TLR Modulators and Their Use

Abstract

This application relates to TLR modulators and their uses. In particular, this application relates to compounds for modulating TLR activity, or their tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharma- ceutically acceptable salts. This application further relates to methods for preparing the compounds of this application and their uses.

Description

[Technical Field]

[0001] Technical Field This application relates to the field of biopharmaceuticals, and in particular to compounds and their uses as TLR modulators. [Background technology]

[0002] background The Toll-like receptor (TLR) family of highly conserved pattern recognition receptor proteins is thought to be involved in innate immunity as a receptor for pathogen-associated molecular patterns (PAMPs). Related compounds that affect TLR activity may have therapeutic implications for diseases including autoimmunity, inflammation, allergy, asthma, transplant rejection, graft-versus-host disease, infectious diseases, cancer, and immunodeficiency. Therefore, there is an urgent need in the art for compounds that can affect TLR activity. Summary of the Invention

[0003] overview The present application provides a compound or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which can have an effect selected from the group consisting of inhibiting tumor growth, affecting Toll-like receptor (TLR) function, and affecting immune system function.

[0004] The present application relates to a compound of formula (II-a): [ka] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0005] In the above formula, R1 and R2 are each independently any group; X1, X2, and X3 are each independently any atom optionally substituted with any group; A is an optionally substituted cyclic structure; W is absent or is an optional group; and B is an optionally substituted aromatic ring, wherein B is substituted with one or more optionally substituted amino groups.

[0006] In another aspect, the present application provides a conjugate comprising a compound of the present application or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a conjugate of the present application, and optionally a pharmaceutically acceptable carrier. In another aspect, the present application provides kits comprising a compound of the present application or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate of the present application, and / or a pharmaceutical composition of the present application. In another aspect, the present application provides a method of affecting the function of a Toll-like receptor (TLR), comprising administering a compound of the present application or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate of the present application, a pharmaceutical composition of the present application, and / or a kit of the present application. In another aspect, the present application provides a method of modulating immune system function, comprising administering a compound of the present application or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate of the present application, a pharmaceutical composition of the present application, and / or a kit of the present application. In another aspect, the present application provides the use of a compound of the present application or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate of the present application, a pharmaceutical composition of the present application, and / or a kit of the present application in the manufacture of a medicament for preventing and / or treating a disease and / or condition. Other aspects and advantages of the present application will become readily apparent to those skilled in the art from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. Those skilled in the art will recognize that the present application will enable them to make changes to the particular embodiments disclosed without departing from the spirit and scope of the invention to which the present application pertains. Accordingly, the description herein is intended to be illustrative rather than limiting. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description Although embodiments of the present invention are described below with reference to specific examples, other benefits and advantages of the present invention will become readily apparent to those skilled in the art from the disclosure herein.

[0008] Definition of Terms In this application, the terms "Toll-like receptor" and "TLR" generally refer to any member of the highly conserved mammalian pattern recognition receptor family that recognizes pathogen-associated molecular patterns (PAMPs) and functions as a key signaling element in innate immunity. TLR polypeptides share a characteristic structure that includes an extracellular domain containing leucine-rich repeats, a transmembrane domain, and an intracellular domain that are involved in TLR signaling. TLRs include, but are not limited to, human TLRs. In this application, the terms "Toll-like receptor 7" and "TLR7" refer to a nucleic acid or polypeptide having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to a published TLR7 sequence, such as the human TLR7 polypeptide of GenBank Accession No. AAZ99026 or the murine TLR7 polypeptide of GenBank Accession No. AAK62676. As used herein, the terms "Toll-like receptor 8" and "TLR8" refer to a nucleic acid or polypeptide having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to a published TLR8 sequence, such as the human TLR8 polypeptide of GenBank Accession No. AAZ95441 or the murine TLR8 polypeptide of GenBank Accession No. AAK62677. In this application, the term "TLR agonist" generally refers to an agent that directly or indirectly binds to a TLR (e.g., TLR7 and / or TLR8) and induces TLR signaling. A detectable difference in TLR signaling can indicate that the agonist stimulates or activates the TLR. Differences in signaling can be manifested by changes in target gene expression, changes in phosphorylation of signaling components, changes in the subcellular localization of downstream elements such as nuclear factor κB (NF-κB), changes in the association of certain components such as IL-1 receptor-associated kinase (IRAK) with other proteins or subcellular structures, or changes in the biochemical activity of components such as kinases (e.g., mitogen-activated protein kinases (MAPKs)). In this application, the term "halogen" generally refers to fluorine, chlorine, bromine or iodine and can be, for example, fluorine or chlorine. In this application, the term "alkyl" generally refers to a residue obtained by removing a hydrogen atom from an alkane. The alkyl may be substituted or unsubstituted, or exchanged or unexchanged. The term "alkyl" generally refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having a residue derived from a parent alkane by removing hydrogen atoms from the same carbon atom or from two different carbon atoms, and may be a straight-chain or branched group containing 1 to 20 carbon atoms, e.g., 1 to 12 carbon atoms, e.g., an alkyl containing 1 to 6 carbon atoms. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, etc. The alkyl may be substituted or unsubstituted, or exchanged or unexchanged. For example, when an alkyl is substituted, substitution with a substituent occurs at any available bonding site, and the substituent is optionally independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo, and the substituent may be, for example, hydrogen, protium, deuterium, tritium, halogen, —NO, —CN, —OH, —SH, —NH, —C(O)H, —COH, —C(O)C(O)H, —C(O)CHC(O)H, —S(O)H, —S(O)H, —C(O)NH, —SONH, —OC(O)H, —N(H)SOH, or C 1-6 It can be an aliphatic group.

[0009] In this application, the term "alkylene" generally refers to a saturated straight-chain or branched-chain aliphatic hydrocarbon group having two residues derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms, and can be a straight-chain or branched group containing 1 to 20 carbon atoms; for example, the term "methylene" can refer to a residue derived from a single carbon atom group by removing two hydrogen atoms. The methylene can be substituted or unsubstituted, or exchanged or unexchanged; for example, alkylene contains 1 to 12 carbon atoms; for example, alkylene contains 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCHCH-), 1,5-butylene (-CHCHCHCHCHCH-), etc. Alkylene may be substituted or unsubstituted, exchanged or unexchanged. For example, when substituted, alkylene may be substituted at any available attachment site with a substituent that may be independently optionally selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo, such as hydrogen, protium, deuterium, tritium, halogen, —NO, —CN, —OH, —SH, —NH, —C(O)H, —COH, —C(O)C(O)H, —C(O)CHC(O)H, —S(O)H, —S(O)H, —C(O)NH, —SONH, —OC(O)H, —N(H)SOH, or C 1-6 It can be an aliphatic group. The methylene or alkylene can be substituted or unsubstituted. In this application, the term "alkenyl" generally refers to a straight-chain or branched-chain hydrocarbon group containing one or more double bonds. Illustrative examples of alkenyl include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, etc. Illustrative examples of C-C6 alkenyl containing one or more double bonds include butadienyl, pentadienyl, hexadienyl, and hexatrienyl, as well as branched forms thereof. The position of the unsaturated bond (double bond) may be at any position on the carbon chain. The alkenyl may be substituted or unsubstituted. In this application, the term "alkenylene" generally refers to a residue derived from an alkene by removing two hydrogen atoms from a carbon atom. For example, alkenylene can be acryl, vinylene, butenylene, pentenylene, hexenylene, etc. Alkenylene can be substituted or unsubstituted. In this application, the term "alkynyl" generally refers to unsaturated straight-chain or branched-chain alkynyl, for example, ethynyl, 1-propynyl, propargyl, or butynyl. Alkynyl may be substituted or unsubstituted. In this application, the term "alkynylene" generally refers to a residue derived from an alkyne by removing two hydrogen atoms from a carbon atom. For example, alkynylene can be ethynylene, propynylene, propargylene, butynylene, etc. Alkynylene can be substituted or unsubstituted.

[0010] In this application, the term "aryl" generally refers to a residue derived from an aromatic ring by removing a hydrogen atom. The term "aromatic ring" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (i.e., rings that share adjacent pairs of carbon atoms) having a conjugated π-electron system, and can be 6 to 10 members, such as benzene and naphthalene. The aromatic ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, in which case the ring connected to the parent structure is an aryl ring. The aryl can be substituted or unsubstituted, and if substituted, the substituents can be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. The aryl can be substituted or unsubstituted.

[0011] In this application, the term "arylene" generally refers to a residue derived from an aromatic ring by removing two hydrogen atoms from a carbon atom. For example, arylene can be phenylene and naphthylene. Arylene can be substituted or unsubstituted. In this application, the term "heteroaryl" generally refers to a residue derived from a heteroaromatic ring by removing a hydrogen atom from a carbon atom. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms can be selected from the group consisting of oxygen, sulfur, and nitrogen. The heteroaryl can be a 5- to 10-membered ring, e.g., a 5- or 6-membered heteroaryl, such as furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, and tetrazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. Heteroaryl can be optionally substituted or unsubstituted, and if substituted, the substituents can be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, carboxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. Heteroaryl can be substituted or unsubstituted. In this application, the term "heteroarylene" generally refers to a residue derived from a heteroaromatic ring by removing two hydrogen atoms from a carbon atom. For example, heteroarylene can be furanylene, thienylene, pyridinylene, pyrrolylene, pyrimidinylene, pyrazinylene, imidazolylene, tetrazolylene, etc. Heteroarylene can be substituted or unsubstituted. In this application, the term "alcyl" generally refers to a residue derived from an aliphatic ring by removing a hydrogen atom from the same carbon atom or from multiple different carbon atoms. The term "cycloalkane" or "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, wherein the carbocyclic ring contains 3 to 20 carbon atoms, can contain 3 to 12 carbon atoms, can contain 3 to 10 carbon atoms, or can contain 3 to 8 carbon atoms. Non-limiting examples of alcyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic carbocyclic rings can include spiro, fused, and bridged carbocyclic rings. Alcyl may be substituted or unsubstituted. In this application, the term "carbocyclyl" generally refers to a residue derived from a carbocyclic ring by removing a hydrogen atom from a carbon atom. The term "carbocycle" generally refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, containing 3 to 20 carbon atoms, including 3 to 12 carbon atoms, 3 to 10 carbon atoms, and 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, and the like, while polycyclic carbocycles include spiro, fused, and bridged carbocycles. Carbocyclyls may be substituted or unsubstituted. In some cases, alicyclic rings and carbocycles are used interchangeably.Cycloalkyl is one or more selected from C1-C6 alkyl, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf, and C(O)NReRf. or with one or more substituents selected from halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl) , —O-phenyl, or phenyl, wherein Re and Rf are each independently selected from H, C-C alkyl, or C-C alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclyl or a 5- or 6-membered nitrogen-containing heteroaryl.

[0012] In this application, the term "partially unsaturated" generally means that the cyclic structure contains at least one double or triple bond within the ring molecule. The term "partially unsaturated" encompasses cyclic structures with multiple sites of unsaturation, but is not intended to include aromatic or heteroaromatic rings as defined herein. The term "unsaturated" means that the moiety has one or more degrees of unsaturation. In this application, the term "alkylene" generally refers to a residue derived from an alicyclic ring by removing two hydrogen atoms from a carbon atom. For example, alkylene can be cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptylene, cycloheptatrienylene, cyclooctylene, etc., and polycyclic carbocycles can include spiro, fused, and bridged carbocycles. alkylene can be substituted or unsubstituted. In this application, the term "aliphatic heterocyclyl" or "heterocyclyl" generally refers to a stable non-aromatic 3- to 12-membered heterocyclyl, such as a 3- to 8-membered, 4- to 8-membered, or 4- to 10-membered heterocyclyl, e.g., a 4- to 8-membered or 4- to 10-membered nitrogen-containing heterocyclyl, preferably a 3- to 7-membered heteromonocyclic structure, a fused 7- to 10-membered heterobicyclic structure, or a bridged 6- to 10-membered heterobicyclic structure. Such cyclic structures may be saturated or partially saturated and further contain one or more heteroatoms in addition to carbon atoms, which heteroatoms may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, the cyclic structure may contain 1 to 4 heteroatoms as defined above. When used to refer to an atom on an aliphatic heterocyclic structure, the term "nitrogen" can include nitrogens that undergo substitution reactions. For example, aliphatic heterocyclyl can include "heterocycloalkyl," which can refer to a stable, non-aromatic 3- to 7-membered monocyclic alkyl structure, a fused 7- to 10-membered heterobicyclic structure, or a bridged 6- to 10-membered heterobicyclic structure. Such ring structures further contain one or more heteroatoms in addition to carbon atoms, which can be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, the ring structure contains 1 to 4 heteroatoms as defined above. Heterocycloalkyl can be substituted or unsubstituted. Aliphatic heterocyclyl can be substituted or unsubstituted. Examples of heterocyclyl include tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl,

[0013] [ka]

[0014] Furthermore, heterocyclyl is one selected from C1-C6 alkyl, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf, and C(O)NReRf. or by one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkylhydroxy, hydroxy, oxo, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-phenyl, or phenyl, wherein Re and Rf are each independently selected from H, C1-C6 alkyl, or C1-C6 alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclyl or a 5- or 6-membered nitrogen-containing heteroaryl. In this application, the term "aliphatic heterocyclylene" generally refers to a residue derived from an alicyclic ring by removing two hydrogen atoms from a carbon atom. The aliphatic heterocyclylene may be substituted or unsubstituted. In this application, the term "ring atom" generally refers to an atom included in a ring structure. For example, a ring atom can be a carbon atom in a benzene ring or a nitrogen atom in a pyridine ring. When a hydrogen atom is bonded to a ring atom, the ring atom can be substituted or unsubstituted. In this application, the term "independently at each occurrence" generally means that a variable applies in each instance, regardless of the presence or absence of variables with the same or different definitions in the same compound. For example, a variable can refer to the type or number of substituents in a compound, the type of atom in a compound, etc. For example, if R appears twice in a compound and R is defined as "independently carbon or nitrogen," then both R can be carbon, both R can be nitrogen, or one R can be carbon and the other R can be nitrogen. In this application, the term "optionally" or "optionally" generally means that the subsequently described event or circumstance may occur, but does not necessarily occur, and that the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclyl group optionally substituted with alkyl" means that alkyl may be present, but is not necessarily present, and that the description can include the heterocyclyl group being substituted or not substituted with alkyl. In this application, the term "substituted" generally means that one or more hydrogen atoms in a group, for example, up to five (e.g., 1 to 3) hydrogen atoms, are each independently replaced with the corresponding number of substituents. Substituents are present only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when bound to a carbon atom having an unsaturated (e.g., olefinic) bond. In this application, the term "zero or more (e.g., zero or one or more, zero or one, or zero) methylene units are replaced" generally means that when a structure contains one or more methylene units, one or more methylene units are not replaced or are replaced by one or more groups that are not methylene (e.g., -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -O-, -S-, -SO-, -SO2-, -PH-, -P(=O)H-, -NHSO2-, -SONH-, -C(=S)-, -C(=NH)-, -N=N-, -C=N-, -N=C-, or -C(=N2)-).

[0015] In this application, the "bond (linkage)" of group X to group Y can generally be in any orientation, which generally means that when group X is used in a linker Y and group Z, the two or more bonding sites of group X can be optionally bonded to either group Y or group Z. In the present application, the term "compound" generally refers to a substance having two or more different elements. For example, the compounds of the present application can be organic compounds. For example, the compounds described herein can be compounds with a molecular weight of 500 or more, or compounds with a molecular weight of 1000 or less, or compounds with a molecular weight of 1000 or more, or compounds with a molecular weight of 10,000 or more, or compounds with a molecular weight of 100,000 or more. In the present application, the term "compound" can also refer to compounds bonded by chemical bonds, for example, compounds in which one or more molecules with a molecular weight of 1000 or less are bonded to a biopolymer via a chemical bond, where the biopolymer can be a polysaccharide, protein, nucleic acid, polypeptide, or the like. For example, the compounds of the present application can be compounds comprising a protein and one or more molecules with a molecular weight of 1000 or less bonded to the protein, compounds comprising a protein and one or more molecules with a molecular weight of 10,000 or less bonded to the protein, or compounds comprising a protein and one or more molecules with a molecular weight of 100,000 or less bonded to the protein. In this application, terms such as "alkyl", "alkenyl" and "cycloalkyl" may be preceded by a designation indicating the number of atoms present in the group under certain circumstances, such as C1-C4 alkyl, C3-C7 cycloalkoxy and C1-C4 alkylcarbonylamino, as known to those skilled in the art, and the subscript following the "C" indicates the number of carbon atoms present in the group. For example, C3 alkyl refers to an alkyl group containing three carbon atoms (e.g., n-propyl or isopropyl). C1- 10 In the formula, the group members can contain any number of carbon atoms in the range of 1 to 10. One or more hydrogen atoms in the group, for example, up to five (e.g., 1 to 3) hydrogen atoms, are each independently replaced with the corresponding number of substituents. Substituents exist only at their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxy group having free hydrogen may be unstable if it is bonded to a carbon atom having an unsaturated (e.g., olefinic) bond. In this application, the compounds of this application include their tautomers, mesomers, racemates, enantiomers, and / or diastereoisomers. In this application, the term "diastereoisomer" generally refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers may have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. In this application, the terms "tautomer" and "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that can be converted into each other by overcoming a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via recombination of some bonding electrons. In this application, the term "mesomer" generally refers to a molecule that contains an asymmetric atom but has a zero total optical rotation due to the presence of symmetry factors. The terms "racemate" or "racemic mixture" mean a composition containing equimolar amounts of two enantiomeric substances.

[0016] In this application, certain atoms of the compounds of this application may exist in one or more isotopic forms. For example, hydrogen is present in protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H), and carbon can exist as three different isotopes ( 12 C. 13 C and 14 Examples of isotopes that can be incorporated into the compounds of the present application include: 15 N, 18 O. 17 O. 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125I or similar isotopes are also included, but are not limited to I. Thus, the compounds of the present application may be enriched in one or more of such isotopes relative to the natural abundance of such isotopes. Such isotopically enriched compounds can be used for various purposes, as known to those skilled in the art. For example, deuterium ( 2 Substitution with heavy isotopes such as H may offer certain therapeutic advantages due to increased metabolic stability. 2 The natural abundance of hydrogen (H) is about 0.015%. Thus, approximately 1 in 6,500 hydrogen atoms is a deuterium atom. Thus, the deuterium abundance at one or more sites (if any) in the deuterium-containing compounds of the present application is greater than 0.015%. Unless otherwise specified, structures depicted herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds having the same structure as those disclosed herein except for the replacement of a hydrogen atom with deuterium or tritium, or the replacement of a carbon atom with carbon-13 or carbon-14, are intended to be within the scope of the present application. In this application, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, as well as other ingredients such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions facilitate administration to an organism and facilitate absorption of the active ingredients, thereby enabling them to exert their biological activity. For the preparation of conventional pharmaceutical compositions, reference can be made to the Chinese Pharmacopoeia. Pharmaceutical compositions can be in the form of sterile aqueous or oily suspensions for injection for intramuscular and subcutaneous administration. Suspensions can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile preparations for injection can also be sterile solutions or suspensions for injection prepared in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol. Furthermore, sterile fixed oils can be conveniently used as solvents or suspending media. For example, any blend of fixed oils, including synthetic monoglycerides or diglycerides, can be used. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injections. In this application, the term "pharmaceutically acceptable salt" generally refers to a salt of a compound or ligand-drug conjugate of the present application, or a salt of a compound described herein. Such salts are safe and / or effective for use in mammals and possess the requisite biological activity, and the antibody-antibody-drug conjugate compounds of the present application can form salts with acids. Non-limiting examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0017] In this application, the term "conjugate" generally refers to a compound prepared by subjecting the compounds of the application to one or more chemical reactions or by linking the compounds to one another via one or more linking structures, such as bridges, spacers, or linkers. In this application, the term "pharmaceutically acceptable carrier" generally refers to a carrier or vehicle for delivering a therapeutic agent, such as an antibody or polypeptide, a gene, or other therapeutic agent. This term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and that can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules, such as proteins, polysaccharides, polylactic acids, polyglycolic acids, poly(amino acids), amino acid copolymers, lipid aggregates, and inactivated virus particles. Such carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol, and ethanol. Auxiliary substances, such as wetting or emulsifying agents, or pH buffering substances, can also be present in these carriers. As used herein, the term "in vivo" generally refers to events that occur within a subject's body. As used herein, the term "in vitro" generally refers to events that occur outside a subject's body. For example, an in vitro assay includes any assay performed outside a subject's body. An in vitro assay includes cell-based assays in which live or dead cells are used. An in vitro assay also includes cell-free assays in which no intact cells are used. As used herein, the terms "treatment" and "treating" generally refer to a method for achieving a beneficial or desired result, including, but not limited to, a therapeutic benefit. A therapeutic benefit includes, but is not limited to, eradicating, suppressing, reducing, or ameliorating the underlying disease being treated. Furthermore, a therapeutic benefit is achieved by eradicating, suppressing, reducing, or ameliorating one or more physiological symptoms associated with the underlying disease, such that the patient experiences improvement, although the patient may still be afflicted by the underlying disease. In this application, the terms "prevention" and "preventing" generally refer to a method for achieving a beneficial or desired result, including, but not limited to, a prophylactic benefit. For prophylactic benefit, pharmaceutical compositions can be administered to patients who are at risk of developing a particular disease or who report having one or more physiological symptoms of the disease, even if the patient has not yet been diagnosed with the disease. In this application, the term "subject" or "patient" generally refers to humans (i.e., males or females of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or the elderly)) and / or other primates (e.g., cynomolgus or rhesus monkeys), mammals (including commercially important mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs), and / or birds (including commercially important birds such as chickens, ducks, geese, quail, and / or turkeys).

[0018] In this application, the terms "comprise," "comprising," "contain," or "containing" are generally intended to include the features expressly specified without excluding other elements. The terms "or more" and "or less" generally refer to a situation in which the number itself is included. In this application, the term "about" generally means a variation of 0.5% to 10% above or below the stated value, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the stated value.

[0019] Detailed Description of the Invention In one embodiment, the present application relates to a compound of formula (II): [ka]

[0020] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0021] In the above formula, R1 and R2 can each independently be any group, X1, X2, and X3 can each independently be any atom optionally substituted with any group, A can be an optionally substituted cyclic structure, W can be absent or can be any group, and B can be an optionally substituted aromatic ring, and B can be substituted with one or more optionally substituted amino groups. For example, substitution with groups including R2 and WB can be located on X1, X2, and / or X3.

[0022] In one embodiment, the present application provides a compound of formula (II-a) [ka] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0023] In the above formula, R1 and R2 can each independently be any group, X1 and X3 can each independently be any atom optionally substituted with any group, A can be an optionally substituted cyclic structure, W can be absent or can be any group, and B can be an optionally substituted aromatic ring, and B can be substituted with one or more optionally substituted amino groups. For example, in compounds comprising the structure of formula (II) or formula (II-a), R1 can be an optionally substituted amino. For example, in compounds comprising the structure of formula (II) or formula (II-a), X1 can be an optionally substituted -CH2-. For example, in a compound having the structure of formula (II) or formula (II-a), X1 may be one or more RX1-1 and may be substituted with one or more R X1-1 can each independently be selected from any group. For example, X can be selected from 1, 2, 3, 4, or 5 R X1-1 can be substituted with For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R X1-1 may each independently be selected from hydrogen and optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. X1-1 When R contains a methylene unit, one or more R X1-1 The methylene units of may be independently unsubstituted or independently substituted with any structure. For example, 1, 2, 3, 4, or 5 R X1-1 Each methylene unit can be independently substituted with any structure. For example, in a compound having a structure of formula (II) or formula (II-a), two R X1-1 can form an optionally substituted cyclic structure together with the atoms to which they are attached. For example, in a compound having a structure of formula (II) or formula (II-a), two R X1-1 can form, together with the atom to which they are attached, an optionally substituted alcyl. For example, in a compound having the structure of formula (II) or formula (II-a), two R X1-1 together with the atom to which they are attached can form an optionally substituted cyclopropyl. For example, in compounds comprising the structure of formula (II), X2 can be selected from optionally substituted -CH- or -N-. For example, in a compound containing the structure of formula (II), X2 is R X2-1 where R X2-1 is selected from any group. For example, in a compound containing the structure of formula (II), R X2-1can be selected from hydrogen and optionally substituted C-C alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl; R X2-1 can contain methylene units, R X2-1 The methylene units of may each independently be unsubstituted or may each independently be substituted with any structure. For example, in a compound containing the structure of formula (II), R X2-1 can include an optionally substituted ethyl. For example, in a compound containing the structure of formula (II), R X2-1 The methylene units that may be contained may be unsubstituted or substituted with C(=O)- and / or optionally substituted -NH-. For example, in a compound containing the structure of formula (II), R X2-1 can contain an optionally substituted -C(=O)NH2.

[0024] For example, in a compound containing the structure of formula (II), R X2-1 may be substituted with -R2 and -WB. For example, -R2 and -WB may be -R2 and -WB in the general formula. For example, R X2-1 For example, if X2 can be substituted with -R2 and -WB, the substitution with -R2 and -WB in the general formula can no longer be located on X1 and / or X3. For example, if X2 can be substituted with -R2 and -WB, the substitution with -R2 and -WB in the general formula can no longer be located on X1 and / or X3. For example, in compounds comprising the structure of formula (II) or formula (II-a), X3 can be selected from optionally substituted -CH- or -N-. For example, in a compound having the structure of formula (II) or formula (II-a), X3 is R X3-1 where R X3-1 is selected from any group. For example, in a compound having a structure of formula (II) or formula (II-a), R X3-1R can be selected from hydrogen and optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. X3-1 can contain methylene units, R X3-1 The methylene units of the formula (I) can each independently be unsubstituted or can each independently be substituted with any structure. For example, in a compound having a structure of formula (II) or formula (II-a), R X3-1 can include an optionally substituted methyl. For example, in a compound having the structure of formula (II) or formula (II-a), each R2 can be independently selected from hydrogen and optionally substituted C1-C6 alkyl, and when R2 can contain a methylene unit, each methylene unit of R2 can be independently unsubstituted or independently substituted with any structure. For example, in compounds comprising the structure of Formula (II) or Formula (II-a), each R2 can be independently selected from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, and optionally substituted pentyl. For example, in compounds comprising the structure of Formula (II) or Formula (II-a), the methylene units of R2 can each independently be unsubstituted or substituted with -O-, -C(=O)-, and / or optionally substituted -NH-.

[0025] For example, in compounds containing the structure of formula (II) or formula (II-a), R2 is optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] is selected from the group consisting of:

[0026] For example, in compounds containing the structure of formula (II) or formula (II-a), R2 is optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0027] For example, in compounds containing the structure of formula (II) or formula (II-a), R2 is optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] is selected from the group consisting of:

[0028] For example, in compounds containing the structure of formula (II) or formula (II-a), R2 is optionally substituted [ka] Possibly replaced [ka] and, optionally, substituted [ka] For example, in the compound having the structure of formula (II) or formula (II-a), R2 is selected from the group consisting of optionally substituted [ka] and, optionally, substituted [ka] is selected from the group consisting of:

[0029] For example, in a compound having the structure of formula (II) or formula (II-a), each R2 independently represents one or more R 2-1 and may be substituted with one or more R 2-1 can be selected from any group. For example, R2 can be 1, 2, 3, 4 or 5 R 2-1 can be substituted with For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R 2-1 may be selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alcyl, and optionally substituted aryl. 2-1 When R contains a methylene unit, one or more R 2-1 Each methylene unit may be independently unsubstituted or independently substituted with any structure. For example, 1, 2, 3, 4, or 5 R 2-1 Each methylene unit may be independently substituted with any structure. For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R 2-1 may be selected from the group consisting of hydrogen, fluorine, optionally substituted methyl, optionally substituted cyclopropyl, and optionally substituted phenyl. For example, in a compound having the structure of formula (II) or formula (II-a), W can be absent or each independently selected from hydrogen and optionally substituted C1-C6 alkylene. When W can contain methylene units, the methylene units of W can each independently be unsubstituted or each independently be substituted with any structure. For example, in compounds comprising the structure of Formula (II) or Formula (II-a), each W can be independently selected from optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted butylene, and optionally substituted pentylene. For example, in compounds comprising the structure of Formula (II) or Formula (II-a), the methylene units of W may each independently be unsubstituted or substituted with -O-, -C(=O)-, and / or optionally substituted -NH-.

[0030] For example, in compounds containing the structure of formula (II) or formula (II-a), W is optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of: For example, in compounds containing the structure of formula (II) or formula (II-a), W is optionally substituted [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0031] For example, in compounds comprising the structure of formula (II) or formula (II-a), B can be selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl. For example, in compounds comprising the structure of Formula (II) or Formula (II-a), B can be selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl. For example, in a compound containing the structure of formula (II) or formula (II-a), B may be one or more R B-1 and optionally substituted with one or more R B-1 can each independently be selected from any group. For example, B can be selected from 1, 2, 3, 4, or 5 R B-1 can be substituted with For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R B-1 may each independently be selected from the group consisting of hydrogen, halogen, and optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. B-1 When R contains a methylene unit, one or more R B-1 The methylene units of R can each independently be unsubstituted or each independently be substituted with any structure. For example, 1, 2, 3, 4, or 5 R B-1 Each methylene unit may be independently substituted with any structure. For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R B-1 may each independently be selected from the group consisting of hydrogen, fluorine, and optionally substituted methyl. For example, in a compound having the structure of formula (II) or formula (II-a), B may be substituted with one or more optionally substituted amino groups, where each of the one or more optionally substituted amino groups may be independently substituted with any structure. For example, B may be substituted with 1, 2, 3, 4, or 5 amino groups. For example, in a compound comprising the structure of Formula (II) or Formula (II-a), B may be substituted with one or more optionally substituted amino groups, wherein the one or more amino groups may each independently be substituted with hydrogen or optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. For example, in compounds comprising the structure of formula (II) or formula (II-a), A can be selected from the group consisting of optionally substituted alcyl, optionally substituted aliphatic heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. For example, in a compound having the structure of formula (II) or formula (II-a), A can be selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl. For example, in a compound having the structure of formula (II) or formula (II-a), A can be selected from optionally substituted phenyl. For example, in a compound containing the structure of formula (II) or formula (II-a), A may be one or more R A-1 and may be substituted with one or more R A-1 can each independently be selected from any group. For example, A can be selected from 1, 2, 3, 4, or 5 R A-1 can be substituted with For example, in a compound having a structure of formula (II) or formula (II-a), R A-1 R can be absent or selected from optionally substituted C1-C6 alkyl. A-1 can contain methylene units, R A-1The methylene units of can each independently be unsubstituted or each independently be substituted with any structure. For example, in a compound having a structure of formula (II) or formula (II-a), R A-1 may be selected from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, or optionally substituted butyl. For example, in a compound having a structure of formula (II) or formula (II-a), R A-1 may comprise a methylene unit that is unsubstituted or substituted by a group selected from the group consisting of -S(=O)-, -C(=O)-, -S(=O)2-, -O-, -S-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkylene, optionally substituted aliphatic heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene. For example, in a compound having a structure of formula (II) or formula (II-a), R A-1is absent or is selected from optionally substituted CH3-, optionally substituted CH(=CH2)-, optionally substituted HC(=O)-, optionally substituted HOC(=O)-, optionally substituted HC(=O)O-, optionally substituted NH2-, optionally substituted HO-, optionally substituted HS-, optionally substituted HS(=O)-, optionally substituted HS(=O)2-, optionally substituted CH3CH2-, optionally substituted CH2=CH-, optionally substituted HC≡C-, optionally substituted HOCH2-, optionally substituted CHO-, optionally substituted CH3NH-, optionally substituted optionally substituted NH2CH2-, optionally substituted HS(=O)2-NH-, optionally substituted NH2-S(=O)2-, optionally substituted HS-CH2-, optionally substituted CH3S-, optionally substituted HS(=O)-CH2-, optionally substituted CH3-S(=O)-, optionally substituted HS(=O)2-CH2-, optionally substituted CH3-S(=O)2-, optionally substituted NHC(=O)-, optionally substituted HC(=O)NH-, optionally substituted HC(=O)CH2-, optionally substituted HC(=O)NHCH2-, optionally substituted CH3NHC(=O)-,

[0032] [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0033] For example, in a compound having a structure of formula (II) or formula (II-a), R A-1 is optionally substituted [ka] may include:

[0034] For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R A-1 are each independently one or more R A-2 and optionally substituted with one or more R A-2 can be independently selected from any group. For example, R A-1 is 1, 2, 3, 4 or 5 R A-2 can be substituted with For example, in a compound having a structure of formula (II) or formula (II-a), R A-2 R may be absent or may be selected from optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. A-2 can contain methylene units, R A-2 The methylene units of may be each independently unsubstituted or each independently substituted with any structure. For example, in a compound having a structure of formula (II) or formula (II-a), R A-2 can contain hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy. For example, in a compound containing the structure of formula (II) or formula (II-a), one or more R A-2 are each independently one or more R A-3 where one or more R A-3 can each independently be selected from any group. For example, in a compound having a structure of formula (II) or formula (II-a), R A-3 may include optionally substituted methyl and / or optionally substituted hydroxy.

[0035] In one embodiment, the present application relates to a compound of formula (II): [ka]

[0036] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0037] wherein R1 can be an optionally substituted amino; X1 can be selected from optionally substituted -CH2-; X2 can be selected from optionally substituted -CH- or -N-; and X2 can be selected from R X2-1 where R X2-1 can contain an optionally substituted —C(═O)NH, and R X2-1 may be substituted with -R2 and -WB, and X3 may be selected from optionally substituted -CH- or -N-;

[0038] R2 is an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] and each R2 can be independently selected from the group consisting of one or more R 2-1 and optionally substituted with one or more R 2-1may be selected from the group consisting of hydrogen, fluorine, optionally substituted methyl, optionally substituted cyclopropyl, and optionally substituted phenyl;

[0039] W is an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] may be selected from the group consisting of

[0040] B can be selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl, and B may be substituted with one or more optionally substituted amino groups; A may be selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl; A is one or more R A-1 where R A-1is absent or optionally substituted CH3-, optionally substituted CH(=CH2)-, optionally substituted HC(=O)-, optionally substituted HOC(=O)-, optionally substituted HC(=O)O-, optionally substituted NH2-, optionally substituted HO-, optionally substituted HS-, optionally substituted HS(=O)-, optionally substituted HS(=O)2-, optionally substituted CH3CH2-, optionally substituted CH2=CH-, optionally substituted HC≡C-, optionally substituted HOCH2-, optionally substituted CHO-, optionally substituted CH3NH-, optionally optionally substituted NH2CH2-, optionally substituted HS(=O)2-NH-, optionally substituted NH2-S(=O)2-, optionally substituted HS-CH2-, optionally substituted CH3S-, optionally substituted HS(=O)-CH2-, optionally substituted CH3-S(=O)-, optionally substituted HS(=O)2-CH2-, optionally substituted CH3-S(=O)2-, optionally substituted NH2C(=O)-, optionally substituted HC(=O)NH-, optionally substituted HC(=O)CH2-, optionally substituted HC(=O)NHCH2-, optionally substituted CH3NHC(=O)-,

[0041] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka]

[0042] It can contain one or more R A-1 are each independently one or more RA-2 where R A-2 can contain hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy, and one or more R A-2 are each independently one or more R A-3 where R A-3 may include optionally substituted methyl and / or optionally substituted hydroxy.

[0043] In one embodiment, the present application provides a compound of formula (II-a) [ka]

[0044] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 can be an optionally substituted amino, X1 can be selected from optionally substituted -CH2-, and X3 can be selected from optionally substituted -CH- or -N-;

[0045] R2 is an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] and each R2 can be independently selected from the group consisting of one or more R 2-1 and wherein said one or more R2-1 may be selected from the group consisting of hydrogen, fluorine, optionally substituted methyl, optionally substituted cyclopropyl, and optionally substituted phenyl; W is an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and optionally substituted [ka] may be selected from the group consisting of

[0046] B can be selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl, and B can be substituted by one or more optionally substituted amino groups; A can be selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl, and A can be selected from the group consisting of one or more R A-1 can be substituted with R A-1is absent or is optionally substituted CH3-, optionally substituted CH(=CH2)-, optionally substituted HC(=O)-, optionally substituted HOC(=O)-, optionally substituted HC(=O)O-, optionally substituted NH2-, optionally substituted HO-, optionally substituted HS-, optionally substituted HS(=O)-, optionally substituted HS(=O)2-, optionally substituted CH3CH2-, optionally substituted CH2=CH-, optionally substituted HC≡C-, optionally substituted HOCH2-, optionally substituted CHO-, optionally substituted CH3NH-, optionally substituted NH2CH2-, optionally substituted HS(=O)2-NH-, optionally substituted NH2-S(=O)2-, optionally substituted HS-CH2-, optionally substituted CH3S-, optionally substituted HS(=O)-CH2-, optionally substituted CH3-S(=O)-, optionally substituted HS(=O)2-CH2-, optionally substituted CH3-S(=O)2-, optionally substituted NH2C(=O)-, optionally substituted HC(=O)NH-, optionally substituted HC(=O)CH2-, optionally substituted HC(=O)NHCH2-, optionally substituted CH3NHC(=O)-,

[0047] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] and

[0048] One or more R A-1 are each independently one or more R A-2 where R A-2 can contain hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy, and one or more R A-2 are each independently one or more R A-3 where R A-3 may include optionally substituted methyl and / or optionally substituted hydroxy. For example, in compounds comprising the structure of formula (II-a), R1 is amino. For example, in a compound comprising the structure of formula (II-a), X1 is -CH2-. For example, in a compound containing the structure of formula (II-a), X3 is -CH=.

[0049] For example, in a compound having the structure of formula (II-a), R2 is [ka] is selected from the group consisting of:

[0050] For example, in a compound comprising the structure of formula (II-a), R2 is [ka] Selected from.

[0051] For example, in a compound comprising the structure of formula (II-a), W is [ka] It can be selected from the group consisting of:

[0052] For example, in a compound having the structure of formula (II-a), W is [ka] Selected from.

[0053] For example, in compounds comprising the structure of formula (II-a), B is selected from phenyl, and B is selected from one or more R B-1 wherein one or more R B-1 can be independently selected from hydrogen, halogen, and C1-C6 alkyl, and preferably R B-1 may each independently be selected from hydrogen, fluorine, and methyl. For example, in a compound comprising the structure of formula (II-a), B is substituted with one or more amino groups, wherein the one or more amino groups may each independently be substituted with hydrogen or C1-C6 alkyl, such as methyl, ethyl, or propyl. For example, in compounds comprising the structure of formula (II-a), A is selected from optionally substituted phenyl or optionally substituted pyridinyl. For example, in a compound comprising the structure of formula (II-a), A is selected from phenyl, and A is selected from one or more R A-1 where one or more R A-1 can each independently be selected from any group. For example, in a compound comprising the structure of formula (II-a), A is selected from pyridinyl, and A is selected from one or more R A-1 where one or more R A-1 can each independently be selected from any group.

[0054] For example, in a compound having the structure of formula (II-a), R A-1 is optionally substituted [ka] Possibly replaced [ka] and optionally substituted NH2C(=O)-.

[0055] For example, in a compound having the structure of formula (II-a), R A-1 is optionally substituted [ka] For example, in a compound having the structure of formula (II-a), R A-1 is optionally substituted [ka] For example, in a compound having the structure of formula (II-a), R A-1 is selected from optionally substituted NH2C(=O)-.

[0056] In one aspect, the present application provides a compound of formula (A): [ka]

[0057] or a tautomer, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, In the above formula, R A-1 is R A2-1 -Lx- selected, Lx is selected from a single bond, C1-C6 alkylene, -O-, -S-, -C(O)-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)-N(C1-C6 alkyl)- or -N(C1-C6 alkylene)-C(O)-; R A2-1 is aryl, heteroaryl or heterocyclyl, preferably phenyl, pyridinyl or isobenzofuranonyl; R A2-1 is one or more substituents R A2-2 and optionally substituted by R A2-2are each independently C1-C6 alkyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, or -C(O)NR e R f Selected from R e and R f are each independently selected from H or C1-C6 alkyl, or R e and R f together with the nitrogen atom to which they are attached form a 5- or 6-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl or piperidinyl, said 5- or 6-membered nitrogen-containing heterocyclyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, oxo, amino, —NH(C1-C6 alkyl) or —N(C1-C6 alkyl)2; or R A2-1 is phenyl, 5- to 6-membered heteroaryl, or isobenzofuranonyl; R A2-1 optionally containing one or more substituents R A2-2 is substituted with R A2-2 are each independently C1-C6 alkyl, cyano, amino, -COOH, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkylphenyl, -phenyl, -O-phenyl, C 3-6 Cycloalkyl, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NR e R f , -C(O)NR e R f, or -NR e R f Selected from R e and R f are each independently selected from H, C1-C6 alkyl, or —C1-C6 alkylhydroxy, or R e and R f are, together with the nitrogen atom to which they are attached, selected from a 4- to 8-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4- to 8-membered nitrogen-containing heterocyclyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, oxo, amino, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; or R A-1 is N(R AN-1 )(R AN-2 )C(O)-, R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, -C1-C6 alkylhydroxy, halogenated C1-C6 alkyl, -C1-C6 alkyl-C1-C6 alkoxy, -C1-C6 alkyl-phenyl, -phenyl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, -C 3-6 cycloalkyl-phenyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl; phenyl, 5- to 10-membered heteroaryl, C 3-6Cycloalkyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl are each independently optionally substituted by one or more substituents, such as C1-C6 alkyl, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, and -S(O)2NR e R f , or -C(O)NR e R f Selected from R e and R f are each independently selected from H, C1-C6 alkyl, or —C1-C6 alkylhydroxy; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl,

[0058] [ka]

[0059] wherein the 4-10-membered nitrogen-containing heterocycle is optionally substituted by one or more substituents independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkylhydroxy, hydroxy, oxo, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -O-phenyl, and phenyl; R2 is selected from -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 alkylenehydroxy, or halogenated C1-C6 alkyl, or R2 is -C1-C6 alkyl-cyclopropyl; W is selected from -C1-C6 alkylene- and -O-C1-C6 alkylene-, preferably W is

[0060] [ka]

[0061] Selected from B is phenyl, optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy; and Z is -NH(R Z-1 ) and R Z-1 is selected from H, —C1-C6 alkyl, or halogenated C1-C6 alkyl.

[0062] In one preferred embodiment, R A-1 is RA 2-1 or N(R AN-1 )(R AN-2 )C(O)-. R A2-1 is phenyl, 5- to 6-membered heteroaryl or isobenzofuranonyl, preferably phenyl, pyridinyl or isobenzofuranonyl, and R A2-1 is one or more substituents R A2-2 where R A2-2 are each independently C1-C6 alkyl, cyano, amino, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkylphenyl, -phenyl, -O-phenyl, C 3-6Cycloalkyl, -C1-C6 alkyl, -C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated selected from C-C alkoxy, —S(O)C-C alkyl, —S(O)C-C alkyl, —S(O)NReRf, —C(O)NReRf, or NReRf, where Re and Rf are each independently selected from H, C-C alkyl, or C-C alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclyl such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4-8 membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl)2, —O-phenyl, and phenyl; R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, -C1-C6 alkylhydroxy, halogenated C1-C6 alkyl, -C1-C6 alkyl-C1-C6 alkoxy, -C1-C6 alkyl-phenyl, -phenyl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, -C 3-6 cycloalkyl-phenyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl; phenyl, 5- to 10-membered heteroaryl, C 3-6Cycloalkyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents, such as hydrogen, C1-C6 alkyl, cyano, amino, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C1-C6 alkylamino, —C1-C6 alkyl-NH(C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, —C1 selected from -C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf, or -C(O)NReRf, where Re and Rf are each independently selected from H, C1-C6 alkyl, or -C1-C6 alkylhydroxy; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl,

[0063] [ka]

[0064] wherein the 4-10 membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; R2 is selected from -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 alkylenehydroxy, -C1-C6 alkyl-cyclopropyl or halogenated -C1-C6 alkyl, preferably R2 is

[0065] [ka]

[0066] More preferably, R2 is selected from [ka]

[0067] Selected from W is selected from -C1-C6 alkylene and -O-C1-C6 alkylene, preferably W is [ka] Selected from

[0068] B is phenyl, optionally substituted with one or more substituents selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy; preferably, B is phenyl and Z is -NH(R Z-1 ) where R Z-1 is selected from H, —C1-C6 alkyl and halogenated C1-C6 alkyl, preferably R Z-1 is selected from H, CH3 and -CH2CH3, more preferably R Z-1 is selected from H.

[0069] For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is R A2-1 or N(R AN-1 )(R AN-2 )C(O)-; R A2-1 is phenyl, pyridinyl or isobenzofuranonyl, R A2-1 optionally, one or more substituents R A2-2 where R A2-2are each independently selected from hydrogen, C-C alkyl, cyano, amino, —C-C alkylamino, halogen, halogenated C-C alkyl, —C-C alkylhydroxy, —S(O)C-C alkyl, —S(O)NReRf, —C(O)NReRf, or NReRf, where Re and Rf are each independently selected from H, C-C alkyl, or C-C alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4-8 membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, C-C alkyl, C-C alkoxy, or C-C alkylhydroxy; R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylhydroxy, phenyl, pyridinyl, C 3-6 cycloalkyl and 4- to 6-membered heterocyclyl, and 3-6 The cycloalkyl and 4- to 6-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, and C1-C6 alkyl, or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, or C1-C6 alkylhydroxy.

[0070] For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is RA2-1 and R A2-1 is phenyl and R A2-1 optionally one or more substituents R A2-2 where R A2-2 are each independently selected from hydrogen, C-C alkyl, cyano, amino, —C-C alkylamino, halogen, halogenated C-C alkyl, —C-C alkylhydroxy, —S(O)C-C alkyl, —S(O)NReRf, —C(O)NReRf, or —NReRf, where Re and Rf are each independently selected from H, C-C alkyl, or —C-C alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4- to 8-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, C-C alkyl, C-C alkoxy, or C-C alkylhydroxy. For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is RA 2-1 and R A2-1 is phenyl and R A2-1 optionally one or more substituents R A2-2 where R A2-2 are each independently selected from -C(O)NReRf and -S(O)2NReRf, where Re and Rf together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4- to 8-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, or -C1-C6 alkylhydroxy.

[0071] For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is R A2-1 and R A2-1 is pyridinyl and R A2-1 optionally one or more substituents R A2-2 where R A2-2 are each independently selected from hydrogen, C-C alkyl, cyano, amino, —C-C alkylamino, halogen, halogenated C-C alkyl, —C-C alkylhydroxy, —S(O)C-C alkyl, —S(O)NReRf, —C(O)NReRf, or —NReRf, where Re and Rf are each independently selected from H, C-C alkyl, or —C-C alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which 4- to 8-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, C-C alkyl, C-C alkoxy, or C-C alkylhydroxy. For example, in one embodiment, there is provided a compound of formula (A), or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is RA 2-1 and R A2-1 is pyridinyl and R A2-1 optionally one or more substituents R A2-2 where R A2-2are each independently selected from hydrogen, C-C alkyl, cyano, amino, —C-C alkylamino, halogen, halogenated C-C alkyl, —C-C alkylhydroxy, —S(O)C-C alkyl, —S(O)NReRf, or —NReRf, where Re and Rf together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, or —C-C alkylhydroxy. For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: R A-1 is N(R AN-1 )(R AN-2 )C(O)—, R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylhydroxy, phenyl, pyridinyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl, and 3-6 The cycloalkyl and 4- to 6-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, and C1-C6 alkyl; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, or -C1-C6 alkylhydroxy. For example, in one embodiment, there is provided a compound of formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: In the above formula, R A-1 is N(R AN-1 )(R AN-2 )C(O)—, R AN-1 and R AN-2 are each independently H, pyridinyl, C 3-6 cycloalkyl and 5- to 7-membered heterocyclyl, where pyridinyl, C 3-6 The cycloalkyl and 5- to 7-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, C1-C6 alkyl, or -C1-C6 alkylhydroxy; R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, oxo, amino, or -C1-C6 alkylhydroxy.

[0072] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, R A-1 is R A2-1 or N(R AN-1 )(R AN-2 )C(O)-; R A2-1 teeth,

[0073] [ka] Selected from R A2-2 , RAN-1 and R AN-2 are each independently as defined in formula (A) above.

[0074] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, R A-1 is R A2-1 or N(R AN-1 )(R AN-2 )C(O)-; R A2-1 teeth, [ka] Selected from R A2-2 , R AN-1 and R AN-2 are each independently as defined in any one of formulas (A).

[0075] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, R A-1 is R A2-1 or N(R AN-1 )(R AN-2 )C(O)-; R A2-1 teeth, [ka] Selected from R A2-2 , R AN-1 and R AN-2 are each independently as defined in any one of formulas (A).

[0076] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, B is [ka] Selected from, and R Z-1 is selected from H or -C1-C6 alkyl, preferably R Z-1 is selected from H, CH or -CHCH, more preferably R Z-1 is selected from H.

[0077] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, B is [ka] Selected from.

[0078] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, -WB is [ka] Selected from, and R Z-1 is selected from H or -C1-C6 alkyl, preferably R Z-1 is selected from H, CH3 or -CH2CH3, more preferably R Z-1 is selected from H.

[0079] For example, in a compound of formula (II-a) or formula (A) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, -WB is [ka] Selected from.

[0080] In some embodiments, a compound of the invention or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, is [ka]

[0081] [ka]

[0082] Selected from R A2-2 are each independently C1-C6 alkyl, cyano, amino, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkylphenyl, -phenyl, -O-phenyl, C 3-6 selected from cycloalkyl, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf, -C(O)NReRf or NReRf, wherein Re and Rf are each independently selected from H, C1-C6 alkyl or C1-C6 alkylhydroxy, or Re and Rf together with the nitrogen atom to which they are attached are to form a 4-8 membered nitrogen-containing heterocyclyl such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein the 4-8 membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxy, oxo, amino, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, -C1-C6 alkylhydroxy, halogenated C1-C6 alkyl, -C1-C6 alkyl-C1-C6 alkoxy, -C1-C6 alkyl-phenyl, -phenyl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, -C 3-6 cycloalkyl-phenyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl; phenyl, 5- to 10-membered heteroaryl, C 3-6 The cycloalkyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents, such as C1-C6 alkyl, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, - selected from C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf or C(O)NReRf, where Re and Rf are each independently selected from H, C1-C6 alkyl or C1-C6 alkylhydroxy; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl,

[0083] [ka] wherein the 4-10-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; R2 is selected from -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 alkylenehydroxy, -C1-C6 alkyl-cyclopropyl or halogenated C1-C6 alkyl, preferably R2 is

[0084] [ka] More preferably, R2 is selected from

[0085] [ka] Selected from R Z-1 is selected from H, —C1-C6 alkyl, and halogenated C1-C6 alkyl, preferably R Z-1 is selected from H, CH3 and CH2CH3, more preferably R Z-1 is selected from H.

[0086] For example, in the compounds of formulae (II-a-1) to (II-a-25), or tautomers, enantiomers or diastereoisomers thereof, or mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, R Z-1 , R2, R A2-2 , R AN-1 and R AN-2 are each independently as defined in any one of formulas (A). For example, in a compound of formula (II-a), formula (A), or formulas (II-a-1) to (II-a-25), or a tautomer, enantiomer, or diastereoisomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof,

[0087] R A-1 teeth, [ka]

[0088] [ka] Selected from.

[0089] In one particularly preferred embodiment, the present invention provides [ka]

[0090] [ka] or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0091] In one particularly preferred embodiment, the present invention provides [ka] [ka]

[0092] [ka] [ka]

[0093] [ka]

[0094] or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0095] This application is [ka]

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] [ka]

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure that can be selected from the group consisting of:

[0104] In one aspect, the present application provides a compound of formula (C) or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0105] In the above formula, R A-1 is R A2-1 or N(R AN-1 )(R AN-2 )C(O)-; R A2-1 is phenyl, 5- to 6-membered heteroaryl or isobenzofuranonyl, preferably phenyl, pyridinyl or isobenzofuranonyl, and R A2-1 is one or more substituents R A2-2 where R A2-2 are each independently C1-C6 alkyl, cyano, amino, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkylphenyl, -phenyl, -O-phenyl, C 3-6selected from cycloalkyl, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf, -C(O)NReRf or -NReRf, wherein Re and Rf are each independently selected from H, C1-C6 alkyl or -C1-C6 alkylhydroxy, or Re and Rf are substituted with the nitrogen atom to which they are attached. together form a 4- to 8-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, wherein the 4- to 8-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; R AN-1 and R AN-2 are each independently H, C1-C6 alkyl, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, -C1-C6 alkylhydroxy, halogenated C1-C6 alkyl, -C1-C6 alkyl-C1-C6 alkoxy, -C1-C6 alkyl-phenyl, -phenyl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, -C 3-6 cycloalkyl-phenyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl; phenyl, 5- to 10-membered heteroaryl, C 3-6Cycloalkyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents, such as hydrogen, C1-C6 alkyl, cyano, amino, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C1-C6 alkylamino, —C1-C6 alkyl-NH(C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, —C selected from 1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)2NReRf or -C(O)NReRf, where Re and Rf are each independently selected from H, C1-C6 alkyl or -C1-C6 alkylhydroxy; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl,

[0106] [ka] wherein the 4-10 membered nitrogen-containing heterocycle is optionally substituted with one or more substituents independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, —C-C alkylhydroxy, hydroxy, oxo, amino, —NH(C-C alkyl), —N(C-C alkyl), —O-phenyl, and phenyl; R2 is selected from -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 alkylenehydroxy, -C1-C6 alkyl-cyclopropyl, or halogenated C1-C6 alkyl, preferably R2 is

[0107] [ka] More preferably, R2 is selected from

[0108] [ka] and W is selected from -OH.

[0109] In one particularly preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. [ka] or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0110] In one embodiment, the present application provides a compound of formula (II-a) [ka]

[0111] or a conjugate thereof, or an isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, having the structure: In the above formula, R1 is optionally substituted amino; X1 is selected from optionally substituted -CH2-; X3 is selected from optionally substituted -CH= or -N=; R2 is selected from hydrogen and optionally substituted C1-C6 alkyl, and when R2 contains methylene units, the methylene units of R2 are each independently unsubstituted or each independently substituted with any structure; W is absent or selected from optionally substituted C1-C6 alkyl, and if W contains methylene units, the methylene units of W are each independently unsubstituted or each independently substituted with any structure; B is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; B is substituted with one or more optionally substituted amino groups, wherein the one or more amino groups are each independently substituted with hydrogen or optionally substituted C1-C6 alkyl; Ring A is selected from optionally substituted alcyl, optionally substituted aliphatic heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; Ring A is m R A-1 may be substituted with R A-1 are each independently selected from any group, and m is selected from 1, 2, 3, 4, or 5. In some embodiments, in the structure of formula (II-a), R 1 is —NH 2 . In some embodiments, in the structure of formula (II-a), X1 is -CH2- or [ka] Selected from.

[0112] In some embodiments, in the structure of formula (II-a), X3 is selected from -CH= or -C(CH3)=. In some embodiments, in the structure of formula (II-a), R2 is 1, 2, or 3 R 2-1 C1-C6 alkyl optionally substituted with R 2-1 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each independently selected from 1, 2, or 3 R 2-2 optionally substituted with R 2-2 are each independently selected from hydrogen, halogen, hydroxy, or amino, wherein each methylene unit of R is independently unsubstituted, substituted with —O—, or substituted with —N(R 2-3 )- and R 2-3 is selected from hydrogen or C1-C3 alkyl.

[0113] In some embodiments, in the structure of formula (II-a), R2-1 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3 or [ka] Selected from.

[0114] In some embodiments, in the structure of formula (II-a), R2 is [ka]

[0115] wherein each methylene unit of R2 is independently unsubstituted, substituted with -O-, or substituted with -NH-.

[0116] In some embodiments, in the structure of formula (II-a), R2 is [ka] For example, R2 is selected from [ka] Selected from.

[0117] In some embodiments, in the structure of Formula (II-a), W is selected from C-C alkyl optionally substituted with 1, 2, or 3 R; w-1 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each independently selected from 1, 2, or 3 R w-2 optionally substituted with R w-2 are each independently selected from hydrogen, halogen, hydroxy, or amino; Each methylene unit of W is independently unsubstituted, substituted with —O—, or substituted with —N(R w-3)-, where R w-3 is selected from hydrogen or C1-C3 alkyl.

[0118] In some embodiments, in the structure of formula (II-a), R w-1 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3 or

[0119] [ka] Selected from.

[0120] In some embodiments, in the structure of formula (II-a), W is [ka] wherein each methylene unit of W is independently unsubstituted, substituted with —O—, or substituted with —NH—.

[0121] In some embodiments, in the structure of formula (II-a), W is [ka] For example, W is selected from

[0122] [ka] Selected from.

[0123] In some embodiments, in the structure of Formula (II-a), B is selected from phenyl and pyridinyl, and phenyl and pyridinyl are each independently selected from 1, 2, or 3 R B-1 optionally substituted with R B-1 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-C3 alkyl, and C1-C3 alkoxy.

[0124] In some embodiments, in the structure of formula (II-a), B is [ka] Preferably, B is selected from

[0125] [ka] For example, is selected from

[0126] [ka] Selected from.

[0127] In some embodiments, in the structure of Formula (II-a), A 1 is selected from phenyl, pyridinyl, pyrrolyl, thienyl, furanyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, in the structure of formula (II-a), A is selected from phenyl and pyridinyl. For example, ring A is selected from phenyl. For example, ring A is selected from pyridinyl.

[0128] In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx-, Lx is -(CH2) t -, -(CH2) t O-, -O(CH2) t -, -(CH2) t N(R L-1 )-, -(CH2) t S-, -(CH2) t C(=O)-, -(CH2) t N(R L-1 )C(=O)-,

[0129] [ka]

[0130] Selected from R L-1 is selected from H or C1-C3 alkyl, and t is selected from 0, 1, 2, or 3; R A2-1 are selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, arcyl, aliphatic heterocyclyl, aryl, and heteroaryl, wherein C1-C6 alkyl, arcyl, aliphatic heterocyclyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R A2-2 optionally substituted with R A2-2 is selected from hydrogen, halogen, hydroxy, amino and C1-C6 alkyl, and 1, 2 or 3 R A2-3 optionally substituted with R A2-3 are each independently selected from hydrogen, halogen, hydroxy, amino, and C1-C3 alkyl; R A2-1 Any methylene unit may have the following structures: -O-, -S-, -S(=O)2-, -NH-, -CO-,

[0131] [ka] and optionally substituted by m is selected from 1, 2 or 3; In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx-, where Lx is a single bond or -NHC(=O)-. In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx- and R A2-1 are each independently hydrogen, halogen, hydroxy, amino, cyano or C1-C6 alkyl,

[0132] [ka] and one, two or three R A2-2optionally substituted with R A2-1 Any methylene unit may have the following structures: -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -C(O)-,

[0133] [ka] can be substituted with

[0134] In some embodiments, in the structure of formula (II-a), R A-1 represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, sulfhydryl, -CH3, -CH(=O), -C(=O)OH, -OCH(=O), -SH(=O), -SH(=O)2, -CH2CH3, -CH2OH, -OCH3, -NHCH3, -CH2NH2, -S(=O)2NH2, -NHSH(=O)2, -SCH3, -CH2SH, -S(=O)CH3, -CH2SH(=O), -S(=O)2CH3, -CH2SH(=O)2, -NHCH(=O), -C(=O)NH2, -CH2CH(=O), -CH2NHCH(=O), -C(=O)NHCH3,

[0135] [ka]

[0136] [ka] [ka] Selected from.

[0137] In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx-, where Lx is a single bond, and R A2-1 each independently represents 1, 2 or 3 R A2-2phenyl and pyridinyl optionally substituted with R A2-2 is selected from hydrogen, halogen, hydroxy, amino and C1-C6 alkyl, and 1, 2 or 3 R A2-3 optionally substituted with R A2-3 are each independently selected from hydrogen, halogen, hydroxy and amino, preferably R 2A-1 teeth,

[0138] [ka]

[0139] More preferably, R A-1 teeth, [ka] Selected from.

[0140] In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx-, where Lx is a single bond, and R A2-1 teeth [ka] Preferably, R A2-2 is -CH2OH.

[0141] In some embodiments, in the structure of formula (II-a), R A-1 is R A2-1 -Lx-, Lx is -NHC(=O)-, and R A2-1 each independently represents 1, 2 or 3 R A2-2 phenyl and pyridinyl optionally substituted with R A2-2 is selected from hydrogen, halogen, hydroxy, amino and C1-C6 alkyl, and 1, 2 or 3 R A2-3 optionally substituted with R A2-3 are each independently selected from hydrogen, halogen, hydroxy and amino, preferably R2A-1 teeth,

[0142] [ka] More preferably, R 2A-1 teeth,

[0143] [ka] Selected from.

[0144] In one aspect, the present application provides a compound of formula (A), or a tautomer, enantiomer or diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0145] In the above formula, R A-1 is R A2-1 -Lx- Selected from Lx is selected from a single bond, C1-C6 alkylene, -O-, -S-, -C(O)-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)-N(C1-C6 alkyl)-, or -N(C1-C6 alkylene)-C(O)-, preferably Lx is selected from a single bond, -C(O)NH-, or -NHC(O)-; R A2-1 is aryl, heteroaryl or heterocyclyl, preferably phenyl, pyridinyl or isobenzofuranonyl, R A2-1 is one or more substituents R A2-2 where R A2-2are each independently selected from C-C alkyl, amino, —NH(C-C alkyl), —N(C-C alkyl)2, —C-C alkylamino, —C-C alkyl-NH(C-C alkyl), —C-C alkyl-N(C-C alkyl)2, hydroxy, —C-C alkoxy, —C-C alkylhydroxy, —C-C alkyl-C-C alkoxy, halogen, halogenated C-C alkyl, halogenated C-C alkoxy, or —C(O)NReRf, where Re and Rf are each independently selected from H or C-C alkyl, or Re and Rf together with the nitrogen atom to which they are attached form a 5- or 6-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl or piperidinyl, which 5- or 6-membered nitrogen-containing heterocyclyl is optionally substituted by one or more substituents independently selected from C-C alkyl, C-C alkoxy, hydroxy, oxo, amino, —NH(C-C alkyl) or —N(C-C alkyl) R2 is selected from -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 alkylenehydroxy, or halogenated C1-C6 alkyl; W is selected from -C1-C6 alkylene- and -O-C1-C6 alkylene-; B is phenyl, optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy; and Z is -NH(R Z-1 ) and R Z-1 is selected from H, —C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0146] In some embodiments, the compound or a conjugate thereof, or an isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof is [ka] [ka]

[0147] Selected from R Z-1 is selected from H or C1-C6 alkyl optionally substituted with 1, 2 or 3 fluorine, chlorine, bromine, iodine, hydroxy or amino; R2 is 1, 2 or 3 R 2-1 C1-C6 alkyl optionally substituted with R 2-1 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, and C3-C6 cycloalkyl, and C1-C6 alkyl and C3-C6 cycloalkyl are each independently selected from 1, 2, or 3 R 2-2 optionally substituted with R 2-2 are each independently selected from hydrogen, halogen, hydroxy, or amino, and the methylene units of R are each independently unsubstituted, substituted with —O—, or substituted with —N(R 2-3 )- and R 2-3 is selected from hydrogen or C1-C3 alkyl; W is 1, 2 or 3 R w-1 C1-C6 alkyl optionally substituted with R w-1 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, and C3-C6 cycloalkyl, and C1-C6 alkyl and C3-C6 cycloalkyl are each independently selected from 1, 2, or 3 R w-2 optionally substituted with R w-2 are each independently selected from hydrogen, halogen, hydroxy, or amino, and the methylene units of W are each independently unsubstituted, substituted with —O—, or substituted with —N(R w-3 )- and R w-3 is selected from hydrogen or C1-C3 alkyl; R A-1 is R A2-1 -Lx- Selected from Lx is selected from a single bond, C1-C6 alkylene, -O-, -S-, -C(O)-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)-N(C1-C6 alkyl)- or -N(C1-C6 alkylene)-C(O)-; R A2-1 is aryl, heteroaryl or heterocyclyl, preferably phenyl, pyridinyl or isobenzofuranonyl, R A2-1 is one or more substituents R A2-2 optionally replaced by R A2-2 are each independently selected from -C1-C6 alkyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkylamino, -C1-C6 alkyl-NH(C1-C6 alkyl), -C1-C6 alkyl-N(C1-C6 alkyl)2, hydroxy, -C1-C6 alkoxy, -C1-C6 alkylhydroxy, -C1-C6 alkyl-C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, or -C(O)NReRf, where Re and Rf are each independently selected from H or C1-C6 alkyl, or Re and Rf together with the nitrogen atom to which they are attached form a 5- or 6-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl or piperidinyl, which 5- or 6-membered nitrogen-containing heterocyclyl is optionally substituted by one or more substituents independently selected from C-C alkyl, C-C alkoxy, hydroxy, oxo, amino, —NH(C-C alkyl), or —N(C-C alkyl).

[0148] In some preferred embodiments of the present invention, in the structures of formulae (II-1A-1), (II-1A-2), (II-1A-3), (II-1A-4), (II-1A-5), and (II-1A-6), R Z-1 , R2, W and R A-1 is as defined in any embodiment of formula (A) or (II-a) of the present application.

[0149] In one particularly preferred embodiment, the present invention provides a compound of formula (A), or a tautomer, enantiomer, diastereoisomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt or solvate thereof, selected from:

[0150] [ka]

[0151] In one aspect, the present application provides a compound that can include the structure of formula (III) or a tautomer, mesonomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0152] wherein R1 and R2 can each independently be any group; X1, X2, and X3 can each independently be any atom optionally substituted with any group; A is an optionally substituted cyclic structure; [ka]

[0153] represents a single bond or a double bond, X3 is not N and R2 may be substituted with one or more optionally substituted amino groups. For example, in compounds comprising the structure of formula (III), R1 can be an optionally substituted amino group. For example, in compounds comprising the structure of formula (III), X1 can be selected from -N= and O-. For example, in compounds comprising the structure of formula (III), X2 can be selected from the group consisting of optionally substituted CH= and optionally substituted NH-. For example, in a compound containing the structure of formula (III), X2 is R X2-1 may be substituted with RX2-1 can be independently selected from any group.

[0154] For example, in a compound containing the structure of formula (III), R X2-1 R can be selected from hydrogen and optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl. X2-1 can contain methylene units, R X2-1 The methylene units may each independently be unsubstituted or may each independently be substituted with any structure. For example, in a compound containing the structure of formula (III), R X2-1 may include optionally substituted butyl. For example, in a compound containing the structure of formula (III), R X2-1 The methylene units that may be contained may be unsubstituted or substituted with O-. For example, in a compound containing the structure of formula (III), R X2-1 may include an optionally substituted -(CH2)3-CH3 or an optionally substituted -CH2-O-CH2-CH3. For example, in compounds comprising the structure of formula (III), X3 can be selected from the group consisting of -O-, -S-, and optionally substituted -CH=. For example, in compounds containing the structure of formula (III), A can include an optionally substituted aromatic ring. For example, in compounds containing the structure of formula (III), A can include an optionally substituted benzene ring. For example, in compounds comprising the structure of formula (III), R2 is selected from hydrogen and optionally substituted C1-C 10 When R2 can contain methylene units, the methylene units of R2 can each independently be unsubstituted or each independently be substituted with any structure. For example, in compounds comprising the structure of formula (III), R2 is an optionally substituted C1-C 10 It can contain alkyl-NH2. When R2 can contain methylene units, each methylene unit of R2 can be independently unsubstituted or independently substituted with any structure. For example, in compounds comprising the structure of formula (III), R2 can comprise an optionally substituted propyl, an optionally substituted butyl, an optionally substituted pentyl, or an optionally substituted hexyl. For example, in compounds comprising the structure of formula (III), the methylene units that R2 may comprise may be unsubstituted or substituted with a group that may be selected from the group consisting of -O-, optionally substituted -NH-, optionally substituted alkylene, and optionally substituted arylene.

[0155] For example, in a compound comprising the structure of formula (III), R2 is Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] optionally substituted, [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0156] For example, in a compound comprising the structure of formula (III), R2 is Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0157] For example, in a compound comprising the structure of formula (III), R2 is Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0158] For example, in a compound containing the structure of formula (III), R2 can be one or more R 2-1 and optionally substituted with one or more R 2-1 may each independently be selected from any group. For example, R2 may be 1, 2, 3, 4, or 5 R 2-1 can be substituted with For example, in a compound comprising the structure of formula (III), one or more R 2-1 may each independently be selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl, for example, optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl; R 2-1 can contain methylene units, R 2-1 Each methylene unit in R may be independently unsubstituted or independently substituted with any structure. For example, 1, 2, 3, 4, or 5 R 2-1 Each methylene unit may be independently substituted with any structure. For example, in a compound comprising the structure of formula (III), one or more R 2-1 may each independently be selected from the group consisting of hydrogen, optionally substituted ethyl, and optionally substituted acetyl. For example, in a compound containing the structure of formula (III), A may be one or more R A-1 wherein one or more R A-1 can each independently be selected from any group. For example, A can be selected from 1, 2, 3, 4, or 5 R A-1 can be substituted with For example, in a compound containing the structure of formula (III), R A-1 can be selected from the group consisting of hydrogen, halogen, optionally substituted amino, optionally substituted hydroxy, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R A-1 can contain methylene units, R 2-1 The methylene units of may each independently be unsubstituted or each independently be substituted with any structure.

[0159] For example, in a compound containing the structure of formula (III), R A-1 is an optionally substituted NH2C(=O)-, an optionally substituted HC(=O)NH-, an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] It can be selected from the group consisting of:

[0160] For example, in a compound containing the structure of formula (III), R A-1 contains hydrogen. For example, in a compound comprising the structure of formula (III), one or more R A-1 are each independently one or more R A-2 and optionally substituted with one or more R A-2 can be independently selected from any group. For example, R A-1 is 1, 2, 3, 4 or 5 R A-2 may be substituted with For example, in a compound containing the structure of formula (III), R A-2 may be absent or may be selected from optionally substituted C1-C6 alkyl, such as optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl; R A-2 can contain methylene units, R A-2 The methylene units of may each independently be unsubstituted or may each independently be substituted with any structure. For example, in a compound containing the structure of formula (III), R A-2 can contain hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy. For example, in a compound comprising the structure of formula (III), one or more R A-2are each independently one or more R A-3 wherein one or more R A-2 can be independently selected from any group. For example, X1 can be selected from 1, 2, 3, 4, or 5 R A-3 may be substituted with For example, in a compound containing the structure of formula (III), R A-3 may include optionally substituted methyl and / or optionally substituted hydroxy.

[0161] In one aspect, the present application provides a compound that can include the structure of formula (III) or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0162] wherein R1 can be an optionally substituted amino; X1 can be selected from the group consisting of -N= and -O-; X2 can be selected from the group consisting of optionally substituted -CH= and optionally substituted -NH-; and X2 can be selected from the group consisting of R X2-1 may be substituted with R X2-1 may comprise an optionally substituted —(CH)—CH or an optionally substituted —CH—O—CH—CH; X may be selected from the group consisting of —O—, —S—, and optionally substituted —CH═; A can include an optionally substituted benzene ring, and R2 can be an optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] A can be selected from the group consisting of one or more R A-1 may be substituted with R A-1 is optionally substituted NHC(=O)-, optionally substituted HC(=O)NH-, optionally substituted [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] Possibly replaced [ka] and, optionally, substituted [ka] may contain one or more RA-1 are each independently one or more R A-2 is replaced by R A-2 can contain hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy, and one or more R A-2 are each independently one or more R A-3 where R A-3 may include optionally substituted methyl and / or optionally substituted hydroxy; R2 is one or more R 2-1 wherein one or more R 2-1 may each independently be selected from the group consisting of hydrogen, optionally substituted ethyl, and optionally substituted acetyl.

[0163] The present application provides a compound comprising the structure, which may be selected from the group consisting of: or a tautomer, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof:

[0164] [ka] [ka]

[0165] In one aspect, the present application provides conjugates that can include a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. For example, conjugates of the present application include antibody-drug conjugates. In one aspect, the present application provides a pharmaceutical composition that can include a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a conjugate described herein, and optionally a pharmaceutically acceptable carrier. In one aspect, the application provides kits that can include a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, and / or a pharmaceutical composition described herein. In one aspect, the present application provides a method of affecting Toll-like receptor (TLR) function comprising administering a compound described herein or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, a pharmaceutical composition described herein, and / or a kit described herein. For example, the TLRs can include TLR7 and / or TLR8.

[0166] In one aspect, the present application provides a method of modulating immune system function comprising administering a compound described herein or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, a pharmaceutical composition described herein, and / or a kit described herein. In one aspect, the present application provides a method for preventing and / or treating a disease and / or condition, e.g., the disease is susceptible to a TLR7- and / or TLR8-induced inflammatory response, comprising administering a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, a pharmaceutical composition described herein, and / or a kit described herein. In one aspect, the present application provides the use of a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, a pharmaceutical composition described herein, and / or a kit described herein in the preparation of a medicament for the prevention and / or treatment of a disease and / or condition, for example, the disease is susceptible to a TLR7- and / or TLR8-induced inflammatory response. In one aspect, the application provides a compound described herein or a tautomer, mesomers, racemates, enantiomers, or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a conjugate described herein, a pharmaceutical composition described herein, and / or a kit described herein for use in the prevention and / or treatment of a disease and / or condition, e.g., the disease is susceptible to a TLR7- and / or TLR8-induced inflammatory response. For example, the disease and / or condition can include a disease and / or condition associated with Toll-like receptor (TLR) signaling. For example, the disease and / or condition may be selected from the group consisting of tumors, autoimmune diseases, inflammation, sepsis, allergies, asthma, transplant rejection, graft-versus-host disease, immunodeficiency, and viral infections. For example, the disease and / or condition is selected from the group consisting of melanoma, lung tumor, liver tumor, basal cell tumor, kidney tumor, myeloma, biliary tract tumor, brain tumor, breast tumor, cervical tumor, chorionic tumor, colon tumor, rectal tumor, head and neck tumor, peritoneal tumor, fallopian tube tumor, endometrial tumor, esophageal tumor, gastric tumor, leukemia, lymphoma, sarcoma, neuroblastoma, oral tumor, ovarian tumor, pancreatic tumor, prostate tumor, testicular tumor, skin tumor, and thyroid tumor. For example, the disease and / or condition is a viral infection selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HPV (human papillomavirus), RSV (respiratory syncytial virus), SARS-CoV (severe acute respiratory syndrome coronavirus), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), MERS-CoV (Middle East respiratory syndrome coronavirus), and influenza virus.

[0167] The compounds described herein can affect the activity of TLRs. The effect on activity can be an increase of 1% or more, 2% or more, 4% or more, 5% or more, 8% or more, 10% or more, 15% or more, 18% or more, 20% or more, 25% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more of TLR activity when a compound of the present application is added to culture medium compared to when a negative control or reference drug is added. For example, the effect on activity can be an increase in EC 50The value (nM) is TLR 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less Lower, 98 or less, 97 or less, 95 or less, 90 or less, 80 or less, 75 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 or less, 8.5 or less, 7 or less, 6.7 or less, 6 or less, 5.9 or less, 5.5 or less, 5.0 or less, 4.8 or less, 4.5 or less, 4.4 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1.0 or less, 0.5 or less, 0.3 or less, 0.29 or less, 0.25 or less, 0.21 or less, 0.20 or less, 0.18 or less, 0.17 or less, 0.15 or less, 0.12 or less, 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. For example, immune cells include, but are not limited to, granulocytes and / or agranulocytes. For example, immune cells include, but are not limited to, B cells, T cells, natural killer cells, monocytes, macrophages, mast cells, and / or dendritic cells. For example, immune cells include PBMCs. For example, TLRs include human TLRs. For example, TLRs include TLR7 and / or TLR8.

[0168] The compounds described herein can affect the ability of immune cells to express and / or release cytokines. The effect on activity can be an increase of 1% or more, 2% or more, 4% or more, 5% or more, 8% or more, 10% or more, 15% or more, 18% or more, 20% or more, 25% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more when the compound described herein is added to a culture medium containing immune cells or administered to a subject, compared to the addition or administration of a negative control or reference drug. For example, immune cells can include, but are not limited to, granulocytes and / or agranulocytes. For example, immune cells can include, but are not limited to, B cells, T cells, natural killer cells, monocytes, macrophages, mast cells, and / or dendritic cells. For example, immune cells can include PBMCs. For example, the cytokine can be an immune cell cytokine. For example, the cytokine can be TNF-α and / or IFN-α. The compounds described herein can affect the activity of immune cells. The effect on activity can be an increase in immune cell activity of 1% or more, 2% or more, 4% or more, 5% or more, 8% or more, 10% or more, 15% or more, 18% or more, 20% or more, 25% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more when the compound of the present application is added to a culture medium containing immune cells, compared to the addition of a negative control or reference drug. For example, the effect on activity can be an increase in EC 50Value (nM) is 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less, 98 or less, 97 or less, 95 or less, 90 or less, 80 or less, 75 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 or less, 8.5 or less, The immunoglobulin level can be 7 or less, 6.7 or less, 6 or less, 5.9 or less, 5.5 or less, 5.0 or less, 4.8 or less, 4.5 or less, 4.4 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1.0 or less, 0.5 or less, 0.3 or less, 0.29 or less, 0.25 or less, 0.21 or less, 0.20 or less, 0.18 or less, 0.17 or less, 0.15 or less, 0.12 or less, 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. For example, immune cells can include, but are not limited to, granulocytes and / or agranulocytes. For example, immune cells include, but are not limited to, B cells, T cells, natural killer cells, monocytes, macrophages, mast cells, and / or dendritic cells. For example, immune cells include PBMCs.

[0169] Pharmaceutical Composition The pharmaceutical compositions described herein may contain, in addition to the active compound, one or more adjuvants which may be selected from the group consisting of the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, excipients, etc. Depending on the method of administration, the composition may contain 0.1 wt% to 99 wt% of the active compound. Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and the compositions can include binders, fillers, lubricants, disintegrants, pharmaceutically acceptable wetting agents, etc., and can further include one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Aqueous suspensions can contain the active substance mixed with excipients suitable for the formulation of aqueous suspensions.Aqueous suspensions can also contain one or more preservatives, such as one or more coloring agents, one or more flavoring agents, and one or more sweeteners.Oil suspensions can be formulated by suspending active ingredients in vegetable oil.Oil suspensions can contain thickeners.The above-mentioned sweeteners and flavoring agents can also be added. Pharmaceutical compositions can also be prepared from dispersible powders or granules that provide the active ingredient for preparation of an aqueous suspension by adding water and mixing the active ingredient with one or more dispersing agents, wetting agents, suspending agents, or preservatives. Other excipients, such as sweeteners, flavoring agents, and coloring agents, can also be added. These compositions are well preserved by the addition of antioxidants, such as ascorbic acid. The pharmaceutical compositions of the present application can also be in the form of oil-in-water emulsions. The pharmaceutical composition can be in the form of a sterile aqueous solution for injection. Acceptable vehicles or solvents include water, Ringer's solution, and isotonic sodium chloride solution. The sterile formulation for injection can be a sterile oil-in-water microemulsion for injection, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution can then be added to a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion can be locally injected in large volumes into the patient's bloodstream. Alternatively, it may be desirable to administer the solution and microemulsion so as to maintain a constant circulating concentration of the compound of the present application. To maintain such a constant concentration, a continuous intravenous delivery device can be used. For example, this device can be a Deltec CADD-PLUS™ 5400 intravenous infusion pump. The pharmaceutical composition can be in the form of an injectable sterile aqueous or oily suspension for intramuscular and subcutaneous administration.The suspension can be prepared according to the existing technology using the above-mentioned suitable dispersing or wetting agent and suspending agent.The sterile preparation for injection can be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable.Alternatively, sterile fixed oil can be conveniently used as a solvent or suspending medium.

[0170] The compounds of the present application can be administered in the form of suppositories for rectal administration. Such pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient. This excipient is solid at ambient temperature but liquid in the rectum, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, and mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. As is well known to those skilled in the art, the dosage of a drug administered depends on various factors, including, but not limited to, the activity of the particular compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the method of administration, the rate of excretion, the combination of drugs, etc. Furthermore, the optimal treatment regimen, e.g., the method of treatment, the compound described herein or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or the daily amount of the compound or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, can be determined according to conventional treatment regimens. Preventive and / or therapeutic methods The present application provides the use of a compound described herein or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition described herein, in the preparation of a medicament for the prevention and / or treatment of a disease and / or condition. The present application provides compounds described herein or their tautomers, mesomers, racemates, enantiomers or diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions described herein, for use in preventing and / or treating diseases and / or conditions. The present application provides methods for preventing and / or treating diseases and / or conditions, which methods can include administering to a subject a compound described herein or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition described herein.

[0171] Synthetic Embodiments To complete the synthetic objectives of this application, the compounds provided by this application can be prepared according to the following embodiments. Reagents that provide bromination conditions include, but are not limited to, aqueous bromine, N-bromosuccinimide, dibromohydantoin, phosphorus tribromide, liquid bromine, liquid bromine / triphenylphosphine, hydrobromic acid, and carbon tetrabromide. Titanium catalysts include, but are not limited to, tetraisopropyl titanate, triisopropoxytitanium chloride, titanium tetrachloride, and triisopropoxytitanium methyl. Palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)dipalladium, bis(acetonitrile)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride dichloromethane complex, bis(benzonitrile)palladium chloride, 1,4-butylenebis(diphenylphosphine)palladium dichloride, allylpalladium chloride dimer, and allyl(cyclopentadienyl)palladium(II). Boric acid dimers include bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bis(hexyleneglycolato)diboron, bis(catecholato)diboron, bis(diisopropyl-L-tartrate glycolato)diboron, bis[(-)pinanediol]diborate, bis[(1S,2S,3R,5S)-pinanediolato]diboron, tetramethyldiborane, bis(N,N,N',N'-tetramethyl-D-tartrate amidate)diboron, and tetrahydro These include, but are not limited to, roxydiboron, bis(N,N,N',N'-tetramethyl-L-tartrate amidate)diboron, bis(diisopropyl-D-tartrate glycolato)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(2,4-dimethyl-2,4-pentanediol)borate, bis(diethyl-L-tartrate glycolato)diboron, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylboronic acid. Metallic copper salts include, but are not limited to, copper sulfate, copper sulfate pentahydrate, cuprous sulfate, cupric chloride, cuprous chloride, cupric carbonate, cupric phosphate, cupric acetate and its hydrates, cupric oxalate, cupric fluoroborate and its hydrates, cupric methoxide, cupric tartrate, copper formate, cuprous iodide, copper(II) trifluoroacetate, copper(II) trifluoromethanesulfonate, copper carbonate, cupric bromide, cuprous bromide, and cuprous oxide. The ligand can be selected from any of the ligands commonly used in the Ullmann reaction, including, but not limited to, L-proline, tyrosine, phenylalanine, 1,10-phenanthroline, N,N'-dimethylethylenediamine, ethylene glycol, 1,1'-binaphthyl-2,2'-diol, ethyl 2-cyclohexanonecarboxylate, and salicylaldehyde hydrazone. Condensing agents include 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphatase, and the like. phosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Reagents that provide basic conditions include organic and inorganic bases, organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, piperidine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc., and inorganic bases include, but are not limited to, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, sodium phosphate, and potassium phosphate. Reagents that provide acidic conditions include protic acids and Lewis acids, protic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, and Lewis acids include, but are not limited to, boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, stannic chloride, and ferric chloride. Hydrogenation conditions include, but are not limited to, Pb / C / hydrogen, Pt / C / hydrogen, palladium chloride / hydrogen, Raney nickel / hydrogen, palladium hydroxide on carbon / hydrogen, and palladium hydroxide / hydrogen.

[0172] Reagents that provide oxidizing conditions include, but are not limited to, Dess-Martin periodinane, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate. Reagents that provide reducing conditions include, but are not limited to, sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. Reagents that provide oxidizing conditions include, but are not limited to, Dess-Martin periodinane, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate. Reagents that provide nitration conditions include, but are not limited to, dilute nitric acid, concentrated nitric acid, concentrated sulfuric acid / nitric acid, and nitric anhydride / acetic acid. Reagents that provide hydroboration include, but are not limited to, borane-tetrahydrofuran, borane-dimethyl sulfide, catecholborane, pinacolborane, 9-borabicyclo[3.3.1]nonane, diisoamylborane, dicyclohexylborane, 1,1,2-trimethylpropylborane, monochloroborane, dichloroborane, monobromoborane, and dibromoborane. Reagents that provide oxidizing conditions include, but are not limited to, Dess-Martin periodinane, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate.

[0173] The basic buffer is selected from the following buffers having a pH of 7 to 11: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above. The structures of the compounds in this application are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was performed using a Quantum-I NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-D), deuterated chloroform (CDC13), and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard, and chemical shifts are given in 10 (ppm). MS is performed using an Agilent 6230 ESI-TOF mass spectrometer (manufacturer: Agilent, type c: 6230). UPLC is performed using a Waters AcquityUPLCSQD liquid chromatograph mass spectrometer (Poroshell 120 EC-C18, 2.1 mm x 50 mm, 1.9 μm column). HPLC is performed using an Agilent 1260 high performance liquid chromatograph (TOSOH G3000 SW SEC column). UV detection is performed using a Thermo Nanodrop 2000 spectrophotometer. Enzyme-linked immunoassays are performed using an EnVision microplate reader (PerkinElmer). Thin layer chromatography (TLC) silica gel plates are typically HSGF254 or GF254 silica gel plates. The diameters of the plates used for TLC are 0.15-0.2 mm, while the diameters of the plates used for thin layer chromatography (TLC) for product separation and purification are 0.4-0.5 mm. Yantai Yellow Sea silica gel with 200-300 mesh is generally used as a carrier for column chromatography. Known starting materials of the present application can be synthesized using or according to methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. and Darui Chemicals. In the examples, unless otherwise noted, all reactions are carried out under an argon or nitrogen atmosphere. By argon or nitrogen atmosphere, it is meant that the reaction flask is attached to a balloon containing about 1 L of argon or nitrogen. By hydrogen atmosphere, it is meant that the reaction flask is attached to a balloon containing about 1 L of hydrogen. In the examples, unless otherwise specified, the solutions used in the reactions are aqueous solutions. In the examples, unless otherwise specified, the reaction temperature is room temperature, which is the optimum reaction temperature, and is in the range of 20°C to 30°C. The eluent systems for column chromatography and the developer systems for thin-layer chromatography used in compound purification include A: dichloromethane and isopropanol system, B: dichloromethane and methanol system, and C: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the different polarities of the compounds, and can also be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent. Some compounds of the present disclosure are characterized by TOF-LC / MS. TOF-LC / MS analysis is performed using an Agilent 6230 time of flight mass spectrometer and an Agilent 1290-Infinity ultra-high performance liquid chromatograph.

[0174] An exemplary preparation route of the present application is as follows: Embodiment 1 [ka]

[0175] Step I: A compound of general formula (P1) is reacted with bromoacetonitrile under heating conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a compound of general formula (Y1) at room temperature to give a compound of general formula (P3). Step III: A compound of general formula (P3) is reacted under reducing conditions to give a compound of general formula (P4). Step IV: The protecting group PG is removed from the compound of general formula (P4) to give a compound of general formula (P5). Step V: optionally in the presence of a condensing agent, optionally under basic conditions, a compound of general formula (P5) is reacted with a compound of general formula (Y2) to obtain a compound of general formula (P6). Step VI: A compound of general formula (P6) is reacted with a compound of general formula (Y3), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P7). In the above formula, PG can be a common carboxy protecting group, X is selected from —O—, —S— and —NR—; Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's are joined to form a heterocycle, bridged heterocycle, or spiro heterocycle, which is optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0176] Embodiment 2 [ka]

[0177] Step I: A compound of general formula (P1) is reacted with a compound of general formula (Y1), optionally catalyzed by a palladium-based reagent, to obtain a compound of general formula (P2). Step II: The protecting group PG is removed from the compound of general formula (P2) to give a compound of general formula (P3). In the above formula, PG is a common amino protecting group; X is selected from —O—, —S— and —NR—; Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's may be joined to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which may be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0178] Embodiment 3 [ka]

[0179] Step I: A protecting group PG is added to a compound of general formula (P1) optionally under acidic or basic conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a boronic acid dimer, optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P3). Step III: A compound of general formula (P3) is reacted with a compound of general formula (Y1), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P4). Step IV: The protecting group PG is removed from the compound of general formula (P4) to give a compound of general formula (P5). In the above formula, PG can be a common amino protecting group; R 2can be hydrogen or a common amino protecting group, X is selected from -O-, -S- and -NR-; Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can be joined to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which can be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0180] Embodiment 4 [ka]

[0181] Step I: A compound of general formula (P1) is subjected to a carbonyl insertion reaction, optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: A protecting group PG1 is added to a compound of general formula (P2) optionally under acidic or basic conditions to give a compound of general formula (P3). Step III: The ester group of the compound of general formula (P3) is hydrolyzed, optionally under basic conditions, to give a compound of general formula (P4). Step IV: A compound of general formula (P4) is reacted with a compound of general formula (Y1) optionally in the presence of a condensing agent, optionally under basic conditions, to give a compound of general formula (P5). Step IV: The protecting groups PG1 and PG2 are removed from the compound of general formula (P5) to give a compound of general formula (P6). In the above formula, PG1 and PG2 can be common amino protecting groups, X is selected from -O-, -S- and -NR-; Y is selected from -O-, -S- and -NR-; R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 2 is optionally selected from C1-C6 alkyl; Ring B is independently selected from optionally substituted aryl or heteroaryl; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene.

[0182] Embodiment 5 [ka]

[0183] Step I: A compound of general formula (P1) and a compound of general formula (Y1) are subjected to a reductive amination reaction, optionally under reducing conditions, to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a compound of general formula (Y2) optionally in the presence of a condensing agent, optionally under basic conditions, to obtain a compound of general formula (P3). Step III: A compound of general formula (P3) is reacted with a compound of general formula (Y3), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P4). Step IV: The protecting group PG is removed from the compound of general formula (P4) to give a compound of general formula (P5). In the above formula, PG can be a common amino protecting group; Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can join to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which can be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxy C1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene.

[0184] Embodiment 6 [ka]

[0185] Step I: A compound of general formula (P1) is subjected to nitration conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is subjected to reducing conditions to give a compound of general formula (P3). Step III: A compound of general formula (P3) is reacted with a compound of general formula (Y1) optionally in the presence of a condensing agent, optionally under basic conditions, to give a compound of general formula (P4). Step IV: The compound of general formula (P4) is subjected to a cyclization reaction under heating conditions to obtain a compound of general formula (P5). Step V: A compound of general formula (P5) is subjected to oxidation conditions to give a compound of general formula (P6). Step VI: A compound of general formula (P6) is reacted in the presence of phosphorus oxychloride to give a compound of general formula (P7). Step VII: A compound of general formula (P7) is reacted with a compound of general formula (Y2) under heating conditions to obtain a compound of general formula (P8). Step VIII: A compound of general formula (P8) is reacted with a compound of general formula (Y3), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P9). Step IX: A compound of general formula (P9) is reacted under reducing conditions to give a compound of general formula (P10). Step X: The protecting groups PG1 and PG2 are removed from the compound of general formula (P10) to give a compound of general formula (P11). In the above formula, PG1 and PG2 can be common amino protecting groups, X is selected from —O— and —S—; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene; R1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, where R 1 If contains a methylene unit, R 1 each methylene unit is independently unsubstituted or R 1 is independently substituted with a group selected from the group consisting of -O-, -S-, and optionally substituted -NH-.

[0186] Embodiment 7 [ka]

[0187] Step I: A compound of general formula (P1) is reacted with a compound of general formula (Y1), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: The protecting groups PG1 and PG2 are removed from the compound of general formula (P2) to give a compound of general formula (P3). In the above formula, PG1 and PG2 can be common amino protecting groups, X is selected from -O- and -S-; Y is selected from —O— and —NH—; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, where R 1 If contains a methylene unit, R1 each methylene unit is independently unsubstituted or R 1 is independently substituted with a group selected from the group consisting of -O-, -S-, and optionally substituted -NH-.

[0188] Embodiment 8 [ka]

[0189] Step I: A compound of general formula (P1) undergoes a carbonyl insertion reaction, optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: A compound of general formula (P2) is subjected to reduction conditions to give a compound of general formula (P3). Step III: A compound of general formula (P3) and a compound of general formula (Y1) are subjected to a substitution reaction under basic conditions to give a compound of general formula (P4). Step IV: The protecting groups PG1 and PG2 are removed from the compound of general formula (P4) to give a compound of general formula (P5). In the above formula, PG1 and PG2 can be common amino protecting groups, X is selected from —O— and —S—; R 2 is selected from halogen, methanesulfonyloxy and p-toluenesulfonyloxy; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, where R 1 If contains a methylene unit, R 1each methylene unit of R is independently unsubstituted or 1 is independently substituted with a group selected from the group consisting of -O-, -S-, and optionally substituted -NH-.

[0190] Embodiment 9 [ka]

[0191] Step I: A compound of general formula (P1) is subjected to a Heck reaction, optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: Compounds of general formula (P2) are subjected to hydroboration and oxidation conditions to give compounds of general formula (P3). Step III: A compound of general formula (P3) and a compound of general formula (Y1) are subjected to a substitution reaction under basic conditions to give a compound of general formula (P4). Step IV: The protecting groups PG1 and PG2 are removed from the compound of general formula (P4) to give a compound of general formula (P5). In the above formula, PG1 and PG2 can be common amino protecting groups, X is selected from —O— and —S—; R 2 is selected from halogen, methanesulfonyloxy and p-toluenesulfonyloxy; Z is absent or selected from C1-C6 alkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, and halogenated C1-C6 alkylene; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, where R 1 If contains a methylene unit, R 1each methylene unit of R is independently unsubstituted or 1 is independently substituted with a group selected from the group consisting of --O--, --S--, and optionally substituted --NH--.

[0192] Embodiment 10 [ka]

[0193] Step I: A compound of general formula (P1) is reacted with aminoacetonitrile under heating conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a compound of general formula (Y1) optionally in the presence of a condensing agent, optionally under basic conditions, to obtain a compound of general formula (P3). Step VI: A compound of general formula (P3) is reacted with a compound of general formula (Y2), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P4). In the above formula, Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can join to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which can be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 , R 2 and R 3are independently selected from hydrogen, protium, deuterium, tritium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0194] Embodiment 11 [ka]

[0195] Step I: A compound of general formula (P1) is reacted with a compound of general formula (Y1), optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: The protecting groups PG1 and PG2 are removed from the compound of general formula (P2) to give a compound of general formula (P3). In the above formula, PG1 can be a common amino protecting group, Ring B is an optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can join to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which is optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl, where each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 , R 2 and R 3are independently selected from hydrogen, protium, deuterium, tritium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0196] Embodiment 12 [ka]

[0197] Step I: A compound of general formula (P1) is reacted with a compound of general formula (Y1) optionally under basic conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a compound of general formula (Y2) optionally under basic conditions to give a compound of general formula (P3). Step III: The protecting group PG2 is removed from the compound of general formula (P3) to give a compound of general formula (P4). Step IV: A compound of general formula (P5) is reacted with a compound of general formula (P4) optionally in the presence of a condensing agent, optionally under basic conditions, to give a compound of general formula (P6). Step V: A compound of general formula (P6) is reacted with a compound of general formula (Y3), optionally catalyzed by a palladium-based reagent, to obtain a compound of general formula (P7). Step VI: The protecting group PG1 is removed from the compound of general formula (P7) to give a compound of general formula (P8). In the above formula, PG1 and PG2 can be common amino protecting groups, X is independently selected from halogen, methanesulfonyloxy, and p-toluenesulfonyloxy; Ring A and Ring B are independently selected from optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can join to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which can be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 is an optionally substituted C1-C6 alkyl; Z is selected from optionally substituted C1-C6 alkylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene.

[0198] Embodiment 13 [ka]

[0199] Step I: A compound of general formula (P1) is reacted with a compound of general formula (Y1) optionally under basic conditions to give a compound of general formula (P2). Step II: A compound of general formula (P2) is reacted with a compound of general formula (Y2) optionally under basic conditions to give a compound of general formula (P3). Step III: The protecting group PG2 is removed from the compound of general formula (P3) to give a compound of general formula (P4). Step IV: A compound of general formula (P5) is reacted with a compound of general formula (P4) optionally in the presence of a condensing agent, optionally under basic conditions, to give a compound of general formula (P6). Step V: optionally, under the catalysis of a palladium-based reagent, a compound of general formula (P6) is reacted with a compound of general formula (Y3) to obtain a compound of general formula (P6); and Step VI: The protecting group PG1 is removed from the compound of general formula (P4) to give a compound of general formula (P7). In the above formula, PG2 can be a common amino protecting group, X is independently selected from halogen, methanesulfonyloxy, and p-toluenesulfonyloxy; Ring A and Ring B are independently selected from optionally substituted aryl or heteroaryl; -B(OR)2 is a boronate monomer, and two R's can join to form a heterocycle, a bridged heterocycle, or a spiro heterocycle, which can be optionally substituted with C1-C6 alkyl, aryl, heteroaryl, carboxy, or acyloxyC1-C6 alkyl; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 1 is an optionally substituted C1-C6 alkyl; Z is selected from optionally substituted C1-C6 alkylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene.

[0200] Embodiment 14 [ka]

[0201] Step I: A compound of general formula (P1) is subjected to a carbonyl insertion reaction, optionally catalyzed by a palladium-based reagent, to give a compound of general formula (P2). Step II: The ester group of the compound of general formula (P2) is hydrolyzed, optionally under basic conditions, to give a compound of general formula (P3). Step III: A compound of general formula (P3) is reacted with a compound of general formula (Y1) optionally in the presence of a condensing agent, optionally under basic conditions, to obtain a compound of general formula (P4). Step IV: The nitro group of the compound of general formula (P4) is reduced under reducing conditions, or the protecting group PG is optionally removed under basic or acidic conditions to give a compound of general formula (P5). In the above formula, Ring B is an optionally substituted aryl or heteroaryl; Z is selected from optionally substituted C1-C6 alkylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene; R 1 are independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy; R 2 is optionally selected from nitro or —NH—PG, where PG can be a common amino protecting group; R is optionally selected from C1-C6 alkyl; Y is selected from —O—, —S— and —NR—; R 3 is optionally selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy. [Example]

[0202] The following examples are intended only to illustrate the compounds, preparation methods, uses, etc. of the present application without being bound by any theory, and are not intended to limit the scope of the present application. example Example 1. Preparation of compounds compound 1 [ka]

[0203] Process 1 EA (180 mL) and 1A (30 g, 79.7 mmol, 1 equiv.) were added to a 500 mL three-neck flask. Bromoacetonitrile (5.73 g, 47.7 mmol, 0.6 equiv.) was added dropwise at room temperature. After the addition, the temperature was raised to 85 °C and the reaction was allowed to proceed overnight. The reaction solution was cooled and directly filtered. The filter cake was washed with 50 mL of EA, and the filtrate was concentrated by rotary evaporation to give the crude dark red solid product 1B (9 g), which was used directly in the next step without calculating the yield. Process 2 1B (9 g, 21.74 mmol, 1 equiv.) from the previous step was (incompletely) dissolved in toluene (90 mL). 1C (5 g, 21.74 mmol, 1 equiv.) was added at room temperature. After the addition, the system was stirred at room temperature overnight. The toluene was removed by rotary evaporation. The residue was subjected to column chromatography (PE:EA = 20:1 to 10:1), concentrated under reduced pressure by rotary evaporation, triturated with PE (50 mL), and filtered to give pale yellow flaky crystals of 1D (5 g, 62.5% yield). Process 3 In a 250 mL three-neck flask, 1D (5 g, 13.6 mmol, 1 equiv.) was added to glacial acetic acid (50 mL). The internal temperature was raised to approximately 60-65 °C, and then iron powder (3.8 g, 68 mmol, 5 equiv.) was added slowly in small portions. After the addition, the internal temperature was raised to 85 °C and the reaction was allowed to proceed for 2 h. The reaction solution was cooled to approximately 60 °C, diluted with DCM (50 mL), and filtered through Celite before cooling. The filter cake was washed with DCM (100 mL), and the filtrate was concentrated by rotary evaporation under reduced pressure to give a dark red oil. The oil was diluted with DCM (50 mL), poured into saturated aqueous sodium bicarbonate (200 mL), and extracted with DCM (100 mL × 4). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. After concentration by rotary evaporation, the mixture was triturated with PE:EA = 2:1 (30 mL) and filtered to give an off-white powder 1E (4.5 g, 97% yield). MS-ESI: m / z 337.1 [M+H]+. Process 4 4 N HCl / dioxane (40 mL) was added to a 100 mL single-neck flask, followed by 1E (4.5 g, 13.4 mmol, 1 equiv). The system was stirred at room temperature overnight. When LCMS showed no starting material, the mixture was concentrated by rotary evaporation to give 1F (4.2 g, 99% yield) as an off-white powder. MS-ESI: m / z 281.0 [M+H]+. Process 5 DMF (60 mL) and 1F (3 g, 9.45 mmol, 1 equiv.) were added to a 250 mL three-neck flask, followed by HBTU (4.3 g, 11.34 mmol, 1.2 equiv.) and DIEA (4.88 g, 37.79 mmol, 4 equiv.) at 0 °C. After the addition, the system was stirred for 10 min, and dipropylamine (1.86 g, 18.42 mmol, 1.95 equiv.) was added dropwise. After the addition, the system was warmed to room temperature and stirred overnight. The reaction solution was poured into water (240 mL) and extracted with EA (100 mL × 5). The organic phase was washed with saturated brine (50 mL × 2), dried over sodium sulfate, concentrated by rotary evaporation, and purified on a silica gel column to give a dark red solid, 1G (3 g, 87.5% yield). MS-ESI: m / z 364.2 [M+H]+. Process 6 In a 25 mL three-neck flask, 1G (200 mg, 0.55 mmol, 1 equiv.), 1H (121 mg, 0.55 mmol, 1 equiv.), and anhydrous potassium phosphate (350 mg, 1.65 mmol, 3 equiv.) were dissolved in a mixture of dioxane (5 mL) and water (0.5 mL). After purging the system twice with argon, Pd(PPh3)4 (50 mg) was added. The mixture was then purged twice with argon and heated to 85 °C for 3 h. After cooling, the reaction solution was dried over sodium sulfate to remove water and directly purified by thin-layer chromatography to give 1 (25 mg, 12% yield) as a dark yellow powder. MS-ESI: m / z 377.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.2, 2.0 Hz, 1H), 6.79 - 6.67 (m, 3H), 6.62 (d, J = 8.6 Hz, 2H), 5.22 (s, 2H), 3.30 - 3.25 (m, 4H), 2.70 (s, 2H), 1.63 - 1.48 (m, 4H), 0.82 (brs, 6H).

[0204] compound 2 [ka]

[0205] Process 1 In a 25 mL three-neck flask, 1G (200 mg, 0.55 mmol, 1 equiv.), 2A (121 mg, 0.55 mmol, 1 equiv.), and anhydrous potassium phosphate (350 mg, 1.65 mmol, 3 equiv.) were dissolved in a mixture of dioxane (5 mL) and water (0.5 mL). After purging the system with argon twice, Pd(PPh3)4 (50 mg) was added. The mixture was then purged with argon twice and heated to 85 °C for 3 h. After cooling, the reaction solution was dried over sodium sulfate to remove water. The mixture was purified by column chromatography (DCM:MeOH = 100:0 to 10:1) to give 2 (23 mg, 11% yield) as a pale yellow powder. MS-ESI: m / z 378.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.16 (t, J = 2.3 Hz, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 3.31 - 3.26 (m, 4H), 2.89 (s, 2H), 1.61 - 1.51 (m, 4H), 0.83 (brs, 6H).

[0206] compound 3 [ka]

[0207] Process 1 In a 25 mL three-neck flask, 1G (400 mg, 1.1 mmol, 1 equiv.), 3A (151 mg, 1.1 mmol, 1 equiv.), and anhydrous potassium phosphate (700 mg, 3.29 mmol, 3 equiv.) were dissolved in a mixture of dioxane (10 mL) and water (1 mL). After purging the system twice with argon, Pd(PPh3)4 (100 mg) was added. The mixture was then purged twice with argon and heated to 85 °C for 3 h. After cooling, the reaction solution was dried over 5 g of sodium sulfate, mixed with silica gel, and subjected to column chromatography to obtain the crude product. The crude product was then purified to obtain 3 (45 mg, 11% yield) as a pale yellow powder. MS-ESI: m / z 377.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.72 - 7.60 (m, 3H), 7.59 - 7.37 (m, 3H), 7.37 - 7.12 (m, 1H), 7.08 (s, 1H), 3.47 (brs, 4H), 3.36 (s, 2H), 1.77 - 1.63 (m, 4H), 0.95 (brs, 6H).

[0208] compound 4 [ka]

[0209] Process 1 4A (2 g, 9.66 mmol, 1 equiv.) was dissolved in toluene (40 mL), and then triethylamine (2.44 g, 24.15 mmol, 2.5 equiv.), DPPA (3.19 g, 11.59 mmol, 1.2 equiv.), and tert-butanol (7.16 g, 96.6 mmol, 10 equiv.) were added at room temperature. After the addition, the system was heated to 100 °C and stirred overnight. The reaction solution was poured into 50 mL of water and extracted with EA (50 mL × 3). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (PE:EA = 5:1) to give an off-white solid 4B (0.6 g, 22.3% yield). Process 2 1G (2 g, 5.49 mmol, 1 equiv.) was dissolved in DCM (40 mL) and then triethylamine (1.67 g, 16.47 mmol, 3 equiv.) was added at room temperature. BocO (1.8 g, 8.24 mmol, 1.5 equiv.) was then added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into 50 mL of water and extracted with DCM (50 mL × 3). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (PE:EA = 5:1) to give a pale yellow solid 4C (1.2 g, 49% yield). Process 3 4C (1.2 g, 2.58 mmol, 1 equiv.) was dissolved in dioxane (20 mL), followed by the addition of bis(pinacolato)diboron (722 mg, 2.84 mmol, 1.1 equiv.) and AcOK (507 mg, 5.17 mmol, 2 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl (0.2 g) was added in one portion. The mixture was purged twice with argon and heated to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature and poured directly onto a silica gel column. The product was eluted with PE:EA = 2:1 to give a yellow solid 4D (600 mg, 45% yield). MS-ESI: m / z 512.3 [M+H] + . Process 4 4B (359 mg, 1.29 mmol, 1.2 equiv.) and 4D (550 mg, 1.08 mmol, 1 equiv.) were added to a mixture of dioxane (10 mL) and water (1 mL), followed by the addition of sodium carbonate (285 mg, 2.69 mmol, 2.5 equiv.). After purging the system twice with argon, Pd(dppf)Cl2 (100 mg) was added in one portion, followed by purging twice with argon, and the mixture was heated to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, dried over sodium sulfate, directly mixed with silica gel, and purified by column chromatography to give a yellow solid, 4E (100 mg, 15.9% yield). MS-ESI: m / z 583.3 [M+H] + . Process 5 4E (100 mg, 0.17 mmol, 1 equiv.) was dissolved in EA (5 mL), and then 4 N hydrochloride salt in dioxane (1 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. After concentration under reduced pressure, the reaction mixture was subjected to preparative chromatography and lyophilized to give a yellow solid 4 (22 mg, 27% yield). MS-ESI: m / z 383.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.35 (d, J = 1.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.26 (dd, J = 8.2, 1.8 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.81 (s, 1H), 6.25 (d, J = 1.6 Hz, 1H), 4.52 - 4.38 (m, 2H), 3.46 - 3.37 (m, 4H), 1.73 - 1.60 (m, 4H), 0.91 (brs, 6H).

[0210] compound 5 [ka]

[0211] Process 1 5A (280 mg, 0.98 mmol, 1 equiv.) and 4D (500 mg, 0.98 mmol, 1 equiv.) were added to a mixture of dioxane (10 mL) and water (2 mL), followed by the addition of sodium carbonate (259 mg, 2.44 mmol, 2.5 equiv.). After purging the system twice with argon, Pd(dppf)Cl (100 mg) was added in one portion, followed by purging twice with argon, and the mixture was heated to 95 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, dried over sodium sulfate, and directly purified by thin-layer chromatography to give a yellow solid, 5B (200 mg, 35% yield). MS-ESI: m / z 591.4 [M+H] + . Process 2 5B (200 mg, 0.33 mmol, 1 equiv.) was dissolved in EA (5 mL), followed by the addition of 4 N hydrochloride salt (0.5 mL) in dioxane in an ice-water bath. The reaction was stirred at room temperature overnight. When LCMS showed no starting material, the mixture was concentrated under reduced pressure, subjected to preparative chromatography, and lyophilized to give a yellow solid 5 (25 mg, 19% yield). MS-ESI: m / z 391.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.20 (d, J = 7.9 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.90 (dd, J = 8.0, 1.9 Hz, 1H), 6.78 (s, 1H), 6.63 - 6.53 (m, 3H), 4.69 - 4.48 (m, 2H), 3.85 (s, 2H), 3.45 - 3.36 (m, 4H), 1.75 - 1.57 (m, 4H), 0.90 (brs, 6H).

[0212] compound 6 [ka]

[0213] Process 1 Methanol (20 mL), 1G (1.2 g, 3.29 mmol, 1 equiv.), and triethylamine (1 g, 9.88 mmol, 3 equiv.) were added to a 50 mL autoclave. After purging the system with argon, Pd(dppf)Cl (0.2 g) was added. The system was then sealed immediately after the addition, purged twice with argon, and then CO (60 psi) was introduced. The system was heated to 80 °C and reacted for 40 h. When LCMS showed a small amount of starting material remained, the mixture was filtered and concentrated under reduced pressure to give the crude dark red oil product 6A (1.5 g), which was used directly in the next step without calculating the yield. MS-ESI: m / z 344.2 [M+H] + . Process 2 The crude product 6A from the previous step (1.5 g, 4.37 mmol, 1 equiv.) was dissolved in DCM (30 mL), and then triethylamine (1.33 g, 13.10 mmol, 3 equiv.) was added at room temperature. Next, BocO (1.43 g, 6.55 mmol, 1.5 equiv.) was added dropwise, and after the addition, the system was stirred at room temperature overnight. The reaction solution was poured into water (50 mL) and extracted with DCM (50 mL × 3). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 5:1) to give a pale yellow solid 6B (0.4 g, 27.6% yield over two steps). MS-ESI: m / z 444.3 [M+H] + . Process 3 6B (400 mg, 0.9 mmol, 1 equiv.) was added to a mixture of water (5 mL) and THF (5 mL), followed by the addition of lithium hydroxide monohydrate (56.77 mg, 1.35 mmol, 1.5 equiv.) at room temperature. The mixture was stirred overnight at room temperature. When TLC showed that the starting material was gone, the reaction solution was adjusted to pH 5 with saturated citric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 6C (350 mg, 90% yield) as a yellow powder. Process 4 6C (150 mg, 0.35 mmol, 1 equiv) was added to DCM (5 mL), followed by the addition of HATU (159 mg, 0.42 mmol, 1.2 equiv) at room temperature. After stirring the system for 10 min, NMM (89 mg, 0.873 mmol, 2 equiv) and 6D (73 mg, 0.35 mmol, 1 equiv) were added. The system was then stirred overnight at room temperature. When TLC showed that the starting material was gone, the reaction solution was poured into water (15 mL) and extracted with EA (30 mL × 4). The organic phases were combined, concentrated under reduced pressure, and directly purified by thin layer chromatography to give 6E (50 mg, 23% yield) as an off-white powder. MS-ESI: m / z 620.4 [M+H] + . Process 5 6E (50 mg, 0.08 mmol, 1 equiv.) was dissolved in ethyl acetate (5 mL), and then hydrochloride salt in dioxane (4 N, 0.5 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure and directly purified by thin layer chromatography to give a pale yellow powder 6 (24 mg, 70.8% yield). MS-ESI: m / z 420.6 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.66 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.1, 1.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.41 - 7.36 (m, 2H), 6.89 (s, 1H), 6.78 - 6.71 (m, 2H), 4.58 (s, 2H), 3.47 - 3.38 (m, 4H), 1.76 - 1.60 (m, 4H), 1.07 - 0.77 (m, 6H).

[0214] compound 7 [ka]

[0215] Process 1 6C (300 mg, 0.70 mmol) was added to a 100 mL flask, followed by DMF (10 mL), 7A (174 mg, 0.84 mmol), DIEA (271 mg, 2.10 mmol), and HATU (372 mg, 0.98 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h until LCMS showed the disappearance of the starting material. Water (100 mL) was added, and the reaction mixture was extracted with EA (100 mL × 3). The organic phase was concentrated by rotary evaporation and purified by column chromatography (EA:PE = 0–20%) to give 7B (300 mg, 69% yield) as a pale yellow oily liquid. MS-ESI: m / z 620.4 [M+H] + . Process 2 7B (300 mg, 0.48 mmol) was added to a 100 mL flask, followed by DCM (8 mL) and TFA (2 mL) at 0 °C. The reaction was stirred at room temperature for 16 h, and LCMS confirmed the disappearance of the starting material. The reaction mixture was rotary evaporated to dryness and purified by reverse-phase column chromatography (NHHCO) to give a pale yellow solid 7 (70 mg, 34% yield). MS-ESI: m / z 420.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.1, 1.9 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 2.0 Hz, 1H), 6.94 (t, J = 7.9 Hz, 1H), 6.91 - 6.81 (m, 3H), 6.77 (s, 1H), 6.33 - 6.26 (m, 1H), 5.04 (s, 2H), 3.31 - 3.26 (m, 4H), 2.71 (s, 2H), 1.64 - 1.49 (m, 4H), 0.83 (brs, 6H).

[0216] compound 8 [ka]

[0217] Process 1 8A (1 g, 8.4 mmol) was dissolved in DCM (20 mL), and then DMAP (102 mg, 0.84 mmol) and BocO (2.2 g, 10.1 mmol) were added. The mixture was then stirred overnight at room temperature. After concentration, the mixture was purified by column chromatography (PE:EA = 1:1) to give a white solid 8B (1.2 g, 65% yield, 95% purity). MS-ESI: m / z 220.0 [M+H] + . Process 2 8B (500 mg, 2.27 mmol) was dissolved in MeOH / NH₃·H₂O (5 mL, v / v = 4 / 1), and then Raney Ni (100 mg) was added at room temperature. The system was purged with H₂ three times and stirred at room temperature overnight. The mixture was filtered and concentrated to give a green solid 8C (450 mg, 85% yield, 84% purity). MS-ESI: m / z 224.2 [M+H] + . Process 1 6C (300 mg, 0.7 mmol) and 8C (156 mg, 0.7 mmol) were dissolved in DMF (3 mL), and then DIEA (271 mg, 2.1 mmol) and HATU (320 mg, 0.84 mmol) were added. The mixture was then stirred at room temperature overnight. The reaction solution was directly subjected to preparative HPLC (MeCN / HO) to give a pale yellow solid, 8D (200 mg, 45% yield, 85% purity). MS-ESI: m / z 635.4 [M+H] + . Process 4 8D (200 mg, 0.3 mmol) was dissolved in DCM (5 mL), followed by the addition of TFA (180 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and adjusted to pH 8–9 with NaHCO3. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and subjected to preparative HPLC (MeCN / HO) to give a yellow solid 8 (52.8 mg, 35% yield, 95.23% purity). MS-ESI: m / z 435.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.77 (m, 2H), 7.64 - 7.58 (m, 1H), 7.52 - 7.44 (m, 1H), 7.40 (dd, J = 8.1, 3.3 Hz, 1H), 7.10 (s, 1H), 6.90 - 6.84 (m, 1H), 4.55 - 4.47 (m, 2H), 3.47 - 3.36 (m, 4H), 3.34 - 3.32 (m, 2H), 1.78 - 1.56 (m, 4H), 1.11 - 0.71 (m, 6H).

[0218] compound 9 [ka]

[0219] Process 1 6C (300 mg, 0.7 mmol) was dissolved in DMF (3 mL), and then 9A (155 mg, 0.7 mmol), DIEA (211 mg, 2.1 mmol), and HATU (320 mg, 0.84 mmol) were added. The mixture was then stirred overnight at room temperature. The reaction solution was directly subjected to preparative HPLC (MeCN / HO) to give a white solid 9B (250 mg, 55% yield, 90% purity). MS-ESI: m / z 634.4 [M+H] + . Process 2 9B (250 mg, 0.4 mmol) was dissolved in DCM (5 mL), and then TFA (135 mg, 1.2 mmol) was added. The reaction solution was incubated at room temperature for 3 h. The mixture was diluted with water and adjusted to pH 8–9 with NaHCO3. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and subjected to preparative HPLC (MeCN / HO) to give a pale yellow solid 9 (26.3 mg, 15% yield, 99.59% purity). MS-ESI: m / z 434.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.61 (d, J = 1.8 Hz, 1H), 7.48 (dd, J = 8.1, 1.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.87 (s, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.71 - 6.66 (m, 1H), 6.62 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H), 4.49 (s, 2H), 3.46 - 3.37 (m, 4H), 1.76 - 1.57 (m, 4H), 1.11 - 0.72 (m, 6H).

[0220] compound 10 [ka]

[0221] Process 1 10A (5 g, 22.60 mmol, 1 equiv.) was added to DCM (100 mL), followed by the addition of n-propylamine (4.01 g, 67.80 mmol, 3 equiv.) at room temperature. After the addition, the system was stirred overnight at room temperature. Sodium cyanoborohydride (2.84 g, 45.20 mmol, 2 equiv.) was added slowly at room temperature. After the addition, the system was stirred overnight at room temperature. The reaction solution was poured into 100 mL of water, and the phases were separated. The aqueous phase was extracted with DCM (100 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (DCM:MeOH = 50:1 to 10:1) to give a white solid, 10B (3 g, 50.3% yield). Process 2 1F (1 g, 3.15 mmol, 1 equiv) was dissolved in DMF (20 mL). The temperature was lowered to approximately 0 °C, and then HBTU (1.43 g, 3.78 mmol, 1.2 equiv) and DIEA (1.63 g, 12.60 mmol, 4 equiv) were added. The system was stirred at 0 °C for 10 min, and then 10B (1 g, 3.78 mmol, 1.2 equiv) was added. After the addition, the system was stirred at room temperature overnight. The reaction solution was poured into water (60 mL) and extracted with EA (50 mL × 5). The combined organic phases were washed with saturated brine (50 mL × 2), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (DCM:MeOH = 20:1 to 10:1). The product was concentrated under reduced pressure to give a yellow solid 10C (550 mg, 30% yield). MS-ESI: m / z 527.2 [M+H] + . Process 3 10C (550 mg, 1.04 mmol, 1 equiv) was added to a mixture of dioxane (20 mL) and water (2 mL), followed by the addition of 10D (243 mg, 1.04 mmol, 1 equiv) and anhydrous potassium phosphate (664 mg, 3.13 mmol, 3 equiv). The system was purged with argon twice, and then Pd(PPh3)4 (110 mg) was added. The mixture was then purged with argon twice and heated to 90 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 50 mL of water and extracted with EA (50 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 2:1 to 0:1) to give 10E (200 mg, 34.7% yield) as a white solid. MS-ESI: m / z 554.4 [M+H] + . Process 4 10E (200 mg, 0.36 mmol, 1 equiv) was added to methanol (10 mL), followed by the slow addition of sodium borohydride (41 mg, 1.08 mmol, 3 equiv) in small portions at room temperature. After the addition, the system was allowed to react at room temperature for 2 h. When LCMS showed the disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride (5 mL), and the mixture was concentrated under reduced pressure to remove the solvent, which was directly purified by thin layer chromatography to give a white solid 10F (160 mg, 80% yield). MS-ESI: m / z 556.3 [M+H] + . Process 5 10F (160 mg, 0.28 mmol, 1 equiv.) was dissolved in EA (5 mL), followed by the addition of 4 N hydrochloride salt (0.5 mL) in dioxane in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed the disappearance of the starting material, the mixture was concentrated under reduced pressure, subjected to preparative chromatography, and lyophilized to give 10 (30 mg, 23% yield) as a white powder. MS-ESI: m / z 456.3 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.88 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.34 (s, 1H), 7.84 - 7.56 (m, 3H), 7.56 - 7.18 (m, 4H), 7.16 (s, 1H), 4.81 (s, 2H), 4.78 (s, 2H), 3.55 - 3.45 (m, 2H), 3.45 - 3.33 (m, 2H), 1.76 - 1.63 (m, 2H), 0.92 (s, 3H).

[0222] compound 11 [ka]

[0223] Process 1 11A (1 g, 4.97 mmol, 1 equiv.) was dissolved in DMF (20 mL), and then DIEA (1.93 g, 14.92 mmol, 3 equiv.) and HATU (2.08 g, 5.47 mmol, 1.1 equiv.) were added at room temperature. After the addition, the system was stirred at room temperature for 5 minutes, and 11B (0.434 g, 4.97 mmol, 1 equiv.) was added. After the addition, the system was stirred at room temperature overnight. The reaction solution was poured into 60 mL of water and extracted with EA (50 mL × 3). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (PE:EA = 5:1) to give a white solid 11C (1 g, 74.6% yield). MS-ESI: m / z 270.0 [M+H] + . Process 2 11C (0.9 g, 3.33 mmol, 1 equiv.) was dissolved in dioxane (20 mL), followed by the addition of bis(pinacolato)diboron (931 mg, 3.67 mmol, 1.1 equiv.) and AcOK (654 mg, 6.66 mmol, 2 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl (0.2 g) was added in one portion. The mixture was then purged twice more with argon and heated to 85 °C for 3 h. When LCMS showed no starting material, the reaction solution was cooled to room temperature and directly loaded onto a silica gel column (PE:EA = 2:1) for purification to give a pale yellow solid, 11D (300 mg, 28.3% yield). MS-ESI: m / z 318.3 [M+H] + . Process 3 10C (300 mg, 0.569 mmol, 1 equiv.) and 11D (180.4 mg, 0.569 mmol, 1 equiv.) were added to a mixture of dioxane (10 mL) and water (1 mL), followed by the addition of sodium carbonate (150.71 mg, 1.42 mmol, 2.5 equiv.). After purging the system twice with argon, Pd(dppf)Cl2 (50 mg) was added in one portion, followed by purging twice with argon and heating to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, dried over sodium sulfate, directly mixed with silica gel, and purified by column chromatography to give a yellow solid, 11E (100 mg, 27.6% yield). MS-ESI: m / z 638.4 [M+H] + . Process 4 11E (100 mg, 0.157 mmol, 1 equiv.) was dissolved in EA (5 mL), and then 4 N hydrochloride salt in dioxane (1 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure, subjected to preparative chromatography, and lyophilized to give a yellow solid 11 (30 mg, 35.7% yield). MS-ESI: m / z 538.3 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.80 (d, J = 7.9 Hz, 2H), 7.76 - 7.66 (m, 4H), 7.66 - 7.30 (m, 3H), 7.25 (s, 2H), 7.14 (s, 1H), 4.78 (s, 2H), 4.45 (d, J = 47.8 Hz, 1H), 3.84 - 3.58 (m, 3H), 3.58 - 3.32 (m, 5H), 2.19 - 1.90 (m, 2H), 1.75 - 1.63 (m, 2H), 0.91 (s, 3H).

[0224] compound 12 [ka]

[0225] Process 1 12A (1 g, 4.69 mmol, 1 equiv.) was dissolved in dioxane (20 mL) and bis(pinacolato)diboron (1.31 g, 5.16 mmol, 1.1 equiv.) and AcOK (921.4 mg, 9.39 mmol, 2 equiv.) were added. After purging the system twice with argon, Pd(dppf)Cl2 (0.1 g) was added in one portion. The mixture was then purged twice more with argon and heated to 85 °C for 3 h. When LCMS showed no starting material, the reaction solution was cooled to room temperature and directly loaded onto a silica gel column (PE:EA = 10:1) for purification to give a white solid, 12B (300 mg, 24.6% yield). MS-ESI: m / z 261.2 [M+H] + . Process 2 10C (250 mg, 0.474 mmol, 1 equiv.) and 12B (247 mg, 0.948 mmol, 2 equiv.) were added to a mixture of dioxane (10 mL) and water (1 mL), followed by potassium phosphate (302 mg, 1.42 mmol, 3 equiv.). After purging the system twice with argon, Pd(dppf)Cl2 (50 mg) was added in one portion, followed by purging twice with argon and heating to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, dried over sodium sulfate, directly mixed with silica gel, and purified by column chromatography to give a yellow solid, 12C (100 mg, 36.4% yield). MS-ESI: m / z 581.2 [M+H] + . Process 3 12C (100 mg, 0.172 mmol, 1 equiv.) was dissolved in EA (5 mL), followed by the addition of 4 N hydrochloride salt (1 mL) in dioxane in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure, subjected to preparative chromatography, and lyophilized to give a yellow solid 12 (23 mg, 28% yield). MS-ESI: m / z 481.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.17 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.84 - 7.70 (m, 3H), 7.70 - 7.27 (m, 3H), 7.27 - 7.06 (m, 3H), 5.47 (s, 2H), 4.77 (s, 2H), 3.54 - 3.44 (m, 2H), 3.44 - 3.32 (m, 2H), 1.77 - 1.64 (m, 2H), 0.92 (s, 3H).

[0226] compound 13 [ka]

[0227] Process 1 13A (5 g, 22.60 mmol, 1 equiv.) was added to DCM (100 mL), followed by the addition of n-propylamine (4.01 g, 67.80 mmol, 3 equiv.) at room temperature. After the addition, the system was stirred overnight at room temperature. Sodium cyanoborohydride (2.84 g, 45.20 mmol, 2 equiv.) was slowly added at room temperature, and after the addition, the system was stirred overnight at room temperature. The reaction solution was poured into 100 mL of water, and the phases were separated. The aqueous phase was extracted with DCM (100 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (DCM:MeOH = 50:1 to 10:1) to give 13B (1.5 g, 25.1% yield) as a white solid. MS-ESI: m / z 265.2 [M+H] + . Process 2 1F (2 g, 6.30 mmol, 1 equiv) was dissolved in DMF (40 mL). The temperature was lowered to approximately 0 °C, and HBTU (2.86 g, 7.56 mmol, 1.2 equiv) and DIEA (3.26 g, 25.20 mmol, 4 equiv) were added in counter-rotation. The mixture was stirred at 0 °C for 10 min, and then 13B (2 g, 7.56 mmol, 1.2 equiv) was added. After the addition, the mixture was stirred at room temperature overnight. When LCMS showed that the starting material 1F had disappeared, the reaction solution was poured into water (120 mL) and extracted with EA (100 mL × 5). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (DCM:MeOH = 20:1 to 10:1). The product was concentrated under reduced pressure to give a yellow solid 13C (1.2 g, 36.1% yield). MS-ESI: m / z 527.2 [M+H] + . Process 3 13C (1.2 g, 2.28 mmol, 1 equiv.) was added to a mixture of dioxane (40 mL) and water (4 mL), followed by the addition of 10D (530.3 mg, 2.28 mmol, 1 equiv.) and anhydrous potassium phosphate (1.45 g, 6.83 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(PPh3)4 (220 mg) was added. The mixture was then purged twice with argon and heated to 90 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 100 mL of water and extracted with EA (100 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 2:1 to 0:1) to give 13D (250 mg, 19.9% ​​yield) as a white solid. MS-ESI: m / z 554.3 [M+H] + . Process 4 13D (250 mg, 0.45 mmol, 1 equiv.) was added to methanol (10 mL), and then sodium borohydride (51.3 mg, 1.35 mmol, 3 equiv.) was added slowly in small portions at room temperature. After the addition, the system was allowed to react at room temperature for 2 h. The reaction was quenched with 5 mL of saturated aqueous ammonium chloride, and the mixture was concentrated under reduced pressure to remove the solvent. The solid was directly purified by thin layer chromatography to give a white solid 13E (124 mg, 49.4% yield). MS-ESI: m / z 556.2 [M+H] + . Process 5 13E (124 mg, 0.22 mmol, 1 equiv.) was dissolved in EA (5 mL), and then 4 N HCl in dioxane (0.5 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed the disappearance of the starting material, the mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO3 solution, extracted with EA (10 mL × 3), concentrated, mixed with silica gel, subjected to column chromatography (DCM:MeOH = 30:1 to 10:1), and lyophilized to give 13 (25 mg, 24.6% yield) as a white powder. MS-ESI: m / z 456.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 2.0 Hz, 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.32 (s, 1H), 7.28 - 7.26 (d, J = 7.7 Hz, 1H), 6.99 - 6.97 (d, J = 7.6 Hz, 1H), 6.86 (s, 2H), 6.47 - 6.45 (d, J = 8.1 Hz, 3H), 5.08 (s, 2H), 4.61 (s, 2H), 4.48 (s, 2H), 3.32 - 3.21 (m, 2H), 2.79 (s, 2H), 1.56 - 1.52 (m, 2H), 1.23 (s, 1H), 0.85 - 0.81 (m, 3H).

[0228] compound 14 [ka]

[0229] Process 1 At room temperature, 14A (4.5 g, 20.2 mmol) and propionic acid (100 mL) were added to a 250 mL three-neck flask. The reaction mixture was heated to 125 °C, and HNO (3.2 g, 50.8 mmol) was added dropwise while controlling the internal temperature between 120 and 130 °C. The reaction mixture was stirred at 125 °C for 1 h, and completion of the reaction was confirmed by LCMS. The reaction mixture was cooled to room temperature, slowly poured into ethanol (500 mL), and filtered. The filter cake was rinsed with ethanol (100 mL), water (100 mL), and ethanol (100 mL), successively. The filter cake was collected and dried to give a yellow solid, 14B (3 g, 55.6% yield). MS-ESI: m / z 269.0 [M+H] + . Process 2 At room temperature, 14B (3 g, 11.2 mmol) was added to a 250 mL one-neck flask and dissolved in EtOH (50 mL) and HO (10 mL). Then, NH4Cl (1.8 g, 33.6 mmol) and iron powder (3.1 g, 56 mmol) were added. The reaction was stirred at 80 °C for 2 h, and LCMS showed the reaction was complete. The reaction solution was filtered before cooling. Ethyl acetate (200 mL) and water (100 mL) were added to the filtrate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography (PE / EA = 10:1 to 3:1) to give 14C (2 g, 75% yield) as a yellow solid. MS-ESI: m / z 241.0 [M+H] + . Process 3 14C (2 g, 8.4 mmol), DCM (20 mL), and TEA (1.3 g, 12.6 mmol) were added to a 100 mL three-neck flask. n-Valeryl chloride (1.2 g, 10.1 mmol) was slowly added in an ice bath, and the reaction mixture was stirred at 25 °C for 1 h. When LCMS showed the reaction was complete, the reaction solution was poured into water (20 mL) and extracted with EA (50 mL × 3). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography (PE / EA = 3 / 1) to isolate 14D (1.5 g, 55.6% yield) as a yellow oily liquid. MS-ESI: m / z 323.0 [M+H] + . Process 4 At room temperature, 14D (1.5 g, 4.7 mmol) and pyridine (50 mL) were added to a 250 mL one-neck flask, followed by the addition of P2S5 (9 g, 47 mmol). The reaction was stirred at 120 °C overnight. The reaction solution was concentrated by rotary evaporation, poured into water (100 mL), and extracted with EA (3 × 100 mL). The organic phase was collected, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography (PE / EA = 10 / 1) to give a yellow solid 14E (1 g, 66.7% yield). MS-ESI: m / z 321.0 [M+H] + . Process 5 At room temperature, 14E (2.6 g, 8.1 mmol) and CHCl3 (50 mL) were added to a 250 mL one-neck flask, and then m-CPBA (3.3 g, 16.2 mmol) was slowly added in an ice bath. The reaction mixture was stirred at 25 °C overnight. The reaction mixture was poured into DCM (200 mL). The mixture was washed successively with 5% sodium thiosulfate (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography (PE / EA = 3 / 1) to give 14F (2 g, 73.5% yield) as a yellow oily liquid. MS-ESI: m / z 337.0 [M+H] + . Process 6 14F (2 g, 5.95 mmol) was added to a 100 mL three-neck flask, followed by the slow addition of POCl3 (27 g, 178.5 mmol) in an ice bath. DIEA (2.3 g, 17.85 mmol) was added dropwise slowly while maintaining the internal temperature at 15 °C, and the reaction mixture was stirred at 100 °C overnight. When LCMS showed the reaction was complete, the reaction solution was cooled to room temperature, concentrated by rotary evaporation under reduced pressure to remove the solvent, and slowly poured into ice water (100 mL). The mixture was adjusted to pH 9 with solid potassium carbonate, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, the crude product was purified by column chromatography (PE / EA = 10 / 1) to give 14G (1.8 g, 85.7% yield) as a yellow oily liquid. MS-ESI: m / z 355.0 [M+H] + . Process 7 A 100 mL single-neck flask was charged with 14G (1.8 g, 5.1 mmol) and toluene (20 mL) at room temperature, followed by 14H (8.5 g, 51 mmol) and 2-chlorobenzoic acid (799 mg, 5.1 mmol) in that order at room temperature. The reaction mixture was stirred at 120 °C overnight. When LCMS showed the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. 100 mL of water was added, and the mixture was extracted with EA (3 × 100 mL). The organic phase was collected, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by reverse-phase column chromatography (neutral system) to give a yellow solid, 14I (2 g, 80% yield). MS-ESI: m / z 486.1 [M+H] + . Process 8 A 100 mL single-neck flask was charged with 14I (0.5 g, 1.03 mmol) and DMF (20 mL) at room temperature, followed by 14J (377 mg, 2.06 mmol), Pd(PPh3)2Cl2 (75 mg, 0.103 mmol), and Cu2O (442 mg, 3.09 mmol) in that order at room temperature. The reaction mixture was stirred overnight at 110 °C under a N2 atmosphere. After completion of the reaction was confirmed by LCMS, 100 mL of water was added to the reaction solution, and the mixture was extracted with EA (100 mL × 3). The organic phase was collected, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography (PE:EA = 3:1) to obtain 14K (0.3 g, 49.5% yield) as a yellow oily liquid. MS-ESI: m / z 589.3 [M+H] + . Process 9 A 100 mL single-neck flask was charged with 14K (0.3 g, 0.51 mmol) and THF (20 mL) at room temperature, followed by the addition of Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight. When LCMS showed the reaction was complete, the reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid 14L (0.2 g, 66.7% yield). MS-ESI: m / z 593.3 [M+H] + . Step 10 14L (200 mg, 0.34 mmol) was added to a 100 mL single-neck flask at room temperature, and then TFA (5 mL) was slowly added in an ice bath. The reaction mixture was stirred at 80 °C for 15 min. After LCMS showed the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by reverse-phase column chromatography (neutral system) to give a white solid 14 (77.6 mg, 66.9% yield). MS-ESI: m / z 343.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.57 (d, J = 8.3 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.18 (d, J = 7.2 Hz, 1H), 3.23 - 3.15 (m, 2H), 3.11 - 3.02 (m, 2H), 2.72 (t, J = 6.7 Hz, 2H), 1.97 - 1.85 (m, 2H), 1.76 - 1.65 (m, 2H), 1.64 - 1.46 (m, 6H), 1.02 (t, J = 7.4 Hz, 3H).

[0230] compound 15 [ka]

[0231] Process 1 15A (5 g, 23.14 mmol, 1 equiv.) was dissolved in acetonitrile (100 mL), and then tert-butyl N-hydroxycarbamate 15B (4.01 g, 30.09 mmol, 1.3 equiv.) was added at 0 °C. DBU (3.52 g, 23.14 mmol, 1 equiv.) was then slowly added dropwise. After the addition, the system was warmed to room temperature and stirred for 3 h. When LCMS showed that 15A had disappeared, the reaction solution was concentrated under reduced pressure, and then saturated potassium carbonate solution (100 mL) was added. The mixture was extracted with DCM (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (PE:EA = 5:1) to give 15C (4.5 g, 72.5% yield) as a white solid. MS-ESI: m / z 291.0 [M+Na] + . Process 2 15C (4.5 g, 16.77 mmol, 1 equiv) was dissolved in DMF (50 mL), and the mixture was cooled to 0 °C. NaH (671 mg, 16.77 mmol, 1 equiv, 60%) was added in one portion, and the mixture was stirred at 0 °C for 10 min. After that, iodopropane (3.14 g, 18.45 mmol, 1.1 equiv) was added dropwise. After the addition, the reaction was warmed to room temperature and reacted overnight. When LCMS showed that the starting material 15C had disappeared, the reaction solution was poured into ice water (150 mL) and extracted with EA (100 mL × 3). The combined organic phase was washed successively with 10% aqueous citric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and saturated brine (100 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography (PE:EA = 5:1) to give a yellow solid 15D (4.5 g, 86.4% yield). MS-ESI: m / z 333.2 [M+Na] + . Process 3 15D (4.5 g, 14.52 mmol, 1 equiv.) was dissolved in EA (50 mL), and then 4 N hydrochloride salt in dioxane (50 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed that 15D had disappeared, the reaction mixture was directly filtered. The filter cake was rinsed with EA (100 mL), immediately transferred to a flask, and dried under vacuum to give a yellow solid 15E (2.5 g, 83.3% yield). MS-ESI: m / z 211.2 [M+H] + . Process 4 1F (3 g, 9.45 mmol, 1 equiv.) and 15E (2.5 g, 10.39 mmol, 1.1 equiv.) were added to a mixture of DMA (30 mL) and DCM (30 mL). After purging the system twice with argon, EDCI (7.24 g, 37.79 mmol, 4 equiv.) was added in one portion, followed by purging twice more with argon. The mixture was then warmed to room temperature and allowed to react overnight. When LCMS showed the reaction was complete, the reaction solution was poured into 100 mL of water and extracted with DCM (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and subjected to column chromatography to give 15F (1.9 g, 42.5% yield) as a yellow solid. MS-ESI: m / z 473.1 [M+H] + . Process 5 15F (1.9 g, 4.01 mmol, 1 equiv.) was added to a mixture of dioxane (50 mL) and water (5 mL), followed by the addition of 10D (936 mg, 4.01 mmol, 1 equiv.) and anhydrous potassium phosphate (2.56 g, 12.04 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(PPh3)4 (200 mg) was added. The mixture was then purged twice with argon and heated to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into water (150 mL) and extracted with EA (150 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (DCM:MeOH = 20:1) to give 15G (900 mg, 45% yield) as a dark red solid. MS-ESI: m / z 500.2 [M+H] + . Process 6 15G (700 mg, 1.4 mmol, 1 equiv.) was added to methanol (20 mL), and then sodium borohydride (32 mg, 0.84 mmol, 0.6 equiv.) was added slowly in small portions at room temperature. After the addition, the system was allowed to react at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), and the reaction solution was extracted with DCM (50 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid 15H (200 mg, 22.2% yield). MS-ESI: m / z 502.2 [M+H] + . Process 7 15H (200 mg, 0.31 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney Ni (0.1 g). The reaction was purged with hydrogen twice and stirred under a hydrogen atmosphere at room temperature for 3 h. When LCMS showed that 15H was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, triturated with petroleum ether (10 mL) and methanol (2 mL), and filtered to give 15 (28 mg, 14.9% yield) as a yellow solid. MS-ESI: m / z 472.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.0, 2.0 Hz, 1H), 7.09 (s, 1H), 6.89 (d, J = 8.1 Hz, 2H), 6.83 (s, 2H), 6.41 (d, J = 8.2 Hz, 2H), 5.37 (t, J = 5.8 Hz, 1H), 5.16 (s, 2H), 4.69 - 4.52 (m, 4H), 3.63 (t, J = 7.0 Hz, 2H), 2.77 (s, 2H), 1.71 - 1.58 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H).

[0232] compound 16 [ka]

[0233] Process 1 16A (0.5 g, 1.03 mmol) and DMF (20 mL) were added to a 100 mL single-neck flask at room temperature, followed by 16B (348 mg, 2.06 mmol), Pd(PPh3)2Cl2 (75 mg, 0.103 mmol), and Cu2O (442 mg, 3.09 mmol) at room temperature. The system was stirred overnight at 110 °C under a N2 atmosphere until LCMS showed the reaction was complete. 100 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 100 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 16C (0.3 g, 50.8% yield) as a yellow oily liquid. MS-ESI: m / z 575.3 [M+H] + . Process 2 A 100 mL single-neck flask was charged with 16C (0.3 g, 0.52 mmol) and THF (20 mL) at room temperature, followed by the addition of Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight until LCMS showed the reaction was complete. The reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid 16D (0.2 g, 66.2% yield). MS-ESI: m / z 579.4 [M+H] + . Process 3 At room temperature, 16D (200 mg, 0.35 mmol) was added to a 100 mL single-neck flask, and then TFA (5 mL) was added slowly in an ice bath. The system was stirred at 80 °C for 15 min until LCMS showed the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by reverse-phase column chromatography (neutral system) to give a white solid 16 (59.4 mg, 52.6% yield). MS-ESI: m / z 329.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.58 (dd, J = 8.4, 1.3 Hz, 1H), 7.47 (dd, J = 8.4, 7.2 Hz, 1H), 7.22 (dd, J = 7.3, 1.3 Hz, 1H), 3.24 - 3.17 (m, 2H), 3.17 - 3.10 (m, 2H), 2.88 - 2.81 (m, 2H), 1.97 - 1.87 (m, 2H), 1.83 - 1.67 (m, 4H), 1.58 - 1.46 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0234] compound 17 [ka]

[0235] Process 1 17A (0.5 g, 1.03 mmol) and DMF (20 mL) were added to a 100 mL single-neck flask at room temperature, followed by 17B (203 mg, 2.06 mmol), Pd(PPh3)2Cl2 (75 mg, 0.103 mmol), and Cu2O (442 mg, 3.09 mmol) at room temperature. The mixture was stirred overnight at 110 °C under a N2 atmosphere until LCMS showed the reaction was complete. 100 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 100 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 17C (0.3 g, 48.4% yield) as a yellow oily liquid. MS-ESI: m / z 603.4 [M+H] + . Process 2 To a 100 mL one-neck flask, 17C (0.3 g, 0.50 mmol) and THF (20 mL) were added at room temperature, followed by Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight until LCMS showed the reaction was complete. The reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid, 17D (0.2 g, 66.2% yield). MS-ESI: m / z 607.4 [M+H] + . Process 3 At room temperature, 17D (200 mg, 0.33 mmol) was added to a 100 mL single-neck flask, and then TFA (5 mL) was added slowly in an ice bath. The system was stirred at 80 °C for 15 min until LCMS showed the reaction was complete. The reaction mixture was concentrated by rotary evaporation under reduced pressure and purified by reverse-phase column chromatography (neutral system) to give a white solid 17 (51.4 mg, 43.7% yield). MS-ESI: m / z 357.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.58 (dd, J = 8.3, 1.3 Hz, 1H), 7.46 (dd, J = 8.4, 7.2 Hz, 1H), 7.20 (dd, J = 7.3, 1.3 Hz, 1H), 3.25 - 3.18 (m, 2H), 3.13 - 3.07 (m, 2H), 2.78 - 2.71 (m, 2H), 1.98 - 1.87 (m, 2H), 1.78 - 1.67 (m, 2H), 1.62 - 1.39 (m, 8H), 1.02 (t, J = 7.4 Hz, 3H).

[0236] compound 18 [ka]

[0237] Process 1 At room temperature, 18A (10 g, 44.8 mmol) and propionic acid (200 mL) were added to a 250 mL three-neck flask. The reaction was heated to 125 °C, and then HNO (8.6 g, 136.6 mmol) was added dropwise while controlling the internal temperature between 120 and 130 °C. The reaction was stirred at 125 °C for 1 h, and LCMS showed the reaction was complete. The reaction solution was cooled to room temperature, poured slowly into ethanol (200 mL), and filtered. The filter cake was rinsed with ethanol (100 mL), water (100 mL), and ethanol (100 mL), successively. The filter cake was collected and dried to give a yellow solid, 18B (7 g, 58% yield). MS-ESI: m / z 269.0 [M+H] + . Process 2 At room temperature, 18B (7 g, 26.1 mmol) was added to a 250 mL one-neck flask and dissolved in EtOH (100 mL) and HO (20 mL). Then, NHCl (4.23 g, 78.3 mmol) and Fe powder (7.31 g, 130.5 mmol) were added. The reaction was stirred at 80 °C for 2 h, and LCMS showed the reaction was complete. The reaction solution was filtered before cooling. Ethyl acetate (200 mL) and water (100 mL) were added to the filtrate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography (DCM / MeOH = 10:1) to give 18C (4.5 g, 72% yield) as a yellow solid. MS-ESI: m / z 239.0[M+H] + . Process 3 18C (2.2 g, 9.2 mmol) and DCM (100 mL) were added to a 250 mL three-neck flask, followed by TEA (1.4 g, 13.8 mmol). 18D (1.35 g, 11.04 mmol) was slowly added in an ice bath, and the reaction was stirred at 25 °C for 1 h until LCMS showed the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with EA (3 × 50 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give a yellow solid 18E (1.6 g, 53.5% yield). MS-ESI: m / z 325.0 [M+H] + . Process 4 At room temperature, 18E (2.8 g, 8.6 mmol) and pyridine (120 mL) were added to a 250 mL one-neck flask, followed by the addition of P2S5 (16.4 g, 86 mmol). The reaction was stirred at 120 °C overnight, and LCMS showed the reaction was complete. The reaction solution was concentrated by rotary evaporation to remove the solvent, poured into water (100 mL), and extracted with EA (3 × 100 mL). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by chromatography (PE / EA = 10 / 1) to give a yellow solid 18F (0.5 g, 18.5% yield). MS-ESI: m / z 323.0 [M+H] + . Process 5 At room temperature, 18F (0.5 g, 1.55 mmol) and CHCl3 (10 mL) were added to a 250 mL one-neck flask, and then m-CPBA (0.53 g, 3.1 mmol) was slowly added in an ice bath. The reaction was stirred at 25 °C for 2 h, and LCMS showed the reaction was complete. The reaction mixture was poured into DCM (50 mL). The mixture was washed successively with 5% sodium thiosulfate (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 18G (0.43 g, 82.6% yield) as a yellow oily liquid. MS-ESI: m / z 339.0 [M+H] + . Process 6 18G (0.43 g, 1.27 mmol) was added to a 50 mL one-neck flask, followed by the slow addition of POCl3 (5.1 g, 33.1 mmol) in an ice bath. DIPEA (0.43 g, 3.31 mmol) was added dropwise slowly while controlling the internal temperature at 15 °C. The system was stirred at 100 °C for 2 h, and LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature, concentrated by rotary evaporation under reduced pressure to remove the solvent, and slowly poured into ice water (50 mL). The mixture was adjusted to pH 9 with solid potassium carbonate, and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography (PE / EA = 10:1) to give 18H (0.32 g, 71.1% yield) as a yellow oil. MS-ESI: m / z 357.0[M+H] + . Process 7 At room temperature, 18H (0.32 g, 0.9 mmol) and toluene (5 mL) were added to a 50 mL one-neck flask, followed by the addition of 2,4-dimethoxybenzylamine (1.5 g, 9 mmol) and 2-chlorobenzoic acid (0.14 g, 0.9 mmol). The reaction was stirred at 120 °C overnight, and LCMS indicated the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added, and the mixture was extracted with EA (3 × 30 mL). The organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (neutral system) to give a yellow solid, 18I (0.14 g, 32.5% yield). MS-ESI: m / z 488.0 [M+H] + . Process 8 At room temperature, 18I (0.14 g, 0.28 mmol) and DMF (5 mL) were added to a 50 mL one-neck flask, followed by the addition of 18J (0.102 g, 0.56 mmol), Pd(PPh3)2Cl2 (0.02 g, 0.028 mmol), and Cu2O (0.12 g, 0.84 mmol) sequentially at room temperature. The system was stirred overnight at 110 °C under a N2 atmosphere until LCMS showed the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 30 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 18K (0.12 g, 70.5% yield) as a yellow oily liquid. MS-ESI: m / z 591.2 [M+H] + . Process 9 At room temperature, 18K (0.12 g, 0.2 mmol) and THF (10 mL) were added to a 50 mL one-neck flask, followed by the addition of Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight until LCMS showed the reaction was complete. The reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid, 18L (0.1 g, 83.3% yield). MS-ESI: m / z 595.3 [M+H] + . Step 10 At room temperature, 18L (0.1 g, 0.17 mmol) was added to a 50 mL one-neck flask, and then TFA (3 mL) was added slowly in an ice bath. The system was stirred at 80 °C for 15 min until LCMS showed the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by reverse-phase column chromatography (neutral system) to give a white solid 18 (18 mg, 31.1% yield). MS-ESI: m / z 345.2[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.59 (dd, J = 8.3, 1.3 Hz, 1H), 7.49 (dd, J = 8.4, 7.2 Hz, 1H), 7.23 (dd, J = 7.2, 1.3 Hz, 1H), 4.98 (s, 2H), 3.77 (q, J = 7.0 Hz, 2H), 3.19 - 3.11 (m, 2H), 2.78 (t, J = 6.9 Hz, 2H), 1.82 - 1.70 (m, 2H), 1.69 - 1.55 (m, 4H), 1.33 (t, J = 7.0 Hz, 3H).

[0238] compound 19 [ka]

[0239] Process 1 19A (2 g, 8.4 mmol) and DCM (100 mL) were added to a 250 mL three-neck flask, followed by TEA (1.27 g, 12.6 mmol). 19B (1.21 g, 10.08 mmol) was slowly added in an ice bath, and the reaction was stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with EA (3 × 50 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give a yellow solid 19C (1.4 g, 51.8% yield). MS-ESI: m / z 323.0 [M+H] + . Process 2 At room temperature, 19C (1.4 g, 4.3 mmol) and pyridine (60 mL) were added to a 100 mL one-neck flask, followed by the addition of P2O5 (6.1 g, 43 mmol). The reaction was stirred at 120 °C overnight, and LCMS showed the reaction was complete. The reaction solution was concentrated by rotary evaporation to remove the solvent, poured into water (100 mL), and extracted with EA (3 × 50 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by chromatography (PE / EA = 10 / 1) to give a yellow solid 19D (0.5 g, 37.8% yield). MS-ESI: m / z 305.1 [M+H] + . Process 3 At room temperature, 19D (0.5 g, 1.6 mmol) and CHCl3 (10 mL) were added to a 50 mL one-neck flask, and then m-CPBA (0.65 g, 3.2 mmol) was slowly added in an ice bath. The reaction was stirred at 25 °C for 2 h, and LCMS showed the reaction was complete. The reaction mixture was poured into DCM (50 mL). The mixture was washed successively with 5% sodium thiosulfate (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 19E (0.4 g, 76% yield) as a yellow oily liquid. MS-ESI: m / z 321.0 [M+H] + . Process 4 19E (0.4 g, 1.25 mmol) was added to a 250 mL three-neck flask, followed by the slow addition of POCl3 (5.75 g, 37.5 mmol) in an ice bath. DIPEA (0.48 g, 3.75 mmol) was added dropwise slowly while controlling the internal temperature at 15 °C. The system was stirred at 100 °C for 2 h, and LCMS indicated the completion of the reaction. The reaction solution was cooled to room temperature, concentrated by rotary evaporation under reduced pressure to remove the solvent, and slowly poured into ice water (50 mL). The mixture was adjusted to pH 9 with solid potassium carbonate, and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography (PE / EA = 10:1) to give 19F (0.35 g, 83.3% yield) as a yellow oily liquid. MS-ESI: m / z 339.0 [M+H] + . Process 5 At room temperature, 19F (0.35 g, 1.04 mmol) and toluene (5 mL) were added to a 50 mL one-neck flask, followed by the addition of 2,4-dimethoxybenzylamine (1.74 g, 10.4 mmol) and 2-chlorobenzoic acid (0.16 g, 1.04 mmol). The reaction was stirred at 120 °C overnight, and LCMS showed the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added, and the mixture was extracted with EA (3 × 30 mL). The organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (neutral system) to give a yellow solid, 19G (0.2 g, 41.1% yield). MS-ESI: m / z 470.0 [M+H] + . Process 6 19G (0.2 g, 0.43 mmol) and DMF (5 mL) were added to a 50 mL one-neck flask at room temperature, followed by the addition of 19H (0.16 g, 0.86 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.043 mmol), and Cu2O (0.18 g, 1.29 mmol) at room temperature. The system was stirred overnight at 110 °C under a N2 atmosphere until LCMS showed the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 30 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 19I (0.12 g, 49.4% yield) as a yellow oily liquid. MS-ESI: m / z 573.4 [M+H] + . Process 7 At room temperature, 19I (0.12 g, 0.21 mmol) and THF (10 mL) were added to a 50 mL one-neck flask, followed by the addition of Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight until LCMS showed the reaction was complete. The reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid 19J (96 mg, 80% yield). MS-ESI: m / z 577.4 [M+H] + . Process 8 At room temperature, 19J (0.096 g, 0.17 mmol) was added to a 50 mL one-neck flask, and then TFA (3 mL) was added slowly in an ice bath. The system was stirred at 80 °C for 15 min until LCMS showed the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by reverse-phase column chromatography (neutral system) to give a white solid 19 (22 mg, 40.5% yield). MS-ESI: m / z 327.3[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.54 (dd, J = 8.5, 1.2 Hz, 1H), 7.45 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 3.25 - 3.17 (m, 2H), 3.08 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.0 Hz, 2H), 1.99 - 1.88 (m, 2H), 1.79 - 1.68 (m, 2H), 1.64 - 1.44 (m, 6H), 1.02 (t, J = 7.4 Hz, 3H).

[0240] compound 20 [ka]

[0241] Process 1 19G (0.28 g, 0.6 mmol) and DMF (6 mL) were added to a 50 mL one-neck flask at room temperature, followed by the addition of 20A (0.254 g, 1.5 mmol), Pd(PPh3)2Cl2 (0.042 g, 0.06 mmol), and Cu2O (0.257 g, 1.8 mmol) sequentially at room temperature. The system was stirred overnight at 110 °C under a N2 atmosphere until LCMS showed the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 30 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 3 / 1) to give 20B (140 mg, 42% yield) as a yellow oily liquid. MS-ESI: m / z 559.2 [M+H] + . Process 2 At room temperature, 20B (0.14 g, 0.25 mmol) and THF (10 mL) were added to a 50 mL one-neck flask, followed by the addition of Pd / C (50 mg) at room temperature. The system was purged with H2 three times and stirred at 25 °C overnight until LCMS showed the disappearance of the starting material. The reaction solution was filtered through Celite and rinsed with THF (3 × 20 mL). The filtrate was concentrated by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give a yellow oily liquid 20C (120 mg, 85% yield). MS-ESI: m / z 563.4 [M+H] + . Process 3 At room temperature, 20C (0.12 g, 0.21 mmol) was added to a 50 mL one-neck flask, and then TFA (4 mL) was added slowly in an ice bath. The system was stirred at 80 °C for 15 min until LCMS showed the reaction was complete. The reaction solution was concentrated by rotary evaporation under reduced pressure and subjected to preparative reverse-phase chromatography (TFA system) to give a white solid 20 (4.2 mg, 6.3% yield). MS-ESI: m / z 313.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.76 - 7.66 (m, 2H), 7.47 (dd, J = 6.9, 1.5 Hz, 1H), 3.36 - 3.32 (m, 2H), 3.15 (t, J = 7.5 Hz, 2H), 3.04 - 2.95 (m, 2H), 2.02 - 1.92 (m, 2H), 1.90 - 1.77 (m, 4H), 1.61 - 1.49 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H).

[0242] compound 30 [ka]

[0243] Process 1 Compound 1A (533.5 g, 1.42 mol) was added to a 5 L three-neck flask at 25 °C, followed by EA (1500 mL). Bromoacetonitrile (10 g, 833.3 mmol) was added with mechanical stirring, and the mixture was heated to 77 °C and reacted overnight. When LCMS showed that 40% bromoacetonitrile remained, the reaction solution was cooled to 25 °C and filtered. The filter cake was washed with EA (500 mL), and the filtrate was concentrated under reduced pressure to give the yellow solid product, compound 1B (148 g, 45.8% yield). MS-ESI: m / z 416.02 [M+H] + . Process 2 Compound 1B (148 g, 356.25 mmol) was added to a 3 L three-neck flask at 25 °C, followed by the addition of toluene (800 mL). Compound 30A (80 g, 347.8 mmol) was added with stirring, and the mixture was allowed to react at room temperature overnight. When TLC showed that compound 30A had disappeared, the reaction solution was concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE / EA = 5 / 1) to give a yellow solid compound 30B (98 g, 72.5% yield). MS-ESI: m / z 347.0 [M+H] + . Process 3 Compound 30C (98 g, 266.88 mmol) was added to a 3 L three-neck flask at 25 °C, followed by the addition of AcOH (800 mL). The internal temperature was raised to 60 °C, and then Fe (74.52 g, 1334.4 mmol) was added slowly in small portions with stirring. After the addition, the system was heated to 85 °C and reacted for 3 h. When TLC showed the disappearance of the starting material, the reaction solution was cooled to approximately 60 °C, diluted with DCM (1000 mL), and filtered before cooling. The filter cake was washed with DCM (1000 mL), and the filtrate was concentrated under reduced pressure. EA (800 mL) was added, and the mixture was adjusted to pH 9 with saturated sodium bicarbonate solution and extracted with EA (800 mL × 3). The organic phase was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1) to give compound 30C (68 g, 79.9% yield) as a pale yellow solid. Process 4 4 N HCl / dioxane (700 mL) was added to a 2 L single-neck flask at 25 °C, followed by compound 30C (68 g, 132.28 mmol) at 0 °C. The system was allowed to react at room temperature overnight. When LCMS showed that the starting material was gone, the reaction solution was concentrated under reduced pressure to give compound 30D (59 g, 92% yield) as an off-white solid. MS-ESI: m / z 261.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 13.99 - 12.29 (m, 2H), 10.03 (s, 1H), 9.09 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.90 - 7.85 (m, 1H), 7.82 - 7.80 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.49 (s, 2H). Process 5 Compound 30D (3 g, 10.11 mmol, 1 equiv.) and compound 15E (2.62 g, 10.62 mmol, 1.05 equiv.) were added to a mixture of DMA (30 mL) and DCM (30 mL). After purging the system twice with argon, EDCI (7.75 g, 40.44 mmol, 4 equiv.) was added in one portion, followed by two additional purgings with argon. The mixture was then warmed to room temperature and allowed to react overnight. When LCMS showed the starting material was gone, the reaction solution was poured into 100 mL of water and extracted three times with DCM (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, mixed with silica gel, and purified by column chromatography to give a yellow solid, 30E (1.7 g, 38% yield). MS-ESI: m / z 453.2 [M+H] + . Process 6 Compound 30E (700 mg, 1.55 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney nickel (0.1 g). The system was purged with hydrogen twice and stirred at room temperature for 3 h. When LCMS showed a prominent peak associated with compound 30F, the mixture was filtered through Celite, and the filtrate was used directly in the next reaction. MS-ESI: m / z 423.2 [M+H] + . Process 7 THF (10 mL) and water (10 mL) were added to the methanolic reaction solution from the previous step, followed by lithium hydroxide monohydrate (208 mg, 4.97 mmol, 3 equiv.). The system was stirred at room temperature for 3 h. When LCMS showed the disappearance of the starting material, the mixture was concentrated under reduced pressure and adjusted to pH 5-6 with 1 N hydrochloric acid. The resulting mixture was filtered, and the yellow filter cake was subjected to preparative HPLC to give a white solid 30 (8 mg, 1.3% yield over two steps). MS-ESI: m / z 409.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 7.52 (s, 1H), 7.42 - 7.40 (d, J = 7.4 Hz, 1H), 7.09 (s, 1H), 6.90 - 6.88 (d, J = 8.0 Hz, 2H), 6.42 - 6.40 (d, J = 8.2 Hz, 2H), 5.19 (s, 2H), 4.61 (s, 2H), 3.68 - 3.64 (t, J = 6.8 Hz, 2H), 2.82 (s, 2H), 1.69 - 1.64 (dd, J = 14.6, 7.6 Hz, 2H), 0.94 - 0.90 (t, J = 7.3 Hz, 3H).

[0244] compound 31 [ka]

[0245] Process 1 Compound 30E (2.4 g, 5.68 mmol, 1 equiv.) was added to a mixture of methanol (20 mL), THF (20 mL), and water (20 mL). The temperature was controlled at 0 °C using an ice-water bath, and lithium hydroxide monohydrate (715 mg, 17.04 mmol, 3 equiv.) was added. The mixture was reacted in an ice-water bath for 3 h. When LCMS showed the starting material was gone, the reaction solution was poured into 50 mL of water, adjusted to pH 5-6 with 1 N hydrochloric acid, and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was triturated with acetonitrile (10 mL) and filtered to give yellow solid 31A (1 g, 43% yield). MS-ESI: m / z 439.1 [M+H] + . Process 2 Compound 31A (400 mg, 0.912 mmol, 1 equiv.) was dissolved in DMF (8 mL), followed by the addition of HATU (382 mg, 1.00 mmol, 1.1 equiv.) and DIEA (484 mg, 3.74 mmol, 4.1 equiv.) while controlling the temperature at 0 °C. After stirring the system for 10 min while maintaining the temperature at 0 °C, choline chloride (140 mg, 1.00 mmol) was added in one portion. The system was then warmed to room temperature and stirred overnight. LCMS showed the formation of product 31B, and the mixture was used directly in the next reaction without further workup. MS-ESI: m / z 524.3 [M] + . Process 3 Raney nickel (100 mg) was added to the reaction solution from the previous step. The system was purged with hydrogen twice and stirred at room temperature for 3 hours. When LCMS showed that the starting material had disappeared and the desired product had formed, the mixture was filtered, and the filtrate was subjected to preparative HPLC to give a white solid 31 (6 mg, 1.3% yield for two steps). MS-ESI: m / z 494.1 [M] + . 1H NMR (400 MHz, DMSO) δ 7.66 (d, J = 1.6 Hz, 1H), 7.51 - 7.49 (dd, J = 8.1, 1.7 Hz, 1H), 7.45 - 7.42 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 6.86 - 6.84 (d, J = 8.2 Hz, 2H), 6.40 - 6.38 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 4.70 (s, 2H), 4.58 (s, 2H), 3.85 - 3.78 (m, 2H), 3.65 - 3.61 (d, J = 7.1 Hz, 2H), 3.20 (s, 9H), 3.10 (s, 1H), 2.73 (s, 2H), 1.67 - 1.61 (dd, J = 14.0, 7.0 Hz, 2H), 0.92 - 0.88 (t, J = 7.4 Hz, 4H).

[0246] Compound 32

change

[0247] Project 1 Compound 15F (1.0 g, 2.11 mmol, 1 equiv.) was added to a mixture of 1,4-dioxane (20 mL) and water (2 mL), followed by the addition of compound 32A (556 mg, 2.11 mmol, 1 equiv.) and anhydrous potassium phosphate (1.35 g, 6.34 mmol, 3 equiv.). The system was purged with argon twice, and then Pd(PPh3)4 (100 mg) was added. The mixture was then purged with argon twice and heated to 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 100 mL of water and extracted three times with ethyl acetate (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give a yellow solid 32B (400 mg, 36% yield). MS-ESI: m / z 530.2 [M+H] + . Process 2 Compound 32B (400 mg, 0.756 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney nickel (0.1 g). The system was purged with hydrogen twice and stirred at room temperature for 3 h. When LCMS showed a prominent product peak, the mixture was filtered through Celite, and the filtrate was used directly in the next reaction. MS-ESI: m / z 500.2 [M+H] + . Process 3 THF (10 mL) and water (10 mL) were added to the reaction solution from the previous step, followed by lithium hydroxide monohydrate (91 mg, 2.27 mmol, 3 equiv.). The system was stirred at room temperature for 3 h. When LCMS showed the disappearance of the starting material, the mixture was concentrated under reduced pressure and adjusted to pH 5-6 with 1 N hydrochloric acid. The resulting mixture was filtered, and the yellow filter cake was subjected to preparative HPLC to give a white solid 32 (21 mg, 5.7% yield over two steps). MS-ESI: m / z 486.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.87 - 11.32 (m, 1H), 9.87 (s, 1H), 9.26 (s, 1H), 9.20 (d, J = 2.2 Hz, 1H), 9.13 - 9.12 (d, J = 1.8 Hz, 1H), 8.55 - 8.54 (t, J = 2.0 Hz, 1H), 7.88 - 7.86 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.70 - 7.68 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 7.01 - 6.99 (d, J = 8.2 Hz, 2H), 6.59 - 6.57 (d, J = 8.1 Hz, 2H), 4.70 (s, 2H), 3.70 (s, 2H), 3.26 (s, 2H), 1.73 - 1.60 (m, 2H), 0.94 - 0.91 (t, J = 7.4 Hz, 3H).

[0248] compound 33 [ka]

[0249] Process 1 Compound 33A (5 g, 23.14 mmol, 1 equiv.) was added to DMF (100 mL), followed by the sequential addition of potassium carbonate (11.20 g, 81.01 mmol, 3.5 equiv.) and compound 33B (2.71 g, 27.77 mmol, 1.2 equiv.). After the addition, the system was stirred at room temperature for 16 h. When LCMS showed that starting material 33A had disappeared, the reaction solution was poured into 300 mL of water and extracted twice with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was mixed with silica gel and purified by column chromatography (PE:EA = 2:1) to give a white solid 33C (2 g, 44% yield). MS-ESI: m / z 197.0 [M+H] + . Process 2 Compound 1F (3.24 g, 10.20 mmol, 1 equiv.) and compound 33C (2 g, 10.20 mmol, 1 equiv.) were added to a mixture of DMA (60 mL) and DCM (60 mL). After purging the system twice with argon, EDCI (7.82 g, 40.81 mmol, 4 equiv.) was added in one portion, followed by two further purgings with argon. The mixture was warmed to room temperature and allowed to react overnight. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 180 mL of water and extracted three times with DCM (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography to give a yellow solid, 33D (1.9 g, 40.5% yield). MS-ESI: m / z 459.2 [M+H] + . Process 3 Compound 33D (1.9 g, 4.14 mmol, 1 equiv.) was added to a mixture of 1,4-dioxane (40 mL) and water (4 mL), followed by the addition of compound 10D (964 mg, 4.14 mmol, 1 equiv.) and anhydrous potassium phosphate (2.63 g, 12.41 mmol, 3 equiv.). The system was purged twice with argon, followed by the addition of Pd(PPh3)4 (200 mg). The system was then purged twice more with argon and heated to 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the mixture was cooled to room temperature and the phases were separated. The organic phase was concentrated under reduced pressure to give the black crude product 33E, which was used directly in the next reaction. MS-ESI: m / z 486.2 [M+H] + . Process 4 The crude product of compound 33E from the previous step (theoretical amount: 2.01 g, 4.14 mmol, 1 equiv.) was added to methanol (50 mL), and then sodium borohydride (157 mg, 4.14 mmol, 1 equiv.) was added slowly in small portions at room temperature. After the addition, the system was allowed to react at room temperature for 2 h. When LCMS showed that the starting material was gone, the reaction was quenched with saturated aqueous ammonium chloride (1 mL). The mixture was concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (MeOH:DCM = 0-8%) to give a brown solid 33F (400 mg, 19.8% yield over two steps). MS-ESI: m / z 488.2 [M+H] + . Process 5 Compound 33F (100 mg, 0.205 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney nickel (0.1 g) in an ice-water bath. The system was purged with hydrogen twice and stirred in an ice-water bath for 3 h. When LCMS showed no starting material, the reaction solution was filtered through Celite, concentrated, and purified by reverse-phase column chromatography to give 33 (20 mg, 21.5% yield) as an off-white solid. MS-ESI: m / z 458.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.00 - 7.99 (t, J = 2.0 Hz, 1H), 7.44 - 7.42 (d, J = 8.2 Hz, 1H), 7.33 - 7.32 (d, J = 1.8 Hz, 1H), 7.28 - 7.26 (dd, J = 8.1, 1.9 Hz, 1H), 7.15 (s, 1H), 7.03 - 7.01 (d, J = 8.3 Hz, 2H), 6.84 (s, 2H), 6.55 - 6.53 (d, J = 8.4 Hz, 2H), 5.38 - 5.35 (t, J = 5.8 Hz, 1H), 5.05 (s, 2H), 4.66 (s, 2H), 4.62 - 4.60 (d, J = 5.7 Hz, 2H), 3.82 - 3.77 (q, J = 7.0 Hz, 2H), 2.82 (s, 2H), 1.01 - 0.97 (t, J = 7.0 Hz, 3H).

[0250] compound 34 [ka]

[0251] Process 1 Compound 15 (100 mg, 0.204 mmol, 1 equiv.) was added to phosphate buffer pH 5.5 (5 mL). The mixture was left at room temperature overnight. When LCMS showed that the starting material was gone, the reaction solution was subjected to preparative HPLC to give a yellow solid 34 (20 mg, 21.5% yield). MS-ESI: m / z 367.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 10.14 (s, 1H), 9.81 (s, 1H), 9.51 (s, 1H), 8.91 - 8.90 (d, J = 2.1 Hz, 1H), 8.65 - 8.64 (d, J = 1.7 Hz, 1H), 8.20 (s, 1H), 7.87 - 7.60 (m, 3H), 7.35 (s, 1H), 4.68 (s, 2H), 3.61 - 3.57 (t, J = 7.0 Hz, 4H), 3.39 (s, 2H), 1.71 - 1.58 (m, 2H), 0.93 - 0.89 (t, J = 7.4 Hz, 3H).

[0252] compound 35 [ka]

[0253] Process 1 Compound 15F (300 mg, 0.63 mmol, 1 equiv.), 1,4-dioxane (6 mL), and water (0.6 mL) were added to a 20 mL microwave reactor, followed by compound 35A (180 mg, 0.63 mmol, 1 equiv.) and anhydrous potassium phosphate (404 mg, 1.9 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (45 mg, 15% w / w) was added. The system was then purged twice more with argon and the reaction was carried out in a microwave reactor at 90 °C for 2 h. When LCMS showed that the starting material was gone, the reaction solution was poured into 15 mL of water and extracted three times with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid 35B (250 mg, 72% yield). MS-ESI: m / z 550.2 [M+H] + . Process 2 Compound 35B (250 mg, 0.45 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney nickel (0.1 g). The system was purged twice with hydrogen and stirred at 13–15°C for 36 h. When LCMS showed 50% conversion of the starting material and an increase in by-products, the reaction was quenched. The reaction solution was filtered through Celite, concentrated, and purified by preparative HPLC to give a yellow solid 35 (30 mg, 12.7% yield). MS-ESI: m / z 520.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.88 (S, 1H), 9.36 (s, 1H), 8.20 (s, 1H), 8.02 - 8.0 (d, J=8, 1H), 7.93 - 7.91 (d, J=8, 1H), 7.79 -7.69(m, 4H), 7.50 (s, 2H), 7.24 (s, 1H), 7.04 - 7.02 (d, J=8, 1H), 6.62 - 6.60 (d, J=8, 2H),, 4.72 (s, 2H), 3.74 - 3.71 (m, 4H), 3.29 (s, 2H), 1.73 - 1.67 (dd, J = 16, 8 Hz, 2H), 0.97 - 0.93 (t, J = 8 Hz, 3H).

[0254] compound 36 [ka]

[0255] Process 1 Compound 36A (1 g, 4.22 mmol, 1 equiv.) was dissolved in dioxane (15 mL), followed by the addition of compound 36B (1.18 mg, 4.64 mmol, 1.1 equiv.) and AcOK (828 mg, 8.44 mmol, 2 equiv.). After purging the system twice with argon, Pd(dppf)Cl2 (0.2 g) was added in one portion, followed by two additional purgings with argon. The reaction was then run in a microwave reactor at 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature and 3 mL of water was added. The mixture was poured directly onto a reverse-phase column, and the product was eluted with water (0.1% TFA). The resulting mixture was lyophilized to give compound 36C (400 mg, 41% yield) as a pale yellow solid. MS-ESI: m / z 203.0 [M+H] + . Process 2 Compound 15F (0.5 g, 1.06 mmol, 1 equiv.) and compound 36C (224 mg, 1.11 mmol, 1 equiv.) were added to a mixture of dioxane (10 mL) and water (1 mL), followed by potassium phosphate (673 mg, 3.17 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl (100 mg) was added in one portion. The mixture was then purged twice more with argon and the reaction was run in a microwave reactor at 85 °C for 2 h. When LCMS showed no starting material, the reaction solution was cooled to room temperature, dried over sodium sulfate, directly mixed with silica gel, and purified by column chromatography to give compound 36D (300 mg, 51% yield) as a yellow solid. MS-ESI: m / z 551.2 [M+H] + . Process 3 Compound 36D (100 mg, 0.172 mmol, 1 equiv.) was dissolved in MeOH (5 mL) with the temperature controlled at 15 °C, and then Raney nickel (20 mg) was added. The system was purged with hydrogen and stirred at 15 °C overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give compound 36 (28 mg, 29.6% yield) as an off-white solid. MS-ESI: m / z 521.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.171 - 9.166 (d, J = 2.0 Hz 1H), 8.939 - 8.934 (d, J = 2.0 Hz 1H), 8.507 - 8.496 (t, J1= 2.0 Hz, J2= 4.4 Hz 1H), 7.6 (s, 2H), 7.48 - 7.459 (d, J = 8.4 Hz 2H), 7.381 - 7.356 (dd, J1= 2.0 Hz, J2= 8.4 Hz, 1H), 7.108 (s, 1H), 6.899 - 6.878 (d, J = 8.4 Hz 3H), 6.425 - 6.404 (d, J = 8.4 Hz, 2H), 5.165 (s, 2H), 4.602 (s, 2H), 3.461 (m, 2H), 2.784 (s, 2H),1.908(S, 1H), 1.678 - 1.625 (m, 2H), 0.926 - 0.889 (t, J1= 7.6 Hz, J2= 14.8 Hz 3H).

[0256] Compound 37

change

[0257] Project 1 Compound 31A (200 mg, 0.456 mmol, 1 equiv.) was dissolved in DMF (5 mL), followed by the sequential addition of HOBT (73.97 mg, 0.547 mmol, 1.2 equiv.), EDCI (104.94 mg, 0.547 mmol, 1.2 equiv.), and DIEA (176.87 mg, 1.37 mmol, 3 equiv.) while controlling the temperature at 0 °C. After stirring at 0 °C for 10 min, compound 37A (67.65 mg, 0.547 mmol, 1.2 equiv.) was added. After the addition, the system was warmed to room temperature and stirred overnight. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted three times with DCM (5 mL × 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the reaction solution was mixed with silica gel and purified by column chromatography (DCM:MeOH = 10:1) to give a pale yellow solid 37B (75 mg, yield 36.8%). MS-ESI: m / z 508.2 [M+H] + . Process 2 Compound 37B (75 mg, 0.140 mmol, 1 equiv.) was dissolved in methanol (10 mL), and then Raney nickel (0.15 g) was added while controlling the temperature at 0 °C. The system was purged with hydrogen twice and stirred at room temperature for 1 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated, and purified by preparative HPLC to give an off-white solid 37 (25.3 mg, 35.7% yield) in the form of hydrochloride salt. MS-ESI: m / z 478.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 9.29 (s, 1H), 7.63 (s, 1H), 7.61 (d, J = 9.7 Hz, 2H), 7.17 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 7.5 Hz, 2H), 4.68 (s, 2H), 4.38 (t, J = 8.5 Hz, 1H), 4.08 (t, J = 9.3 Hz, 2H), 3.82 (dd, J = 9.9, 5.4 Hz, 3H), 3.71 (s, 1H), 3.69 (s, 1H), 3.67 (s, 1H), 3.57 (s, 1H), 3.55 (s, 1H), 3.23 (s, 2H), 2.76 (s, 1H), 1.67 (dd, J = 14.3, 7.2 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0258] compound 38 [ka]

[0259] Process 1 Compound 31A (200 mg, 0.456 mmol, 1 equiv) was dissolved in DMF (5 mL), followed by the addition of HOBT (73.97 mg, 0.547 mmol, 1.2 equiv), EDCI (104.94 mg, 0.547 mmol, 1.2 equiv), and DIEA (176.87 mg, 1.37 mmol, 3 equiv) sequentially at 0 °C. After stirring at 0 °C for 10 min, compound 38A (62.51 mg, 0.547 mmol, 1.2 equiv) was added. After the addition, the system was warmed to room temperature and stirred overnight. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted three times with DCM (5 mL × 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure to give a pale yellow solid 38B (crude, 180 mg). MS-ESI: m / z 535.3 [M+H]+ . Process 2 Compound 38B (150 mg, 0.280 mmol, 1 equiv.) was dissolved in methanol (10 mL), and then Raney nickel (0.15 g) was added while controlling the temperature at 0 °C. The system was purged with hydrogen twice and stirred at room temperature for 1 h. The reaction solution was filtered through Celite, concentrated, and purified by reverse-phase column chromatography (HO:ACN = 3:2) to give an off-white solid 38 (14.9 mg, 10.6% yield for two steps). MS-ESI: m / z 505.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.26 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.92 - 6.79 (m, 3H), 6.41 (s, 1H), 5.18 (s, 1H), 4.59 (s, 1H), 3.65 (t, J = 6.9 Hz, 3H), 2.89 - 2.63 (m, 3H), 2.18 (s, 2H), 1.95 (s, 2H), 1.74 (s, 2H), 1.63 (dd, J = 16.6, 9.3 Hz, 3H), 0.91 (t, J = 7.4 Hz, 2H).

[0260] compound 39 [ka]

[0261] Process 1 Compound 31A (200 mg, 0.456 mmol, 1 equiv.) was dissolved in DMF (5 mL), followed by the sequential addition of HOBT (73.97 mg, 0.547 mmol, 1.2 equiv.), EDCI (104.94 mg, 0.547 mmol, 1.2 equiv.), and DIEA (176.87 mg, 1.37 mmol, 3 equiv.) at 0 °C. Compound 39A (47.69 mg, 0.547 mmol, 1.2 equiv.) was added after stirring at 0 °C for 10 min. After the addition, the system was warmed to room temperature and stirred overnight. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted three times with DCM (5 mL × 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the reaction solution was mixed with silica gel and purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid 39B (175 mg, yield 72.5%). MS-ESI: m / z 508.2 [M+H] + . Process 2 Compound 39B (150 mg, 0.295 mmol, 1 equiv.) was dissolved in methanol (10 mL), and then Raney nickel (0.15 g) was added while controlling the temperature at 0 °C. The system was purged with hydrogen twice and stirred at room temperature for 1 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated, and purified by reverse-phase column chromatography (HO:CAN = 3:2) to give an off-white solid 39 (22 mg, 15.7% yield). MS-ESI: m / z 478.0 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.36 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 6.97 - 6.85 (m, 5H), 6.42 (d, J = 8.3 Hz, 2H), 5.19 (s, 2H), 4.60 (s, 2H), 3.88 - 3.41 (m, 10H), 2.76 (s, 2H), 1.65 (d, J = 7.1 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H).

[0262] compound 40 [ka]

[0263] Process 1 Compound 30E (1.5 g, 3.32 mmol, 1 equiv.) was dissolved in a mixture of MeOH (10 mL), THF (10 mL), and HO (10 mL). After cooling the mixture to 0 °C, LiOH(HO) (417.35 mg, 9.95 mmol, 3 equiv.) was added in one portion and the mixture was allowed to react at 0 °C–10 °C for 3 h. When LCMS showed the starting material was gone, the reaction solution was poured into 50 mL of water and adjusted to pH 5–6 with 1 N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with water (10 mL) and dried to give 40A (0.5 g, 45% yield) as an off-white solid. MS-ESI: m / z 439.2 [M+H] + . Process 2 Compound 40A (100 mg, 0.228 mmol, 1 equiv.) was dissolved in DMF (5 mL), and TCFH (95.99 mg, 0.342 mmol, 1.5 equiv.) and NMI (74.91 mg, 0.912 mmol, 4 equiv.) were added sequentially while controlling the temperature at 0 °C. After stirring at 0 °C for 10 min, compound 40B (25.76 mg, 0.274 mmol, 1.2 equiv.) was added. After the addition, the system was warmed to room temperature and stirred overnight. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with DCM (5 mL × 3). The organic phases were combined, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was triturated with methanol. The mother liquor was concentrated under reduced pressure to give a pale yellow solid 40C (65 mg, 40% yield). Process 3 Compound 40C (50 mg, 0.097 mmol, 1 equiv.) was dissolved in methanol (5 mL), followed by the addition of Raney nickel (5 mg). The system was purged with hydrogen twice and stirred at room temperature for 3 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give a yellow solid 40 (3 mg, 13% yield). MS-ESI: m / z 485.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 9.89 (s, 1H), 8.99 (s, 2H), 8.39 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.48 (dd, J = 8.4, 4.8 Hz, 1H), 7.23 (s, 1H), 6.91 (d, J = 7.9 Hz, 2H), 6.46 (d, J = 7.9 Hz, 2H), 4.67 (s, 2H), 3.75 - 3.67 (m, 3H), 3.25 (s, 2H), 1.73 - 1.62 (m, 2H), 1.24 (s, 1H), 0.94 (t, J = 7.4 Hz, 3H).

[0264] compound 41 [ka]

[0265] Process 1 41A (2.0 g, 7.83 mmol, 1 equiv) was dissolved in DCM (20 mL). Triethylamine (3.96 g, 39.14 mmol, 5 equiv) was added at 0 °C, followed by the slow dropwise addition of 41B (1.29 g, 11.74 mmol, 1 equiv). The system was warmed to room temperature and stirred for 3 h after the addition. When LCMS showed the disappearance of the starting material, the reaction solution was washed with 10 mL of water. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 3:1) to give a white solid 41C (1.2 g, 52.5% yield). MS-ESI: m / z 292.0 [M+H] + . Process 2 Compound 41C (1.2 g, 4.11 mmol, 1 equiv.), potassium acetate (0.8 g, 8.21 mmol, 2 equiv.), B2Pin2 (1.2 g, 4.11 mmol, 1 equiv.), and 1,4-dioxane (15 mL) were added to a 20 mL microwave reactor. The system was purged with argon twice and reacted in a microwave reactor at 100 °C for 3 h. When LCMS showed the reaction was complete, the reaction solution was poured into 15 mL of ice water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 3:1) to give yellow oily substance 41D (0.7 g, 53% yield). MS-ESI: m / z 340.2 [M+H] + . Process 3 Compound 15F (209 mg, 0.44 mmol, 1 equiv.), dioxane (6 mL), and water (0.6 mL) were added to a 20 mL microwave reactor, followed by the addition of compound 41D (150 mg, 0.44 mmol, 1 equiv.) and anhydrous potassium phosphate (280 mg, 1.32 mmol, 3 equiv.). The system was purged with argon twice, followed by the addition of Pd(dppf)Cl2 (40 mg, 15% w / w). The system was then purged with argon twice more and the reaction was run in a microwave reactor at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 41E (200 mg, 72% yield) as a pale yellow solid. MS-ESI: m / z 606.2 [M+H] + . Process 4 Compound 41E (200 mg, 0.33 mmol, 1 equiv.) was dissolved in methanol (10 mL), followed by the addition of Raney nickel (0.1 g). The system was purged with hydrogen twice and stirred under a hydrogen atmosphere at 13–15°C for 16 h. When LCMS showed no starting material, the reaction solution was filtered through Celite, concentrated by rotary evaporation, purified by preparative HPLC, and lyophilized to give 41 (27 mg, 10.7% yield) as an off-white solid. MS-ESI: m / z 576.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.149-8.123 (m, 1H), 7.988 (s, 1H), 7.812-7.799 (d, J=5.2, 2H), 7.461 - 7.350 (m, 3H), 7.112 (s, 1H), 6.908 -6.888(d, J=8, 1H), 6.435-6.414 (d, J=8.4, 2H), 5.755-5.741 (d, J=5.6, 1H), 5.17 (s, 2H), 4.608 (s, 2H), 4.316-4.302 (m, 1H), 3.977-3.939 (dd, J1=7.2, J2=8.4, 2H), 3.663-3.628 (t, J1=6.8, J2=14, 2H), 2.806 (s, 2H), 1.683 - 1.629 (dd, J1= 7.2, J2=14.4 Hz, 2H), 0.931 - 0.894 (t, J1= 7.2, J2=14.8 Hz, 3H).

[0266] compound 42 [ka]

[0267] Process 1 Compound 42A (0.5 g, 2.49 mmol, 1 equiv.) was dissolved in DMF (10 mL), and then DIEA (0.96 g, 7.46 mmol, 3 equiv.) and HATU (1.04 g, 2.87 mmol, 1.1 equiv.) were added at room temperature. After the addition, the system was stirred at room temperature for 5 minutes, and compound 42B (0.217 g, 2.49 mmol, 1 equiv.) was added. After the addition, the system was stirred at room temperature overnight. When LCMS showed the reaction was complete, the reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 5:1) to give compound 42C (0.5 g, 74% yield) as a white solid. MS-ESI: m / z 270.0 [M+H] + . Process 2 Compound 42C (0.3 g, 1.11 mmol, 1 equiv.) was dissolved in dioxane (20 mL), followed by the addition of HY-515_12 (310 mg, 1.22 mmol, 1.1 equiv.) and AcOK (218 mg, 2.22 mmol, 2 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (45 mg) was added in one portion. The mixture was then purged twice more with argon and subjected to a microwave reaction at 100 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature and poured directly onto a silica gel column. The product was eluted with PE:EA = 2:1 to give compound 42D (150 mg, 42.3% yield) as a pale yellow solid. MS-ESI: m / z 318.2 [M+H] + . Process 3 Compound 42D (223 mg, 0.49 mmol, 1.05 equiv.) and compound 15F (150.4 mg, 0.47 mmol, 1 equiv.) were added to a mixture of dioxane (10 mL) and water (1 mL), followed by potassium phosphate (296 mg, 1.4 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (40 mg) was added in one portion. The mixture was then purged twice more with argon and subjected to a microwave reaction at 90 °C for 3 h. When LCMS showed no starting material, the reaction solution was cooled to room temperature, added to 15 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 42E (100 mg, 36% yield) as a yellow solid. MS-ESI: m / z 584.2 [M+H] + . Process 4 Compound 42E (100 mg, 0.172 mmol, 1 equiv.) was dissolved in MeOH (5 mL) with the temperature controlled at 15° C., and then Raney nickel (20 mg) was added. The system was purged with hydrogen and stirred at 15° C. overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give compound 42 (27 mg, 28.4% yield) as an off-white solid. MS-ESI: m / z 554.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.802 - 7.782 (d, J = 8.0 Hz, 2H), 7.664 - 7.633 (t, J 1= 4.4 Hz, J 2= 12.4 Hz 2H), 7.568 - 7.526 (t, J 1= 8 Hz, J 2= 16.8 Hz 2H), 7.157 (s, 1H), 6.91 - 6.89 (d, J = 8.0 Hz, 1H), 6.433 - 6.412 (d, J = 8.4 Hz, 1H), 5.20 (s, 1H), 5.044 - 4.964 (d, J = 32 Hz, 1H), 4.627 (s, 1H), 4.348 - 4.256 (d, J = 36.8 Hz, 1H), 3.681 - 3.277 (m, 8H), 3.065 (s, 2H), 2.017 - 1.811 (m, 3H), 1.689 - 1.635 (dd, J 1= 7.2 Hz, J 2= 14.4 Hz 2H), 0.935 - 0.898 (t, J 1= 7.6 Hz, J 2= 14.8 Hz 3H).

[0268] Compound 43

change

[0269] Project 1 Compound 43A (0.5 g, 2.35 mmol, 1 equiv.) was dissolved in dioxane (10 mL), followed by the addition of B2Pin2 (0.65 mg, 2.58 mmol, 1.1 equiv.) and AcOK (460 mg, 4.69 mmol, 2 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (45 mg, 15% w / w) was added in one portion. The mixture was then purged twice more with argon and the reaction was carried out in a microwave reactor at 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was directly poured onto a silica gel column. The product was eluted with PE:EA = 2:1 to give a pale yellow solid, compound 43B (300 mg, 49.1% yield). MS-ESI: m / z 261.1 [M+H] + . Process 2 Compound 15F (300 mg, 0.57 mmol, 1.0 equiv.), dioxane (8 mL), and water (0.8 mL) were added to a 20 mL microwave reactor, followed by the addition of compound 43B (148 mg, 0.57 mmol, 1 equiv.) and anhydrous potassium phosphate (360 mg, 1.7 mmol, 3 equiv.). The system was purged with argon twice, and then Pd(dppf)Cl2 (45 mg, 15% w / w) was added. The mixture was then purged with argon twice more and reacted in a microwave reactor at 90 °C for 2 h. When LCMS showed that the starting material was gone, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 43C (200 mg, 60.5% yield) as a pale yellow solid. MS-ESI: m / z 527.2 [M+H] + . Process 3 Compound 43C (200 mg, 0.172 mmol, 1 equiv.) was dissolved in MeOH (5 mL) with the temperature controlled at 15 °C, and then Raney nickel (20 mg) was added. The system was purged with hydrogen and stirred at 15 °C overnight. When LCMS showed that the starting material was gone, the mixture was concentrated under reduced pressure, purified by preparative HPLC, and lyophilized to give compound 43 (36 mg, 19.7% yield) as an off-white solid. MS-ESI: m / z 554.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.14 - 8.116 (dd, J1= 1.6 Hz J2= 8 Hz, 1H), 8.066 (s, 1H), 7.782 - 7.762 (d, J = 8 Hz, 1H), 7.423 - 7.347 (m, 3H), 7.098 (s, 1H), 6.905 - 6.884 (d, J = 8.4 Hz, 1H), 6.430 - 6.409 (d, J = 8.4 Hz, 1H), 5.473 (s, 2H), 5.170 (s, 1H), 4.601 (s, 2H), 3.649-3.614 (t, J1= 7.2Hz J2= 14 Hz 2H), 2.782 (s, 2H), 1.875 (s, 6H), 1.674 - 1.620 (dd, J1= 7.2 Hz J2= 14.4 Hz, 2H), 0.91 (t, J1= 7.6 Hz J2= 14.8 Hz 3H).

[0270] compound 44 [ka]

[0271] Process 1 Compound 44A (5 g, 23.14 mmol, 1 equiv.) was dissolved in acetonitrile (100 mL), and then BocNHOH (4.01 g, 30.09 mmol, 1.3 equiv.) was added at 0 °C. DBU (3.52 g, 23.14 mmol, 1 equiv.) was then slowly added dropwise. After the addition, the system was warmed to room temperature and stirred for 3 h. When LCMS showed that the starting material was gone, the reaction solution was concentrated under reduced pressure, and then 100 mL of saturated potassium carbonate solution was added. The mixture was extracted with DCM (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 5:1) to give compound 44B (4.6 g, 74% yield) as a white solid. MS-ESI: m / z 291.0 [M+Na] + . Process 2 Compound 44B (4.5 g, 16.77 mmol, 1 equiv.) was dissolved in DMF (50 mL) and the mixture was cooled to 0 °C. NaH (671 mg, 16.77 mmol, 1 equiv., 60%) was added in one portion, and the mixture was stirred at 0 °C for 10 min. After that, iodopropane (3.14 g, 18.45 mmol, 1.1 equiv.) was added dropwise. After the addition, the reaction was allowed to warm to room temperature and react overnight. When LCMS showed that the starting material had disappeared, the reaction solution was poured into 150 mL of ice water and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed successively with 10% aqueous citric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and saturated brine (100 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 5:1) to give a yellow solid compound 44C (3.4 g, 65% yield). MS-ESI: m / z 333.2 [M+Na] + . Process 3 Compound 44C (3.4 g, 10.96 mmol, 1 equiv.) was dissolved in EA (40 mL), and then 4 N hydrochloride salt in dioxane (40 mL) was added in an ice-water bath. The system was stirred at room temperature overnight. When LCMS showed that the starting material was gone, the reaction solution was concentrated by rotary evaporation, triturated with EA (100 mL), and dried under vacuum to give a yellow solid, compound 44D (2.0 g, 85% yield). MS-ESI: m / z 211.2 [M+H] + . Process 4 Compound 44D (1 g, 4.05 mmol, 1.1 equiv.) and compound 1F (1.17 g, 3.69 mmol, 1 equiv.) were added to a mixture of DMA (10 mL) and DCM (10 mL). After purging the system twice with argon, EDCI (2.83 g, 14.74 mmol, 4 equiv.) was added in one portion, followed by purging twice more with argon. The mixture was then warmed to room temperature and allowed to react overnight. When LCMS showed the reaction was complete, the reaction solution was poured into 30 mL of water and extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and purified by column chromatography to give compound 44E (0.7 g, 41.2% yield) as a yellow solid. MS-ESI: m / z 473.1 [M+H] + . Process 5 Compound 44E (0.6 g, 1.27 mmol, 1 equiv.) was added to a mixture of dioxane (10 mL) and water (1 mL), followed by the addition of compound 10D (295.45 mg, 1.27 mmol, 1 equiv.) and anhydrous potassium phosphate (807.23 mg, 3.8 mmol, 3 equiv.). The system was purged with argon twice, followed by the addition of Pd(PPh3)4 (60 mg). The mixture was then purged with argon twice more and heated to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give a dark red solid 44F (350 mg, 48% yield). MS-ESI: m / z 500.2 [M+H] + . Process 6 Compound 44F (300 mg, 0.6 mmol, 1 equiv.) was added to methanol (10 mL), followed by the slow addition of sodium borohydride (13.63 mg, 0.36 mmol, 0.6 equiv.) in small portions at room temperature. After the addition, the system was allowed to react at room temperature for 2 hours. When LCMS showed that a small amount of starting material remained, the reaction was quenched with saturated aqueous ammonium chloride (50 mL), and the reaction solution was extracted with DCM (50 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid 44G (120 mg, 38% yield). MS-ESI: m / z 502.2 [M+H] + . Process 7 Compound 44G (100 mg, 0.199 mmol, 1 equiv.) was dissolved in methanol (5 mL), followed by the addition of Raney nickel (0.01 g). The system was purged with hydrogen twice and stirred under a hydrogen atmosphere at room temperature for 3 hours. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give 44 (29 mg, 14.9% yield) as a white solid. MS-ESI: m / z 472.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 9.31 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 7.79 (dd, J = 8.1, 1.6 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.28 (s, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 6.6 Hz, 2H), 6.72 (d, J = 7.3 Hz, 1H), 4.80 (s, 2H), 4.68 (s, 2H), 3.74 (s, 2H), 3.71 (s, 2H), 3.32 (s, 2H), 1.69 (dd, J = 14.3, 7.2 Hz, 2H), 0.93 (t, J = 7.4 Hz, 2H).

[0272] Compound 45

change

[0273] Project 1 Compound 15C (4.5 g, 16.77 mmol, 1 equiv.) was dissolved in DMF (50 mL) and the mixture was cooled to 0 °C. NaH (671 mg, 16.77 mmol, 1 equiv., 60%) was added in one portion, and the mixture was stirred at 0 °C for 10 min. Compound 45A (3.36 g, 18.45 mmol, 1.1 equiv.) was then added dropwise. After the addition, the reaction mixture was warmed to room temperature and allowed to react overnight. When LCMS showed that the starting material had disappeared, the reaction solution was poured into 150 mL of ice water and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed successively with 10% aqueous citric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and saturated brine (100 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (PE:EA = 5:1) to give a yellow solid, compound 45B (3.5 g, 60% yield). MS-ESI: m / z 267.1 [M+H-C4H8] + . Process 2 Compound 45B (3.4 g, 10.96 mmol, 1 equiv.) was dissolved in EA (40 mL), followed by the addition of 4 N hydrochloride salt (40 mL) in dioxane in an ice-water bath. The system was stirred overnight at room temperature. When LCMS showed the disappearance of the starting material, the reaction solution was concentrated by rotary evaporation, triturated with EA (100 mL), and dried under vacuum to give a yellow solid, compound 45C (2.9 g, 75% yield). MS-ESI: m / z 223.0 [M+H] + . Process 3 Compound 45C (1 g, 3.87 mmol, 1.1 equiv.) and 1F (1.12 g, 3.51 mmol, 1 equiv.) were added to a mixture of DMA (10 mL) and DCM (10 mL). After purging the system twice with argon, EDCI (2.69 g, 14.06 mmol, 4 equiv.) was added in one portion, followed by purging twice more with argon. The mixture was then warmed to room temperature and allowed to react overnight. When LCMS showed the reaction was complete, the reaction solution was poured into 30 mL of water and extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and purified by column chromatography to give compound 45D (0.71 g, 40% yield) as a yellow solid. MS-ESI: m / z 485.1 [M+H] + . Process 4 Compound 45D (0.8 g, 1.65 mmol, 1 equiv.) was added to a mixture of dioxane (10 mL) and water (1 mL), followed by the addition of compound 10D (384.19 mg, 1.65 mmol, 1 equiv.) and anhydrous potassium phosphate (1.05 g, 4.95 mmol, 3 equiv.). The system was purged with argon twice, followed by the addition of Pd(PPh3)4 (80 mg). The mixture was then purged with argon twice more and heated to 85 °C for 3 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 45E (400 mg, 46% yield) as a dark red solid. MS-ESI: m / z 512.2 [M+H] + . Process 5 Compound 45E (300 mg, 0.6 mmol, 1 equiv.) was added to methanol (5 mL), followed by the slow addition of sodium borohydride (13.31 mg, 0.35 mmol, 0.6 equiv.) in small portions at room temperature. After the addition, the mixture was allowed to react at room temperature for 2 hours. When LCMS showed a small amount of starting material remained, the reaction was quenched with saturated aqueous ammonium chloride (15 mL), and the reaction solution was extracted with DCM (15 mL × 3). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid, compound 45F (110 mg, 25% yield). MS-ESI: m / z 514.2 [M+H] + . Process 6 Compound 45F (100 mg, 0.195 mmol, 1 equiv.) was dissolved in methanol (5 mL), followed by the addition of Raney nickel (0.01 g). The system was purged twice with hydrogen and stirred under a hydrogen atmosphere at room temperature for 3 h. When LCMS showed no starting material, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give a yellow solid 45 (37 mg, 35% yield). MS-ESI: m / z 484.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 9.56 (s, 1H), 8.96 (s, 1H), 8.69 (s, 1H), 8.27 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 4.81 (s, 2H), 4.71 (s, 2H), 3.65 (d, J = 6.8Hz, 2H), 3.32 (s, 2H), 1.20 (s, 1H), 0.58 (d, J = 7.3 Hz, 2H), 0.35 (d, J = 4.4 Hz, 2H).

[0274] compound 46 [ka]

[0275] Process 1 Compound 40A (100 mg, 0.228 mmol, 1 equiv.) and compound 46A (19.87 mg, 0.228 mmol, 1 equiv.) were dissolved in DMA (3 mL), and EDCI (174.90 g, 0.912 mmol, 4 equiv.) was added in one portion. The system was stirred at room temperature overnight. When LCMS showed that compound 40A had disappeared, the reaction solution was used directly in the next reaction without further workup. MS-ESI: m / z 508.2 [M+H] + . Process 2 Raney nickel (0.5 g) was added to the solution of untreated compound 46B from the previous step. The system was purged with hydrogen twice and stirred under a hydrogen atmosphere at room temperature overnight. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite and purified by preparative HPLC to give a yellow solid compound 46 (8.2 mg, 7.5% yield over two steps). MS-ESI: m / z 478.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.38 (d, J = 6.5 Hz, 2H), 7.17 (d, J = 20.9 Hz, 2H), 7.06 (s, 1H), 6.87 (d, J = 7.4 Hz, 2H), 6.41 (d, J = 7.3 Hz, 2H), 4.59 (s, 2H), 4.28 (d, J = 37.6 Hz, 2H), 3.59 (dd, J = 23.4, 7.9 Hz, 7H), 3.25 (d, J = 10.5 Hz, 1H), 2.82 (d, J = 14.7 Hz, 1H), 1.88 (d, J = 56.6 Hz, 3H), 1.63 (d, J = 6.4 Hz, 2H), 0.89 (s, 3H).

[0276] Compounds 46A and 46B [ka]

[0277] Compound 46 was subjected to chiral resolution by conventional methods to give compounds 46A (1.8 mg) and 46B (2.1 mg). Compound 46A: MS-ESI: m / z 478.2 [M+H] + . Compound 46B: MS-ESI: m / z 478.2 [M+H] + .

[0278] compound 47 [ka]

[0279] Process 1 Compound 40A (150 mg, 0.342 mmol, 1 equiv) was dissolved in DMF (5 mL), followed by the addition of HOBT (55.48 mg, 0.411 mmol, 1.2 equiv), EDCI (78.70 mg, 0.411 mmol, 1.2 equiv), and DIEA (132.65 mg, 1.03 mmol, 3 equiv) at 0 °C. After stirring at 0 °C for 10 min, compound 47A (62.65 mg, 0.411 mmol, 1.2 equiv) was added. After the addition, the mixture was warmed to room temperature and stirred overnight. When the reaction was complete as indicated by LCMS, the reaction solution was poured into 15 mL of water and extracted with DCM (5 mL × 3). The organic phases were combined, washed with saturated brine (15 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (DCM:MeOH = 20:1) to give a brown solid compound 47B (100 mg, 50% yield). MS-ESI: m / z 538.3 [M+H] + . Process 2 Compound 47B (100 mg, 0.186 mmol, 1 equiv.) was dissolved in methanol (10 mL), and then Raney nickel (0.01 g) was added while controlling the temperature at 0 °C. The system was purged with hydrogen twice and stirred at room temperature for 1 h under a hydrogen atmosphere. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give 47 (18 mg, 18% yield) as an off-white solid in the form of a trifluoroacetate salt. MS-ESI: m / z 508.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.58 (dd, J = 20.0, 8.4 Hz, 2H), 7.43 (dd, J = 10.8, 2.7 Hz, 2H), 7.17 (s, 1H), 6.95 (d, J = 8.2 Hz, 2H), 6.57 (dd, J = 49.2, 8.4 Hz, 3H), 4.67 (s, 2H), 3.71 - 3.64 (m, 3H), 3.24 (s, 2H), 2.53 (d, J = 1.9 Hz, 10H), 2.07 (s, 1H), 1.67 (dd, J = 14.3, 7.2 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0280] compound 48 [ka]

[0281] Process 1 Compound 40A (150 mg, 0.342 mmol, 1 equiv) was dissolved in DMF (5 mL), followed by the addition of HOBT (55.48 mg, 0.411 mmol, 1.2 equiv), EDCI (78.70 mg, 0.411 mmol, 1.2 equiv), and DIEA (132.65 mg, 1.03 mmol, 3 equiv) at 0 °C. After stirring at 0 °C for 10 min, ethanolamine (25.08 mg, 0.411 mmol, 1.2 equiv) was added. After the addition, the mixture was warmed to room temperature and stirred overnight. When LCM showed the reaction was complete, the reaction solution was poured into 15 mL of water and extracted with DCM (5 mL × 3). The combined organic phases were washed with saturated brine (15 mL), dried over sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow solid compound 48A (90 mg, 50% yield). MS-ESI: m / z 482.2 [M+H] + . Process 2 Compound 48A (90 mg, 0.187 mmol, 1 equiv.) was dissolved in methanol (10 mL), and then Raney nickel (0.01 g) was added while controlling the temperature at 0 °C. The system was purged with hydrogen twice and stirred under a hydrogen atmosphere at room temperature for 1 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give an off-white solid, trifluoroacetate salt of 48 (12 mg, 13% yield). MS-ESI: m / z 452.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.90 - 7.83 (m, 2H), 7.59 (dd, J = 26.0, 8.4 Hz, 2H), 7.17 (s, 1H), 6.95 (d, J = 8.3 Hz, 2H), 6.63 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 8.2 Hz, 2H), 4.67 (s, 2H), 3.70 (t, J = 6.9 Hz, 3H), 3.56 - 3.51 (m, 5H), 3.40 - 3.34 (m, 3H), 3.22 (s, 1H), 2.07 (s, 1H), 1.67 (dd, J = 14.3, 7.2 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0282] compound 49 [ka]

[0283] Process 1 Compound 15F (1.0 g, 2.11 mmol, 1 equiv.) was dissolved in 20 mL of methanol, and then Raney nickel was added. The system was reacted for 6 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite. The filter cake was washed with 10 mL of methanol, and the collected filtrate was concentrated under reduced pressure to give yellow foamy solid 49A (0.7 g, 75% yield). MS-ESI: m / z 443.1 [M+H] + . Process 2 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by the addition of compound 49B (54 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and subjected to a microwave reaction at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid 49 (19 mg, 17.7% yield). MS-ESI: m / z 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.847-8.842 (d, J=2, 1H), 8.579-8.573 (d, J=2.4, 1H), 8.224-8.214 (t, J1=2, J2=4, 2H), 7.449-7.427 (dd, J=8.8, 3H), 7.063 (s, 1H), 6.83 -6.809(d, J=8.4, 1H), 6.356-6.335 (d, J=8.4, 2H), 4.543 (s, 2H), 3.6-3.565 (m, 1H), 2.838 (s, 2H), 1.614 - 1.561 (dd, J1= 7.2, J2=14 Hz, 2H), 0.861 - 0.824 (t, J1= 7.2, J2=14.8 Hz, 3H).

[0284] compound 50 [ka]

[0285] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 50A (52 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 50 (21 mg, 19.8% yield). MS-ESI: m / z 467.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.145- 9.141 (d, J=1.6, 1H), 8.385- 8.379 (d, J=2.4, 1H), 8.122- 8.101 (d, J=8.4, 1H), 7.475- 7.405 (m, 3H), 7.100 (s, 1H), 6.888 - 6.867 (d, J=8.4, 4H), 6.416 - 6.395 (d, J=8.4, 2H), 5.163 (s, 2H), 4.595 (s, 2H), 3.652- 3.617 (t, J=6.8, J=14, 4H), 2.773 (s, 2H), 1.674 - 1.620 (dd, J1=7.2, J2=14, 2H), 0.923 - 0.886 (t, J1=7.2, J2=14.8, 3H).

[0286] compound 51 [ka]

[0287] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 51A (52 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 51 (19 mg, 18.1% yield). MS-ESI: m / z 467.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ9.229-9.223 (d, J=2.4, 1H), 9.003-8.998 (d, J=2, 1H), 8.685- 8.675 (d, J1=2, J2=4, 1H), 7.469- 7.372 (m, 3H), 7.100 (s, 1H), 6.892- 6.871 (d, J=8.4, 4H), 6.419 - 6.398 (d, J=8.4, 2H), 5.164 (s, 2H), 4.597 (s, 2H), 3.652- 3.617 (t, J=6.8, J=14, 4H), 2.769 (s, 2H), 1.674 - 1.621 (dd, J1=6.8, J2=14, 2H), 0.923 - 0.886 (t, J1=7.2, J2=14.8, 3H).

[0288] compound 52 [ka]

[0289] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 52A (66 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 52 (20 mg, 19.2% yield). MS-ESI: m / z 457.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ8.087-8.082 (d, J=2, 1H), 7.978-7.972 (d, J=2.4, 1H), 7.546-7.484 (m, 3H), 7.206- 7.195 (t, J1=2, J2=4.4, 1H), 7.145 (s, 1H), 6.910- 6.889 (d, J=8.4, 2H), 6.435 - 6.415 (d, J=8, 2H), 5.502 (s, 2H), 4.626 (s, 2H), 3.681 - 3.646 (t, J1=6.8, J2=14, 2H), 3.098 (s, 2H), 1.689 - 1.635 (dd, J1=7.2, J2=14.4 2H), 0.933 - 0.896 (t, J1=7.2, J2=14.8, 3H).

[0290] compound 53 [ka]

[0291] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 53A (61.6 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 53 (22 mg, 19.1% yield). MS-ESI: m / z 510.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ9.261- 9.256 (d, J=2, 1H), 8.990 (s, 1H), 8.502 (s, 1H), 7.592- 7.535 (m, 3H), 7.142 (s, 1H), 6.899- 6.878 (d, J=8.4, 2H), 6.424 - 6.403 (d, J=8.4, 2H), 4.615 (s, 2H), 3.674-3.639 (t, J1=6.8, J2=14, 2H), 2.920 (s, 2H), 1.685 - 1.632 (dd, J1=7.2, J2=21.2, 2H), 0.932 - 0.895 (t, J1=7.6, J2=14.8, 3H).

[0292] compound 54 [ka]

[0293] Process 1 Compound 54A (0.5 g, 1.74 mmol, 1 equiv.) was dissolved in dioxane (15 mL), and B2Pin2 (530 mg, 2.09 mmol, 1.1 equiv.) and AcOK (342 mg, 3.48 mmol, 2 equiv.) were added. After purging the system twice with argon, Pd(dppf)Cl2 (75 mg, 15% w / w) was added in one portion. The mixture was then purged twice more with argon and the reaction mixture was heated in a microwave reactor at 90 °C for 3 h. When LCMS showed no starting material, the reaction solution was cooled to room temperature, extracted three times with water (15 mL) and EA (20 mL), dried over sodium sulfate, and concentrated to give crude brown solid 54B (400 mg, 60% purity, 51% yield). MS-ESI: m / z 253.2 [M+H] + . Process 2 Compound 54B (100 mg, 0.198 mmol, 1 equiv.) was added to a mixture of dioxane (5 mL) and water (0.5 mL), followed by the addition of compound 49A (125.63 mg, 0.198 mmol, 1 equiv.) and anhydrous potassium phosphate (126.31 mg, 0.595 mmol, 3 equiv.). The system was purged with argon twice, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged with argon twice more and heated to 90 °C for 4 h. When LCMS showed the disappearance of the starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to give crude brown solid 54C (90 mg, 70% purity, 40% yield). MS-ESI: m / z 571.4 [M+H] + . Process 3 Compound 54C (90 mg, 0.157 mmol, 1 equiv.) was dissolved in DCM (3 mL), and then TFA (1 mL) was added. The system was stirred at room temperature for 2 h. When LCMS showed that the starting material was gone, the reaction solution was filtered through Celite, concentrated by rotary evaporation, and purified by preparative HPLC to give a pale yellow solid 54 in the form of the trifluoroacetate salt (20 mg, 14% yield). MS-ESI: m / z 471.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 9.61 (s, 1H), 9.00 (s, 1H), 8.74 (s, 1H), 8.34 (d, J = 26.7 Hz, 4H), 7.76 (dd, J = 17.2, 5.8 Hz, 3H), 7.26 (s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 7.7 Hz, 2H), 4.73 (s, 2H), 4.23 (d, J = 5.3 Hz, 3H), 3.74 (s, 1H), 3.73 (s, 1H), 3.71 (s, 1H), 3.30 (s, 2H), 1.70 (dd, J = 14.2, 7.1 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0294] compound 55 [ka]

[0295] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 55A (66 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed no starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 55 (15 mg, 12.8% yield). MS-ESI: m / z 527.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.528-8.523 (d, J=2, 1H), 7.954-7.932 (d, J=8.8, 1H), 7.364-7.344 (d, J=8, 1H), 7.285 (s, 1H), 7.253-7.233 (d, J=8, 1H), 7.095 (s, 1H), 6.954 -6.901(m, 4H), 6.450 -6.430 (d, J=8, 2H), 5.185 (s, 2H), 4.610 (s, 2H), 3.741-3.729 (d, J=4.8, 4H), 3.645-3.628 (d, 0.936 - 0.899 (t, J1=7.6, J2=14.8, 3H).

[0296] compound 56 [ka]

[0297] Process 1 Compound 49A (100 mg, 0.22 mmol, 1 equiv.), dioxane (4 mL), and water (0.4 mL) were added to a 10 mL microwave reactor, followed by compound 56A (64 mg, 0.22 mmol, 1 equiv.) and anhydrous potassium phosphate (143 mg, 0.66 mmol, 3 equiv.). The system was purged twice with argon, and then Pd(dppf)Cl2 (15 mg, 15% w / w) was added. The mixture was then purged twice more with argon and heated in a microwave reactor at 90 °C for 2 h. When LCMS showed no starting material, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to give solid compound 56 (22 mg, 18.7% yield). MS-ESI: m / z 520.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.280-9274 (d, J=2.4, 1H), 9.040-9035 (d, J=2, 1H), 8.584-8.574 (t, J1=2, J2=4, 1H), 7.520-7.432 (m, 3H), 7.116 (s, 1H), 6.902 -6.863(m, 4H), 6.428 -6.407 (d, J=8.4, 2H), 5.168 (s, 2H), 4.607 (s, 2H), 3.664-3.629 (t, J1=6.8, J2=14, 2H), 3.43 (s, 3H), 2.781 (s, 2H), 1.702 - 1.612 (m, 2H), 0.932 - 0.895 (t, J1=7.2, J2=14.8, 3H).

[0298] Synthesis of Compounds 58-73: The following compounds were synthesized using the same synthetic method as for Compound 45. [Table 1]

[0299] [Table 2]

[0300] Synthesis of Compounds 74-99: The following compounds were synthesized using the same synthetic method as for Compound 37. [Table 3]

[0301] [Table 4]

[0302] [Table 5]

[0303] Synthesis of Compounds 100-199: The following compounds were synthesized using the same synthetic method as for Compound 37. [Table 6]

[0304] [Table 7]

[0305] [Table 8]

[0306] [Table 9]

[0307] [Table 10]

[0308] [Table 11]

[0309] [Table 12]

[0310] [Table 13]

[0311] [Table 14]

[0312] [Table 15]

[0313] [Table 16]

[0314] [Table 17]

[0315] Synthesis of Compounds 200-287: The following compounds were synthesized using the same synthetic method as for Compound 45. [Table 18]

[0316] [Table 19]

[0317] [Table 20]

[0318] Table 21

[0319] Table 22

[0320] Table 23

[0321] Table 24

[0322] Table 25

[0323] Table 26

[0324] Table 27

[0325] Table 28

[0326] Table 29

[0327] Table 30

[0328] Example 2 In this example, the compounds of the present application were evaluated for their agonistic activity against hTLR7 (human Toll-like receptor 7) and hTLR8 (human Toll-like receptor 8), and the compounds were evaluated for their ability to induce TNF-α and IFN-α production in human PBMCs (human peripheral blood mononuclear cells). All compounds were prepared in DMSO at 30 mM stock solutions and stored at 4°C. The reference compound (WuXi AppTec, catalog number tlrl-r848-5) was purchased from InvivoGen, prepared in DMSO at 5 mg / mL stock solutions, and stored in a freezer at -20°C. HEK-Blue hTLR7 and HEK-Blue hTLR8 cell lines were purchased from InvivoGen, and human PBMCs were purchased from Shanghai Saily Biotechnology Co., Ltd. (catalog number XFB-HP100B).

[0329] Other common reagents are commercially available, e.g. [Table 31] The main instruments used in this study were the multifunctional microplate readers Flexstation III (Molecular Device), Envision (Perkin Elmer), M2e (Molecular Device), and Echo555 (Labcyte).

[0330] 2.1 Agonistic activity of compounds against hTLR7 (human Toll-like receptor 7) and hTLR8 (human Toll-like receptor 8) Compound dilution: The compounds of the present application are diluted in DMSO, for example, to about 15 mM. After dilution, the reference compounds are added to the plate in order. The compounds are serially diluted 3-fold to a concentration of 10 and added in duplicate to a 96-well plate. DMSO is added to negative control wells at 0.2 μL / well, and the reference compound is added to positive control wells. The final concentration of DMSO is 0.2%. Cell seeding: When HEK Blue hTLR7&8 cells in the culture flask reached 80% confluence under a microscope, the culture medium was discarded, 10 mL of detection medium was added, and the cells were separated by pipetting. The cells were counted using a cytometer and diluted to 500,000 cells / mL. The cells were seeded into a 96-well plate containing compounds at 100 μL / 50,000 cells / well. The compounds and cells were co-cultured for 24 hours at 37°C in a 5% CO2 incubator. Compound activity detection: 20 μL of cell supernatant was taken from each well and added to a plate containing QUANTI-Blue™ reagent at 180 μL / well. The plate was incubated at 37°C for 1 hour and the absorbance at 650 nm (OD ) was measured using a multifunctional microplate reader, Flexstation III. 650 ) was measured. Detection of cell viability: Chemiluminescence signals (RLU) were detected with a multifunctional microplate reader, Flexstation III, according to the instructions of Celltiter-Glo. Compound Activity Data Analysis: OD 650 The values ​​were analyzed using GraphPad Prism software and fitted to obtain the compound dose-response curves. 50 values ​​were calculated. Cell viability data analysis: Cell viability % was calculated as follows: Cell viability % was analyzed with GraphPad Prism software and fitted to obtain the dose-response curve of the compound. CC of the compound in the cells 50 values ​​were calculated. Cell viability % = RLU compound / RLU DMSOControl × 100% The agonist activities of the compounds of the present application against hTLR7 (human Toll-like receptor 7) and hTLR8 (human Toll-like receptor 8) are summarized in Tables 1-1 and 1-2.

[0331] [Table 32]

[0332] [Table 33]

[0333] [Table 34]

[0334] [Table 35]

[0335] [Table 36]

[0336] [Table 37]

[0337] [Table 38]

[0338] [Table 39] Note: "+" indicates EC50 > 1000 nM. "++" indicates 1000 nM ≥ EC50 > 100 nM. "+++" indicates 100 nM ≥ EC50 > 10 nM. "++++" indicates EC50 ≤ 10 nM. The results show that the compounds of the present application have significant agonist activity against TLRs, such as TLR7 and / or TLR8.

[0339] 2.2 Compound induction activity against TNF-α and IFN-α in human PBMC In this example, the compounds of the present application were evaluated for their ability to induce TNF-α and IFN-α production in human PBMCs (human peripheral blood mononuclear cells). Human PBMCs were purchased from Shanghai Saily Biotechnology Co., Ltd. (Catalog No. XFB-HP100B). PBMC cells were treated with the compounds. The compounds of the present application were diluted in DMSO, for example, to approximately 15 mM. Reference compounds were diluted to 5 mg / mL and then serially added to the plate. The compounds were serially diluted 3-fold or 4-fold to eight concentrations and added to the plate in duplicate (Table 2-1 for serial 3-fold dilutions and Table 2-2 for serial 4-fold dilutions). DMSO was added to negative control wells at 0.4 μL / well, and a 5 mg / mL reference compound solution was added to positive control wells at 0.4 μL / well. The final DMSO concentration was 0.2%. Frozen human PBMCs in a cryopreservation tube were quickly thawed in a 37°C water bath and transferred to a 50 mL centrifuge tube. Pre-warmed RPMI 1640 medium was gradually added, mixed well, and centrifuged for 15 minutes. The supernatant was then discarded. The cells were resuspended in culture medium and counted. ...

Claims

1. Formula (II-a): 【Chemistry 1】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, [In the above formula, R 1 is optionally substituted amino; R 2 is selected from hydrogen and optionally substituted C 1 -C 6 alkyl, and when R 2 contains methylene units, the methylene units of R 2 may each independently be unsubstituted or each independently be substituted by any structure; X 1 is selected from —CH 2 — optionally substituted with one or more R X1-1 , wherein one or more R X1-1 are independently selected from hydrogen and optionally substituted C 1 -C 6 alkyl, and two R X1-1 are each independently taken together with the atom to which they are attached to form an optionally substituted cyclopropyl; X3 is selected from optionally substituted -CH- or -N-; W is absent or selected from hydrogen and optionally substituted C 1 -C 6 alkylene; When W contains methylene units, each methylene unit of W may be independently unsubstituted or independently substituted with any structure; B is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; A is selected from the group consisting of optionally substituted aliphatic cyclyl, optionally substituted aliphatic heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

2. R 2 is optionally substituted 【Chemistry 2】 Possibly replaced 【Transformation 3】 Possibly replaced 【Chemistry 4】 Possibly replaced 【Transformation 5】 Possibly replaced 【Transformation 6】 Possibly replaced 【Transformation 7】 Possibly replaced 【Transformation 8】 Possibly replaced 【Chemistry 9】 Possibly replaced 【Chemistry 10】 Possibly replaced 【Chemistry 11】 Possibly replaced 【Chemistry 12】 and, optionally, substituted 【Chemistry 13】 or R 1 is an optionally substituted 【Chemistry 14】 Possibly replaced 【Chemistry 15】 Possibly replaced 【Chemistry 16】 Possibly replaced 【Chemistry 17】 and, optionally, substituted [Chemistry 18] 2. The compound of claim 1 selected from the group consisting of: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. R 2 is optionally substituted 【Chemistry 19】 and, optionally, substituted 【Chemistry 20】 3. The compound of claim 2, selected from the group consisting of: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

4. R 2 is one or more R 2-1 is replaced by The one or more R 2-1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkyl, optionally substituted aliphatic cyclyl, and optionally substituted aryl; When the one or more R 2-1 contain a methylene unit, the methylene units of the one or more R 2-1 are each independently unsubstituted or each independently substituted with any structure; For example, a compound according to claim 1, wherein R 2-1 is selected from the group consisting of hydrogen, fluorine, optionally substituted methyl, optionally substituted cyclopropyl, and optionally substituted phenyl, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. 2. The compound of claim 1, wherein W is selected from optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted butylene, and optionally substituted pentylene, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

6. W is an optionally substituted 【Chemistry 21】 Possibly replaced 【Chemistry 22】 Possibly replaced 【Chemistry 23】 Possibly replaced 【Chemistry 24】 and, optionally, substituted 【Chemistry 25】 selected from the group consisting of: For example, W can be optionally substituted 【Chemistry 26】 and, optionally, substituted 【Chemistry 27】 6. The compound of claim 5, selected from the group consisting of: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. 2. The compound of claim 1, wherein B is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl, for example, B is optionally substituted phenyl, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

8. B is one or more R B-1 and wherein said one or more R B-1 are each independently selected from the group consisting of hydrogen, halogen, and optionally substituted C 1 -C 6 alkyl, and when the one or more R B-1 contain a methylene unit, the methylene units of the one or more R B-1 are each independently unsubstituted or each independently substituted with any structure, for example, the one or more R B-1 are each independently selected from the group consisting of hydrogen, fluorine, and optionally substituted methyl, or 8. The compound of claim 7, wherein B is substituted with one or more optionally substituted amino groups, and said one or more optionally substituted amino groups are each independently substituted with hydrogen or optionally substituted C1-C6 alkyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, wherein A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, and optionally substituted pyrazinyl, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

10. A is one or more R A-1 and one or more of R A-1 is absent or optionally substituted C 1 -C 6 alkyl, R A-1 When contains a methylene unit, R A-1 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

11. R A-1 is selected from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, or optionally substituted butyl, for example, R A-1 The methylene units are unsubstituted or -S(=O)-, -C(=O)-, -S(=O) 2 11. The compound of claim 10, substituted by a group selected from the group consisting of -, -O-, -S-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted aliphatic cyclylene, optionally substituted aliphatic heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

12. R A-1 is absent or optionally substituted CH 3 -, optionally substituted CH(=CH 2 )-, optionally substituted HC(=O)-, optionally substituted HOC(=O)-, optionally substituted HC(=O)O-, optionally substituted NH-, optionally substituted HO-, optionally substituted HS-, optionally substituted HS(=O)-, optionally substituted HS(=O) 2 -, optionally substituted CH 3 CH 2 -, optionally substituted CH 2 =CH-, optionally substituted HC≡C-, optionally substituted HOCH 2 -, optionally substituted CH 3 O-, optionally substituted CH 3 NH-, optionally substituted NH 2 CH 2 -, optionally substituted HS(=O) 2 -NH-, optionally substituted NH 2 -S(=O) 2 -, optionally substituted HS-CH 2 -, optionally substituted CH 3 S-, optionally substituted HS(=O)-CH 2 -, optionally substituted CH 3 -S(=O)-, optionally substituted HS(=O) 2 -CH 2 -, optionally substituted CH 3 -S(=O) 2 -, optionally substituted NH 2 C(=O)-, optionally substituted HC(=O)NH-, optionally substituted HC(=O)CH 2 -, optionally substituted HC(=O)NHCH 2 -, optionally substituted CH 3 NHC(=O)-, optionally substituted 【Chemistry 28】 Possibly replaced 【Chemistry 29】 Possibly replaced 【Transformation 30】 Possibly replaced 【Chemistry 31】 Possibly replaced 【Chemistry 32】 Possibly replaced 【Transformation 33】 Possibly replaced 【Transformation 34】 Possibly replaced 【Chemistry 35】 Possibly replaced 【Transformation 36】 Possibly replaced 【Chemistry 37】 Possibly replaced 【Transformation 38】 Possibly replaced 【Chemistry 39】 Possibly replaced 【Chemistry 40】 Possibly replaced 【Chemistry 41】 Possibly replaced 【Chemistry 42】 Possibly replaced 【Chemistry 43】 Possibly replaced 【Chemistry 44】 Possibly replaced 【Chemistry 45】 Possibly replaced 【Chemistry 46】 Possibly replaced 【Chemistry 47】 Possibly replaced 【Chemistry 48】 Possibly replaced 【Chemistry 49】 Possibly replaced [Transformation 50] Possibly replaced 【Chemistry 51】 Possibly replaced 【Chemistry 52】 Possibly replaced 【Chemistry 53】 Possibly replaced 【Chemistry 54】 Possibly replaced 【Transformation 55】 Possibly replaced 【Transformation 56】 and, Possibly replaced 【Chemistry 57】 selected from the group consisting of: For example, R A-1 can be an optionally substituted 【Transformation 58】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

13. The one or more R A-1 are each independently one or more R A-2 and one or more of R A-2 are each independently selected from any group; For example, R A-2 is absent or selected from optionally substituted C 1 -C 6 alkyl, and when R A-2 contains a methylene unit, the methylene units of R A-2 are each independently unsubstituted or each independently substituted with any structure, or a compound according to claim 4, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

14. R A-2 is hydrogen, halogen, optionally substituted methyl, and / or optionally substituted hydroxy, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

15. The one or more R A-2 are each independently one or more R A-3 and one or more of R A-3 are each independently selected from any group; For example, a compound according to claim 14, wherein R A-3 comprises optionally substituted methyl and / or optionally substituted hydroxy, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

16. The compound has the formula (A) 【Chemistry 59】 2. The compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, In the above formula, R A-1 is R A2-1 -Lx- selected, Lx is a single bond, C 1 -C 6 Alkylene, -O-, -S-, -C(O)-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)-N(C 1 -C 6 alkyl)- or -N(C 1 -C 6 alkylene)-C(O)-; R A2-1 is aryl, heteroaryl or heterocyclyl, preferably phenyl, pyridinyl or isobenzofuranonyl; R A2-1 is one or more substituents R A2-2 optionally substituted by R A2-2 are each independently C 1 -C 6 Alkyl, amino, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -C 1 -C 6 Alkylamino, -C 1 -C 6 Alkyl-NH(C 1 -C 6 alkyl), -C 1 -C 6 Alkyl-N(C 1 -C 6 alkyl) 2 , hydroxy, -C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylhydroxy, -C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy or -C(O)NR e R f Selected from R e and R f are each independently H or C 1 -C 6 alkyl, or R e and R f together with the nitrogen atom to which they are attached form a 5- or 6-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl or piperidinyl, said 5- or 6-membered nitrogen-containing heterocyclyl optionally substituted with one or more substituents, the substituents being C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxy, oxo, amino, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 independently selected from, or R A2-1 is phenyl, 5- to 6-membered heteroaryl, or isobenzofuranonyl; R A2-1 optionally containing one or more substituents R A2-2 is substituted with R A2-2 are each independently C 1 -C 6 Alkyl, cyano, amino, -COOH, -C 1 -C 6 Alkylamino, -C 1 -C 6 Alkyl-NH(C 1 -C 6 alkyl), -C 1 -C 6 Alkyl-N(C 1 -C 6 alkyl) 2 , hydroxy, -C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylhydroxy, -C 1 -C 6 Alkylphenyl, -phenyl, -O-phenyl, C 3-6 Cycloalkyl, -C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy, -S(O)C 1 -C 6 Alkyl, -S(O) 2 C 1 -C 6 Alkyl, -S(O) 2 NR e R f , -C(O)NR e R f , or -NR e R f Selected from R e and R f are each independently H, C 1 -C 6 Alkyl or -C 1 -C 6 alkylhydroxy, or R e and R f together with the nitrogen atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclyl, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, and azetidinyl, which is optionally substituted with one or more substituents, such as halogen, hydroxy, oxo, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylhydroxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -O-phenyl and phenyl, or R A-1 is N(R AN-1 )(R AN-2 )C(O)-, R AN-1 and R AN-2 are each independently H, C 1 -C 6 Alkyl, -C 1 -C 6 Alkylamino, -C 1 -C 6 Alkyl-NH(C 1 -C 6 alkyl), -C 1 -C 6 Alkyl-N(C 1 -C 6 alkyl) 2 , -C 1 -C 6 Alkylhydroxy, halogenated C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, -C 1 -C 6 Alkyl-phenyl, -phenyl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, -C 3-6 cycloalkyl-phenyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl; 3-6 The cycloalkyl, 7- to 10-membered bicyclic heterocyclyl, and 3- to 8-membered heterocyclyl are each independently optionally substituted by one or more substituents, the substituents being selected from the group consisting of C 1 -C 6 Alkyl, cyano, amino, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -C 1 -C 6 Alkylamino, -C 1 -C 6 Alkyl-NH(C 1 -C 6 alkyl), -C 1 -C 6 Alkyl-N(C 1 -C 6 alkyl) 2 , hydroxy, -C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylhydroxy, -C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy, -S(O)C 1 -C 6 Alkyl, -S(O) 2 C 1 -C 6 Alkyl, -S(O) 2 NR e R f , or -C(O)NR e R f Selected from R e and R f are each independently H, C 1 -C 6 Alkyl or -C 1 -C 6 alkylhydroxy; or R AN-1 and R AN-2 together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocycle, such as tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, 【Transformation 60】 wherein the 4- to 10-membered nitrogen-containing heterocycle is optionally substituted with one or more substituents, such as hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylhydroxy, hydroxy, oxo, amino, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -O-phenyl and phenyl; R 2 -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy, -C 1 -C 6 Alkylene hydroxy or halogenated C 1 -C 6 alkyl, or R 2 Ha-C 1 -C 6 alkyl-cyclopropyl, W is -C 1 -C 6 Alkylene- and -OC 1 -C 6 alkylene-, preferably W is selected from 【Chemistry 61】 Selected from B is phenyl, optionally substituted with one or more substituents, including halogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl and C 1 -C 6 alkoxy, and Z is -NH(R Z-1 ) and R Z-1 is H, -C 1 -C 6 Alkyl or halogenated C 1 -C 6 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from: alkyl

17. R A2-1 teeth, 【Transformation 62】 Selected from R A2-2 , R AN-1 and R AN-2 17. The compound of claim 16, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

18. R A-1 teeth, 【Chemistry 63-1】 【Chemistry 63-2】 【Chemistry 64】 17. The compound of claim 16, selected from: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

19. B is 【Transformation 65】 Selected from R Z-1 is H, -C 1 -C 6 Alkyl and halogenated C 1 -C 6 17. The compound of claim 16, wherein the compound is selected from the group consisting of alkyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

20. The compound is 【Chemical Formula 66】 【Transformation 67】 Selected from R AN-1 , R AN-2 , R A2-2 and R 2 17. A compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 21】 【Chemistry 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure selected from the group consisting of:

22. 10. A conjugate comprising the compound of claim 1 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for example, the conjugate is an antibody-drug conjugate.

23. 10. A pharmaceutical composition comprising a compound according to claim 1 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

24. 10. A pharmaceutical composition for affecting the function of Toll-like receptors (TLRs) or modulating the function of the immune system, comprising the compound of claim 1 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the TLRs include TLR7 and / or TLR8.

25. 10. A pharmaceutical composition for preventing and / or treating a disease and / or condition comprising the compound of claim 1 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease and / or condition includes a disease and / or condition associated with Toll-like receptor (TLR) signaling.

26. 26. The pharmaceutical composition of claim 25, the disease and / or condition is selected from the group consisting of tumors, autoimmune diseases, inflammation, sepsis, allergies, asthma, transplant rejection, graft-versus-host disease, immunodeficiency, and viral infections; the disease and / or condition is selected from the group consisting of melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumors, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer; or The pharmaceutical composition, wherein the disease and / or symptom is a viral infection selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HPV (human papillomavirus), RSV (respiratory syncytial virus), SARS-CoV (severe acute respiratory syndrome coronavirus), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), MERS-CoV (Middle East respiratory syndrome coronavirus), and influenza virus.

Images