, 4 mL), and lithium hydroxide monohydrate (463 mg, 10.99 mmol) was added. The reaction was allowed to proceed at room temperature for 3 hours. The mixture was then extracted with water (100 mL), the pH adjusted to 2–3 with 2N dilute hydrochloric acid, and EA (50 × 2 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid IM18 (950 mg, 91%). MS: [MH] - 285.20; 1 HNMR (400MHz, CDCl3): δ7.35-7.30(m,2H),7.27(m,1H),7.03-6.95(m,2H),6.90-6.87(m,1H),3.77(s,3H),3.36-3.24(m,4H).

[0299] Example 19: Synthesis of intermediate IM19

[0300] Synthesis of intermediate 81:

[0301] Under nitrogen protection, a THF solution of LDA (2N, 0.47 mL, 0.94 mmol) was added dropwise to a THF solution of intermediate 4 (200 mg, 0.78 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h, then heated to -60 °C and stirred for another 1 h. The mixture was then cooled to -78 °C, and a THF solution of 3-bromopropanecyanate (1.26 g, 9.41 mmol) at -2 mL was added. The mixture was stirred at -78 °C and -60 °C for 0.5 h, then allowed to cool to room temperature and stirred overnight. EA (30 mL) was added to the reaction mixture, which was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the intermediate 81 (78 mg) was obtained by column chromatography (using a petroleum ether solution containing 15% ethyl acetate). 1HNMR (400MHz, DMSO): δ7.40 (s, 1H), 7.33-7.31 (dd, J1=8Hz, J2=1.6Hz, 1H), 7.18-7.15 (d, J=8Hz, 1H ),3.64(s,3H),3.38-3.28(m,2H),3.00-2.90(m,2H),2.52-2.48(m,2H),2.06-2.02(t,J=8Hz,2H).

[0302] Synthesis of intermediate 82:

[0303] Intermediate 81 (1.40 g, 4.54 mmol), pyridine-2-tri-n-butyltin (2.52 g, 6.81 mmol), and tetra-triphenylphosphine palladium (1.00 g, 0.91 mmol) were added to 1,4-dioxane (15 mL), purged with nitrogen three times, and stirred at 100 °C for 6 hours. The reaction mixture was poured into a saturated potassium fluoride solution (100 mL), stirred for half an hour, filtered, and extracted with ethyl acetate (150 mL). The organic phase was washed successively with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 15% ethyl acetate) to obtain a yellow oily intermediate 82 (0.75 g). MS: [MH] + 307.35.

[0304] Synthesis of IM19:

[0305] Intermediate 82 (0.75 g, 2.45 mmol) and Raney nickel (3.0 g) were added to methanol (20 mL), purged three times with hydrogen, and stirred overnight at room temperature. Raney nickel (1.0 g) was then added, purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, and the mixture was concentrated to dryness to give a white solid IM19 (0.59 g). MS: [MH] + 279.35.

[0306] Example 20: Synthesis of intermediate IM20

[0307] Synthesis of intermediate 83:

[0308] Intermediate 81 (1.20 g, 4.98 mmol), (2,5-difluoro)phenylboronic acid (0.79 g, 4.98 mmol), Pd(PPh3)2Cl2 (0.20 g, 0.49 mmol), and potassium phosphate (2.12 g, 9.96 mmol) were added to Tol / EtOH / H2O (30 mL / 12 mL / 6 mL). After purging with nitrogen three times, the mixture was heated to 80 °C for 6 hours. The reaction solution was filtered, washed with ethyl acetate (100 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using petroleum ether solution containing 15% ethyl acetate) to obtain a yellow oily intermediate 83 (1.10 g).

[0309] Synthesis of IM20:

[0310] Intermediate 83 (0.27 g, 0.79 mmol) and Raney nickel (2.0 g) were added to methanol (10 mL), purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, and the mixture was concentrated to dryness to give a white solid IM20 (0.18 g). MS: [MH] + 314.05.

[0311] Example 21: Synthesis of intermediate IM21

[0312] Synthesis of intermediate 84:

[0313] Intermediate 4 (1.00 g, 3.95 mmol), pyridine-2-tri-n-butyltin (2.16 g, 5.88 mmol), and tetra-triphenylphosphine palladium (0.23 g, 0.20 mmol) were added to 1,4-dioxane (10 mL), and the mixture was purged with nitrogen three times before being heated to 100 °C and stirred for 6 hours. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 10%-20% ethyl acetate) to obtain a pale yellow oil intermediate 84 (0.60 g, 60%).

[0314] Synthesis of intermediate 85:

[0315] Under nitrogen protection, an LDA (2N, 1.5 mL, 3.0 mmol) THF solution was added dropwise to a THF solution of intermediate 84 (0.65 g, 2.57 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h, then heated to -60 °C and stirred for another 1 h. The mixture was then cooled to -78 °C, and 2-(bromomethyl)acrylonitrile (0.45 g, 3.08 mmol) was added. The mixture was stirred at -78 °C and -60 °C for 0.5 h, then allowed to cool to room temperature and stirred overnight. EA (30 mL) was added to the reaction mixture, which was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 20% ​​ethyl acetate) to obtain intermediate 85 as a pale yellow oil (0.15 g, 18%). MS: [MH] + 319.75; 1 HNMR (400MHz, CDCl3): δ8.67 (d, J=4.8Hz, 1H), 7.85 (s, 1H), 7.78-7.67 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 7.25-7.21 (m, 1H), 5.97 (s, 1H), 5.72 ( s,1H),4.09(d,J=6.8Hz,1H),3.76(s,1H),3.58(d,J=16.4Hz,2H),3.08-3.02(m,2H),2.70(s,1H),2.04-1.94(m,2H),0.99(d,J=6.8Hz,3H).

[0316] Synthesis of IM21:

[0317] Intermediate 85 (35 mg, 0.11 mmol) and Raney nickel (1.0 g) were added to methanol (10 mL), purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, and the mixture was concentrated to dryness to give a white solid IM21 (22 mg). MS: [MH] + 293.45.

[0318] Example 22: Synthesis of intermediate IM22

[0319] Synthesis of intermediate 86:

[0320] Under nitrogen protection, a THF solution containing LDA (2N, 6 mL, 11.76 mmol) was added dropwise to a THF solution containing intermediate 4 (2.0 g, 7.84 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h, then heated to -60 °C and stirred for another 1 h. The mixture was then cooled to -78 °C, and 2-bromoethylcyanide (1.26 g, 9.41 mmol) was added. The mixture was stirred at -78 °C and -60 °C for 0.5 h, then allowed to cool to room temperature and stirred overnight. EA (30 mL) was added to the reaction mixture, which was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 10%–20% ethyl acetate) to obtain intermediate 86, a pale yellow oil (1.49 g, 62%).

[0321] Synthesis of intermediate 87:

[0322] Intermediate 86 (0.75 g, 2.55 mmol), pyridine-2-tri-n-butyltin (1.41 g, 3.82 mmol), and tetra-triphenylphosphine palladium (0.29 g, 0.25 mmol) were added to 1,4-dioxane (15 mL), purged with nitrogen three times, and stirred at 100 °C for 4 hours. The reaction mixture was poured into a saturated potassium fluoride solution (100 mL), stirred for half an hour, filtered, and extracted with ethyl acetate (150 mL). The organic phase was washed successively with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 10%-20% ethyl acetate) to obtain a pale yellow oil intermediate 87 (0.62 g, 83%).

[0323] Synthesis of IM22:

[0324] Intermediate 87 (0.62 g, 2.12 mmol) and Raney nickel (0.60 g) were added to methanol (15 mL), purged three times with hydrogen, and stirred overnight at room temperature. Raney nickel (1.0 g) was then added, purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, the mixture was concentrated to dryness, and slurried with EA (5 mL) and petroleum ether (10 mL). The mixture was filtered to obtain a white solid IM22 (0.32 g, 57%). MS: [MH] + 265.00; 1 HNMR (400MHz, DMSO-d6): δ8.67 (d, J=4Hz, 1H), 7.95-7.87 (m, 4H), 7.77 (s, 1H),7.36-7.33(m,2H),3.29-3.18(m,4H),2.96-2.88(m,2H),2.06(t,2H).

[0325] Example 23: Synthesis of intermediate IM23

[0326] Synthesis of intermediate 88:

[0327] Under nitrogen protection, a THF solution of butyllithium (1.6N, 3mL, 7.11mmol) was added dropwise to a THF solution of 1,3-dithiane (0.91g, 7.58mmol) at -78℃, and the mixture was stirred at -60 to -40℃ for 1 h. The mixture was then cooled to -78℃, and a THF solution of intermediate 1 (1.00g, 4.74mmol) at -60 to -40℃ was added, and the mixture was stirred for 2 h, then allowed to rise naturally to room temperature and stirred overnight. EA (30mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 10%–20% ethyl acetate) to obtain intermediate 88, a brown oily substance (1.20g, 76%).

[0328] Synthesis of intermediate 89:

[0329] Intermediate 88 (1.20 g, 3.62 mmol) and p-toluenesulfonic acid (0.091 g, 0.54 mmol) were added to toluene (10 mL), purged three times with nitrogen, and refluxed for 4 h to remove water. Ethyl acetate (20 mL) was added, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether) to obtain brown solid intermediate 89 (0.50 g, 44%). 1 HNMR (400MHz, CDCl3): δ8.12(d,J=8.4Hz,1H),7.40(s,1H),7.35(dd,J1=1.2 Hz, J2=8.4Hz,1H),3.08-2.99(m,6H),2.94-2.90(m,2H),2.27-2.20(m,2H).

[0330] Synthesis of intermediate 90:

[0331] Intermediate 89 (1.70 g, 5.4 mmol) was dissolved in AcOH (30 mL), and hydrochloric acid (12 N, 10 mL) was added. The mixture was heated to 100 °C and reacted for 3 h. The solution was concentrated, water was replaced with THF, and the solution was dried to obtain a white solid – Intermediate 90 (1.2 g, 100%), which was used directly in the next step without purification.

[0332] Synthesis of intermediate 91:

[0333] Intermediate 90 (1.20 g, 5.4 mmol) was dissolved in MeOH (10 mL), and thionyl chloride (1.2 mL) was added dropwise. The mixture was reacted at room temperature for 1 h. The solution was concentrated and purified by silica gel column chromatography (petroleum ether solution containing 2% ethyl acetate) to give intermediate 91 (0.97 g, 70%), which was a pale yellow oil.

[0334] Synthesis of intermediate 92:

[0335] Under nitrogen protection, a THF solution of LDA (2N, 2.3 mL, 4.6 mmol) was added dropwise to a THF solution of intermediate 91 (0.95 g, 3.72 mmol) at -78 °C (15 mL). The mixture was stirred at -78 °C for 1 h, then heated to -60 °C and stirred for another 1 h. The mixture was then cooled to -78 °C, and 3-bromoacrylonitrile (0.55 g, 4.10 mmol) was added. The mixture was stirred at -78 °C to -60 °C for 0.5 h, then allowed to cool to room temperature and stirred overnight. EA (50 mL) was added to the reaction mixture, which was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 10% ethyl acetate) to obtain intermediate 92, a pale yellow oil (0.65 g, 57%).

[0336] Synthesis of intermediate 93:

[0337] Intermediate 92 (0.30 g, 0.97 mmol), pyridine-2-tri-n-butyltin (0.54 g, 1.46 mmol), and tetra-triphenylphosphine palladium (0.12 g, 0.10 mmol) were added to 1,4-dioxane (5 mL), purged with nitrogen three times, and stirred at 100 °C for 6 hours. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether solution containing 10% ethyl acetate) to obtain a pale yellow oil intermediate 93 (0.32 g, 100%). MS: [MH] + 307.55; 1 HNMR (400MHz, CDCl3): δ8.68-8.60(m,1H),7.88(s,1H),7.82-7.80(m,1H),7.82-7.80(m,1H),7.56-7.52(m,1H),7.48-7.43(m,1H),7.37-7 .35(m,1H),7.24-7.21(m,2H),3.70(s,3H),3.21-2.99(m,2H),2.82- 2.74(m,1H),2.59-2.51(m,1H),2.39-2.35(m,2H),2.19-2.03(m,2H).

[0338] Synthesis of IM23:

[0339] Intermediate 93 (318 mg, 1.03 mmol) and Raney nickel (3.0 g) were added to methanol (10 mL), purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, and the mixture was concentrated to dryness to give a white solid IM23 (150 mg). MS: [MH]+ 279.35.

[0340] Example 24: Synthesis of intermediate IM24

[0341] Synthesis of intermediate 95:

[0342] At 0 °C, NBS (0.91 g, 5.12 mol) was added to a solution of intermediate 94 (1.0 g, 4.65 mol) and DCM (20 mL), and stirred at room temperature for 16 h. The reaction solution was washed successively with saturated sodium sulfite and saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a white solid intermediate 95 (0.73 g, 53%). MS: [MH] - 294.10.

[0343] Synthesis of intermediate 96:

[0344] Under nitrogen protection, NaH (0.85 g, 21.43 mmol) was added fractionally to a THF (30 mL) solution of Boc-ethanolamine (1.27 g, 7.86 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then, a THF solution of intermediate 95 (2.19 g, 7.14 mmol, 5 mL) was added, and the mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 1 h. The reaction mixture was then added to EA (50 mL), washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 33% ethyl acetate) to give intermediate 96 as a white solid (1.78 g, 67%). MS: [MH] - 373.75.

[0345] Synthesis of intermediate 97:

[0346] Intermediate 96 (1.60 g, 4.28 mmol), (2,5-difluoro)phenylboronic acid (0.68 g, 4.28 mmol), Pd(PPh3)2Cl2 (0.31 mg, 0.43 mmol), and potassium phosphate (1.82 g, 8.56 mmol) were added to Tol / EtOH / H2O (15 mL / 6 mL / 2 mL). After purging with nitrogen three times, the mixture was heated to 60 °C for 4 hours. The reaction solution was filtered, washed with ethyl acetate (200 mL), and the filtrate was washed successively with water (150 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using DCM solution containing 3.3% MeOH) to obtain a yellow solid intermediate 97 (1.0 g, 57%). 1HNMR (400MHz, CDCl3): δ8.20 (d, J = 8.4Hz, 2H), 7.66 (d, J = 8.4Hz, 2H), 7.21-7.13 (m, 2H), 1.37-1.17 (m, 2H), 1.25 (s, 9H), 0.95-0.77 (m, 2H).

[0347] Synthesis of IM24:

[0348] Intermediate 97 (2.1 g, 5.15 mmol) was added to HCl / 1,4-dioxane (10 mL) and reacted at room temperature for 3 hours. The solution was concentrated to dryness, and then replaced three times with THF (100 mL) to give a pale yellow solid IM24 (1.3 g, 73%). MS: [MH] + 308.20.

[0349] Example 25: Synthesis of intermediate IM25

[0350] Synthesis of intermediate 99:

[0351] Intermediate 98 (5.00 g, 21.64 mol), tert-pentanal (2.80 g, 32.46 mol), and p-toluenesulfonic acid (0.29 g, 2.16 mol) were added to toluene and pentane (25 mL, 25 mL each). After purging with nitrogen three times, the mixture was refluxed to remove water for 4 h. Ethyl acetate and saturated sodium bicarbonate solution were added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether solution containing 1% ethyl acetate) to obtain a yellow solid intermediate 99 (4.06 g, 63%).

[0352] Synthesis of intermediate 100:

[0353] Intermediate 99 (4.00 g, 13.37 mol), (2,5-difluoro)phenylboronic acid (2.32 g, 14.71 mmol), Pd(dppf)Cl2 (0.28 mg, 0.60 mmol), and potassium phosphate (5.68 g, 26.74 mmol) were added to Tol / EtOH / H2O (30 mL / 12 mL / 6 mL). After purging with nitrogen three times, the mixture was heated to 70 °C for 4 hours. The reaction solution was filtered, washed with ethyl acetate (200 mL), and the filtrate was washed successively with water (150 mL) and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using a petroleum ether solution containing 2% ethyl acetate) to obtain a yellow solid intermediate 100 (3.2 g, 72%).

[0354] Synthesis of intermediate 101:

[0355] Under nitrogen protection at -78℃, LDA (3.2 mL, 6.36 mol) was added dropwise to a THF (30 mL) solution of intermediate 100 (1.41 g, 4.24 mol). After the addition was complete, the mixture was stirred at -78℃ to -60℃ for 0.5 h, and then at -40℃ to 0℃ for 0.5 h. The mixture was then cooled again to -78℃, and 3-bromopropanecyanate (0.68 g, 5.09 mol) was added. The mixture was stirred at -78℃ to -60℃ for 0.5 h, and then allowed to rise naturally to room temperature overnight with stirring. EA (30 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. After drying with anhydrous sodium sulfate, the mixture was purified by silica gel column chromatography (using petroleum ether solution containing 10% ethyl acetate) to obtain a pale yellow solid intermediate 101 (0.50 g, 31%). 1 HNMR (400MHz, CDCl3): δ7.78 (d, J=8.4Hz, 2H), 7.65 (dd, J1=8.4Hz, J2=1.2Hz ,2H),7.20(s,2H),7.10(s,1H),5.50(s,1H),2.56-2.26(m,4H),1.07(s,9H).

[0356] Synthesis of IM25:

[0357] Intermediate 101 (1.00 g, 2.59 mmol) and Raney nickel (0.41 g) were added to methanol (20 mL), purged three times with hydrogen, and stirred overnight at room temperature. The catalyst was removed by filtration, the mixture was concentrated to dryness, EA (2 mL) was added and stirred into a slurry, and then filtered to obtain a white solid IM25 (0.5 g, 63%). 1 HNMR (400MHz, CDCl3): δ7.87(s,1H),7.57(d,J=1.6Hz,1H),7.55(d,J=1.6Hz,1H),7.51(s,1H),7.49(s,1H),7.45-7.3 6(m,2H),7.31-7.25(m,1H),5.57(s,1H),3.31-3.27(m,2H),2.08-1.96(m,2H),1.87-1.81(m,1H),1.61-1.53(m,1H).

[0358] Example 26: Synthesis of intermediate IM26

[0359] Synthesis of intermediate 102:

[0360] Under nitrogen protection at -78°C, a THF (72 mL) solution of intermediate 4 (12 g, 47.04 mmol) was added dropwise to a THF (60 mL) solution of LiHMDS (94 mL, 94.08 mmol). The reaction was carried out at -78°C for 1 hour. Maintaining the temperature between -40°C and -78°C, iodomethane (20.03 g, 141.12 mmol) dissolved in dry THF (60 mL) was added dropwise to the reaction solution. The mixture was stirred at room temperature for 2 hours after the addition was complete. The reaction solution was diluted with ethyl acetate (200 mL), washed successively with water (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 2% ethyl acetate) yielded a colorless oily intermediate 102 (9.0 g, 71%). MS: [MH] + 270.10; 1 HNMR (400MHz, CDCl3): δ7.32-7.28(m,2H),7.05(d,J=8.0Hz,1H),3.72(s,3H),3.48-3.38(m,2H),2.78(t,J=15.6Hz,2H),1.35(s,3H).

[0361] Synthesis of intermediate 103:

[0362] Intermediate 102 (3.4 g, 12.63 mmol), pyridine-2-tri-n-butyltin (5.58 g, 15.16 mmol), and Pd(PPh3)4 (1.46 g, 1.26 mmol) were added to dioxane (70 mL), purged with nitrogen three times, and heated to 100 °C with stirring for 2 hours. Potassium fluoride was added and stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. Purification by silica gel column chromatography (using petroleum ether solution containing 3%-6% ethyl acetate) yielded a colorless oily intermediate 103 (2.1 g, 63%). MS: [MH] + 268.35; 1 HNMR (400MHz, CDCl3): δ8.72-8.70(m,1H),7.89(s,1H),7.81-7.72(m,3H),7.34-7.32(m,1 H),7.27-7.23(m,1H),3.77(s,3H),3.60-3.55(m,2H),2.93(t,J=12.0Hz,2H),1.43(s,3H).

[0363] Synthesis of intermediate 104:

[0364] Intermediate 103 (2.1 g, 7.86 mmol) was dissolved in THF / MeOH / H2O (20 mL / 10 mL / 10 mL), and LiOH H2O (1.32 g, 31.42 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to remove THF / MeOH, and the pH was adjusted to 6-7 with 2N hydrochloric acid. The solution was then concentrated to obtain intermediate 104, which was directly proceeded to the next step without purification.

[0365] Synthesis of intermediates 105a and 105b:

[0366] Intermediate 104 was prepared and resolved to yield the chiral isomer intermediate 105a (400 mg), with a retention time of 12 min. MS: [MH] + 254.45; 1 HNMR (400MHz, CDCl3): δ8.71 (d, J = 8Hz, 1H), 7.84 (s, 1H), 7.77-7.68 (m, 3H), 7.30-7. 28(m,1H),7.25-7.21(m,1H),3.61-3.55(m,2H),2.92(t,J=16.0Hz,2H),1.45(s,3H).

[0367] Intermediate 104 was prepared and resolved to yield another chiral isomer, intermediate 105b (250 mg), with a retention time of 13.5 min. MS: [MH] + 254.45; 1 HNMR (400MHz, CDCl3): δ8.70(d,J=4Hz,1H),7.82(s,1H),7.75-7.67(m,3H),7.27-7.20(m,2H),3.58-3.52(m,2H),2.95-2.82(m,2H),1.39(s,3H).

[0368] Synthesis of IM26a and IM26b:

[0369] Intermediate 105a (50.0 mg, 0.20 mmol) was dissolved in dry DCM (2 mL), cooled to 0 °C, and oxalyl chloride (1 mL) and one drop of DMF were added. The mixture was stirred at 0 °C for 2 h. The reaction solution was concentrated to dryness to give the crude product, a brown solid IM26a (60 mg, 100%). MS: [MH] + 253.35.

[0370] Intermediate 105b (50.0 mg, 0.20 mmol) was dissolved in dry DCM (2 mL), cooled to 0 °C, and oxalyl chloride (1 mL) and one drop of DMF were added. The mixture was stirred at 0 °C for 2 h. The reaction solution was concentrated to give the crude product, a brown solid IM26b (60 mg, 100%). MS: [MH] + 253.35.

[0371] Example 27: Synthesis of intermediate IM27

[0372] Synthesis of intermediate 106:

[0373] Intermediate 5 (2.0 g, 7.32 mmol), (2,5-difluoro)phenylboronic acid (1.27 g, 8.06 mmol), Pd(dppf)Cl2 (0.54 mg, 0.73 mmol), and potassium phosphate (3.11 g, 14.65 mmol) were added to 1,4-dioxane / H2O (20 mL / 2 mL). After purging with nitrogen three times, the mixture was heated to 60 °C and reacted for 4 hours. The reaction solution was filtered, washed with ethyl acetate (50 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using petroleum ether solution containing 2% EA) to give intermediate 106 (1.85 g, 82%), an off-white solid. 1 HNMR(400MHz, CDCl3): δ7.41(d,J=12.0Hz,2H),7.34(d,J=8.0Hz,1H),7.14-7.0 7(m,2H),7.02-6.96(m,1H),3.88(s,3H),3.75-3.61(m,2H),3.50-3.38(m,2H).

[0374] Synthesis of IM27:

[0375] Intermediate 106 (2.15 g, 7.02 mmol) was dissolved in THF / MeOH / H2O (22 mL / 11 mL / 11 mL), and LiOH H2O (1.18 g, 28.08 mmol) was added. The mixture was stirred at room temperature for 2 hours. Petroleum ether (50 mL × 2) and water (70 mL) were added. The aqueous layer was adjusted to pH 4–5 with 6N hydrochloric acid, extracted with ethyl acetate (50 mL × 2), and the organic layer was washed with saturated brine (50 mL). The mixture was dried over sodium sulfate and concentrated to give IM27 (1.8 g, 88%). 1HNMR (400MHz, DMSO-d6): δ13.62(s,1H),7.48(s,1H),7.44-7.34(m,4H),7.28-7.23(m,1H),3.66-3.53(m,2H),3.41-3.40(m,2H).

[0376] Example 28: Synthesis of intermediate IM28

[0377] Synthesis of intermediate 108:

[0378] Intermediate 107 (5.0 g, 0.02 mol), pyridine-2-tri-n-butyltin (7.08 g, 0.02 mmol), and Pd(PPh3)4 (2.13 g, 1.84 mmol) were added to dioxane (70 mL), purged with nitrogen three times, and heated to 100 °C with stirring for 2 hours. Potassium fluoride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. Purification by silica gel column chromatography (using a petroleum ether solution containing 5%-10% ethyl acetate) yielded a pink solid intermediate 108 (3.0 g, 60%). MS: [MH] + 269.95; 1 HNMR (400MHz, CDCl3): δ8.75(m,1H),8.70-8.69(m,1H),8.30(d,J=8Hz,1H),8.16-8.18(d,J=8Hz,1 H),8.06-8.04(d,J=8Hz,1H),7.94-7.90(m,1H),7.40-7.37(m,1H),7.30-7.26(m,1H),3.90(s,3H).

[0379] Synthesis of intermediate 109:

[0380] Intermediate 108 (1.50 g, 5.55 mmol) was dissolved in MeOH (500 mL), and magnesium powder (0.67 g, 27.87 mmol) was added. The mixture was stirred at room temperature for 5 hours. The solution was quenched with 2N hydrochloric acid, adjusted to pH 8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL × 2), washed with saturated brine (250 mL), dried over sodium sulfate, and purified by silica gel column chromatography (using petroleum ether solution containing 15% ethyl acetate) to obtain a pale yellow oily intermediate 109 (0.13 g, 5.2%). MS: [MH] + 272.40; 1HNMR (400MHz, CDCl3): δ8.66 (d, J = 4.0Hz, 1H), 7.88 (br, 1H), 7.76-7.66 (m, 3H), 7.24 -7.18(m,2H),4.53-4.49(m,1H),3.76(s,3H),3.79-3.73(m,1H),3.58-3.51(m,1H).

[0381] Synthesis of IM28:

[0382] Intermediate 109 (0.130 g, 0.47 mmol) was dissolved in THF / MeOH / H₂O (2 mL / 0.5 mL / 0.5 mL), and LiOH H₂O (0.101 g, 2.40 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to remove THF / MeOH, and the pH was adjusted to 6–7 with 2N hydrochloric acid. The solution was filtered and dried to obtain a white solid intermediate IM₂₈ (0.083 g, 67%). MS: [MH] + 258.70; 1 HNMR (400MHz, DMSO-d6): δ8.63(d,J=8.0Hz,1H),7.98(s,1H),7.92-7.82(m,3H ),7.33-7.29(m,2H),4.66-4.62(m,1H),3.63-3.57(m,1H),3.52-3.45(m,1H).

[0383] Example 29: Synthesis of intermediate IM29

[0384] Synthesis of intermediate 111:

[0385] Intermediate 110 (1.0 g, 3.69 mmol), pyridine-2-tri-n-butyltin (1.63 g, 4.43 mmol), and Pd(PPh3)4 (0.42 g, 0.37 mmol) were added to 1,4-dioxane (70 mL), purged with nitrogen three times, and heated to 100 °C with stirring for 2 hours. Potassium fluoride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. Purification was performed by silica gel column chromatography (using petroleum ether solution containing 5%-10% ethyl acetate) to obtain pink solid intermediate 111 (0.65 g, 65%). MS: [MH] + 270.30; 1HNMR (400MHz, CDCl3): δ8.73 (d, J = 4.0Hz, 1H), 8.55 (s, 1H), 8.09 (s, 1H), 8.06-8.0 1(m,1H),7.96(d,J=8.0Hz,1H),7.85-7.76(m,2H),7.30-7.26(m,1H),3.96(s,3H).

[0386] Synthesis of intermediate 112:

[0387] Intermediate 111 (0.100 g, 0.37 mmol) was dissolved in MeOH (5 mL), and magnesium powder (0.089 g, 3.70 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with 2N hydrochloric acid, adjusted to pH 8 with saturated sodium bicarbonate, extracted with ethyl acetate (50 mL × 2), washed with saturated brine (50 mL), dried over sodium sulfate, and purified by silica gel column chromatography (using petroleum ether solution containing 5% ethyl acetate) to obtain a pale yellow oily intermediate 112 (0.012 g, 11.5%). MS: [MH] + 272.60; 1 HNMR (400MHz, CDCl3): δ8.65(d,J=4.0Hz,1H),7.81(br,1H),7.76-7.70(m,1H),7.69-7.63(m,2H),7.29( d,J=8.0Hz,1H),7.24-7.19(m,1H),4.53-4.47(m,1H),3.76(s,3H),3.75-3.69(m,1H),3.55-3.47(m,1H).

[0388] Synthesis of IM29:

[0389] Intermediate 112 (0.085 g, 0.31 mmol) was dissolved in THF / MeOH / H₂O (2 mL / 0.5 mL / 0.5 mL), and LiOH H₂O (0.066 g, 1.56 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated to remove THF / MeOH, and the pH was adjusted to 6–7 with 2N hydrochloric acid. The solution was extracted with ethyl acetate (50 mL × 2), and the organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, and purified by silica gel column chromatography (using DCM solution containing 10% MeOH and 0.5% AcOH) to obtain a white solid intermediate IM₂₹ (0.073 g, 90%). MS: [MH] + 258.30; 1HNMR (400MHz, DMSO-d6): δ8.65-8.61(m,1H),7.94-7.90(m,2H),7.88-7.82(m,1H),7.79- 7.74(m,1H),7.37-7.31(m,2H),4.64-4.58(m,1H),3.60-3.53(m,1H),3.49-3.42(m,1H).

[0390] Example 30: Synthesis of intermediate IM30

[0391] Synthesis of intermediate 113:

[0392] Intermediate 110 (1.53 g, 5.65 mmol), (2,5-difluoro)phenylboronic acid (1.16 g, 7.34 mmol), Pd(dppf)Cl2 (0.41 mg, 0.56 mmol), and potassium phosphate (2.39 g, 11.30 mmol) were added to 1,4-dioxane / H2O (20 mL / 2 mL). After purging with nitrogen three times, the mixture was heated to 80 °C for 4 hours. The reaction solution was filtered, washed with ethyl acetate (50 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using petroleum ether solution containing 2% EA) to obtain a white solid intermediate 113 (1.15 g, 67%). 1 HNMR (400MHz, DMSO-d6): δ8.32(s,1H),8.27(s,1H),8.13(d,J=8Hz,1H),7.70-7. 67(m,1H),7.56-7.51(m,1H),7.46-7.40(m,1H),7.35-7.29(m,1H),3.91(s,3H).

[0393] Synthesis of intermediate 114:

[0394] Intermediate 113 (0.150 g, 0.49 mmol) was dissolved in THF / MeOH (10 mL, 10 mL), and magnesium powder (0.119 g, 4.84 mmol) and ammonium chloride (0.105 g, 1.97 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solid was removed by filtration, and the filtrate was extracted with ethyl acetate (50 mL). The extract was washed with saturated brine (50 mL), dried over sodium sulfate, and purified by silica gel column chromatography (using petroleum ether solution containing 10% ethyl acetate) to give intermediate 114 (0.031 g, 21%) as a white solid. 1HNMR (400MHz, DMSO-d6): δ7.42-7.33(m,4H),7.28-7.22(m,2H),4.74-4.71(m,1H),3.68(s,3H),3.63-3.58(m,1H),3.53-3.47(m,1H).

[0395] Synthesis of IM30:

[0396] Intermediate 114 (0.125 g, 0.41 mmol) was dissolved in THF / MeOH / H₂O (2 mL / 0.5 mL / 0.5 mL), and LiOH H₂O (0.086 g, 2.04 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to remove THF / MeOH, and the pH was adjusted to 6–7 with 2N hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid intermediate IM₃₀ (0.10 g, 84%). MS: [MH] - 290.90; 1 HNMR (400MHz, DMSO-d6): δ7.41-7.16(m,6H),4.51(t,J=8Hz,1H),3.56-3.50(m,1H),3.38-3.32(m,1H).

[0397] Example 31: Synthesis of intermediate IM31

[0398] Synthesis of intermediate 115:

[0399] Intermediate 4 (15.00 g, 58.80 mmol) was dissolved in THF / EtOH / H2O (150 mL / 60 mL / 30 mL), and LiOH H2O (3.70 g, 88.20 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to remove THF / MeOH, and the pH was adjusted to 5-6 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product solid intermediate IM115 (12.10 g, 87%) was obtained by concentration. MS: [MH] - 240.65.

[0400] Synthesis of IM31:

[0401] Intermediate 115 (5.00 g, 20.74 mmol), (2,5-difluoro)phenylboronic acid (3.60 g, 22.81 mmol), Pd(dppf)Cl2 (1.46 g, 2.07 mmol), and potassium phosphate (8.80 g, 41.48 mmol) were added to Tol / EtOH / H2O (100 mL / 20 mL / 20 mL). After purging with nitrogen three times, the mixture was heated to 80 °C for 8 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, and the pH was adjusted to 6–7 with 2N hydrochloric acid. The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (using DCM solution containing 2% MeOH) to obtain a white solid IM31 (4.85 g, 85%). MS: [MH] - 273.00; 1 HNMR (400MHz, DMSO-d6): δ7.41(s,1H),7.38-7.32(m,2H),7.17-7.09(m,2H),7.03-6.97(m,1H),3.51-3.41(m,1H),3.38-3.30(m,4H).

[0402] Example 32: Synthesis of Compound I-1

[0403] IM20 (0.180 g, 0.57 mmol), IM5 (0.183 g, 0.86 mmol), Pd2(dba)3 (0.053 g, 0.057 mmol), Xantphos (0.033 g, 0.057 mmol), and sodium tert-butoxide (0.111 g, 1.15 mmol) were added to Tol (10 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 6 hours. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (petroleum ether solution containing 20% ​​ethyl acetate and DCM solution containing 3.3% MeOH). The purified product was then purified again by plate preparation (dichloromethane solution containing 5% methanol) to obtain a white solid I-1 (0.019 g, 7%). MS: [MH] + 489.85; 1HNMR (400MHz, DMSO): δ7.63 (s, 1H), 7.41-7.32 (m, 5H), 7.26-7.15 (m, 1H), 4.15-4.12 (t, J = 5.6Hz, 2H), 3.54-3.47 (dd, J 1=16.4Hz, J2=4.8Hz, 2H), 3.09-3.04(dd, J1=16.4Hz, J2=4.8Hz, 2H), 2.49 (s, 3H), 2.08-2.00 (m, 2H), 1.97-1.90 (m, 2H).

[0404] Example 33: Synthesis of Compound I-2

[0405] IM19 (0.300 g, 1.08 mmol), IM5 (0.344 g, 1.62 mmol), Pd2(dba)3 (0.099 g, 0.11 mmol), Xantphos (0.062 g, 0.11 mmol), and sodium tert-butoxide (0.209 g, 2.16 mmol) were added to Tol (10 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 6 hours. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified twice by stencil preparation (using a dichloromethane solution containing 5% methanol) to give an off-white solid I-2 (0.025 g, 5%). MS: [MH] + 455.70; 1 HNMR (400MHz, DMSO): δ8.64-8.63(d,J=4Hz,1H),7.93-7.89(t,J=15.6Hz,3H) ,7.88-7.83(td,J1=7.6Hz,J2=2Hz,1H),7.64(s,2H),7.33-7.31(d,J=8Hz,2H ),4.15-4.12(t,J=5.6Hz,2H),3.54-3.47(dd,J1=16.4Hz,J2=9.6Hz,2H),3.1 0-3.03(t,J=16.4Hz,2H),2.49(s,3H),2.06-2.01(m,2H),1.98-1.90(m,2H).

[0406] Example 34: Synthesis of Compound I-2a

[0407] Compound I-2a is a chiral isomer obtained by preparative resolution of compound I-2, with a retention time of 7.702 min, as follows:

[0408] MS:[MH]+ 455.25; 1 HNMR (400MHz, DMSO): δ8.71 (d, J = 4.8Hz, 1H), 8.03 (br, 2H), 7.94 (s, 1H),

[0409] 7.92(d,J=8.0Hz,1H),7.66(s,2H),7.47-7.45(m,1H),7.39(d,J=8.0Hz,1H),4.16(t,J=5.6Hz ,2H),3.57-3.45(m,2H),3.14-3.07(m,2H),2.51(s,3H),2.07-2.03(m,2H),2.01-1.98(m,2H).

[0410] Example 35: Synthesis of Compound I-2b

[0411] Compound I-2b is another chiral isomer of compound I-2 obtained by preparative resolution, with a retention time of 20.049 min. MS: [MH] + 455.15; 1 HNMR (400MHz, DMSO): δ8.74(d,J=4.8Hz,1H),8.07(d,J=3.6Hz,1H),7.95(s,1H),7.93(d,J=8.0Hz,1H),7.68(s,2H),7.52-7.49(m,1H) ,7.42(d,J=8.0Hz,1H),4.19(t,J=5.6Hz,2H),3.62-3.52(m,2H),3.16-3.09(m,2H),2.53(s,3H),2.08-2.05(m,2H),2.03-1.99(m,2H).

[0412] Example 36: Synthesis of Compound I-13

[0413] IM21 (0.030 g, 0.14 mmol), IM5 (0.037 g, 0.17 mmol), Pd2(dba)3 (0.013 g, 0.014 mmol), Xantphos (0.008 g, 0.014 mmol), and sodium tert-butoxide (0.027 g, 0.28 mmol) were added to DMSO (5 mL), purged three times with nitrogen, and then heated to 100 °C for 6 hours. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified four times using a treadmill (dichloromethane solution containing 5% methanol) to obtain an off-white solid I-13 (0.010 g). MS: [MH] + 469.95; 1 HNMR (400MHz, CDCl3): δ8.72-8.71(m,1H),7.92-7.73(m,4H),7.37-7.25(m,3H),5.04(s,2H),4.66-4.62(m,1H),4.02-3.98(m,1H),3.52-3.4 5(m,2H),3.22-3.14(t,J=15.2Hz,1H),2.98-2.94(t,J=15.2Hz,1H),2. 65(s,3H),2.39-2.32(m,1H),2.09-2.05(m,2H),1.19(d,J=6.4Hz,3H).

[0414] Example 37: Synthesis of Compound I-31

[0415] IM22 (0.140 g, 0.53 mmol), IM5 (0.169 g, 0.79 mmol), Pd2(dba)3 (0.049 g, 0.053 mmol), Xantphos (0.031 g, 0.053 mmol), and sodium tert-butoxide (0.103 g, 1.06 mmol) were added to Tol (10 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 6 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether solution containing 20% ​​ethyl acetate and DCM solution containing 3.3% MeOH) and then purified again by plate preparation (dichloromethane solution containing 5% methanol) to obtain an off-white solid I-31 (0.025 g, 5%). MS: [MH] + 441.25; 1HNMR (400MHz, DMSO): δ8.64-8.63(d,J=4.4Hz,1H),7.96-7.91(dd,J1=15.6Hz,J2=4.8Hz,3H),7.88-7.83(td,J1=7.6Hz,J2=2Hz,1H),7.72(s,2H),7.36 -7.31(m,2H),4.09-4.06(t,J=6.8Hz,2H),3.36-3.29(t,J=6.8Hz,2H),3.16 -3.09(dd,J1=16Hz,J2=12Hz,2H),2.49(s,3H),2.28-2.25(t,J=7.2Hz,2H).

[0416] Example 38: Synthesis of Compound I-46

[0417] IM23 (0.100 g, 0.36 mmol), IM5 (0.115 g, 0.54 mmol), Pd2(dba)3 (0.066 g, 0.07 mmol), Xantphos (0.042 g, 0.07 mmol), and sodium tert-butoxide (0.070 g, 0.72 mmol) were added to Tol (20 mL), and the mixture was purged with nitrogen three times and then heated to 100 °C for 6 hours. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified three times using stencils (dichloromethane solution containing 5% methanol) to give an off-white solid I-46 (0.008 g). MS: [MH] + 455.10; 1 HNMR (400MHz, DMSO): δ8.68-8.67 (d, J=4.8Hz, 1H), 7.92 (s, 1H), 7.78-7.6 8(m,3H),7.24-7.21(t,J=6Hz,1H),7.17-7.15(d,J=8Hz,1H),4.98(s,2H), 4.48-4.391(m,1H),4.26-4.17(m,1H),3.27-3.20(m,1H),3.15-3.07(m,1 H),2.85-2.75(m,1H),2.62(s,3H),2.276-2.18(m,3H),2.13-2.00(m,2H).

[0418] Example 39: Synthesis of Compound I-52

[0419] Synthesis of intermediate I-52-1:

[0420] IM24 (0.100 g, 0.325 mmol), IM5 (0.105 g, 0.488 mmol), Pd(dppf)Cl2 (0.071 g, 0.098 mmol), and DBU (0.099 g, 0.65 mmol) were added to DMF (5 mL), and the mixture was purged with nitrogen three times and then heated to 100 °C for 6 hours. The reaction was quenched with water, extracted with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by stencil preparation (using a dichloromethane solution containing 10% methanol) to obtain a light brown solid intermediate I-52-1 (0.120 g, 76%). MS: [MH] + 484.60.

[0421] Synthesis of I-52:

[0422] Intermediate I-52-1 (0.070 g, 0.145 mmol), EDCI (0.056 g, 0.290 mmol), and HOBT (0.039 g, 0.290 mmol) were added to DMF (3 mL), purged three times with nitrogen, and heated to RT for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by stencil preparation (dichloromethane solution containing 5% methanol) to obtain a white solid I-52 (0.012 g). MS: [MH] + 465.80; 1 HNMR (400MHz, CD3OD): δ7.63(br,2H),7.57-7.49(m,4H),7.49-7.38(m,2H),7.33-7.28(m,1H),5.60(s,1H),4.36-4.18(m,4H),2.54(s,3H).

[0423] Example 40: Synthesis of Compound I-53

[0424] IM25 (0.020 g, 0.066 mmol), IM5 (0.020 g, 0.099 mmol), Pd2(dba)3 (0.030 g, 0.033 mmol), Xantphos (0.019 g, 0.033 mmol), and sodium tert-butoxide (0.013 g, 0.131 mmol) were added to toluene (5 mL), and the mixture was purged with nitrogen three times and then heated to 110 °C for 4 hours. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified twice by stencil preparation (using a dichloromethane solution containing 5% methanol) to obtain a pale yellow solid I-53 (0.004 g). MS: [MH] + 480.40; 1 HNMR (400MHz, CD3OD): δ7.61 (dd, J1=8.4Hz, J2=1.6Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 7.30-7.21 (m, 2H), 7.16-7.1 0(m,1H),4.60(s,1H),4.35-4.27(m,2H),2.62(s,3H),2.44-2.31(m,2H),2.26-2.20(m,1H),1.99-1.92(m,1H).

[0425] Example 41: Synthesis of compound II-1a

[0426] IM1a (50.0 mg, 0.19 mmol), IM3 (63 mg, 0.29 mmol), and 50% T3P / EA (990 mg, 1.49 mmol) were added to DMF (2 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was pulped (in a dichloromethane solution containing 10% methanol) to give an off-white solid II-1a (25 mg, 28%). MS: [MH] + 456.40; 1HNMR (400MHz, DMSO-d6): δ8.66-8.65(m,1H),8.59(d,J=4.0Hz,1H),8.03(s,1H),7.98-7.94(m,2H),7.90-7.85(m,1H),7.62( s,2H),7.43-7.40(m,2H),7.36-7.33(m,1H),4.47-4.42(m,2H),3.96-3.81(m,2H),3.63-3.49(m,2H),3.28(d,J=8.0Hz,2H).

[0427] Example 42: Synthesis of compound II-1b

[0428] IM1b (105 mg, 0.409 mmol), IM3 (106 mg, 0.49 mmol), and 50% T3P / EA (2.08 g, 3.27 mmol) were added to DMF (4 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was pulped (in dichloromethane solution containing 9% methanol) to give a white solid II-1b (10 mg, 5.4%). MS: [MH] + 456.30; 1 HNMR (400MHz, DMSO-d6): δ8.66-8.65(m,1H),8.58(d,J=4.0Hz,1H),8.03(s,1H),7.96(d,J=8.0Hz,1H),7.90-7.85(m,1H),7. 62(br,2H),7.43-7.40(m,3H),7.36-7.33(m,1H),4.47-4.42(m,2H),3.96-3.81(m,2H),3.63-3.50(m,2H),3.29-3.27(m,2H).

[0429] Example 43: Synthesis of compound II-4a

[0430] IM1a (40.0 mg, 0.16 mmol), IM4 (36 mg, 0.16 mmol), and 50% T3P / EA (792 mg, 2.49 mmol) were added to DMF (2 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative plate purification (using dichloromethane solution containing 10% methanol) yielded an off-white solid, II-4a (40 mg, 55%). MS: [MH] + 470.15; 1 HNMR (400MHz, DMSO-d6): δ8.70-8.68(m,1H),8.48(d,J=8.0Hz,1H),8.04-7.95(m,4H),7.64(s,2H),7.48-7.41 (m,3H),5.14-5.09(m,1H),4.11-3.98(m,1H),3.77-3.47(m,4H),2.80(d,J=16.0Hz,1H),1.27(d,J=4.0Hz,3H).

[0431] Example 44: Synthesis of compound II-7a

[0432] IM1a (50 mg, 0.19 mmol), IM2S (48 mg, 0.19 mmol), and 50% T3P / EA (990 mg, 1.55 mmol) were added to DMF (2 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative plate purification (using dichloromethane solution containing 10% methanol) yielded an off-white solid, II-7a (20 mg). MS: [MH] + 488.05; 1HNMR (400MHz, DMSO-d6): δ8.67-8.65(m,1H),8.47(d,J=4.0Hz,1H),8.05(s,1H), 7.98-7.94(m,2H),7.90-7.85(m,1H),7.63(s,2H),7.45(d,J=12.0Hz,1H),7.39( d,J=8.0Hz,1H),7.36-7.33(m,1H),5.35-5.26(m,1H),4.64(d,J=4.0Hz,1H),4.5 2(d,J=4.0Hz,1H),4.07-3.94(m,1H),3.73-3.50(m,4H),3.10(d,J=16.0Hz,1H).

[0433] Compound II-7a can be detected and separated by chiral HPLC using the following method, with a retention time of 18.742 min.

[0434] Example 45: Synthesis of Compound II-7b

[0435] IM1b (50 mg, 0.19 mmol), IM2S (48 mg, 0.19 mmol), and 50% T3P / EA (990 mg, 1.55 mmol) were added to DMF (2 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative plate purification (using dichloromethane solution containing 10% methanol) yielded an off-white solid, II-7b (30 mg, 32%). MS: [MH] + 488.35; 1 HNMR (400MHz, DMSO-d6): δ8.66-8.64(m,1H),8.48(d,J=4.0Hz,1H),8.00(s,1H ),7.99-7.93(m,2H),7.89-7.85(m,1H),7.63(s,2H),7.46-7.43(m,2H),7.36- 7.32(m,1H),5.35-5.28(m,1H),4.64(d,J=4.0Hz,1H),4.52(d,J=4.0Hz,1H),4 .04-3.91(m,1H),3.80-3.66(m,2H),3.62-3.47(m,2H),3.10(d,J=16.0Hz,1H).

[0436] Compound II-7b can be detected and separated by chiral HPLC using the following method, with a retention time of 23.993 min.

[0437] Example 46: Synthesis of Compound II-9

[0438] IM27 (70.0 mg, 0.24 mmol), IM2S (60 mg, 0.24 mmol), and 50% T3P / EA (1.22 g, 1.92 mmol) were added to DMF (2 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (60 mL), and the organic phase was washed successively with semi-saturated brine (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative plate purification (using dichloromethane solution containing 10% methanol) yielded a white solid, II-9 (40 mg, 55%). MS: [MH] + 523.05; 1 HNMR (400MHz, DMSO-d6): δ8.47(d,J=4.0Hz,1H),7.63(s,2H),7.55-7.34(m,6H),7.28-7.25(m,1H),5.35-5.26(m ,1H),4.63(d,J=4.0Hz,1H),4.52(d,J=4.0Hz,1H),4.05-3.91(m,1H),3.73-3.47(m,4H),3.09(d,J=16.0Hz,1H).

[0439] Example 47: Synthesis of Compound II-9a

[0440] Compound II-9a is a chiral isomer obtained by chiral preparation and resolution of compound II-9, as follows:

[0441] White solid (15.5 mg), retention time 15.58 min, MS: [MH] + 523.05; 1 HNMR (400MHz, DMSO-d6): δ8.47(d,J=4.0Hz,1H),7.63(s,2H),7.52(s,1H),7.46-7.35(m,5H),7.29-7.23(m,1H),5.34- 5.28(m,1H),4.63(d,J=4.0Hz,1H),4.52(d,J=4.0Hz,1H),4.05-3.87(m,1H),3.78-3.48(m,4H),3.12(d,J=20.0Hz,1H).

[0442] Example 48: Synthesis of Compound II-9b

[0443] Compound II-9b is another chiral isomer of compound II-9 obtained by chiral preparation and resolution. It is a white solid (12.4 mg) with a retention time of 19.30 min. MS: [MH] + 523.00; 1 HNMR (400MHz, DMSO-d6): δ8.47(d,J=4.0Hz,1H),7.63(s,2H),7.48(s,1H),7.45-7.34(m,5H),7.28-7.23(m,1H),5.33- 5.27(m,1H),4.63(d,J=4.0Hz,1H),4.52(d,J=4.0Hz,1H),4.04-3.91(m,1H),3.74-3.47(m,4H),3.11(d,J=16.0Hz,1H).

[0444] Example 49: Synthesis of Compound II-35

[0445] IM28 (100 mg, 0.39 mmol), IM4 (98 mg, 0.43 mmol), and 50% T3P / EA (1.98 g, 3.00 mmol) were added to DMF (3 mL), and the mixture was stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate (60 mL), and the organic phase was washed successively with semi-saturated brine (25 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative plate purification (using a dichloromethane solution containing 5% methanol) yielded a white solid, II-35.

[0446] Example 50: Synthesis of Compound II-35a

[0447] Compound II-35a is a chiral isomer of compound II-35 obtained by preparative ablation. Preparation method: dichloromethane solution containing 5% methanol, Rf = 0.6, white solid (47 mg). MS: [MH] + 470.40; 1HNMR (400MHz, DMSO-d6): δ8.64-8.63(m,1H),8.45(d,J=8.0Hz,1H),8.03(s,1H),7.95-7.84(m,3H),7.59(s,2H),7.41(d,J=8.0Hz,1H),7. 34-7.30(m,2H),4.98-4.94(m,1H),4.69-4.63(m,1H),3.85-3.80(m,1H),3.61-3.47(m,2H),2.83(d,J=16.0Hz,1H),1.30(d,J=8.0Hz,3H).

[0448] Example 51: Synthesis of Compound II-35b

[0449] Compound II-35b is another chiral isomer of compound II-35, prepared by a preparative plate assay using a dichloromethane solution containing 5% methanol (Rf = 0.5), yielding a white solid (57 mg). MS: [MH] + 470.40; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.42(d,J=4.0Hz,1H),8.00(s,1H),7.94-7.83(m,3H),7.60(s,2H),7.40-7.31(m, 3H),5.18-5.15(m,1H),4.97(t,J=8.0Hz,1H),3.73-3.57(m,2H),3.51-3.45(m,1H),2.79(d,J=16.0Hz,1H),1.29(d,J=8.0Hz,3H).

[0450] Example 52: Synthesis of Compound II-36

[0451] IM28 (200 mg, 0.78 mmol), IM3 (202 mg, 0.93 mmol), and EDCI (224 mg, 1.17 mmol) were added to pyridine (8 mL), and the mixture was stirred overnight at 50 °C under nitrogen protection. The reaction solution was quenched in ice water and filtered to obtain a crude solid product. Preparative purification (using a dichloromethane solution containing 1.6% methanol) yielded a white solid, II-35 (280 mg). MS: [MH] + 456.20; 1HNMR (400MHz, DMSO-d6): δ8.63(d,J=4.0Hz,1H),8.49(d,J=8.0Hz,1H),8.03(s,1H),7.95-7.84(m,3H),7.58(s,2H),7.37-7. 31(m,3H),5.01-4.98(m,1H),4.39-4.33(m,1H),4.14-4.09(m,1H),3.85-3.79(m,1H),3.55-3.49(m,1H),3.29-3.24(m,2H).

[0452] Example 53: Synthesis of Compound II-36a

[0453] Compound II-36a is a chiral isomer obtained by chiral preparation and resolution of compound II-36, as follows:

[0454] White solid (79 mg), retention time 11.594 min, MS: [MH] + 456.10; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.47(d,J=8.0Hz,1H),8.03(s,1H),7.95-7.84(m,3H),7.58(br,2H),7.37-7 .31(m,3H),5.01-4.98(m,1H),4.39-4.33(m,1H),4.16-4.09(m,1H),3.84-3.79(m,1H),3.55-3.49(m,1H),3.29-3.23(m,2H).

[0455] Example 54: Synthesis of Compound II-36b

[0456] Compound II-36b is another chiral isomer of compound II-36 obtained by chiral preparation and resolution. It is a white solid (73 mg) with a retention time of 18.571 min, and its MS concentration is [MH]. + 456.15; 1HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.47(d,J=8.0Hz,1H),8.03(s,1H),7.95-7.84(m,3H),7.59(s,2H),7.37-7. 31(m,3H),5.01-4.98(m,1H),4.39-4.33(m,1H),4.15-4.09(m,1H),3.84-3.79(m,1H),3.55-3.49(m,1H),3.31-3.25(m,2H).

[0457] Example 55: Synthesis of Compound II-40

[0458] IM29 (50 mg, 0.19 mmol), IM2S (48 mg, 0.19 mmol), and 50% T3P / EA (988 g, 1.55 mmol) were added to DMF (4 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed successively with semi-saturated brine (15 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give the crude product, compound II-40.

[0459] Example 56: Synthesis of Compound II-40a

[0460] Compound II-40a is a chiral isomer of compound II-40 obtained by preparative ablation. Preparation method: dichloromethane solution containing 5% methanol, Rf = 0.5, white solid (21 mg). MS: [MH] + 488.35; 1 HNMR (400MHz, DMSO-d6): δ8.62(d,J=4.0Hz,1H),8.43(d,J=8.0Hz,1H),7. 95-7.89(m,2H),7.88-7.82(m,1H),7.81-7.77(m,1H),7.57(s,2H),7.42-7 .36(m,2H),7.35-7.30(m,1H),5.04-4.91(m,2H),4.77-4.58(m,1H),4.56- 4.37(m,1H),3.80-3.72(m,1H),3.59-3.48(m,2H),2.99(d,J=16.0Hz,1H).

[0461] Example 57: Synthesis of Compound II-40b

[0462] Compound II-40b is another chiral isomer of compound II-40 obtained by preparative ablation. Preparation method: dichloromethane solution containing 5% methanol, Rf = 0.4, white solid (57 mg). MS: [MH] + 488.40; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.38(d,J=4.0Hz,1H),7.97-7.91(m,2H),7.89-7.83(m,1H),7.81-7.77(m,1H),7.5 9(s,2H),7.41-7.31(m,3H),5.28-5.11(m,2H),4.72-4.40(m,2H),3.60(d,J=8.0Hz,2H),3.59-3.48(m,1H),3.00(d,J=16.0Hz,1H).

[0463] Example 58: Synthesis of Compound II-41

[0464] IM29 (40 mg, 0.15 mmol), IM4 (36 mg, 0.15 mmol), and 50% T3P / EA (789 mg, 1.24 mmol) were added to DMF (3 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed successively with semi-saturated brine (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give the crude product, compound II-41.

[0465] Example 59: Synthesis of Compound II-41a

[0466] Compound II-41a is a chiral isomer of compound II-41 obtained by preparative ablation. Preparation method: dichloromethane solution containing 5% methanol, Rf = 0.4, off-white solid (23 mg). MS: [MH] + 470.90; 1HNMR (400MHz, DMSO-d6): δ8.63(d,J=4.0Hz,1H),8.45(d,J=4.0Hz,1H),7.94 -7.89(m,2H),7.89-7.82(m,1H),7.80(d,J=8.0Hz,1H),7.57(s,2H),7.42-7 .37(m,2H),7.36-7.31(m,1H),4.98-4.92(m,1H),4.72-4.62(m,1H),3.83-3 .75(m,1H),3.60-3.46(m,2H),2.82(d,J=16.0Hz,1H),1.30(d,J=4.0Hz,3H).

[0467] Example 60: Synthesis of Compound II-41b

[0468] Compound II-41b is another chiral isomer of compound II-41, prepared by a preparative plate assay using a dichloromethane solution containing 5% methanol (Rf = 0.3), yielding a white solid (7 mg). MS: [MH] + 470.50; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.42(d,J=8.0Hz,1H),7.97-7.91(m,2H),7.90-7.84(m,1H),7.80(d,J=8.0Hz,1H),7.59(s,2H ),7.41-7.32(m,3H),5.18-5.11(m,1H),5.02-4.91(m,1H),3.71-3.53( m,2H),3.53-3.43(m,1H),2.79(d,J=16.0Hz,1H),1.29(d,J=4.0Hz,3H).

[0469] Example 61: Synthesis of Compound II-42

[0470] IM29 (210 mg, 0.82 mmol), IM3 (211 mg, 0.98 mmol), and EDCI (235 mg, 1.22 mmol) were added to pyridine (3 mL), and the mixture was stirred overnight at 50 °C under nitrogen protection. The reaction solution was concentrated and purified by preparative plate (using a dichloromethane solution containing 5% methanol) to give a gray solid compound II-42.

[0471] Example 62: Synthesis of compound II-42a

[0472] Compound II-42a is a chiral isomer of compound II-42 obtained by preparation and isolation. It is a white solid (90 mg) with a retention time of 0.917 min, as follows:

[0473] MS:[MH] + 456.85; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.48(d,J=8.0Hz,1H),7. 94-7.92(m,2H),7.88-7.83(m,1H),7.81-7.79(m,1H),7.55(br,2H),7.41( d,J=8.0Hz,1H),7.36-7.32(m,1H),4.99-4.96(m,1H),4.39-4.33(m,1H),4 .16-4.09(m,1H),3.81-3.76(m,1H),3.52-3.46(m,1H),3.30-3.23(m,2H).

[0474] Example 63: Synthesis of Compound II-42b

[0475] Compound II-42b is another chiral isomer of compound II-42, obtained through preparation and isolation. It is a white solid (95 mg) with a retention time of 1.572 min. MS: [MH] + 456.90; 1 HNMR (400MHz, DMSO-d6): δ8.64(d,J=4.0Hz,1H),8.48(d,J=8.0Hz,1H),7. 94-7.92(m,2H),7.88-7.83(m,1H),7.81-7.79(m,1H),7.57(br,2H),7.41( d,J=8.0Hz,1H),7.36-7.32(m,2H),4.99-4.96(m,1H),4.39-4.33(m,1H),4 .16-4.09(m,1H),3.81-3.76(m,1H),3.52-3.46(m,1H),3.30-3.21(m,2H).

[0476] Example 64: Synthesis of Compound II-43

[0477] IM30 (60 mg, 0.21 mmol), IM2S (66 mg, 0.27 mmol), and 50% T3P / EA (1.04 g, 1.64 mmol) were added to DMF (3 mL), and the mixture was stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate (25 mL), and the organic phase was washed successively with semi-saturated brine (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give the crude product, compound II-43.

[0478] Example 65: Synthesis of Compound II-43a

[0479] Compound II-43a is a chiral isomer of compound II-43 obtained by preparative ablation. Preparation method: dichloromethane solution containing 4% methanol, Rf = 0.6, white solid (16 mg). MS: [MH] + 523.10; 1 HNMR (400MHz, DMSO-d6): δ8.44-8.43(m,1H),7.58(s,2H),7.41-7.32(m,5H),7.27-7.22(m,2H),5.01-4.9 4(m,2H),4.75-4.60(m,1H),4.54-4.38(m,1H),3.78-3.73(m,1H),3.57-3.49(m,2H),2.99(d,J=16Hz,1H).

[0480] Example 66: Synthesis of Compound II-43b

[0481] Compound II-43b is another chiral isomer of compound II-43 obtained by preparative ablation. Preparation method: dichloromethane solution containing 4% methanol, Rf = 0.5, white solid (16 mg). MS: [MH] + 523.10; 1 HNMR (400MHz, DMSO-d6): δ8.38(d,J=8Hz,1H),7.59(s,2H),7.43-7.33(m,5H),7.27-7.24(m,2H), 5.26-5.12(m,2H),4.67-4.41(m,2H),3.60(d,J=8Hz,2H),3.55-3.48(m,1H),2.99(d,J=16Hz,1H).

[0482] Example 67: Synthesis of Compound II-44

[0483] IM30 (100 mg, 0.34 mmol), IM4 (87 mg, 0.38 mmol), and 50% T3P / EA (1.04 g, 1.74 mmol) were added to DMF (3 mL), and the mixture was stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate (25 mL), and the organic phase was washed successively with semi-saturated brine (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give the crude product, compound II-44.

[0484] Example 68: Synthesis of Compound II-44a

[0485] Compound II-44a is a chiral isomer of compound II-44 obtained by preparative ablation. Preparation method: dichloromethane solution containing 5% methanol, Rf = 0.6, white solid (51 mg). MS: [MH] + 505.00; 1 HNMR (400MHz, DMSO-d6): δ8.45(d,J=8.0Hz,1H),7.58(s,2H),7.40-7.33(m,5H),7.27-7.21(m,2H),4.94-4.91 (m,1H),4.69-4.62(m,1H),3.80-3.75(m,1H),3.57-3.47(m,2H),2.81(d,J=16.0Hz,1H),1.30(d,J=8.0Hz,3H).

[0486] Example 69: Synthesis of Compound II-44b

[0487] Compound II-44b is another chiral isomer of compound II-44, prepared by a preparative plate assay using a dichloromethane solution containing 5% methanol (Rf = 0.5), yielding a white solid (43 mg). MS: [MH] + 505.00; 1 HNMR (400MHz, DMSO-d6): δ8.41(d,J=8.0Hz,1H),7.60(s,2H),7.43-7.34(m,5H),7.28-7.23(m,2H),5 .15-5.12(m,1H),4.99-4.92(m,1H),3.68-3.45(m,3H),2.79(d,J=16.0Hz,1H),1.28(d,J=8.0Hz,3H).

[0488] Example 70: Synthesis of Compound II-45

[0489] IM30 (55 mg, 0.19 mmol), IM3 (82 mg, 0.38 mmol), and 50% T3P / EA (0.871 g, 1.37 mmol) were added to DMF (3 mL) and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate (25 mL), and the organic phase was washed successively with semi-saturated brine (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purification using a preparative plate (containing 4% methanol in dichloromethane solution) yielded a white solid compound II-45 (35 mg). MS: [MH] + 491.00; 1 HNMR (400MHz, DMSO-d6): δ8.48-8.47(m,1H),7.57(s,2H),7.41-7.32(m,5H),7.27-7.24(m,2H),4.98-4. 95(m,1H),4.39-4.32(m,1H),4.15-4.08(m,1H),3.81-3.76(m,1H),3.51-3.45(m,1H),3.29-3.27(m,2H).

[0490] Example 71: Synthesis of Compound II-45a

[0491] Compound II-45a is a chiral isomer of compound II-45 obtained by preparation and isolation. It is an off-white solid (46 mg) with a retention time of 5.067 min, as follows:

[0492] MS:[MH] + 491.05; 1 HNMR (400MHz, DMSO-d6): δ8.48(d,J=8.0Hz,1H),7.58(s,2H),7.42-7.33(m,5H),7.28-7.22(m,2H ),4.98-4.95(m,1H),4.36-4.33(m,1H),3.80-3.75(m,1H),3.51-3.45(m,1H),3.31-3.21(m,2H).

[0493] Example 72: Synthesis of Compound II-45b

[0494] Compound II-45b is a chiral isomer of compound II-45, obtained through preparative isolation. It is a white solid (46 mg) with a retention time of 6.191 min. MS: [MH] + 491.00; 1HNMR (400MHz, DMSO-d6): δ8.48(d,J=8.0Hz,1H),7.58(s,2H),7.42-7.33(m,5H),7.28-7.22(m,2H),4.98-4 .95(m,1H),4.38-4.32(m,1H),4.15-4.08(m,1H),3.80-3.75(m,1H),3.51-3.45(m,1H),3.31-3.23(m,1H).

[0495] Example 73: Synthesis of Compound II-67

[0496] IM7 (0.150 g, 0.50 mmol), IM5 (0.160 g, 0.75 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol), Xphos (0.119 g, 0.25 mmol), and potassium carbonate (0.172 g, 1.25 mmol) were added to Tol (5 mL). After purging with nitrogen three times, the mixture was microwaved to 120 °C for 1 hour. The reaction solution was filtered, washed with ethyl acetate (20 mL), and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (PE solution containing 20%–33% EA) and preparative chromatography (dichloromethane solution containing 5% methanol) to obtain a white solid II-67 (0.020 g). MS: [MH] + 475.15; 1 HNMR (400MHz, DMSO-d6): δ8.29(d,J=8.0Hz,1H),7.81(br,1H),7.73(br,2H),7.54-7.49(m,1H),7.49- 7.35(m,2H),7.29-7.20(m,1H),6.64(s,1H),4.52(t,J=6.0Hz,2H),3.34(t,J=8.0Hz,2H),2.51(s,3H).

[0497] Example 74: Synthesis of compounds II-73 and II-76

[0498] A mixture of IM8a and IM8b (0.300 g, 1.00 mmol), IM5 (0.256 g, 1.20 mmol), Pd2(dba)3 (0.459 g, 0.50 mmol), Xphos (0.779 g, 1.00 mmol), and potassium carbonate (0.346 g, 2.51 mmol) were added to Tol (5 mL). After purging with nitrogen three times, the mixture was heated to 110 °C and reacted for 5 hours. The reaction solution was filtered, washed with ethyl acetate (100 mL), and the filtrate was washed successively with water (80 mL) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (PE solution containing 50% EA) and preparative chromatography (dichloromethane solution containing 5% methanol) to give an off-white solid (0.013 g). MS: [MH] + 475.9; 1 HNMR (400MHz, DMSO-d6): δ8.17-8.15(m,1H),7.91(s,1H),7.79(s,2H),7.64-7.62(m,1H),7.52-7.47( m,1H),7.41-7.37(m,1H),7.32-7.25(m,1H),3.94(t,J=8.0Hz,2H),2.72(t,J=8.0Hz,2H),1.78(s,3H).

[0499] Example 75: Synthesis of Compound II-85a

[0500] IM26a (61 mg, 0.20 mmol), IM2S (61 mg, 0.24 mmol), and DIPEA (0.5 mL) were added to DCM (4 mL) under nitrogen protection at 0 °C and stirred overnight at room temperature. DCM (40 mL) and water (20 mL) were added, and the mixture was separated. The organic phase was washed sequentially with saturated brine (24 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (using a dichloromethane solution containing 5% methanol) to give compound II-85a (8.6 mg, 9%). MS: [MH] + 484.40; 1HNMR (400MHz, CD3OD): δ8.72(s,1H),8.42(t,J=8.0Hz,1H),8.20(d,J=8.0Hz,1H),7.81(t,J=4.0Hz,1H),7.76-7.71(m,2H),7.44(d,J=8.0Hz,1H) ,7.05-6.97(m,2H),4.47-4.14(m,2H),3.51-3.44(m,2H),3.22-3.15(m, 1H), 2.94 (d, J = 16.0Hz, 2H), 2.85-2.79 (m, 1H), 1.94 (s, 1H), 1.38 (s, 3H).

[0501] Example 76: Synthesis of Compound II-85b

[0502] IM26b (50 mg, 0.20 mmol), IM2S (61 mg, 0.24 mmol), and DIPEA (0.5 mL) were added to DCM (4 mL) under nitrogen protection at 0 °C and stirred overnight at room temperature. DCM (40 mL) and water (20 mL) were added, and the mixture was separated. The organic phase was washed sequentially with saturated brine (24 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (using a dichloromethane solution containing 5% methanol) to give compound II-85b (5.1 mg, 5%). MS: [MH] + 484.10; 1 HNMR (400MHz, CD3OD): δ8.68(d,J=8.0Hz,1H),8.28(t,J=8.0Hz,1H),8.09(d,J=8 .0Hz,1H),7.75-7.67(m,3H),7.40(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.98( d,J=8.0Hz,1H),4.48-4.40(m,1H),4.36-4.30(m,1H),4.21-4.13(m,1H),3.50-3 .43(m,3H),3.22-3.13(m,1H),2.96-2.90(m,2H),2.85-2.79(m,1H),1.37(s,3H).

[0503] Example 77: Synthesis of Compound II-99

[0504] IM14 (0.300 g, 1.22 mmol), IM5 (0.311 g, 1.46 mmol), Pd2(dba)3 (1.117 g, 0.122 mmol), Xantphos (0.706 g, 0.122 mmol), and cesium carbonate (0.795 g, 2.44 mmol) were added to Tol (5 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 6 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (using a dichloromethane solution containing 10% methanol) and then slurried again with a dichloromethane solution containing 10% methanol (50 mL) to obtain a white solid II-99 (0.280 g). MS: [MH] + 423.55; 1 HNMR (400MHz, DMSO): δ8.52(s,1H),7.91(s,1H),7.58-7.54(m,1H),7.50(s,2H),7.46-7.40(m,1H),7.3 3-7.28(m,1H),4.35-4.32(t,J=6.0Hz,2H),3.16-3.09(t,J=6.0Hz,2H),2.50(s,3H),2.12-2.03(m,2H).

[0505] Example 78: Synthesis of Compound III-3

[0506] IM9 (49 mg, 0.23 mmol), IM3 (60 mg, 0.28 mmol), DIPEA (108 mg, 0.28 mmol), and HATU (106 mg, 0.28 mmol) were added sequentially to DMF (4 mL), and the mixture was stirred for 2 h under nitrogen protection. The mixture was quenched with water (25 mL), extracted with ethyl acetate (60 mL), and the organic phase was washed successively with water (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative chromatography (using a dichloromethane solution containing 5% methanol) to obtain a white solid compound III-3 (32 mg). MS: [MH] + 412.00; 1 HNMR (400MHz, DMSO-d6): δ8.70-8.67(m,1H),8.56-8.55(m,1H),8.10-8.07(m,2H),7.99-7.97(m,1H),7.93-7.89 (m,1H),7.59(s,2H),7.44(d,J=8Hz,2H),7.39-7.34(m,2H),4.29(t,J=8Hz,2H),3.96(s,2H),3.27(t,J=8Hz,2H).

[0507] Example 79: Synthesis of Compound III-12

[0508] IM9 (55 mg, 0.26 mmol), IM2S (64 mg, 0.26 mmol), DIPEA (100 mg, 0.78 mmol), and HATU (118 mg, 0.31 mmol) were added sequentially to DMF (4 mL), and the mixture was stirred for 2 h under nitrogen protection. The mixture was quenched with water (25 mL), extracted with ethyl acetate (60 mL), and the organic phase was washed successively with water (24 mL) and saturated brine (24 mL). The mixture was dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative chromatography (using a dichloromethane solution containing 6% methanol) to obtain a white solid compound III-12 (32 mg). MS: [MH] + 444.35; 1 HNMR (400MHz, DMSO-d6): δ8.67-8.66(m,1H),8.44(s,1H),8.05(d,J=8Hz,2H),7.95(d,J=8Hz,1H),7.90-7.86(m,1H),7.58(s,2H),7.42(d,J=8 Hz,2H),7.38-7.33(m,2H),5.16(s,1H),4.73-4.44(m,2H),4.11(d,J=1 6Hz,1H),3.95(d,J=16Hz,1H),3.52-3.45(m,1H),2.99(d,J=16Hz,1H).

[0509] Example 80: Synthesis of Compound III-13

[0510] Synthesis of Ⅲ-13-1:

[0511] IM11 (162 mg, 0.65 mmol), IM10 (246 mg, 0.78 mmol), and EDCI (188 mg, 0.98 mmol) were added to pyridine (4 mL), and the mixture was stirred overnight at 50 °C under nitrogen protection. The reaction solution was concentrated and purified by preparative plate (PE solution containing 25% EA) to give a pink solid compound III-13-1 (330 mg, 91%). MS: [MH] + 445.00; 1 HNMR (400MHz, CDCl3): δ8.88(d,J=8Hz,1H),7.52(d,J=8Hz,2H),7.39(d,J=8Hz,2H) ,7.16-6.96(m,4H),4.21-4.16(m,2H),3.85(s,2H),3.30-3.24(m,5H),1.40(s,9H).

[0512] Synthesis of III-13:

[0513] Trifluoroacetic acid (2 mL) was added to a solution of intermediate III-13-1 (0.15 g, 0.28 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness and purified by silica gel column chromatography (using DCM solution containing 3.2% MeOH) to give a white solid compound III-13 (100 mg, 82%). MS: [MH] + 445.35; 1 HNMR (400MHz, DMSO-d6): δ8.57(d,J=8Hz,1H),7.55(d,J=8Hz,2H),7.44-7.33(m,5H),7.29- 7.23(m,1H),4.55(s,1H),4.27(t,J=8Hz,2H),3.93(s,2H),3.29-3.24(m,2H),3.12(s,3H).

[0514] Example 81: Synthesis of Compound III-13a

[0515] Compound III-13a is a chiral isomer of compound III-13 obtained by preparative isolation, with a retention time of 1.668 min, as follows:

[0516] Off-white solid (81 mg). MS: [MH] + 445.05; 1 HNMR (400MHz, DMSO-d6): δ8.57(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.44-7.33(m,5H),7.29- 7.23(m,1H),4.58(s,1H),4.27(t,J=8.0Hz,2H),3.93(s,2H),3.26(t,J=8.0Hz,2H),3.12(s,3H).

[0517] Example 82: Synthesis of Compound III-13b

[0518] Compound III-13b is another chiral isomer of compound III-13 obtained through preparation and isolation. It has a retention time of 2.337 min and is a white solid (83 mg). MS: [MH] + 445.05; 1HNMR (400MHz, DMSO-d6): δ8.57(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.44-7.34(m,5H),7.29-7 .23(m,1H),4.59(br,1H),4.27(t,J=8.0Hz,2H),3.93(s,2H),3.26(t,J=8.0Hz,2H),3.12(s,3H).

[0519] Example 83: Synthesis of Compound III-15

[0520] Synthesis of Ⅲ-15-1:

[0521] IM9 (200 mg, 0.94 mmol), IM10 (354 mg, 1.13 mmol), and EDCI (270 mg, 1.41 mmol) were added to pyridine (4 mL), and the mixture was stirred overnight at 50 °C under nitrogen protection. The reaction solution was concentrated and purified by preparative plate chromatography (PE solution containing 50% EA, DCM solution containing 50% EA) to give a gray solid compound III-15-1 (460 mg, 96%). MS: [MH] + 510.75; 1 HNMR (400MHz, DMSO-d6): δ8.68-8.64(m,1H),8.57(d,J=8.0Hz,1H),8.06(d,J=8.0Hz,2H),7.98-7.93(m,1H),7.91-7.84(m, 1H),7.47-7.39(m,3H),7.37-7.32(m,1H),4.28(t,J=10.0Hz,2H),3.95(s,2H),3.38(s,3H),3.31-3.24(m,2H),1.24(s,9H).

[0522] Synthesis of Ⅲ-15:

[0523] Trifluoroacetic acid (2 mL) was added to a solution of intermediate III-15-1 (0.20 g, 0.39 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness and purified by preparative plate (using DCM solution containing 5% MeOH) to give a white solid compound III-15 (100 mg, 40%). MS: [MH] + 410.65; 1HNMR (400MHz, CD3OD): δ8.80-8.77(m,1H),8.75(d,J=8.0Hz,1H),8.50-8.44(m,1H),8.28-8.24(m,1H),7.94(d,J=8.0Hz,2H),7.88 -7.83(m,1H),7.60(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,1H),4.36(t,J=8.0Hz,2H),4.06(s,2H),3.56(s,3H),3.39(t,J=8.0Hz,2H).

[0524] Example 84: Synthesis of Compound III-24

[0525] Synthesis of Ⅲ-24-1:

[0526] IM12 (173 mg, 0.38 mmol), IM10 (142 mg, 0.45 mmol), and EDCI (108 mg, 0.56 mmol) were added to pyridine (5 mL), and the mixture was stirred overnight at 50 °C under nitrogen protection. The reaction solution was concentrated to remove pyridine, diluted with ethyl acetate (30 mL), washed successively with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel plate (using a dichloromethane solution containing 5% methanol) yielded a light purple solid, III-24-1 (190 mg, 90%). MS: [MH] + 463.05; 1 HNMR (400MHz, CDCl3): δ8.85 (d, J = 8.0Hz, 1H), 7.45-7.41 (m, 1H), 7.33-7.28 (m, 2H), 7. 16-6.99(m,4H),4.29-4.23(m,2H),3.90-3.81(m,2H),3.33-3.29(m,5H),1.39(s,9H).

[0527] Synthesis of III-24:

[0528] Trifluoroacetic acid (1.5 mL) was added to a solution of intermediate III-24-1 (0.19 g, 0.34 mmol) in DCM (1.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness and purified by preparative plate chromatography (using DCM solution containing 5% MeOH) to give a white solid compound III-24 (120 mg, 76%). MS: [MH] + 463.10; 1HNMR (400MHz, DMSO-d6): δ8.53(d,J=8.0Hz,1H),7.51-7.47(m,1H),7.47-7.43(m,2H),7.42-7.35(m,3 H),7.33-7.28(m,1H),4.54(s,1H),4.33(t,J=8.0Hz,2H),3.98(s,2H),3.29-3.27(m,2H),3.12(s,3H).

[0529] Example 85: Synthesis of Compound III-24a

[0530] Compound III-24a is a chiral isomer of compound III-24 obtained by preparative isolation. It is a white solid (65 mg) with a retention time of 0.927 min, as follows:

[0531] MS:[MH] + 463.75; 1 HNMR (400MHz, CDCl3): δ8.77 (d, J = 8.0Hz, 1H), 7.45-7.41 (m, 1H), 7.34-7.26 (m, 2H), 7. 16-7.02(m,4H),4.28(t,J=8.0Hz,2H),3.87(s,2H),3.32(t,J=8.0Hz,2H),3.23(s,3H).

[0532] Example 86: Synthesis of Compound III-24b

[0533] Compound III-24b is another chiral isomer of compound III-24, obtained through preparative isolation. It is a white solid (59 mg) with a retention time of 1.290 min. MS: [MH] + 463.75; 1 HNMR (400MHz, CDCl3): δ8.77 (d, J = 8.0Hz, 1H), 7.45-7.41 (m, 1H), 7.34-7.26 (m, 2H), 7.15-7.0 2(m,4H),4.28(t,J=8.0Hz,2H),3.87(s,2H),3.32(t,J=8.0Hz,2H),3.23(s,3H),3.02(br,1H).

[0534] Example 87: Synthesis of Compound III-39

[0535] Synthesis of Ⅲ-39-1:

[0536] IM17 (360 mg, 1.36 mmol), IM16 (356 mg, 2.04 mmol), EDCI (521 mg, 2.72 mmol), and HOBT (367 mg, 2.72 mmol) were added to DMF (5 mL), and the mixture was stirred overnight under nitrogen protection. The reaction mixture was quenched in water, extracted with ethyl acetate (50 mL), and the organic layer was washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (PE solution containing 10% EA and PE solution containing 33% EA) to obtain a white solid, III-39-1 (300 mg). MS: [MH] + 421.20.

[0537] Synthesis of Ⅲ-39-2:

[0538] III-39-1 (160 mg, 0.43 mmol), TBDMSCl (115 mg, 0.76 mmol), and imidazole (78 mg, 1.14 mmol) were added to DCM (5 mL), and stirred for 3 h under nitrogen protection. The reaction solution was quenched in water, and extracted with DCM (30 mL). The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a yellow oily substance III-39-2 (230 mg). No purification was required for the next step.

[0539] Synthesis of Ⅲ-39-3:

[0540] III-39-2 (230 mg, 0.43 mmol), iodophenyl diacetic acid (277 mg, 0.86 mmol), and ammonium carbamate (101 mg, 1.29 mmol) were added sequentially to methanol (5 mL), and the mixture was stirred at room temperature for 3 h. The reaction solution was quenched in water, extracted with DCM (50 mL), and the organic layer was washed sequentially with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, a yellow oily substance III-39-3 (245 mg), which was directly proceeded to the next step without further purification.

[0541] Synthesis of Ⅲ-39:

[0542] III-39-3 (245 mg, 0.43 mmol) was dissolved in THF (5 mL), and TBAF (1 mL, 1 M THF solution) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was quenched in water, and extracted with EA (50 mL). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative plate chromatography (using DCM solution containing 5% MeOH) to give a white solid compound III-39 (44 mg). MS: [MH] +452.95; 1 HNMR (400MHz, DMSO): δ9.62 (s, 1H), 7.41-7.38 (t, J = 8Hz, 1H), 7.21-7.16 (m, 2H), 7.11-7.04 (m, 2H), 6.9 7-6.94(dd,J1=8.8Hz,J2=4.8Hz,1H),4.71(s,1H),4.26(s,2H),3.76(s,3H),3.17(s,3H),2.53(s,3H).

[0543] Example 88: Synthesis of Compound III-44

[0544] IM3 (44 mg, 0.20 mmol) and bisphosgene (45 mg, 0.37 mmol) were added to THF (1.5 mL), reacted at room temperature for 2 h, and then concentrated to dryness. A solution of IM13 (50 mg, 0.19 mmol) in DMF (4 mL) was added to the above intermediate, and triethylamine was added dropwise to pH 8–9. Translation was carried out at room temperature for 4 h. The reaction solution was quenched in water, extracted with ethyl acetate (20 mL), and the organic layer was washed three times with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel plate (dichloromethane solution containing 6% methanol) yielded an off-white solid, III-44 (35 mg). MS: [MH] + 439.10; 1 HNMR (400MHz, DMSO-d6): δ8.67(d,J=4.0Hz,1H),8.08-8.03(m,2H),7.97(d,J=8.0Hz,1H),7.87-7.91(m,1H),7.71(d,J=4.0Hz,1H),7.55(s ,2H),7.47(d,J=8.0Hz,1H),7.38-7.35(m,1H),7.29(d,J=12.0Hz,1H),4.90(d,J=8.0Hz,4H),4.17(t,J=8.0Hz,2H),3.22(t,J=8.0Hz,2H).

[0545] Example 89: Synthesis of Compound III-45

[0546] IM15 (58 mg, 0.22 mmol), IM13 (50 mg, 0.19 mmol), and DIPEA (72 mg, 0.56 mmol) were added to DMF (4 mL), and the mixture was stirred at room temperature for 2 h. HATU (85 mg, 0.22 mmol) was then added, and the mixture was stirred at room temperature for 16 h under nitrogen protection. The mixture was quenched with water (30 mL), extracted twice with ethyl acetate (30 mL), washed three times with water (30 mL) of the organic phase, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product was purified by preparative chromatography (using a dichloromethane solution containing 6% methanol) to give a white solid compound III-45 (30 mg). MS: [MH] + 438.45; 1 HNMR (400MHz, DMSO-d6): δ8.68-8.66(m,1H),8.12-8.05(m,2H),8.02-7.97 (m,1H),7.93-7.88(m,1H),7.58-7.55(m,3H),7.52-7.48(m,1H),7.39-7.3 6(m,1H),7.33(d,J=8.0Hz,1H),5.23-5.08(m,2H),4.84-4.73(m,2H),4.42 (t,J=6.0Hz,1H),3.12-2.93(m,2H),2.56-2.48(m,1H),2.28-2.18(m,1H).

[0547] Example 90: Synthesis of Compound III-52

[0548] IM31 (200 mg, 0.73 mmol), IM6 (169 mg, 0.80 mmol), EDCI (279 mg, 1.46 mmol), and HOBT (197 mg, 1.46 mmol) were added to DMF (5 mL), and the mixture was stirred at 40 °C for 3 h under nitrogen protection. The reaction solution was quenched in water, and extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (using DCM solution containing 2% MeOH and DCM solution containing 5% MeOH) to give a white solid (0.22 g). MS: [MH] + 467.35; 1 HNMR (400MHz, DMSO-d6): δ7.66(s,2H),7.46(s,2H),7.42-7.35(m,4H),4.15-4.05(m,1H),3.49-2.24(m,2H),2.51(s,3H).

[0549] Two chiral isomers were obtained by preparation and resolution, with retention times of 5.331 min and 6.316 min, respectively, as follows:

[0550] Compound III-52 had a retention time of 6.316 min. MS: [MH] + 467.20; 1 HNMR (400MHz, DMSO): δ7.63(s,2H),7.43(s,1H),7.39-7.33(m,4H),7.26-7.20(m,1H),4.13-4.05(m,1H),3.44-3.26(m,4H),2.49(s,3H).

[0551] Example 91: Synthesis of Compound III-54

[0552] IM18 (400 mg, 1.40 mmol), IM6 (323 mg, 1.54 mmol), EDCI (536 mg, 2.79 mmol), and HOBT (378 mg, 2.79 mmol) were added to DMF (5 mL), and the mixture was stirred overnight under nitrogen protection. The reaction solution was quenched in water, and extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (using DCM solution containing 2% MeOH and DCM solution containing 5% MeOH) to obtain a white solid, III-54 (1.10 g).

[0553] Example 92: Synthesis of Compound III-54a

[0554] Compound III-54a is a chiral isomer obtained by preparative resolution of III-54, with a retention time of 9.400 min, as follows:

[0555] MS:[MH] + 479.30; 1 HNMR (400MHz, DMSO): δ7.63(s,2H),7.35(s,1H),7.30(s,2H),7.20-7.10(m,3H),4 .15-4.05(m,1H),3.41-3.34(m,2H),3.31-3.25(m,2H),3.76(s,3H),2.52(s,3H).

[0556] Example 93: Synthesis of Compound III-54b

[0557] Compound III-54b is another chiral isomer obtained by preparative resolution of III-54, with a retention time of 11.166 min. MS: [MH] + 479.45; 1 HNMR (400MHz, DMSO): δ7.64(s,2H),7.33(s,1H),7.30(s,2H),7.17-7.08(m,3H),4 .11-4.03(m,1H),3.38-3.31(m,2H),3.31-3.25(m,2H),3.73(s,3H),2.49(s,3H).

[0558] Using the same method as in the previous examples, the following compounds were synthesized:

[0559] Example 94. In vitro bioactivity study

[0560] The antiviral activity of the test compounds against HSV was tested using the cytopathic effect (CPE) method, while cytotoxicity was also determined. EC 50 The test started at a concentration of 1 μM, CC 50 The tests started at a concentration of 100 μM. All compounds were tested at eight concentrations, with 3-fold serial dilutions and double-duplicate testing.

[0561] Vero cells were seeded at a specific density in microplates and cultured overnight at 37°C and 5% CO2. The next day, the compound and virus (HSV-2MS) were added, setting up cell controls (no compound treatment or virus infection) and virus-infected controls (cells infected with the virus, no compound treatment). The final concentration of DMSO in the cell culture medium was 0.5%. Cells were cultured at 37°C and 5% CO2 for 5 days until the cytotoxicity rate in the virus control wells reached 80%-95%. Cytotoxicity assays were performed similarly to antiviral assays, but without virus infection. Cell viability was assessed using the CCK-8 assay, and the raw data were used to calculate the compound's antiviral activity and cytotoxicity. GraphPadPrism software was used to analyze the compound's dose-response curve and calculate EC50. 50 and CC 50 value.

[0562] The results are shown in Table 1. The control compound was Pritelivir, with EC 1000 mg / L. 50 ≤10nM is denoted as “A”, 10nM <EC 50 <100nM is denoted as "B", EC 50 ≥100nM is denoted as "C".

[0563] Table 1. In vitro cell antiviral activity of compounds

[0564] The antiviral activity of the compounds against HSV-2 was tested using the cytopathic effect (CPE) method, with pritelivir as a control compound. Table 1 shows that the activities of II-1a, II-4a, II-7a, II-35a, II-36a, II-40b, II-41b, II-42b, II-43b, II-44b, II-45b, II-61, II-62, II-64, and II-65 were significantly higher than those of pritelivir; the activities of I-2, I-2b, I-28, and I-29 were 2-4 times higher than those of pritelivir; and the activities of III-3, III-12, III-13, III-13b, III-24, III-24a, III-44, III-52, and III54b were comparable to those of pritelivir. This class of compounds aims to target the CNS and develop antiviral inhibitors that can penetrate the brain.

[0565] Example 95. Stability test of liver microsomes in humans / monkeys / dogs / rat

[0566] Experimental protocol: This experiment was conducted in a 96-well plate. The reaction conditions were as follows: ① Microsomal protein concentration: 0.7 mg / mL ② Compound concentration: 1 μM ③ NADPH concentration: 1 mM ④ Phosphate concentration: 100 mM ⑤ Incubation volume: 100 μL ⑥ Acetonitrile concentration: 0.1%. The reaction was terminated by adding a stop solution after incubation for 0 min, 15 min, 30 min, 60 min, and 90 min, respectively. The remaining amount of the compound was detected using liquid chromatography-mass spectrometry (LC-MS). Positive controls for the human and rat liver microsomal systems were testosterone and diclofenac, while positive controls for the monkey and dog liver microsomal systems were testes and propranolol.

[0567] Data Analysis: Analyte / Internal Standard Peak Area Ratio (A) analyte / A IS The remaining percentage (%Control) will be determined by the instrument, calculated from the A values ​​of the samples at non-zero time points and the sample at time zero. analyte / A IS The ratio was calculated. Ln (%Control) was plotted against incubation time and linearly fitted. The scavenging constant (k, min) of the test compound was determined. -1 ), elimination half-life (T) 1 / 2 (min) with clearance rate ( The μL / min / mg concentration was calculated using the following equation, and the results are shown in Table 2. k = -slope

[0568] Table 2 Results of the study on the stability of compounds in liver microsomes

[0569] The data in Table 2 show that most compounds have good stability in the liver microsomes of rats, dogs, monkeys and humans. Even though some compounds are metabolized relatively quickly in rat liver microsomes, they are very stable in human liver microsomes. It is expected that these compounds will have a long half-life in humans.

[0570] Example 96. Rat PK

[0571] (1) Intravenous administration

[0572] Compounds I-2b and III-52 were administered intravenously to SD rats, with three male SD rats in each group. Rats were fasted overnight before the experiment but allowed free access to water. They were fed uniformly 1 hour after administration. The intravenous dose for each group was 0.25 mg / kg. At 0.03, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 24.0, 48.0, and 72.0 hours after administration, 0.15–0.2 mL of blood was collected via the jugular vein or other suitable vein, placed in EDTA-K2 anticoagulant tubes, gently mixed, centrifuged at 4000 rpm for 10 min, and the plasma was separated and frozen at -80°C for analysis. The plasma concentrations of the corresponding compounds in each group were determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The results are shown in Table 3.

[0573] Table 3: Pharmacokinetic parameters of a single intravenous injection of the compound in SD rats

[0574] Table 3 shows that, taking I-2b and III-52 as examples, the compounds have good in vivo exposure and long half-life, indicating that this type of compound has typical long-acting characteristics.

[0575] (2) Oral administration via gavage

[0576] Compounds II-1a, II-4a, II-7a, II-43b, reference A, and reference B were administered orally to SD rats via gavage. Three male SD rats were used in each group. Rats were fasted overnight but allowed free access to water. They were fed uniformly 1 hour after administration. The gavage dose for each group was 5 mg / kg, with a solvent of DMSO:0.5% methylcellulose-PBS solution = 2:98 (v / v). At 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 24.0, and 48.0 hours after administration, 0.15–0.2 mL of blood was collected via the jugular vein or other suitable vein, placed in EDTA-K2 anticoagulant tubes, gently mixed, centrifuged at 4000 rpm for 10 min, and the plasma was separated and frozen at -80°C for analysis. The plasma concentrations of the corresponding compounds in each group were determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The results are shown in Table 4. Note: The compounds in Example 125 (reference A) and Example 35 (reference B) were synthesized according to the published patent WO 2023 / 225162A1.

[0577] Table 4: Pharmacokinetic parameters of the compound administered via single oral gavage to SD rats

[0578] The data in Table 4 show that II-1a, II-4a, and II-7a possess good drug exposure levels and moderate metabolic rates, making them suitable for developing long-acting oral compounds. Compared to controls A and B, the introduction of the α-position F atom in the amide slows down the metabolic rate and significantly increases the half-life, especially for compound II-7a, which significantly increases in vivo exposure by approximately two times compared to control A. Notably, II-7a also maintains high anti-HSV activity, indicating significant development potential. Although compound II-43b exhibits poor absorption in rats, resulting in lower exposure levels, its relatively long half-life, possibly due to poor solubility, suggests that it is metabolically very stable in human liver microsomes. Further formulation technologies can be used to improve its solubility in the human gastrointestinal tract, making it a promising compound for developing long-acting oral drugs.

[0579] Example 97. Beagle PK

[0580] (1) Intravenous injection

[0581] Drug concentrations were determined in beagle dogs after a single intravenous administration of I-2b and III-52. Three male beagle dogs were used in each group. All animals were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. All animals had free access to water throughout the experiment. Each group received a cephalic intravenous injection of 0.15 mg / kg. Approximately 0.5 mL of blood was collected from the jugular vein at 0.08, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, 72, 96, and 120 hours post-administration. The collected whole blood was placed in an EDTA-K2 anticoagulant tube, thoroughly mixed by inverting several times, stored on moist ice, and centrifuged (1500–1600 g) for 10 minutes within 30 minutes to separate the plasma. The plasma samples were stored at -90 to -60°C for biological sample analysis. An LC-MS / MS method was established to determine the concentrations of I-2b and III-52 in beagle plasma, which was used to determine the concentrations of biological samples obtained in this experiment. The corresponding pharmacokinetic parameters were calculated using a non-compartmental model in PhoenixWinNonlin 8.3, and the results are shown in Table 5.

[0582] Table 5: Pharmacokinetic parameters of the compound after a single intravenous injection in beagle dogs

[0583] The data in Table 5 show that compounds I-2b and III-52 have the potential to be developed into long-acting compounds, especially compound I-2b, which performs exceptionally well, far exceeding compound III-52. Consistent with rat PK data, compound I-2b, with its unique spirocyclic structure, significantly improves the pharmacokinetic parameters of the compound. Compared with non-spirocyclic compounds, the drug exposure in dogs after oral administration is about 10 times higher, and it has an excellent half-life. This finding is highly innovative.

[0584] (2) Oral administration via gavage

[0585] Drug concentrations were determined in beagles after a single oral gavage administration of II-1a and II-7a. Three male beagles were used in each group. All animals were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. All animals had free access to water throughout the experiment. The gavage dose was 5 mg / kg, with a solvent of DMSO:0.5% methylcellulose-PBS solution = 2:98 (v / v). At 0.083, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, and 72 hours post-administration, approximately 0.5 mL of blood was collected from the jugular vein. The collected whole blood was placed in an EDTA-K2 anticoagulant tube, thoroughly mixed by inverting several times, and stored on moist ice. The tubes were centrifuged (1500–1600 g) for 10 minutes within 30 minutes to separate the plasma. The plasma samples were stored at -90 to -60°C for biological sample analysis. An LC-MS / MS method was established to determine the concentrations of II-1a and II-7a in beagle plasma, which was used to determine the concentrations of biological samples obtained in this experiment. The corresponding pharmacokinetic parameters were calculated using a non-compartmental model in PhoenixWinNonlin 8.3, and the results are shown in Table 6.

[0586] Table 6: Pharmacokinetic parameters of the compound after a single oral gavage in beagle dogs

[0587] According to the data in Table 6, the pharmacokinetic parameters of II-1a and II-7a beagle dogs after a single oral gavage were compared, and both showed good absorption. The formation of salts from these structural compounds will further improve their pharmacokinetic properties.

[0588] Example 98. Caco-2 Permeability Test

[0589] Experimental design and results:

[0590] (1) Preparation of working solutions of control compound and test compound

[0591] The hypotonic control compound (atenolol), hypertonic control compound (minoxidil), P-glycoprotein substrate control compound (digoxin), and working solutions of the test compound were prepared by diluting the stock solution with transport buffer (HBSS containing 10 mM HEPES, pH 7.4) (1% BSA may be added to the working solution of the test compound depending on its solubility and adsorption). The final concentrations were as follows: working solution of the test compound: 10 μM; atenolol: 5 μM; minoxidil: 5 μM; digoxin: 5 μM.

[0592] (2) Culture of Caco-2 cells

[0593] Caco-2 cells were seeded and cultured in 24-well Transwell plates. After culture, they should have completely merged and differentiated. The transmembrane resistance was measured using a resistance meter, and only monolayer cells with a transmembrane resistance (TEER) ≥ 230 ohms·cm were observed. 2 Only cell pores with specific TEER values ​​(ohm·cm) can be used for the penetration test. 2 = Measured resistance (ohms) × Film area (cm²) 2 ).

[0594] (3) Drug penetration test

[0595] a) Remove the Transwell plate from the incubator. Rinse the cell membrane twice with preheated transport buffer and incubate at 37°C for 30 minutes.

[0596] b) Determine the transport rate of the compound from the top to the base. Add 210 μL of the dosing end solution to each well of the upper chamber (top), then immediately remove 10 μL of the dosing end solution and add it to a new 96-well plate, mixing it with 90 μL of transport buffer and 300 μL of quenching solution (acetonitrile, containing 5 ng / mL verapamil and 50 ng / mL glibenclamide). This sample is used as the starting dosing end sample TA0 (A→B). Add 1300 μL of the receiving end solution to each well of the lower chamber (base).

[0597] c) Determine the transport rate of the compound from the base end to the top end. Add 1310 μL of the drug-end solution to each well in the lower chamber (base end), then immediately remove 10 μL of the drug-end solution and add it to a 96-well plate, mixing it with 90 μL of transport buffer and 300 μL of quenching solution. This sample is used as the initial drug-end sample TB0 (B→A). Add 200 μL of the receiver end solution to each well in the upper chamber (top end).

[0598] d) Transwell plates were incubated at 37°C for 120 minutes.

[0599] e) Preparation of drug delivery end sample: After the Transwell plate incubation is completed, 10 μL of drug delivery end solution is transferred to a 96-well plate and mixed with 90 μL of transport buffer solution and 300 μL of quenching solution.

[0600] f) Sample preparation for receiver: After incubation on the Transwell plate, 100 μL of receiver solution was transferred to a 96-well plate and mixed with 300 μL of quenching solution.

[0601] g) After centrifuging all samples, transfer the supernatant to a new 96-well plate, mix it with water in a certain proportion, and then perform LC-MS / MS analysis. Each experimental sample is tested in duplicate.

[0602] (4) Data Analysis

[0603] a) Apparent permeability coefficient (P) app cm / s×10 -6 It is calculated using the following formula:

[0604] In the formula: C R The concentration at the receiver after incubation

[0605] C D0 Initial concentration at the dosing end

[0606] V R The volume of the solution at the receiving end is 1.3 mL for A→B and 0.2 mL for B→A.

[0607] A represents the area of ​​a single cell membrane (0.33 cm²). 2 )

[0608] T represents the incubation time (7200 seconds).

[0609] b) The efflux ratio is calculated using the following formula:

[0610] In the formula: P app(B→A) The apparent permeability coefficient from the base to the tip.

[0611] P app(A→B) The apparent permeability coefficient from the top to the base.

[0612] c) Recovery rate is calculated using the following formula:

[0613] In the formula: C R The concentration at the receiver after incubation

[0614] V R The volume of the solution at the receiving end is 1.3 mL for A→B and 0.2 mL for B→A.

[0615] C D Concentration at the dosing end after incubation

[0616] V D The volume of the solution at the administration end is 0.2 mL for A→B and 1.3 mL for B→A.

[0617] C D0 Concentration at the initial dosing point

[0618] d) See Table 7 for parameter standards.

[0619] Table 7. Caco-2 Results Parameter Standards

[0620] (5) The data results are shown in Table 8.

[0621] Table 8. Permeability results of compound Caco-2

[0622] Long-acting compounds generally require moderate permeability. The data in Table 8 show that I-2b, II-1a, II-7a and III-52 have good permeability and are not efflux transporter substrates.

[0623] Example 99. Thermodynamic Solubility Test

[0624] Experimental Procedure: Accurately weigh approximately 2 mg of the compound per pH, and add appropriate volumes of buffer solution (PB buffer, pH = 7.4) or simulated fasting gastrointestinal fluid (FaSSIF-V2 (pH = 6.5) and FaSSGF (pH = 1.6)) to obtain a solution with a concentration of 2 mg / mL. After sonication for 10 minutes, fix the solution on a shaker and shake at room temperature for 8 hours. After shaking, sonicate for 10 minutes and centrifuge at 13000 rpm for 15 minutes. Transfer 0.1 mL of the supernatant to a new tube, shake and rinse for 5 minutes, then discard the liquid. Transfer another 0.5 mL of the supernatant to a new tube, centrifuge at 13000 rpm for 15 minutes, and collect the supernatant (dilute with water if necessary). Analyze the supernatant by LC-MS / MS. The results are shown in Table 9. Note: The compound in Example 35 (control B) was synthesized according to the published patent WO 2023 / 225162A1.

[0625] Table 9. Solubility results of compounds

[0626] The data in Table 9 show that, compared with control B, the solubility of II-4a and II-7a was improved to some extent in simulated fasted human gastric and intestinal fluids; especially II-7a, which showed an improvement of approximately 6-10 times in gastric and intestinal fluids compared with control B, suggesting that drug absorption will be improved in clinical use. II-1a can be further developed into salt forms to improve solubility. I-2b and III-52 showed poor solubility in PB buffer (pH = 7.4) and have the potential to be developed into long-acting injectable compounds, such as subcutaneous or intramuscular injections.

[0627] Example 100. Stability study in human plasma

[0628] Experimental protocol: The test compounds were co-incubated with human plasma in a 200 μL incubation system with a final concentration of 1 μM. At different time points (0, 10, 30, 60, 120, and 180 min), 20 μL of incubated plasma sample was collected and transferred to an appropriate amount of acetonitrile containing an internal standard. After protein precipitation, the supernatant was collected by centrifugation. The test compounds in the supernatant were analyzed by LC-MS / MS, with two replicates per sample. An LC-MS / MS analytical method for detecting the test compounds was established, and the ratio of analyte / internal standard peak area (A0) was determined. analyte / A IS The remaining percentage (%Control) will be determined by the instrument, calculated from the A values ​​of the samples at non-zero time points and the sample at time zero. analyte / A IS The ratio was calculated. Ln (%Control) was plotted against incubation time and linearly fitted. The scavenging constant (k, 1 / min) and scavenging half-life (T) of the test compound were calculated. 1 / 2 The value of (k = -slope; T) is calculated by the following equation (k = -slope; T). 1 / 2 =0.693 / k). See Table 10 for specific results.

[0629] Table 10 Results of stability studies of the compounds in human plasma

[0630] Note: NA in the table indicates not applicable.

[0631] The data in Table 10 show that I-2b, II-1a, II-7a, and III-52 are all stable in human plasma.

[0632] Example 101. Stability Study in Buffers

[0633] Protocol for stability study under phosphate buffer: (1) Stock solution preparation: Prepare a stock solution of the compound at 1 mg / mL using DMSO; (2) Labeling: Take four 96-well plates and label them as: incubation plates T0, T4, T8, and T24; (3) Dilute the compound with DMSO to a working solution of 20 μg / mL in a 1.5 mL centrifuge tube; (4) Add 10 μL of the 20 μg / mL working solution to plates T0, T4, T8, and T24; (5) Add 190 μL of phosphate buffer to plates T0, T4, T8, and T24 in sequence. (6) Add 200 μL of cold acetonitrile (containing 1 μg / mL internal standard) to plates T0, T4, T8, and T24 sequentially at time points, and mix at 1200 rpm for 2 min; (7) Transfer 40 μL to a 96-well plate containing 360 μL of cold acetonitrile, mix at 1200 rpm for 2 min, and place in a -20℃ freezer. Inject all samples together after preparation; (8) Analyze the test compounds in the samples by LC-MS / MS method, with three replicates per sample. The results of the phosphate buffer stability study under different pH conditions are shown in Table 11.

[0634] Table 11 Results of phosphate buffer stability studies of compounds under different pH conditions

[0635] The data in Table 11 show that I-2b, II-1a, II-7a and III-52 are stable in phosphate buffer under different pH conditions.

[0636] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt, said heterocyclic derivative having the structure shown in formula (I) or formula (IIa): in: (1) Each R1 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-12 Aromatic compounds, R1′ is selected from H, CN, OH, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl or C 3-6 The cycloalkyl group, or R1′, is selected from the prodrug group that yields the parent compound in vivo via chemical hydrolysis or enzymatic degradation, and R1″ is selected from C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 3-6 Cycloalkyl; n is 1, 2, 3 or 4; (2) R2 is selected from H, halogen, cyano, hydroxyl, -SO2NH2, C 1-6 Alkyl or halogenated C 1-6 alkyl; (3) R3 is selected from unsubstituted or substituted groups of the following: saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, aromatic carbocyclic group, wherein the substituent used for substitution is selected from one or more of the following groups: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, oxo, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne group, unsubstituted or substituted 5-10 membered aliphatic heterocyclic group or 5-10 membered heteroaromatic group; (4) R4 is selected from H, D, halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, amino, C 2-6 Alkyne group; or R4 is absent; (5) Each R5 is independently selected from H, D, hydroxyl, halogen, cyano, amide, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne group, where m is 0, 1, 2, 3 or 4; or, m is 2, and two R5 groups are attached to one or two carbon atoms to form a first ring, which is a monocyclic, bridged, spirocyclic, fused or polycyclic ring; (6) A is selected from saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, and aromatic carbocyclic group; (7) B does not exist, or B is selected from C. 1-3 Alkylene, O, S or NR6′, where R6′ is selected from H or C. 1-6 alkyl; (8) T and V are independently CH or N; (9) X and Y are independently selected from one bond, O, and O-(CR2′R3′). t S, NCH3, (CR2′R3′) t Or a broken key; R2′ and R3′ are independently selected from H, D, and C. 1-3 Alkyl, halogen, or R2′ and R3′ connected to the same carbon atom and forming a spirocyclic ring with the ring containing X and Y, or R2′ and R3′ connected to different carbon atoms and forming a fused ring with the ring containing X and Y, or one of R2′ and R3′ is H or D, and the other is connected to W to form a ring; t is 0, 1, 2, or 3; (10) In equation (I), M is C or N, and satisfies: when M is N, Y is a broken bond and X is a bond; Q is CH2, O, or S; (11) P is selected from a bond or (CR4′R5′). a R4′ and R5′ are independently selected from H, D, and deuterated C. 1-3 Alkyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, F, or R4′ and R5′ are attached to the same carbon atom and form a spiro ring with the ring containing P; a is 1, 2 or 3; (12) R6 and R7 are independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl groups, or atoms connected to R6 and R7 and connected to each other together to form a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is substituted by 0, 1, 2 or more R5s; (13) In equation (IIa), W is C, CH or N, and satisfies: when W is N, R4 does not exist; when W is C and R4 does not exist, there is a double bond between W and X or a double bond between W and Y. E is CH or N; (14) The heteroatoms in the saturated heterocyclic group, unsaturated heterocyclic group, aliphatic heterocyclic group, and heteroaromatic group are independently selected from one or more of O, S, N and oxo.

2. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, Both T and V are CH; or, one of T and V is CH and the other is N; and / or, Q is CH2 or O, B does not exist, and M is C.

3. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, The prodrug group is selected from...

4. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, The heterocyclic derivative has the structure shown in formula (IA): Wherein: R1, R2, R3, R5, P, m, n, X, Y, A are defined as in claim 1.

5. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-4, characterized in that, X, Y, and the carbon atoms and M connected to them together form a 4-8 membered ring, and the 4-8 membered ring contains 0 or 1 heteroatom.

6. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 5, characterized in that, X, Y, and the carbon atoms and M connected to them together form a 5-6 membered carbon ring, a 5-6 membered oxygen heterocycle, or a 5-6 membered sulfur heterocycle.

7. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1 or 4, characterized in that, P is a single bond, methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, or fluoroethyl; and / or, the first ring is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ...

8. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 4, characterized in that, Selected from the following groups:

9. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, Selected from the following groups:

10. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, In equation (IIa), W represents N and E represents CH; Alternatively, in formula (IIa), W is N, E is N, and R6 and R7 are connected together with the atoms they are connected to to form a 5-8 membered nitrogen heterocycle; or, in formula (IIa), W is CH, one of X and Y is a broken bond, and the other is a bond.

11. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, In equation (IIa), one of X and Y is O and S, and the other is (CR2′R3′). t W is C or CH, E is N, and R6 and R7 are connected together with the atoms they are connected to to form a 5-8 membered nitrogen heterocycle. The substituent on the 5-8 membered nitrogen heterocycle is R5, and t is 0, 1, 2, or 3.

12. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, In formula (IIa), The definitions of R1, R5, m, and n are the same as in claim 1; or, The heterocyclic derivative has the structure shown in formula (IIa-A): Wherein: R1, R2, R3, R4, R5, m, n, X, Y are defined as in claim 1.

13. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1 or 12, characterized in that, Both X and Y are (CR2′R3′). t R4 is selected from halogen, cyano, methyl, ethyl, propyl, hydroxy, amino, methoxy or ethoxy, and t is 0 or 1; Alternatively, X and Y can be independently selected from O, S, or (CR2′R3′). t And not both of them are (CR2′R3′). t R4 is selected from H, D, halogen, cyano, methyl, ethyl, propyl, hydroxy, amino, methoxy, or ethoxy, and t is 1.

14. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 12, characterized in that, In formula (IIa) or formula (IIa-A), X is selected from a bond, and Y is a broken bond.

15. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 12, characterized in that, Selected from the following groups:

16. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 12, characterized in that, Selected from the following groups:

17. A heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, The heterocyclic derivatives have the structures shown in formulas (IIb-1) and (IIb-2): in: (1) Each R1 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 alkyl, R1′ is selected from H, CN, OH, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl or cyclopropyl, R1″ is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl group; n is 1, 2, 3 or 4; (2) R2 is selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 alkyl; (3) R3 is selected from unsubstituted or substituted groups of the following: saturated heterocyclic group, unsaturated heterocyclic group, saturated carbocyclic group, unsaturated carbocyclic group, heteroaromatic group, aromatic carbocyclic group, wherein the substituent used for substitution is selected from one or more of the following groups: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, oxo, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 2-6 Alkyne group, unsubstituted or substituted 5-10 membered aliphatic heterocyclic group or 5-10 membered heteroaromatic group; (4) A is selected from heteroaryl and aromatic carbocyclic groups; (5) Z is selected from CH or N; (6) The heteroatoms in saturated heterocyclic groups, unsaturated heterocyclic groups, aliphatic heterocyclic groups, and heteroaromatic groups are independently selected from one or more of O, S, N, and oxo.

18. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, 4, or 17, characterized in that, Selected from the following groups:

19. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, 4, 12, or 17, characterized in that, R2 is selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, methyl, ethyl, halomethyl, or haloethyl; and / or, R3 is selected from unsubstituted or substituted aromatic carbocyclic groups, or from unsubstituted or substituted 5-10 membered heterocyclic groups; and / or, The heterocyclic derivatives are the racemic forms, R configurations, or S configurations of the corresponding compounds.

20. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, 4, 12, or 17, characterized in that, R3 is selected from the following groups, whether unsubstituted or substituted: benzene ring, pyrrole, indoin, imidazole, pyrazole, furan, oxazole, isoxazole, thiophene, thiazole, pyridine, quinoline, pyrimidine, indazole, benzothiazole.

21. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, 4, 12, or 17, characterized in that, R3 is selected from 22. The heterocyclic derivative or its stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, The heterocyclic derivatives are selected from the following structures:

23. A pharmaceutical composition comprising a heterocyclic derivative or its stereoisomer as described in any one of claims 1-22, or a pharmaceutically acceptable salt; further, the pharmaceutical composition is an antiviral pharmaceutical composition, further comprising one or more therapeutic agents selected from the following categories: nucleoside analogs, protease inhibitors, non-nucleoside inhibitors, neutralizing antibodies, etc.

24. Use of the heterocyclic derivative or stereoisomer of any one of claims 1-22, a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 23 in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases.

25. Use of the heterocyclic derivative or stereoisomer of any one of claims 1-22, a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 23 in the preparation of a medicament for the prevention and / or treatment of HSV viral infections.

26. The use according to claim 25, characterized in that, The heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 23 as a helicase-primase inhibitor in a medicament for the prevention and / or treatment of HSV viral infection; Furthermore, the HSV virus in the HSV viral infection is HSV-1 or HSV-2; the HSV viral infection includes herpes simplex keratitis, genital herpes, cold sores, herpes simplex encephalitis, disseminated herpes simplex virus, and other diseases or complications caused by HSV viral infection, including Alzheimer's disease and dementia directly related to HSV infection.

27. The use of a heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt thereof as a long-acting compound for the prevention and / or treatment of viral infectious diseases in the preparation of a pharmaceutical composition for the prevention and / or treatment of viral infectious diseases, wherein the pharmaceutical composition has a long-acting effect; further, the pharmaceutical composition comprises an oral formulation, an injectable formulation, or a topical formulation.

Images