CN104860935A

CN104860935A - Thiophene adopted as hepatitis C virus inhibitor or variant derivative thereof, and pharmaceutical uses thereof

Info

Publication number: CN104860935A
Application number: CN201410058355.6A
Authority: CN
Inventors: 陈曙辉; 朱文元; 王建非; 黎健; 魏于全; 余洛汀; 陶鑫
Original assignee: CHANGZHOU YINSHENG PHARMACEUTICAL CO LTD; Sichuan University
Current assignee: CHANGZHOU YINSHENG PHARMACEUTICAL CO LTD; Sichuan University
Priority date: 2014-02-21
Filing date: 2014-02-21
Publication date: 2015-08-26
Also published as: CN108084172A; CN107954997A; WO2015124064A1

Abstract

The present invention discloses a series of thiophene adopted as a hepatitis C virus (HCV) inhibitor or variant derivatives thereof, and combinations of the thiophene or the variant derivatives thereof, and relates to applications of the thiophene, or the variant derivatives or the compositions thereof in preparation of chronic hepatitis C virus infection drugs, particularly to a series of compounds adopted as a NS5A inhibitor and compositions thereof, and pharmaceutical uses of the compounds and the compositions.

Description

Thiophene or variant derivative thereof as hepatitis C virus inhibitor and pharmaceutical application thereof

Technical Field

The invention relates to thiophene or variant derivatives thereof as Hepatitis C Virus (HCV) inhibitors, compositions thereof, and uses thereof in preparing medicaments for treating chronic hepatitis C virus infection. In particular, the invention relates to a series of compounds serving as NS5A inhibitors, and compositions and pharmaceutical applications thereof.

Background

HCV is one of the major human pathogens, and is estimated to be about 1.7 billion globally infected with chronic HCV, 5 times as many as people infected with human immunodeficiency virus type 1. Chronic HCV infected persons develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is therefore a leading cause of death from liver disease in patients worldwide.

Currently, the standard chronic HCV infection therapy is a combination of interferon-alpha and ribavirin with one of the Direct Acting Antiviral (DAA) drugs approved for the last two years. Although the curative effect is obviously improved compared with the prior combined use of the alpha-interferon and the ribavirin, the traditional Chinese medicine composition is still ineffective for partial chronic HCV infection patients, and the virus can generate drug resistance. Plus interferon-alpha and ribavirin have significant side effects. Therefore, new effective drugs for the treatment of chronic HCV infection are currently urgently needed.

HCV is a single-stranded positive-stranded RNA virus. Genus Flaviviridae (Flaviviridae family) within a single genus. All members of the flaviviridae family are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins via translation of a single uninterrupted Open Reading Frame (ORF).

There is considerable heterogeneity in the nucleotide and encoded amino acid sequences of the HCV genome. At least 6 major genotypes have been identified, with over 50 subgenotypes. The major genotypes of HCV vary in their distribution throughout the world, and despite the large number of genotypes studied for pathogenesis and therapeutic role, the clinical importance of the genetic heterogeneity of HCV remains unclear.

The HCV RNA genome is approximately 9500 nucleotides in length, has a single open reading frame, and encodes a single polyprotein of about 3000 amino acids. In infected cells, the polyprotein is cleaved at multiple sites by cellular and viral proteases, producing structural and non-structural (NS) proteins. In the case of HCV, the formation of mature nonstructural proteins (NS 2, NS3, NS4A, NS4B, NS5A and NS5B) is achieved by two viral proteases. The first (NS 2) is generally considered to be a metalloprotease, which cleaves at the NS2-NS3 junction; the second protease is a serine protease contained in the N-terminal region of NS3 (also referred to herein as NS3 protease) which mediates all subsequent cleavage downstream of NS3 in cis at the NS3-NS4A cleavage site and in trans at NS4A-NS4B, NS4B-NS5A, NS5A-NA5B sites. The NS4A protein appears to have multiple functions, acting as a cofactor for NS3 protease and possibly assisting in membrane localization of NS3 and other viral replicase components. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The functions of both NS4B and NS5A proteins are not fully understood, but play an important role in HCV replication. NS4B is a transmembrane protein involved in the formation of viral replication complexes. NS5A is a phosphorylated protein involved in viral RNA replication and viral particle formation. NS5B (also known as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV genomic RNA replication.

Documents WO2013095275, WO2012122716, CN102863428A and the like each report a series of compounds as HCV inhibitors, whose effects in terms of activity, solubility and the like are to be improved.

Disclosure of Invention

The invention aims to provide a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

E₁、E₇each independently represents a structural unit represented by the formula (a),

wherein,

R₁selected from the group consisting of C = O, C = S, S (= O), S (= O)₂、C（R_1a）（R_1b）；

R₃Is selected from C (R)_3a）（R_3b）、C=O、C=S、S（=O）、S（=O）₂；

R₄Selected from more than two substituted [ chain hydrocarbon group, heterochain hydrocarbon group, chain hydrocarbon hetero group, cyclic hydrocarbon group, heterocyclic group, cyclic hetero group]；

R₂、R₅、R_1a、R_1b、R_3a、R_3bEach independently selected from H, F, Cl, Br, I, CN or optionally substituted [ OH, SH, NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

n₁Or n₄Each independently selected from 0 or 1;

n₂selected from 0, 1,2,3, 4, 5 or 6;

n₃selected from 0, 1,2,3, 4, 5 or 6;

n₅selected from 1,2,3 or 4;

when n is₁、n₂、n₃Or n₄When 0, the corresponding structural unit represents a single bond which serves only for linking;

E₂、E₆are respectively and independently selected from-C (= O) N (R)_6a)C(R_6b)(R_6c)、CH₂O, S, C = O, C = S, S (= O), S (= O)₂Or a structural unit represented by the formula (b),

R_6a、R_6b、R_6ceach independently selected from H, C_1-6Alkyl or alkoxy;

W₅、W₆each independently represents C, N, optionally substituted [ CH₂、CH、NH、CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]C ≡ C, a single bond, O, S, C = O, C = S, S (= O), S (= O) 2;

W₇、W₈each independently represents H, F, Cl, Br, I, CN, = O, = S or optionally substituted [ OH, SH, NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]Optionally W₇And W₈W between₇And W₇W between₈And W₈Are connected into a ring;

m₇、m₈selected from 0, 1, 2;

E₃、E₅are each independently selected from CH₂O, S, C = O, C = S, S (= O), S (= O)₂Or a structural unit represented by the formula (c);

L₁each independently selected from C, N, optionally substituted [ NH, CH₂、CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]、C≡C、O、S、C=O、C=S、S（=O）、S（=O）₂Or a single bond;

L₂、L₃、L₄、L₅、L₈、L₉each independently selected from C, N, optionally substituted [ NH, CH₂、

CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]、C≡C、O、S、C=O、C=S、S（=O）、S（=O）₂；

L₆、L₇Each independently selected from H, F, Cl, Br, I, CN, = O, = S or optionally substitutedSubstituted [ OH,

SH、NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

p₁、p₆、p₇Each independently selected from 0, 1,2,3, 4, 5 or 6;

E₄selected from structural units represented by the formula (d) or (e),

wherein Z is₁、Z₂、X₁、X₂Each independently selected from a single bond, O, S, C = O, C = S, S = O, S (= O)₂Or optionally substituted [ CH₂NH, PH, hydrocarbyl, heterohydrocarbyl, hydrocarby, heterohydrocarbyl]；

Z₃、Z₄、X₃、X₄Each independently selected from H, F, Cl, Br, I, CN, = O, = S or optionally substituted [ OH, SH, NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]Optionally Z₃And Z₄Are connected into a ring;

q₃、q₄each independently selected from 0, 1,2 or 3;

represents a single bond or a double bond;

represents a single bond, a double bond or no bond whenWherein represents that the structural unit is absent when no bond is formed;

optionally, the compound or pharmaceutically acceptable salt thereof comprises one or more chiral centers.

Preferably, the above-mentioned sub-structural unit of the structural unit (b) is represented by the formula (g),

wherein,

T_1aeach independently selected from C, N, optionally substituted [ CH₂-CH₂、CH=CH、CH₂CH, NH, 3-to 6-membered hydrocarbon group or 3-to 6-membered heterohydrocarbon group]C ≡ C, a single bond, O, S, C = O, C = S, S (= O), S (= O) 2;

T_2a、T_3a、T_4aeach independently selected from C, N, optionally substituted [ CH₂、CH₂-CH₂CH = CH, NH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]、C≡C、O、S、C=O、C=S、S（=O）、S（=O）2；

T_5aSelected from H, F, Cl, Br, I, CN, = O, = S or optionally substituted [ OH, SH, NH ]₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

m_5aSelected from 0, 1,2,3, 4, 5 or 6;

W_5a、W_6aeach independently represents C, N, optionally substituted [ CH₂、NH、CH、CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]C ≡ C, a single bond, O, S, C = O, C = S, S (= O), S (= O) 2;

T_6a、T_7aeach independently selected from O, S, optionally substituted [ NH, CH₂、CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]C ≡ C, single bond, C = O, C = S, S (= O), S (= O)₂；

T_8aFrom H, F, Cl, Br, I,CN, = O, = S or optionally substituted [ OH, SH, NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

m_6aIs selected from 0, 1,2 or 3, when m_6aAt 0, the corresponding structural unit represents a single bond which serves only for linking;

m_8aselected from 0, 1,2,3, 4, 5 or 6;

represents a single bond or a double bond;

represents a single bond, a double bond or no bond whenWherein represents the structural unit and its auxiliary structural units are absent when no bond is formed, T_1a、T_2aThe two sides are not simultaneously double bonds.

Preferably, the substructure unit of the above formula (g) is selected from:

or

Preferably, the structural unit represented by the above formula (c) is selected from:

or

Preferably, the sub-structural unit of the structural unit represented by the above formula (d) is represented by the formula (d-1):

wherein,

Z₁、Z₂each independently selected from a single bond, O, S, C = O, C = S, S = O, S (= O)₂Or optionally substituted [ CH₂NH, PH, hydrocarbyl, heterohydrocarbyl, hydrocarby, heterohydrocarbyl](ii) a And

Z₅、Z₆、Z₇、Z₈each independently selected from optionally substituted [ CH₂-CH₂、CH=CH、CH₂CH, NH, 3-to 6-membered hydrocarbon group or 3-to 6-membered heterohydrocarbon group]C ≡ C, single bond, O, S, C = O, C = S, S (= O), S (= O)₂，Z₅、Z₆、Z₇、Z₈Not all four of them are simultaneously single bonds.

Preferably, Z is as defined above₁、Z₂Each independently selected from the group consisting of optionally substituted:

phenyl, phenyl,Biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-oxypentanyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2, 3-oxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,3, 4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1, 4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3, 5-trithianyl, 1,3, 5-triazinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl or quinoxalinyl.

Preferably, the above formula (d)_-1) The sub-building blocks of the building blocks shown are selected from: or

Preferably, the sub-structural units of the structural unit represented by the above formula (e) are selected from:

preferably, R is as defined above₄Is selected from more than two substituted 3-10 membered cyclic group or heterocyclic group or cyclohetero group, and the heteroatom or heteroatom group is selected from N, O, S, S (= O) or S (= O)₂。

Preferably, R is as defined above₄Selected from the following groups substituted by two or more positions: or

Preferably, R is as defined above₄Selected from the following groups substituted by two or more positions:

orFurther preferably, when R is₄When selected from the above groups, R₁Is C = O, R₅Is H, n₁、n₄And n₅Is 1, n₂And n₃Is 0, R₁And R₄Forming an amide bond.

Preferably, the substructure unit of formula (a) is selected from:

or

Preferably, R is as defined above₂、R₅、R_1a、R_1b、R_3a、R_3bEach independently selected from H, F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, NH₂Alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylamino]And the heterocyclic group is selected from furyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, pyrazolyl or imidazolyl.

Preferably, the number of carbon atoms in the alkyl moiety of the above alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl and alkoxycarbonylamino is 1,2,3, 4, 5 or6, and the number of carbon atoms in the cycloalkyl group is 3,4, 5 or 6.

Preferably, R is as defined above₂、R₅、R_1a、R_1b、R_3a、R_3bEach independently selected from H, F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, NH₂Methyl, isopropyl, cyclopropyl, butyl, tert-butyl, trifluoromethyl, hydroxymethyl, -CH (OH) CH₃、-CH₂CH₂OH、-CH₂CH₂（OH）、-CH（OH）CH₃Methoxy, methoxymethyl, -CH (CH)₃）OCH₃、-CH₂CH₂OCH₃、Methylthio group, ethoxycarbonyl group,Or

Preferably, the above substituted substituents are selected from the group consisting of F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, SH, NH₂、PH₂A hydrocarbon group, a heterohydrocarbon group and/or a heterohydrocarbon group]。

Preferably, the above-mentioned hydrocarbon group, heterohydrocarbon group and heterohydrocarbon group are selected from optionally substituted [ C_1-12Hydrocarbyl radical, C_1-12Heterohydrocarbyl radical, C_1-12Hydrocarbon hetero group, C_1-12Hydrocarbon hetero group C_1-12Hydrocarbyl radical, -C_1-12OH、-C_0-12COOH、-OC_1-12COOH、-C_1-12CN、-C_0-12CONH₂、-C_0-12O C_1-12、-C_0-12CO C_1-12、-C_0-12COO C_1-12、-C_0-12O（O=）CC_1-12、-C_0-12S(=O)C_1-12or-C_0-12S(=O)₂C_1-12]Wherein the above groups are present as aromatic rings, heteroaromatic rings, aliphatic rings, heteroaliphatic rings, aliphatic chains and/or heteroaliphatic chains, and the number of aromatic rings, heteroaromatic rings, aliphatic rings, heteroaliphatic rings, aliphatic chains and/or heteroaliphatic chains, the number of ring-forming atoms and the number thereof, the manner of connection between rings or chains is arbitrary, provided that it is chemically stable, the heteroatoms or heteroatom groups each being independently selected from O, S, N, S (= O) and/or S (= O)₂The number of heteroatoms or groups of heteroatoms is arbitrary provided that it is chemically stable.

Preferably, the substituent is selected from the group consisting of F, Cl, Br, I, CN, = O, = S, OH, SH, NH₂Halogen or hydroxy or amino or unsubstituted C_1-6Alkyl or heteroalkyl, heteroatom or heteroatom group each independently selected from C_1-6Alkyl or unsubstituted-CONH-, -CO₂-、C_1-6Alkyl or unsubstituted-NH-, -O-, -S-, C_1-6Alkyl or unsubstituted-C = NH, -C = O, -C = S, S (= O) and/or S (= O)₂The number of substituents, heteroatoms or groups of heteroatoms being arbitrary provided that it is chemically stable

Preferably, the substituent is selected from halogen, OH, SH, NH₂、PH₂、CN、=O、=S、CF₃、-OCF₃、-OCH₃Protecting groups and/or leaving groups.

In addition, the following variants exist for the structure with chiral center in any of the above technical solutions: the chiral centers of which are located at other sites and the number of which is chemically stable to be achieved is arbitrary; alternatively, it is arbitrary provided that it also has other chiral centers and the number thereof is chemically stable to be achieved; alternatively, it does not have a chiral center.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Another object of the present invention is the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the manufacture of a medicament for the treatment of HCV.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e = O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and the kind and number of the substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent, unless otherwise specified. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a bond of a group or substituent may cross-link two atoms on a ring, such group or substituent may be bonded to any atom on the ring. When no atom through which a group or substituent is attached to a compound included in the general chemical structure formula but not specifically mentioned is specified in the listed group or substituent, such group or substituent may be bonded through any atom thereof. Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hydrocarbyl" or a subset thereof (e.g., alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means a straight, branched, or cyclic hydrocarbon radical, or combination thereof, that may be fully saturated, mono-, di-, or poly-unsaturated, that may be mono-, di-, or poly-substituted, that may include divalent or polyvalent radicals, that has the specified number of carbon atoms (e.g., C)₁-C₁₀Representing 1 to 10 carbons). The alkyl group includes aliphatic alkyl groups including chain and cyclic, specifically including but not limited to alkyl, alkenyl, alkynyl, and aromatic alkyl groups including but not limited to 6-12 membered aromatic alkyl groups such as benzene, naphthalene, etc. In some embodiments, the term "alkyl" denotes a straight or branched chain radical or a combination thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups have one or more double or triple bonds, examples of which include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.

Unless otherwise specified, the term "heterohydrocarbyl, heterocyclyl, hydrocarbadiyl, cycloheteroalkyl, heterohydrocarbadiyl, heterocyclylheteroalkyl" means that the specified group contains a heteroatom or heteroatom group, heteroatom or heteroatomRadicals include, but are not limited to N, NH, substituted or protected NH, O, S (= O)₂The term "heterohydrocarbyl", or "heterocyclyl" is intended to mean a group attached to the remainder of the molecule through a carbon atom, i.e., the heteroatom may be located at any internal position within the group (other than the position at which the group is attached to the remainder of the molecule); the term hydrocarbohetero, cyclohetero, is taken to mean attached to the remainder of the molecule through a heteroatom, i.e., a heteroatom is positioned at a position where the group is attached to the remainder of the molecule; the term heterocarbyl, heterocyclylheteroaryl is intended to mean a group attached to the remainder of the molecule through a heteroatom, which heteroatom may be located at any internal position within the group (including the position at which the group is attached to the remainder of the molecule).

Unless otherwise specified, the term "heterohydrocarbyl" or a subset thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like) by itself or in combination with another term means a stable straight-chain, branched, or cyclic hydrocarbon radical, or combination thereof, consisting of a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heterocarbyl" or subset thereof (e.g., heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH=CH-O-CH₃、-CH₂-CH=N-OCH₃and-CH = CH-N (CH)₃)-CH₃. At most twoThe hetero atoms may be continuous, e.g. -CH₂-NH-OCH₃。

Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in a conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, amino group or sulfur atom, respectively.

Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", "cyclohydrocarbacyl" or their derivatives (such as cycloalkyl, heterocycloalkyl, cycloheteroalkyl, cycloalkenyl, heterocycloalkenyl, cycloheteroalkenyl, cycloalkynyl, heterocycloalkynyl, cycloheteroalkynyl, and the like) by themselves or in combination with other terms mean cyclized "hydrocarbyl", "heterocarbyl", or "hydrocarbacyl", respectively. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1, 2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like.

Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di-or poly-substituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 4-pyridyl, and the like, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Unless otherwise specified, for the sake of simplicity, aryl when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The so-called ring includes fused rings. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5 to 7 membered ring" includes, for example, phenylpyridine and piperidinyl; in another aspect, the term "5-to 7-membered heterocycloalkyl ring" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

The term "heteroatom" as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), and the like.

Unless otherwise specified, the term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.

Unless otherwise specified, the term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxyl protecting group," or a "thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

Unless otherwise specified, examples of haloalkyl include, but are not limited to: trifluoromethaneMesityl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C_1-6Alkoxy radicals comprising C₁、C₂、C₃、C₄、C₅And C₆Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl radicals including C₃、C₄、C₅、C₆And C₇A cycloalkyl group. "alkenyl" includes hydrocarbon chains in either a straight or branched configuration, wherein one or more carbon-carbon double bonds, such as ethenyl and propenyl, are present at any stable site along the chain.

The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, unless otherwise specified.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which contains carbon atoms and 1,2,3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a benzene ring to form a bicyclic ring.

Unless otherwise specified, examples of heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino, isobenzofuranyl, pyran, isoindolyl, indolyl, etc, Isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthine, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiothienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.

Unless otherwise specified, the compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.

Unless otherwise specified, the structure of a compound is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LCMS). NMR shift () at 10^-6The units in (ppm) are given. NMR was measured using a Brukeravence-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

Unless otherwise specified, the absolute configuration is determined by conventional methods of single crystal X-Ray diffraction using a Bruker APEX-II CCD, radiation type Cu-K \ a.

Unless otherwise specified, the measurement liquid portion of the liquid mass spectrum LCMS was performed using Agilent 1200 (Xitinate C182.1X 30mm column) and the mass spectrum portion was performed using Agilent 6110 (ion source: ESI).

Unless otherwise specified, HPLC measurements were performed using shimadzu LC10AD high pressure liquid chromatograph (Xtimate C182.1 × 30mm column).

Unless otherwise specified, the silica gel plate for Thin Layer Chromatography (TLC) is HSGF254 silica gel plate of tobacco yellow sea or GF254 silica gel plate of Qingdao, the silica gel plate for Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification for separating and purifying products for thin layer chromatography is 0.4 mm-0.5 mm.

Unless otherwise specified, the column chromatography generally uses 200-300 mesh silica gel of Futai Huanghai silica gel as a carrier.

Unless otherwise specified, known starting materials of the present invention can be synthesized by 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, TCI, Alfa, Shaoyuan chemical technologies (Accela ChemBio Inc), Beijing coupling, and the like.

Unless otherwise specified, the reactions can be carried out in an argon atmosphere or a nitrogen atmosphere without specific mention in the examples. An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

Unless otherwise specified, hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L volume.

Unless otherwise specified, the pressure hydrogenation reaction used a Parr3916EKX model hydrogenator and a Qinglan QL-500 model hydrogen generator or HC2-SS model hydrogenator. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

Microwave reactions, unless otherwise specified, used either CEM Discover-S908860 or Biotage Initiator60 microwave reactors.

Unless otherwise specified, the solutions refer to aqueous solutions without specific mention in the examples.

Unless otherwise stated, the reaction temperature is room temperature and is 20 ℃ to 30 ℃ unless otherwise specified in the examples.

Unless otherwise specified, the progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC), using a system of developing reagents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.

Unless otherwise specified, the system of eluents for column chromatography and developer system for thin layer chromatography used for purifying compounds include: a: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.

Unless otherwise specified, all solvents used in the present invention are commercially available and can be used without further purification.

Unless otherwise specified, the following abbreviations are used in the present invention: aq represents water; HATU represents O-7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-diMethyl formamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl as an amine protecting group; HOAc represents acetic acid; NaCNBH₃Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc₂O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl₂Represents thionyl chloride; CS₂Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu₄NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents the melting point.

Unless otherwise specified, the compounds are either by hand orThe software names, and the commercial compounds are under the supplier catalog name.

Compared with the prior art, the compound has high efficiency and low toxicity, makes remarkable and even unexpected progress in the aspects of activity, half-life period, solubility, pharmacokinetics and the like, and is more suitable for pharmacy.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Reference example 1: fragment BB-1

The synthetic route is as follows:

step 1: synthesis of Compound BB-1-3

Compound BB-1-1(1.38g,5.0mmol) was dissolved in acetonitrile (15mL), compound BB-1-2(1.08g,5.0mmol) was added, followed by the gradual addition of DIPEA (0.65g,5.0 mmol). After the addition was complete, the reaction was stirred at room temperature overnight. The solvent was removed from the reaction solution under reduced pressure using a rotary evaporator, the resulting oil was diluted with 30mL of water and extracted with ethyl acetate (20 mL. times.2), the resulting organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was removed the solvent under reduced pressure to give the title compound BB-1-3(2.0g, 9%). LCMS M/z,314.0(M-100)⁺

Step 2: synthesis of Compound BB-1-4

Compound BB-1-3(2.0g,4.82mmol) was dissolved in toluene (40mL), ammonium acetate (5.6g,72.44mmol) was added, and the reaction was heated under reflux overnight. The reaction solution was cooled, the solvent was removed under reduced pressure, the resulting oil was diluted with 60mL of water and extracted with ethyl acetate (30 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give the title compound BB-1-4(1.8g, 95%). LCMS M/z,394.1(M +1)⁺

And step 3: synthesis of Compound BB-1-5

Compound BB-1-4(1.8g,4.56mmol) was dissolved in methylene chloride (20mL), and the above solution was cooled to 0 ℃ and trifluoroacetic acid (6mL) was gradually added dropwise thereto, followed by stirring at room temperature for 5 hours. The reaction solution was subjected to solvent removal under reduced pressure using a rotary evaporator, the obtained oil was neutralized with a saturated sodium bicarbonate solution (pH =8) and extracted with ethyl acetate (20mL × 2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to solvent removal under reduced pressureThe title compound BB-1-5(1.1g,82%) was obtained. LCMS M/z,294.0(M +1)⁺

And 4, step 4: synthesis of Compound BB-1-7

Compound BB-1-5(588mg,2.0mmol) was dissolved in methylene chloride (20mL), and compound BB-1-6(382mg,2.0mmol), HATU (912mg,2.4mmol) and DIPEA (309.6mg,2.4mmol) were added in this order and the mixture was stirred at room temperature for 2 hours. 30mL of water was added, and the organic phase obtained after separation was washed once with NaCl solution, dried over anhydrous sodium sulfate, and the solvent concentrate was removed under reduced pressure to give an oil, which was purified by preparative silica gel plate separation (eluent, EtOAc/PE, 3/1) to give the title compound BB-1-7(510mg, 55%).

LCMS:m/z,467.1(M+1)⁺

And 5: synthesis of Compound BB-1

Compound BB-1-7(200mg,0.428mmol) was dissolved in DMF (6mL), and borane BB-1-8 (163 mg, 0.642 mmol), KOAc (84mg,0.856mmol) and Pd (dppf) Cl2(15mg,0.02mmol) were added successively. The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 3 hours under nitrogen protection. The reaction solution was cooled, diluted with water (30mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give a crude product, which was purified and isolated using preparative silica gel plate (eluent, EtOAc/PE, 3/1) to give the title compound BB-1(70mg, 32%).

LCMS:m/z,515.3(M+1)⁺

Reference example 2: fragment BB-2

The synthetic route is as follows:

step 1: synthesis of Compound BB-2-3

Compound BB-2-1(3.74g,20mmol) was dissolved in DMF (100mL), and compound BB-2-2(4.3g,20mmol), HATU (8.36g,22mmol) and DIPEA (3.87g,30mmol) were added successively and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 200mL of water, extracted with ethyl acetate (200 mL. times.2), and the organic phase obtained after separation was washed once with a saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent concentrate was removed under reduced pressure to obtain the title compound BB-2-3(6.1g, 79%). LCMS M/z,384.1(M +1)⁺

Step 2: synthesis of Compound BB-2-4

Compound BB-2-3(6.0g,15.63mmol) was dissolved in acetic acid (40mL), and ammonium acetate (12g,155.6mmol) was added in portions. The reaction solution was heated to 90 ℃ and reacted for 3 hours. The reaction solution was cooled, diluted with 150mL of water and neutralized with 4N NaOH (pH =8), extracted with ethyl acetate (50mL × 2), the obtained organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to obtain the title compound 2-4(4.5g, 79%). LCMS M/z 366.1(M +1)⁺

And step 3: synthesis of Compound BB-2-5

Compound BB-2-4(4.5g,12.28mmol) was dissolved in methylene chloride (45 mL), and the above solution was cooled to 0 ℃ and trifluoroacetic acid (9 mL) was gradually added dropwise thereto, followed by stirring at room temperature overnight. The reaction solution was subjected to solvent removal under reduced pressure using a rotary evaporator, the resulting oil was neutralized with a saturated sodium bicarbonate solution (pH =8) and extracted with ethyl acetate (50mL × 2), the obtained organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to solvent removal under reduced pressure to obtain the title compound BB-2-5(2.5g, 76.5%). LCMS M/z,266.0(M +1)⁺

And 4, step 4: synthesis of Compound BB-2

The compound BB-2-5(532mg,2.0mmol) was dissolved in methylene chloride (15mL), and the compounds BB-2-6(385mg,2.2mmol), HATU (836mg,2.2mmol) and DIPEA (368mg,2.9mmol) were added in this order at room temperatureStirring was continued overnight. 20mL of water was added, the organic phase obtained after separation was washed once with a saturated NaCl solution, the organic phase obtained after separation was dried over anhydrous sodium sulfate, the filtrate after filtration was subjected to removal of the solvent concentrate under reduced pressure to obtain an oil, which was purified and separated (eluent, EtOAc/PE, 3/1) using a preparative silica gel plate to obtain the title compound BB-2(200mg, 24%). LCMS M/z,423.1(M +1)⁺

Reference example: fragment BB-3

The synthetic route is as follows:

step 1: synthesis of Compound BB-3-2

Compound BB-2-5(532mg,2.0mmol) was dissolved in methylene chloride (20mL), and compound BB-1-6(420mg,2.2mmol), HATU (912mg,2.4mmol) and DIPEA (388mg,3.0mmol) were sequentially added thereto, and the mixture was stirred at room temperature overnight. 30mL of water was added, the organic phase obtained after separation was washed once with a saturated NaCl solution, the organic phase obtained after separation was dried over anhydrous sodium sulfate, the filtrate after filtration was subjected to removal of the solvent concentrate under reduced pressure to obtain an oil, which was purified and separated (eluent, EtOAc/PE, 3/1) using a preparative silica gel plate to obtain the title compound BB-3-2(750mg, 85%). LCMS M/z,439.1(M +1)⁺

Step 2: synthesis of Compound BB-3

The compound BB-3-2(300mg,0.68mmol) was dissolved in 1, 4-dioxane (6mL), and the pinacolinate dimer (258mg, 1.02mmol), KOAc (135mg,1.38mmol) and Pd (dppf) Cl were added in this order₂(30mg,0.04 mmol). The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 3 hours under nitrogen protection. The reaction mixture was cooled, diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.2) 2 timesThe resulting organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was filtered to remove the solvent under reduced pressure to give the crude product, which was purified on a preparative silica gel plate (eluent, EtOAc/PE, 3/1) to give the title compound BB-3(235mg, 71%).

LCMS:m/z,487.3(M+1)⁺

Reference example 4: fragment BB-4

The synthetic route is as follows:

step 1: synthesis of Compound BB-4-2

Compound BB-8(292mg,1.0mmol) was dissolved in methylene chloride (6mL), and compound BB-4-1(208mg,1.1mmol), HATU (456mg,1.2mmol) and DIPEA (260mg,2.0mmol) were sequentially added thereto, and the mixture was stirred at room temperature overnight. 30mL of water was added, the organic phase obtained after separation was washed once with a saturated NaCl solution, the obtained organic phase was dried over anhydrous sodium sulfate, and the filtered filtrate was subjected to removal of the solvent concentrate under reduced pressure to obtain the title compound BB-4-2(320mg, 69%). LCMS M/z,463.1(M +1)⁺

Step 2: synthesis of Compound BB-4

Compound BB-4-2(320mg,0.69mmol) was dissolved in DMF (10mL), and the pinacoline borate duplex (262 mg, 1.03mmol), KOAc (135mg,1.38mmol) and Pd (dppf) Cl were added in that order₂(30mg,0.04 mmol). The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 3 hours under nitrogen protection. The reaction solution was cooled, diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, the filtrate obtained by filtration was freed of the solvent under reduced pressure to give the crude product, which was purified and separated on a preparative silica gel plate (eluent, EtOAc/PE,1/1) gave the title compound BB-4(260mg, 74%).

LCMS:m/z,511.3(M+1)⁺

Reference example 5: fragment BB-5

The synthetic route is as follows:

step 1: synthesis of Compound BB-5-2

Compound BB-1-1(1.38g,5.0mmol) was dissolved in acetonitrile (15mL), compound BB-5-1(0.95g,5.0mmol) was added, and DIPEA (0.65g,5.0mmol) was gradually added. After the addition was complete, the reaction was stirred at room temperature overnight. The solvent was removed from the reaction solution under reduced pressure using a rotary evaporator, the resulting oil was diluted with 30mL of water and extracted with ethyl acetate (20 mL. times.2), the resulting organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was removed the solvent under reduced pressure to give the title compound BB-5-2(1.8g, 94%). LCMS M/z 285.0(M-100)⁺

Step 2: synthesis of Compound BB-5-3

Compound BB-5-2(1.8g,4.66mmol) was dissolved in toluene (50mL), ammonium acetate (5.39g,69.91mmol) was added, and the reaction was heated under reflux overnight. The reaction solution was cooled, the solvent was removed under reduced pressure, the resulting oil was diluted with 80mL of water and extracted with ethyl acetate (60 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give the title compound BB-5-3(1.6g, 94%). LCMS M/z 366.1(M +1)⁺

And step 3: synthesis of Compound BB-5-4

Compound BB-5-3(1.6g,4.36mmol) was dissolved in bisMethyl chloride (20mL), the solution was cooled to 0 ℃ and trifluoroacetic acid (6mL) was gradually added dropwise, and the reaction was stirred at room temperature for 5 hours. The reaction solution was subjected to solvent removal under reduced pressure using a rotary evaporator, the resulting oil was neutralized with a saturated sodium bicarbonate solution (pH =8) and extracted with ethyl acetate (20mL × 2), the obtained organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to solvent removal under reduced pressure to obtain the title compound BB-5-4(1.0g, 86%). LCMS M/z,266.0(M +1)⁺

And 4, step 4: synthesis of Compound BB-5-5

Compound BB-5-4(532mg,2.0mmol) was dissolved in methylene chloride (20mL), and compound BB-1-6(382mg,2.0mmol), HATU (912mg,2.4mmol) and DIPEA (516mg,2.4mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 3 hours. 30mL of water was added, and the organic phase obtained after separation was washed once with NaCl solution, dried over anhydrous sodium sulfate, and the solvent concentrate was removed under reduced pressure to give an oil, which was purified by preparative silica gel plate separation (eluent, EtOAc/PE, 3/1) to give the title compound BB-5-5(400mg, 46%).

LCMS:m/z,439.1(M+1)⁺

And 5: synthesis of Compound BB-5

The compound BB-5-5(400mg,0.91mmol) was dissolved in 1, 4-dioxane (20mL), and the pinacolinate diacetate (345mg, 1.36mmol), KOAc (178mg,1.82mmol) and Pd (dppf) Cl were added in this order₂(35mg,0.047 mmol). The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 3 hours under nitrogen protection. The reaction solution was cooled, diluted with water (30mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give a crude product, which was purified and separated using preparative silica gel plate (eluent, EtOAc/PE, 2/1) to give the title compound BB-5(300mg, 68%).

LCMS:m/z,487.3(M+1)⁺

Reference example 6: fragment BB-6

The synthetic route is as follows:

step 1: synthesis of Compound BB-6-2

Compound BB-6-1(4.6g,20mmol) was dissolved in acetonitrile (70mL), compound BB-1-1(5.56g,20mmol) was added, followed by the gradual addition of DIPEA (2.58g,20 mmol). After the addition was complete, the reaction was stirred at room temperature overnight. The solvent was removed from the reaction solution under reduced pressure using a rotary evaporator, the resulting oil was diluted with 100mL of water and extracted with ethyl acetate (60 mL. times.2), the resulting organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give the title compound BB-6-2(8.4g, 99%).

LCMS:m/z,326.0(M-100)⁺

Step 2: synthesis of Compound BB-6-3

Compound BB-6-2(8.4g,19.7mmol) was dissolved in toluene (120mL), ammonium acetate (22.9g,297.4mmol) was added, and the reaction was heated under reflux overnight. The reaction solution was cooled, the solvent was removed under reduced pressure, the resulting oil was diluted with 200mL of water and extracted with ethyl acetate (150 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give the title compound BB-6-3(7.8g, 98%). LCMS M/z,406.0(M +1)⁺

And step 3: synthesis of Compound BB-6-4

Compound BB-6-3(7.1g,17.5mmol) was dissolved in methylene chloride (75mL), and the above solution was cooled to 0 ℃ and trifluoroacetic acid (30mL) was gradually added dropwise thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was subjected to removal of the solvent under reduced pressure using a rotary evaporator, and the resulting oily substance was neutralized with a saturated sodium bicarbonate solution (pH =8) and extracted with ethyl acetate (100mL × 2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to obtain the title compound BB-6-4(5.0g, 93%). LCMS M/z,306.0(M +1)⁺

And 4, step 4: synthesis of Compound BB-6-5

Compound BB-6-4(305mg,1.0mmol) was dissolved in methylene chloride (10mL), and compound BB-1-6(191mg,1.0mmol), HATU (456mg,1.2mmol) and DIPEA (258mg,2.0mmol) were sequentially added thereto, followed by stirring at room temperature for 3 hours. 15mL of water was added, the organic phase obtained after separation was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent concentrate was removed under reduced pressure to give an oil, which was purified by preparative silica gel plate separation (eluent, EtOAc/PE, 3/1) to give the title compound BB-6-5(250mg, 52%).

LCMS:m/z,479.0(M+1)⁺

And 5: synthesis of Compound BB-6

Compound BB-6-5(160mg,0.33mmol) was dissolved in DMF (4mL), and the pinacoline diacetate (129mg,0.51mmol), KOAc (65mg,0.66mmol) and Pd (dppf) Cl were added in that order₂(12mg,0.016 mmol). The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 2 hours under nitrogen protection. The reaction was cooled, diluted with water (10mL) and extracted with ethyl acetate (10mL), the resulting organic phases combined and dried over anhydrous sodium sulfate, the filtrate obtained by filtration was filtered to remove the solvent under reduced pressure to give the crude product, which was purified and separated using preparative silica gel plates (eluent, EtOAc/PE, 1/1) to give the title compound BB-6(90mg, 52%). LCMS M/z,527.2(M +1)⁺

Reference example 7: fragment BB-7

The synthetic route is as follows:

step 1: synthesis of Compound BB-7-1

Compound BB-6-4(305mg,1.0mmol) was dissolved in methylene chloride (10mL), and compound BB-2-6(175mg,1.0mmol), HATU (456mg,1.2mmol) and DIPEA (258mg,2.0mmol) were sequentially added thereto, followed by stirring at room temperature for 3 hours. 15mL of water was added, the organic phase obtained after separation was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent concentrate was removed under reduced pressure to give an oil which was purified by preparative silica gel plate separation (eluent, EtOAc/PE, 3/1) to give the title compound 7-1(260mg, 56%).

LCMS:m/z,463.0(M+1)⁺

Step 2: synthesis of Compound BB-7

Compound BB-7-1(160mg,0.33mmol) was dissolved in DMF (4mL), and the pinacoline diacetate (129mg,0.49mmol), KOAc (65mg,0.66mmol) and Pd (dppf) Cl were added in that order₂(12mg,0.016 mmol). The air was replaced with nitrogen 3 times, and the reaction mixture was reacted at 110 ℃ for 2 hours under nitrogen protection. The reaction was cooled, diluted with water (10mL) and extracted with ethyl acetate (10mL), the resulting organic phases combined and dried over anhydrous sodium sulfate, the filtrate obtained by filtration was filtered to remove the solvent under reduced pressure to give the crude product, which was purified and separated using preparative silica gel plates (eluent, EtOAc/PE, 1/1) to give the title compound BB-7(110mg, 62%).

LCMS:m/z,511.2(M+1)⁺

Reference example 8: fragment BB-8

The synthetic route is as follows:

step 1: synthesis of Compound BB-8-2

Compound BB-2-2(2.15g,10mmol) was dissolved in acetonitrile (40mL), compound BB-1-1(2.78g,10mmol) was added, followed by the gradual addition of DIPEA (1.29g,10 mmol). After the addition was complete, the reaction was stirred at room temperature overnight. The solvent was removed from the reaction solution under reduced pressure using a rotary evaporator, the resulting oil was diluted with 50mL of water and extracted with ethyl acetate (30 mL. times.2), the resulting organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was removed the solvent under reduced pressure to give the title compound BB-8-2(3.9g, 95%).

LCMS:m/z,312.0(M-100)⁺

Step 2: synthesis of Compound BB-8-3

Compound BB-8-2(3.9g,9.47mmol) was dissolved in toluene (70mL), ammonium acetate (7.3g,94.8mmol) was added, and the reaction was heated under reflux overnight. The reaction solution was cooled, the solvent was removed under reduced pressure, the resulting oil was diluted with 50mL of water and extracted with ethyl acetate (40 mL. times.2), the organic phases obtained 2 times were combined and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to removal of the solvent under reduced pressure to give the title compound BB-8-3(3.2g, 86%). LCMS M/z,392.1(M +1)⁺

And step 3: synthesis of Compound BB-8

Compound BB-8-3(3.0g,7.65mmol) was dissolved in methylene chloride (60mL), and the above solution was cooled to 0 ℃ and trifluoroacetic acid (20mL) was gradually added dropwise thereto, followed by stirring at room temperature for 5 hours. The reaction solution was subjected to solvent removal under reduced pressure using a rotary evaporator, the resulting oil was neutralized with a saturated sodium bicarbonate solution (pH =8) and extracted with ethyl acetate (40mL × 2), the obtained organic phases were combined 2 times and dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to solvent removal under reduced pressure to obtain the title compound BB-8(2.2g, 99%). LCMS M/z 292.0(M +1)⁺

Reference example 9: fragment BB-9

The synthetic route is as follows:

step 1: synthesis of Compound BB-9-2

The compound N-Boc-L-proline (4.30g,20mmol) and potassium carbonate (3.86g,27.97mmol) were suspended in acetonitrile (100ml), and compound BB-9-1 (3.31 g,10.75mmol) was added at room temperature. After stirring at room temperature for 4 hours and TLC detection, the solvent was evaporated to give the desired compound BB-9-2 (white solid, 1.26g, 14% yield). The product was used directly in the next step without purification. MS M/z 343.7[ M-Boc + H]⁺Step 2: synthesis of Compound BB-9-3

Compound BB-9-2(0.80g,1.81mmol) was dissolved in toluene (50ml) at room temperature, and ammonium acetate (7.67g,99.61mmol) was added. The mixture was heated to reflux under nitrogen, stirred overnight, cooled to room temperature after completion of the TLC detection reaction, quenched with water (30ml), and extracted with ethyl acetate (50 ml. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =3:2 → pure ethyl acetate) to give the objective compound BB-9-3 (white powder, 0.29g, yield 38%). MS M/z 422.0[ M + H ]]⁺.

And step 3: synthesis of Compound BB-9-4

Compound BB-9-3(5.00g,11.84mmol) was added to a hydrogen chloride/ethyl acetate solution (HCl/EA,4mol/L,20mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. And (4) after TLC detection reaction is finished, drying the solvent by spinning to obtain a white solid intermediate BB-9-4. The product was used directly in the next step without purification.

And 4, step 4: synthesis of Compound BB-9-5

At room temperature, mixingThe above white solid intermediate BB-9-4(0.242g,0.67mmol), N-Moc-L-valine (BB-2-6,0.18g,0.94mmol), diisopropylethylamine (0.31g,2.39mmol) was dissolved in DMF (3ml), and HATU (0.39g,1.02mmol) was added. After stirring at room temperature for 3 hours and completion of the TLC detection, the reaction was quenched by addition of water (10ml) and extracted with ethyl acetate (50 ml. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =3:2 → pure ethyl acetate) to give the title compound BB-9-5 (yellow solid, 0.22g, yield 68%). MS M/z 481.0[ M + H ]]⁺.

And 5: synthesis of Compound BB-9

Compound BB-9-5(0.22g,0.46mmol), bis-pinacolato borate (0.14g,0.55mmol) were dissolved in dioxane (4ml) at room temperature, and potassium acetate (0.09g,0.93mmol) and Pd (dppf) Cl were added under nitrogen protection₂(0.03g,0.04 mmol). The reaction was carried out by microwave at 120 ℃ for 45 minutes, after completion of the TLC detection, the reaction was cooled to room temperature, filtered, and after the solvent was evaporated from the filtrate, the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =3:2 → pure ethyl acetate) to obtain the objective compound BB-9(0.17g, yield 70%). MS M/z 527.1[ M + H ]]⁺.

Reference example 10: fragment BB-10

The synthetic route is as follows:

step 1: synthesis of Compound BB-10-2

Compound BB-10-2 can be prepared according to Synthesis procedures 1 to 4 of reference example 9 (BB-9). LCMS M/z 479.1[ M + H ]]⁺

Step 2: synthesis of Compound BB-10

Compound BB-10 was prepared according to Synthesis step 5 of reference example 9 (BB-9). LCMS M/z 527.1[ M + H ]]⁺Reference example 11: fragment BB-11

The synthetic route is as follows:

step 1: synthesis of Compound BB-11-2

Compound BB-11-2 was prepared according to Synthesis procedures 1 to 4 of reference example 9 (BB-9). MS M/z 465.1[ M + H ]]⁺.

Step 2: synthesis of Compound BB-11

Compound BB-11 was prepared according to Synthesis step 5 of reference example 9 (BB-9). MS M/z 511.3[ M + H ]]⁺.

Reference example 12: fragment BB-12

The synthetic route is as follows:

step 1: synthesis of Compound BB-12-2

Compound BB-12-2 was prepared according to Synthesis procedures 1 to 4 in reference example 9 (BB-9). LCMS m/z 464.9

[M+H]⁺

Step 2: synthesis of Compound BB-12

Compound BB-12 was prepared according to Synthesis step 5 of reference example 9 (BB-9). LCMS M/z 488.0[ M + Na ]]⁺

Reference example 13: fragment BB-13

The synthetic route is as follows:

step 1: synthesis of Compound BB-13-2

Compound BB-13-2 was prepared according to Synthesis procedures 1 to 4 of reference example 9 (BB-9). MS M/z 485.1[ M + H ]]⁺.

Step 2: synthesis of Compound BB-13

Compound BB-13 was prepared according to Synthesis step 5 of reference example 9 (BB-9). MS M/z 531.2[ M + H ]]⁺.

Reference example 14: fragment BB-14

The synthetic route is as follows:

step 1: synthesis of BB-14

BB-14-1(600mg,1.90mmol) was dissolved in ethyl acetate (5mL), and a hydrogen chloride/ethyl acetate solution was added

(HCl/EA,4mol/L,20mL) and stirred at room temperature for 3 hours. After the TLC detection reaction is finished, the solvent is dried by spinning to obtain white

Intermediate (410mg) as a colored solid. The above white solid intermediate (410mg,1.63mmol), N-Moc-L-valine (BB-2-6,399mg,2.09mmol), diisopropylethylamine (735mg,5.70mmol) was dissolved in DMF (10mL), and HATU (1.08g,2.84mmol) was added. After stirring overnight at room temperature and TLC detection, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1 → pure ethyl acetate) to obtain the objective compound BB-14 (white solid, 306mg, yield 43.2%). MS M/z 374.9[ M + H ]]⁺.

Reference example 15: fragment BB-15

The synthetic route is as follows:

step 1: synthesis of Compound BB-15

Compound BB-15 was prepared according to Synthesis procedure 1 of reference example 14 (BB-14).¹H NMR(CDCl₃400MHz) 6.90(s,1H),5.23 to 5.22(m,1H),4.58 to 4.40(m,1H),4.13 to 3.88(m,4H),3.70(s,3H),3.21 to 3.20(m,2H),2.88 to 2.51(m,2H),2.16 to 2.07(m,3H),1.97 to 1.79(m,2H). Ref.16: fragment BB-16

The synthetic route is as follows:

step 1: synthesis of Compound BB-16-2

Compound BB-16-1(4.1g,26.2mmol) was dissolved in tetrahydrofuran (20mL) at room temperature, and cis-1, 2-cyclohexanedicarboxylic anhydride (AA _013-1,2.0g,13.0mmol) was added under nitrogen. After stirring at room temperature for 6 hours and TLC detection, the solvent was dried by spin-drying to give the desired compound BB-16-2 (colorless gum, 3.5g, yield 83.2%). The product was used directly in the next step without purification.¹H NMR(CDCl₃,400MHz):7.78(s,1H),5.23-5.22(m,1H),3.47(s,2H),3.06-3.03(m,1H),2.78-2.60(m,2H),2.08(brs,1H),1.86(m,1H),1.65-1.51(m,2H),1.27-1.23(m,4H),1.20(d,J=6.4Hz,6H),0.80-0.63(m,2H),0.58-0.57(m,2H).

Step 2: synthesis of Compound BB-16-3

Compound BB-16-2(3.5g,10.79mmol) and potassium carbonate (3.1g,22.5mmol) were suspended in DMF (25mL), and 2, 4' -dibromoacetophenone (BB-1-1,3.1g,11.2mmol) was added at room temperature. After stirring at room temperature for 2 hours, TLC detected completion of the reaction, the reaction was quenched by addition of water (20mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =4:1 → 1:4) to obtain the objective compound BB-16-3(4.8g, yield 87.8%). MS M/z 530.7[ M + Na ]]⁺.

And step 3: synthesis of Compound BB-16

Compound BB-16-3(1.50g,2.96mmol) was dissolved in toluene (200mL) at room temperature, and ammonium acetate (11.88g,154.09mmol) was added. The mixture was heated to reflux under nitrogen, stirred overnight, cooled to room temperature after TLC detection, quenched with water (30mL), and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:3 → pure ethyl acetate) to obtain the objective compound BB-16 (pale yellow powder, 0.95g, yield 66.0%). MS m/z 489.3[M+H]⁺.

Reference example 17: fragment BB-17

The synthetic route is as follows:

step 1: synthesis of Compound BB-17-2

Compound BB-17-1(5g,22.3mmol) was dissolved in a mixed solvent of methanol/water (15mL/15mL) at room temperature, and sodium hydroxide (1.8g,45mmol) was added thereto. After stirring at room temperature for 2 hours, TLC detected completion of the reaction, water (30mL) was added and extracted with ethyl acetate (52 mL). The pH of the aqueous phase was adjusted to 1-2 with 6N hydrochloric acid, and the precipitated solid was collected and dried to obtain the objective compound BB-17-2 (white solid, 4.0g, yield 85%).¹H NMR(DMSO-d₆,400MHz):2.97(t,J=7.6Hz,2H),2.87(t,J=7.6Hz,2H),2.49(s,3H),2.39(t,J=7.6Hz,2H).

Step 2: synthesis of Compound BB-17-3

Compound BB-17-2(5g23.8mmol) and triethylamine (4.8g,47.6mmol) were dissolved in t-butanol (50mL), and DPPA (9.8g,35.6mmol) was added. The mixture was heated to reflux under nitrogen atmosphere, stirred overnight, after completion of the TLC detection reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (200mL) and washed with water (50 mL. times.3) and saturated brine (50mL) in this order. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the objective compound BB-17-3 (white solid, 5g, yield 75%). The product was used directly in the next step without purification.¹H NMR(CDCl₃,400MHz):6.91(s,1H),2.91(t,J=7.6Hz,2H),2.56(t,J=7.6Hz,2H),2.42-2.39(m,5H),1.52(s,9H).

And step 3: synthesis of Compound BB-17-4

Compound BB-17-3(5g,17.8mmol) was dissolved in ethyl acetate (30mL), and a hydrogen chloride/ethyl acetate solution (HCl/EA,4M,20mL) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the TLC detection reaction, the solvent was dried by rotary evaporation to obtain the objective compound BB-17-4 (white solid, 3.6g, yield 93%). The product was used directly in the next step without purification.¹H NMR(Methanol-d₄400MHz):3.10-3.06(m,2H),2.68(t,J=7.6Hz,2H),2.59-2.56(m,5H).

And 4, step 4: synthesis of Compound BB-17-5

Compound BB-17-4(2.9g,13.32mmol), isoamyl nitrite (2.3g,19.64mmol) was dissolved in acetonitrile (20mL) at room temperature, and cupric bromide (3.3g,14.8mmol) was added. After stirring at room temperature for 3 hours under nitrogen, TLC detection of the completion of the reaction was followed by addition of water (10mL) to quench the reaction, and extraction was carried out with ethyl acetate (30 mL. times.4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20:1 → 10:1) to obtain the objective compound BB-17-5 (dark brown solid, 1.6g, yield 49%).¹H NMR(CDCl₃,400MHz):3.05(t,J=7.2Hz,2H),2.58(t,J=7.2Hz,2H)2.5-2.45(m,2H),2.42(s,3H).

And 5: synthesis of Compound BB-17-6

Compound BB-17-5(1.0g,4.08mmol) was dissolved in glacial acetic acid (10 mL). A solution of liquid bromine (653mg,4.09mmol) in glacial acetic acid (1mL) was added dropwise. After stirring overnight at room temperature, after completion of the reaction by LCMS, t-butyl methyl ether (100mL) was added, and the mixture was washed with water (30 mL. times.5) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the objective compound BB-17-6 (dark brown solid, 1.2g, yield 91%). The product was used directly in the next step without purification. MS M/z 324.6[ M + H ]]⁺.

Step 6: synthesis of Compound BB-17-7

N-Boc-L-proline (400mg,1.856mmol) and potassium carbonate (510mg,3.7mmol) were suspended in DMF (5mL), stirred at room temperature for 10 min, then compound BB-17-6 (b: (b) ((b))600mg,1.85 mmol). After completion of the TLC detection reaction, ethyl acetate (100mL) was added, and the mixture was washed with water (20 mL. times.4) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20:1 → 5:1) to obtain the objective compound BB-17-7(644m g, yield 76%). MS M/z 359.9[ M-Boc + H]⁺.

And 7: synthesis of Compound BB-17-8

Compound BB-17-7(650mg,1.42mmol) was dissolved in toluene (50mL) at room temperature, and ammonium acetate (1.1g,14.3mmol) was added. The mixture was heated to 120 ℃ under nitrogen, stirred overnight, cooled to room temperature after TLC detection, quenched with water (30mL), and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =5:1 → 1:1) to obtain the objective compound BB-17-8 (pale yellow powder, 349mg, yield 56%).¹H NMR(CDCl₃,400MHz):6.94(s,1H),4.92(d,J=5.2Hz,1H),3.38(S,2H),3.00-2.93(m,1H),2.81-2.76(m,1H),2.60-2.56(m,2H),2.44-2.39(m,2H),2.14-2.07(m,1H),1.98-1.91(m,1H),1.90-1.56(m,2H),1.46(s,9H).MS m/z:439.9[M+H]⁺.

And 8: synthesis of Compound BB-17-9

Compound BB-17-8(600mg, 1.37mmol) was dissolved in ethyl acetate (10mL), cooled to 0 ℃, and then added dropwise with a hydrogen chloride/ethyl acetate solution (HCl/EA,4mol/L,10mL) and stirred at 0 ℃ for 1 hour. After completion of the TLC detection reaction, the solvent was dried by rotary evaporation to obtain the objective compound BB-17-9 (yellow solid, 510mg, yield 99.4%). The product was used directly in the next step without purification. MS M/z 339.8[ M + H ]]⁺.

And step 9: synthesis of Compound BB-17

The compound BB-17-9(573mg,1.53mmol), N-Moc-L-valine (BB-2-6,323mg,1.69mmol) and diisopropylethylamine (594mg,4.60mmol) were dissolved in DMF (10mL) at room temperature, and HATU (746mg,1.96mmol) was added. Stirring at room temperatureAfter completion of the TLC detection, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1 → pure ethyl acetate) to obtain the objective compound BB-17 (yellow solid, 317mg, yield 41.9%). MS M/z 497.1[ M + H ]]⁺.

Reference examples 18 to 20

Table xx: compounds BB-18, BB-19 and BB-20 in the following table were obtained by synthesizing compound BB-17-9 as a raw material according to step 9 of reference example 17.

Reference example 21: fragment BB-21

The synthetic route is as follows:

step 1: synthesis of Compound BB-2-6

L-valine (100g,751mmol) was added to a sodium hydroxide solution (2mol/L,535 mL). The ice bath was cooled to below 5 ℃ and methyl chloroformate (118.13g,1.25mmol) was added dropwise and stirred at room temperature overnight. After TLC detection reaction is finished, cooling to below 5 ℃ in ice bath, dropwise adding concentrated hydrochloric acid to adjust the pH value to about 5, collecting precipitated solid, washing with water (100mL), and drying to obtain a target compound BB-2-6 (white)Colored solid, 141g, yield 98.2%). The product was used directly in the next step without purification.¹H NMR(CDCl₃400MHz):5.19(d,J=8.8Hz,1H),4.32(dd,J=8.8Hz,J=4.4Hz,1H),3.71(s,3H),2.26-2.18(m,1H),1.01(d,J=7.2Hz,3H),0.94(d,J=6.4Hz,3H).

Step 2: synthesis of Compound BB-21-1

EDC.HCl (26.3g,136.9mmol), N-Moc-L-valine (BB-2-6,17.6g,92.05mmol) and diisopropylethylamine (35.4g,274.4mmol) were dissolved in dry dichloromethane (500mL), stirred at room temperature for 10 min, then added to compound BB-8 (reference example 8, 30g,102.7mmol) and stirred at room temperature under nitrogen overnight. After TLC detection reaction, adding water (20mL) to quench the reaction, washing the organic phase with 10% hydrochloric acid until the pH value is 5-6, then washing with saturated saline (100mL), and drying with anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain compound BB-21-1 (gray foamy solid, 35g, yield 76%). The product was used directly in the next step without purification. MS M/z 449.0[ M + H ]]⁺.

And step 3: synthesis of Compound BB-21

At room temperature, compound BB-21-1(80g,178mmol), bis (pinacolato) borate (90g,354mmol) were dissolved in dioxane (600mL), and potassium acetate (35g,357mmol) and Pd (dppf) Cl were added under nitrogen protection₂(13g,1.78 mmol). The reaction was heated to 90 ℃ under nitrogen and stirred overnight. And cooling to room temperature after TLC detection reaction is finished. After filtration, the filtrate was spin-dried of the solvent, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20:1 → 8:1) to obtain the objective compound BB-21 (gray solid, 70g, yield 80%). MS M/z 519.1[ M + Na ]]⁺.

Reference example 22: fragment BB-22

The synthetic route is as follows:

step 1: synthesis of Compound BB-22-2

Methyl carbazate (BB-22-1,3g,33mmol) was dissolved in acetone (30mL) at room temperature, anhydrous magnesium sulfate (8g,67mmol) was added under nitrogen, and the reaction was heated to reflux and stirred for 2 hours. And cooling to room temperature after TLC detection reaction is finished. After filtration, the solvent was removed from the filtrate by rotary evaporation to obtain the desired compound BB-22-2 (white solid, 3.8g, yield 87.8%). The product was used directly in the next step without purification.¹H NMR(CDCl₃,400MHz):3.82(brs,3H),2.06(d,J=1.6Hz,3H),1.85(s,3H).

Step 2: synthesis of Compound BB-22

Compound BB-22-2(3g,23.1mmol) was dissolved in a mixed solvent of ethyl acetate/glacial acetic acid (30mL/3mL) at room temperature, and platinum dioxide (0.3g) was added under nitrogen protection. The reaction was carried out at 50 ℃ under 50psi of hydrogen for 12 hours and cooled to room temperature. After filtration, the solvent was evaporated from the filtrate to give the objective compound BB-22 (colorless oil, 2.9g, yield 95.1%). The product was used directly in the next step without purification.¹H NMR(CDCl₃,400MHz):3.62(s,3H),3.25(brs,1H),1.04(d,J=6.4Hz,6H).

Reference example 23: fragment BB-23

The synthetic route is as follows:

step 1: synthesis of Compound BB-23-2

At room temperature, 3-Jia is mixedBenzenesulfonyltetrahydrofuran (BB-23-1,3g,12.4mmol), diphenylmethyleneglycine methyl ester (1.49g,5.88mmol) were dissolved in toluene (30mL), and LiHMDS (1mol/L in THF,7.1mL,7.1mmol) was slowly added dropwise under nitrogen. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. After completion of the TLC detection, the reaction was cooled to room temperature, quenched by addition of water (20mL), and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =35:1 → 5:1) to obtain the objective compound BB-3-2 (orange-yellow oil, 1.52g, yield 80%).¹H NMR(CDCl₃,400MHz):7.67-7.65(m,2H),7.48-7.36(m,6H),7.22-7.20(m,2H),4.10(t,J=7.6Hz,1H),3.94-3.92(m,1H),3.79-3.46(m,5H),3.64-3.46(m,1H),3.05-3.01(m,1H),2.07-2.02(m,1H),1.81-1.61(m,1H).

Step 2: synthesis of Compound BB-23-3

Compound BB-23-2(12.2g,37.8mmol) was dissolved in tetrahydrofuran (100mL) at room temperature, and hydrochloric acid (2mol/L, 75.5mL, 151mmol) was slowly added dropwise thereto, followed by stirring at room temperature for 4 hours. After TLC detection reaction, spin-drying the solvent, washing with petroleum ether (50mL × 3), adding sodium hydroxide into the system to adjust the pH value to 8-9, and extracting with ethyl acetate (50mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was solvent-dried by rotary evaporation to give the objective compound BB-23-3 (orange-yellow oil, 3.2g, 53.4% yield).¹H NMR(CDCl₃,400MHz):3.90-3.85(m,2H),3.73-3.68(m,5H),3.37(dd,J=20.8,J=7.2Hz,1H),2.52-2.46(m,1H),1.99-1.96(m,1H),1.78-1.77(m,1H).

And step 3: synthesis of Compound BB-23-4

Compound BB-23-3(2.88g,18.1mmol) was dissolved in dichloromethane (50mL) at room temperature, diisopropylethylamine (7.0g,54.3mmol) was added, methyl chloroformate (1.88g,19.9mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After completion of the TLC detection reaction, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20:1 → 2:1) to obtain the objective compound BB-23-4 (yellow oil, 2.8g, yield 71.2%).¹H NMR(CDCl₃,400MHz):5.38(brs,1H),4.42-4.38(m,1H),3.92-3.90(m,2H),3.78(s,3H),3.75-3.68(m,6H),2.71-2.67(m,1H),2.08-1.81(m,2H).

And 4, step 4: synthesis of Compound BB-23-5

Compound BB-23-4(3.25g,15.0mmol) was dissolved in a mixed solvent of methanol/water (100mL/100mL) at room temperature, and sodium hydroxide (1.2g,30.0mmol) was added thereto. And (3) heating the reaction system to 75 ℃, stirring for 3 hours, adjusting the pH value to 1-2 by using 2N hydrochloric acid after TLC detection reaction is finished, and extracting by using ethyl acetate (200mL multiplied by 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was then dried on the filtrate to obtain the objective compound BB-23-5 (orange-yellow oil, 2.9g, yield 95.4%).¹H NMR(CDCl₃,400MHz):5.60(dd,J=26.4,J=8.4Hz,1H),4.40(brs,1H),3.99-3.89(m,2H),3.79-3.72(m,5H),2.80-2.77(m,1H),2.13-2.07(m,1H),1.92-1.80(m,1H).

And 5: synthesis of Compound BB-23-6

The compound BB-23-5(550mg,2.71mmol), BB-8(400mg,1.37mmol), diisopropylethylamine (763mg,5.91mmol) was dissolved in DMF (10mL) at room temperature, and HATU (958mg,2.52mmol) was added. After stirring at room temperature for 3 hours, TLC showed completion of the reaction and the solvent was removed under reduced pressure, the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =10:1 → pure ethyl acetate) to give the target compound BB-2-6 (yellow solid, 540mg, yield 82.5%). MS M/z 476.8[ M + H ]]⁺

Step 6: synthesis of Compound BB-23

Compound BB-23 was prepared according to Synthesis step 3 of reference example 21 (BB-21). MS M/z 525.0[ M + H ]]⁺

Reference example 24: fragment BB-24

The synthetic route is as follows:

step 1: synthesis of Compound BB-24-2

Compound BB-24-2 was prepared according to Synthesis step 5 of reference example 23 (BB-23). MS M/z 492.9[ M + H ]]⁺

Step 2: synthesis of Compound BB-24

Compound BB-24 was prepared according to Synthesis step 3 of reference example 21 (BB-21). MS M/z 539.2[ M + H ]]⁺

Reference example 25: fragment BB-25

The synthetic route is as follows:

step 1: synthesis of Compound BB-25-2

Compound BB-25-1 (18.0 g,77.2 mmol) was dissolved in ethyl acetate (50mL), and ethyl acetate hydrochloride solution (4mol/L,50mL) was added thereto, followed by stirring at room temperature for 2 hours, and after completion of the TLC detection reaction, the solvent was removed under reduced pressure to obtain the objective compound BB-25-2 (pale yellow, 13.0g, yield 100%). The product was used directly in the next step without purification.¹H NMR(400MHz,DMSO-d6):8.37(brs,3H),3.81-3.88(m,2H),3.23(s,3H),1.20(d,J=6.4Hz,3H).

Step 2: synthesis of Compound BB-25-3

Sodium hydroxide (12.2g, 305 mmol) was dissolved in 200mL of water, cooled to 0 deg.C, and compound BB-25-2 (13.0 g,76.6 mmol) was added. After complete dissolution, methyl chloroformate (7.2 g, 76.2 mmol) was added dropwise. Dropwise additionAfter completion, stir at room temperature overnight. After completion of the TLC detection, 1N hydrochloric acid was added to adjust the pH to 3, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give compound BB-25-3 (white solid, 8.0g, yield 54.8%). The product was used directly in the next step without purification.¹H NMR:(400MHz,DMSO-d6)12.65(brs,1H),7.02(d,J=9.0Hz,1H),4.04-4.01(m,2H),3.76-3.74(m,1H),3.51(s,3H),3.81(s,3H),1.96(s,3H).

And step 3: synthesis of Compound BB-25-4

Compound BB-25-4 was prepared according to Synthesis step 5 of reference example 23 (BB-23). MS M/z 465.0[ M + H ]]⁺And 4, step 4: synthesis of Compound BB-25

Compound BB-25 was prepared according to Synthesis step 3 of reference example 21 (BB-21). MS M/z 513.1[ M + H ]]⁺

Reference example 26: fragment BB-26

The synthetic route is as follows:

step 1: synthesis of Compound BB-26-2

Compound BB-26-2 was prepared according to Synthesis step 5 of reference example 23 (BB-23). MS M/z 422.9[ M + H ]]⁺Step 2: synthesis of Compound BB-26

Compound BB-26 was prepared according to Synthesis step 3 of reference example 21 (BB-21). MS M/z 469.2[ M + H ]]⁺

Reference example 27: fragment BB-27

The synthetic route is as follows:

step 1: synthesis of Compound BB-27-2

N-Moc-L-valine (BB-2-6,10g,52.3mmol) was dissolved in THF (200ml) at room temperature, cooled to-30 ℃ and triethylamine (11.6g,114.9mmol) and isobutyl chloroformate (9.36g,68.1mmol) were added. After 1 hour at-30 ℃ L-serine hydrochloride (BB-27-1, 10.6g,68.4mmol) was added, and the reaction was continued at-30 ℃ for 3 hours, then warmed to room temperature and stirred overnight. After completion of the TLC detection, the solvent was evaporated, and the residue was dissolved in ethyl acetate (200mL) and washed with saturated brine (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate to obtain the objective compound BB-27-2 (white solid, 12.34g, 765.3% yield). The product was used directly in the next step without purification. MS M/z 276.8[ M + H ]]⁺

Step 2: synthesis of Compound BB-27-3

Compound BB-27-2(20g,72.39mmol), p-toluenesulfonic acid monohydrate (3.64g,19.14mmol) was dissolved in THF (200mL) at room temperature, and 2, 2-dimethoxypropane (37.7g,36.22mmol) was added. The reaction was warmed to reflux and stirred at reflux overnight. After completion of the TLC detection, ethyl acetate (400mL) was added, and the mixture was washed with saturated sodium bicarbonate solution (50 mL. times.2) and saturated brine (50 mL. times.2) in this order. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate to obtain the objective compound BB-27-3 (yellow oil, 5.0g, yield 21.8%). The product was used directly in the next step without purification. MS M/z 339.1[ M + Na ]]⁺

And step 3: synthesis of Compound BB-27-4

Compound BB-27-3(1.8g,5.69mmol) was added to a tetrahydrofuran/t-butanol/water (36mL/9mL/9mL) mixed solution, lithium hydroxide monohydrate (478.38mg, 11.39mmol) was added, the mixture was stirred at 30 ℃ for 2 hours, the reaction was completed by TLC, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated brine (20mL), then dried over anhydrous sodium sulfate, filtered, and the solvent was dried by rotary evaporation of the filtrate to give a yellow solid intermediate (1.7g, 98.8% yield). The above intermediate (1.7g,5.62mmol), 2, 4' -dibromoacetophenone (BB-1-1,1.99g, 17.15mmol) was dissolved in acetonitrile (60mL), and triethylamine (1.49g, 14.7mmol) was added at room temperature. After completion of the TLC detection, the solvent was evaporated, and the residue was dissolved in ethyl acetate (200mL) and washed with saturated brine (40 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the objective compound BB-27-4 (yellow solid, 2.8g, yield 99.6%). The product was used directly in the next step without purification. MS M/z 500.9[ M + H ]]⁺And 4, step 4: synthesis of Compound BB-27-5

Compound BB-27-4(2.8g,5.61mmol) was dissolved in dioxane (100mL), and ammonium acetate (8.64g, 112.2mmol) was added. The reaction system was warmed to 110 ℃ under nitrogen and stirred overnight. After completion of the TLC detection reaction, it was cooled to room temperature, filtered, and the solvent was evaporated from the filtrate, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:1) to obtain the target compound BB-27-5 (yellow solid, 1.2g, yield 44.4%). MS M/z 481.3[ M + H ]]⁺

And 5: synthesis of Compound BB-27

Compound BB-27 was prepared according to Synthesis step 3 of reference example 21 (BB-21). MS M/z 527.3[ M + H ]]⁺

Reference example 28: fragment BB-28

The synthetic route is as follows:

step 1: synthesis of Compound BB-28-2

N-Moc-L-valine (BB-2-6,5.0g,26.15mmol) was dissolved in dichloromethane (60mL) at room temperature, and triethylamine (6.07g,60.1mmol) and HATU (10.85g,28.54mmol) were added. After stirring at room temperature for 10 minutes, 4-hydroxyproline methyl formate hydrochloride (BB-28-1,5.19g,28.54mmol) was added. After completion of the TLC detection, the reaction was quenched by addition of saturated sodium bicarbonate solution (30mL), separated, and the aqueous phase was extracted with dichloromethane (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1) to obtain the objective compound BB-28-2 (white solid, 2.0g, yield 23.2%). MS M/z 303.0[ M + H ]]⁺

Step 2: synthesis of Compound BB-28-3

Compound BB-28-2(2.0g,6.62mmol) was dissolved in DCM (50mL), Dess-Martin oxidant (DMP,5.71g,13.46mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. After completion of the TLC detection, the reaction was quenched by addition of 5% sodium thiosulfate solution (50mL), followed by addition of saturated sodium bicarbonate solution (100mL), stirring for 10 minutes, and extraction with dichloromethane (100 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1) to obtain the objective compound BB-28-3 (white solid, 1.0g, yield 50.3%). MS M/z 301.0[ M + H ]]⁺

And step 3: synthesis of Compound BB-28-4

Compound BB-28-3(1.0g,3.33mmol), ethylene glycol (2.68g, 43.28mmol) were dissolved in toluene (75mL), and p-toluenesulfonic acid monohydrate (126.15mg,660mmol) was added. Heating the reaction system to reflux under the protection of nitrogen, stirring overnight, cooling to room temperature after TLC detection reaction, adding ethyl acetate (30mL), and sequentially saturatingSodium bicarbonate solution (50mL × 3), saturated brine (50mL), dried the organic phase over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1) to obtain the objective compound BB-28-4 (white solid, 900mg, yield 78.3%). MS M/z 344.9[ M + H ]]⁺And 4, step 4: synthesis of Compound BB-28-5

Compound BB-28-4(900mg,2.62mmol) was added to a mixed solution of tetrahydrofuran/t-butanol/water (20mL/5mL/5mL), lithium hydroxide monohydrate (239.82g,5.71mmol) was added thereto, the mixture was stirred at room temperature overnight, after completion of the TLC detection, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, washed with saturated brine (20mL), then dried over anhydrous sodium sulfate, filtered, and the solvent was dried by rotary evaporation of the filtrate to give the desired compound BB-28-5 (white solid, 680mg, 78.8% yield). The product was used directly in the next step without purification. MS M/z 352.9[ M + Na ]]⁺

And 5: synthesis of Compound BB-28-6

Compound BB-28-5(680mg,2.06mmol), 2, 4' dibromoacetophenone (BB-1-1,685mg, 2.47mmol) were dissolved in acetonitrile (30mL), and triethylamine (385.8mg, 3.82mmol) was added at room temperature. After completion of the TLC detection, the solvent was evaporated, and the residue was dissolved in ethyl acetate (100mL) and washed with saturated brine (20 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the objective compound BB-28-6 (yellow solid, 1.02g, yield 93.9%). The product was used directly in the next step without purification. MS M/z 528.8[ M + H ]]⁺

Step 6: synthesis of Compound BB-28-7

Compound BB-28-7(1.02g,1.93mmol) was dissolved in dioxane (20mL), and ammonium acetate (1.6g, 21mmol) was added. Heating the reaction system to 110 ℃ under the protection of nitrogen, stirring overnight, cooling to room temperature after TLC detection reaction, filtering, drying the solvent from the filtrate by spinning, and performing silica gel column chromatography (petroleum ether/ethyl acetate =1:1) on the residue to obtain a target compound BB-28-7 (yellow solid, 650mg, yield 6)6.3%)。MS m/z:508.8[M+H]⁺And 7: synthesis of Compound BB-28

Compound BB-28-6(100mg,0.20mmol), bis-pinacolato borate (55.05mg,0.22mmol) were dissolved in dioxane (2mL) at room temperature, and potassium acetate (63.74mg,0.65mmol) and Pd (dppf) Cl were added under nitrogen₂(11mg, 0.02 mmol). Heating to reflux under nitrogen, stirring for 4 hours, cooling to room temperature after TLC detection, filtering, spin-drying the solvent from the filtrate, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl acetate =1:1) to give the target compound BB-28 (yellow solid, 45mg, yield 40.6%). MS M/z 555.0[ M + H ]]⁺

Reference example 29: fragment BB-29

The synthetic route is as follows:

step 1: synthesis of Compound BB-29-2

Sodium hydride (1.96g,48.9mmol) was suspended in tetrahydrofuran (60mL), cooled to 0 deg.C, compound BB-29-1(8.0g,32.6mmol) was added dropwise under nitrogen, after completion of the addition, the mixture was stirred at 0 deg.C for 2 hours, methyl iodide (8.0g,48.9mmol) was added at 0 deg.C, stirring was continued at this temperature for 2.5 hours, after completion of the TLC detection reaction, water (10mL) was added to quench the reaction, and ethyl acetate (80 mL. times.3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 1:1) to obtain the objective compound BB-29-2 (colorless oil, 5.5g, yield 65.2%).¹HNMR(CDCl₃,400MHz):4.33-4.25(m,1H),3.93-3.89(m,1H),3.70(s,3H),3.59-3.47(m,2H),3.44(s,3H),2.03-1.98(m,2H),1.43(s,9H).

Step 2: synthesis of Compound BB-29-3

Compound BB-29-2(5.5g,21.3mmol) was dissolved in a mixed solvent of methanol/water (30mL/30mL) at room temperature, and sodium hydroxide (1.7g,42.6mmol) was added thereto. Heating the reaction system to 60 ℃, stirring for 8 hours, reducing pressure to remove most of the solvent after TLC detection reaction is finished, cooling to 0 ℃, dropwise adding 2N hydrochloric acid to adjust the pH value to 3-4, and extracting with ethyl acetate (80mL multiplied by 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried on the filtrate to obtain the objective compound BB-29-3 (yellow oil, 5.0g, yield 95.8%); the product was used directly in the next step without purification.¹H NMR(CDCl₃,400MHz):4.42-4.14(m,1H),3.99-3.98(m,1H),3.65-3.53(m,2H),3.33(s,3H).2.31-2.05(m,2H),1.47(s,9H).

And step 3: synthesis of Compound BB-29-4

Compound BB-29-3(5.0g,20.3mmol) and 2, 4' -dibromoacetophenone (BB-1-1,6.2g,22.3mmol) were dissolved in DMF (50mL) and potassium carbonate (5.6g,40.6mmol) was added slowly. After stirring overnight at room temperature, TLC detected completion of the reaction, the reaction was quenched by addition of water (30mL) and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20:1 → 1:1) to obtain the objective compound BB-29-4 (red solid, 3.5g, yield 41.7%).¹HNMR(CDCl₃,400MHz):7.79-7.76(m,2H),7.67-7.65(m,2H),5.58-5.18(m,2H),4.55-4.50(m,1H),4.16-4.05(m,1H).3.67-3.37(m,2H),3.36(s,3H),2.50-2.40(m,2H),1.47(s,9H).

And 4, step 4: synthesis of Compound BB-29-5

Compound BB-29-4(3.5g,7.9mmol) was dissolved in toluene (70mL) at room temperature, and ammonium acetate (6.1g,79.1mmol) was added. The reaction was warmed to 120 ℃ under nitrogen, stirred for 6 hours, cooled to room temperature after TLC detection, added with ethyl acetate (50mL), and washed with water (30 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering, removing solvent from the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 1:1)To the desired compound BB-29-5 (red oil, 3.0g, 88.9% yield). LC/MS M/z 424.0[ M + H ]]⁺

And 5: synthesis of Compound BB-29-6

Compound BB-29-5(2.0g,4.7mmol) was dissolved in ethyl acetate (5mL), cooled to 0 deg.C, hydrogen chloride/ethyl acetate solution (HCl/EA,4M,30mL) was added and stirred at 0 deg.C for 2 hours. After TLC detection reaction, the solvent was removed under reduced pressure at room temperature to obtain compound BB-29-6 (green solid, 1.69g, yield 99.4%); the product was used directly in the next step without purification. LC/MS M/z 323.9[ M +3 ]]⁺

Step 6: synthesis of Compound BB-29

The compound BB-29-6(885mg,2.96mmol), N-Moc-L-valine (BB-2-6,518.2mg,2.96mmol) and diisopropylethylamine (954mg,7.4mmol) were dissolved in DMF (10mL) at room temperature, and HATU (1.41g,3.7mmol) was added. After stirring at room temperature for 1 hour and TLC detection of completion of the reaction, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:1 → pure ethyl acetate) to give the title compound BB-29 (red oil, 841mg, yield 71.3%). LC/MS M/z 480.4[ M + H ]]⁺.501.1[M+Na]⁺

Reference example 30: fragment BB-30

The synthetic route is as follows:

step 1: synthesis of Compound BB-30

The compound BB-29-6(885mg,2.46mmol), the compound BB-1-6(566mg,2.96mmol), diisopropylethylamine (954mg,7.4mmol), HATU (1.41g,3.7mmol) as a starting material, according to the synthesis method of step 6 of reference example 29 (BB-29), Compound BB-30(1.1g, yield 90.2%) was obtained. LCMS M/z 496.4[ M + H ]]⁺.

Reference example 31: fragment BB-31

The synthetic route is as follows:

step 1: synthesis of Compound BB-31-1

Compound BB-2-2(1.40g,6.50mmol) and diisopropylethylamine (1.01g,7.81mmol) were dissolved in acetonitrile (15mL), cooled to 0 deg.C, and compound AA _108-2(2.00g,7.15mmol) was added slowly. After stirring at 0 ℃ for 0.5 hour, TLC detection showed that the reaction was complete, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:1) to give the objective compound BB-31-1 (white solid, 1.26g, yield 33%). LC/MS M/z 435.0[ M + Na ]]⁺.

Step 2: synthesis of Compound BB-31-2

Compound BB-31-1(1.26g,3.04mmol) was dissolved in toluene (50mL) at room temperature, and ammonium acetate (2.34g,30.39mmol) was added. The reaction was warmed to reflux under nitrogen, stirred overnight, cooled to room temperature after TLC detection, added ethyl acetate (50mL), and washed with water (30mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:3 → pure ethyl acetate) to obtain the objective compound BB-31-2 (white solid, 0.72g, yield 60%). LC/MS M/z 394.8[ M + H ]]⁺.

And step 3: synthesis of Compound BB-31

Compound BB-31-2(0.72g,1.82mmol) was dissolved in ethyl acetate (10mL), cooled to 0 ℃, and then added with a hydrogen chloride/ethyl acetate solution (HCl/EA,4M,30mL) and stirred at room temperature for 1 hour. After TLC detection reaction, removing the solvent at room temperature under reduced pressure to obtain a white solid; the product was used in the next step without purification.

The above white solid, compound BB-1-6(0.52g,2.73mmol), diisopropylethylamine (1.06g,8.19mmol) was dissolved in DMF (4mL) at room temperature, and HATU (1.04g,2.73mmol) was added. After stirring at room temperature for 3 hours and TLC detection of completion of the reaction, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:3 → pure ethyl acetate) to give the title compound BB-31 (yellow solid, 0.85g, 92% yield). LC/MS M/z 466.0[ M + H ]]⁺.

Reference example 32: fragment BB-32

The synthetic route is as follows:

step 1: synthesis of Compound BB-32-1

Compound BB-2-2(1.96g,9.22mmol) and diisopropylethylamine (1.43g,11.06mmol) were dissolved in acetonitrile (15mL), cooled to 0 deg.C, and compound AA-117-2 (3.00g,10.14mmol) was added slowly. After stirring at 0 ℃ for 1 hour, TLC detection was completed and the solvent was removed under reduced pressure, the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2:1) to obtain the objective compound BB-32-1 (brown gum, 3.7g, yield 94.4%). LC/MS M/z 329.8[ M-Boc + H]⁺.

Step 2: synthesis of Compound BB-32-2

Using BB-32-1(3.93g,9.13mmol) and ammonium acetate (7.04g,91.34mmol) as starting materials, the synthesis method of step 2 of reference example 31 (BB-31) was performed to obtain compound BB-32-2(3.0g, 85.0% yield). LCMSM/z 310.0[ M-Boc + H ]]⁺.

And step 3: synthesis of Compound BB-32

Starting from compound BB-32-2(3.0g,7.31mmol), a hydrogen chloride/ethyl acetate solution (HCl/EA,4M,100mL), compound BB-1-6(566mg,2.96mmol), diisopropylethylamine (1.31g,10.10mmol) and HATU (1.65g,4.33mmol), the synthesis method of step 3 of reference example 31 (BB-31) was carried out to obtain compound BB-32 (yellow solid, 0.60g, 43% yield).¹H NMR(CDCl₃,400MHz):7.49(dd,J=8.0Hz,J=2.8Hz,1H),7.34(d,J=8.0Hz,1H),7.27(s,1H),7.19(s,1H),5.70(d,J=8.0Hz),5.31(m,1H),4.58(m,1H),3.73(m,2H),3.70(s,3H),3.27(s,3H),2.85(m,1H),2.22(m,1H),1.44(m,1H),1.19(d,J=8.0Hz,1H),0.88(m,1H).

Example 1: AL _001

The synthetic route is as follows:

step 1: synthesis of Compound AL 001

The compound BB-17 (40mg, 0.081mmol), BB-21(44.4mg,0.090mmol) was dissolved in DMF/THF/H at room temperature₂O (1.5mL/1.5mL/1.5mL) mixed solvent, sodium carbonate (17.3mg,0.163mmol) and Pd (dppf) Cl were added under nitrogen protection₂(6mg,0.0081 mmol). Heating to 100 ℃ under the protection of nitrogen, stirring overnight, cooling to room temperature after TLC detection reaction,after filtration and solvent rotary drying of the filtrate, the residue was isolated by hplc to give the title compound AL 001 (yellow solid, 14.3mg, 22.4% yield). MS M/z 785.3[ M + H ]]⁺.

Referring to the synthesis procedure of step 1 in AL — 001, compounds in the following table were synthesized:

example 20: AL _023

The synthetic route is as follows:

step 1: synthesis of Compound AL _023-2

Compound AL _023-1(1.5g,5.75mmol), N, O-dimethylhydroxylamine hydrochloride (613mg,6.29mmol), diisopropylethylamine (1.5g,11.63mmol) was dissolved in DMF (10mL) at room temperature and HATU (2.4g,6.32mmol) was added. After stirring at room temperature for 1 hour and TLC detection of completion of the reaction, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (50 mL. times.3). Combining the organic phases, drying over anhydrous sodium sulfate, filtering, removing the solvent from the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl ether)Ethyl acid =9:1 → 3:2) to give the amide intermediate (yellow solid, 1.65g, 94.3% yield). Dissolving the amide intermediate (1.4g,4.6mmol) in tetrahydrofuran (20mL), cooling to-20 ℃, slowly adding a methyl magnesium bromide ether solution (3mol/L, 5mL, 15mmol), stirring at room temperature for 1 hour after finishing the dropping, adding water (10mL) after the TLC detection reaction is finished, quenching the reaction, and extracting with ethyl acetate (50mL multiplied by 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 5:2) to obtain the objective compound AL _023-2 (yellow liquid, 0.9g, yield 75.6%).¹H NMR(CDCl₃,400MHz):3.04(m,2H),2.57(m,2H),2.47(s,3H),1.78-1.76(m,4H).

Step 2: synthesis of Compound AL _023-3

Compound AA _023-2(2.5g,9.65mmol) was dissolved in tetrahydrofuran (100mL), cooled in an ice bath to below 5 ℃ and phenyltrimethylammonium tribromide (4.3g,9.65mmol) was added. After stirring at room temperature for 12 hours, TLC detected completion of the reaction, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 2:1) to obtain the objective compound AL _023-3 (yellow liquid, 3.3g, yield 85.3%). MSm/z 338.7[ M + H]⁺.

And step 3: synthesis of Compound AL _023-4

Compound AL _023-3(3.3g,9.76mmol) and potassium carbonate (4g,28.99mmol) were suspended in DMF (20mL) and Boc-L-proline (3.1g,14.41mmol) was added at room temperature. After stirring at room temperature for 1 hour, TLC detected that the reaction was complete, water (10mL) was added to quench the reaction, and extraction was performed with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was spin-dried from the filtrate to give a yellow intermediate. The above intermediate was dissolved in toluene (100mL) and ammonium acetate (3.42g,44.5mmol) was added. The mixture was heated to reflux under nitrogen, stirred for 12 hours, cooled to room temperature after TLC detection, quenched with water (30mL), and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfateThen, the filtrate was filtered, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =3:2 → 1:4) to give the objective compound AL _023-4 (pale yellow powder, 2.75g, yield 62.3%). MS M/z 454.0[ M + H ]]⁺.

And 4, step 4: synthesis of Compound AL _023-5

Compound AL _023-4(0.25g,0.553mmol) was added to a hydrogen chloride/ethyl acetate solution (HCl/EA,4mol/L,5mL) and stirred at room temperature for 1 h. After completion of the TLC detection reaction, the solvent was dried by spinning to obtain the objective compound AL _023-5 (off-white solid, 0.190g, yield 88.3%). The product was used directly in the next step without purification. MS M/z 353.8[ M + H ]]⁺.

And 5: synthesis of Compound AL _023-6

Compound AL _023-5(195mg,0.502mmol), N-Moc-L-valine (BB-2-6,117mg,0.612mmol), diisopropylethylamine (143mg,1.11mmol) were dissolved in DMF (10mL), HATU (253mg,0.661mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the TLC detection, the reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 1:1) to obtain the objective compound AL _023-6 (pale yellow powder, 225.6mg, yield 88.3%). MS M/z 511.0[ M + H ]]⁺.

Step 6: synthesis of Compound AL _023

Compound AL _023-6(40mg,0.078mmol), BB-24(51mg,0.094mmol) was dissolved in DMF/THF/H at room temperature₂O (2mL/2mL/2mL) mixed solvent, sodium carbonate (17mg,0.157mmol) and Pd (dppf) Cl were added under nitrogen protection₂(4mg,0.005 mmol). Heating to 100 deg.C under nitrogen, stirring for 8 hr, TLC detecting, cooling to room temperature, filtering, removing solvent from the filtrate, and separating the residue by HPLC to obtain the desired compound AL _023 (white solid, 24mg, 36% yield). MS M/z 421.5[ M/2+ H]⁺.

Example 21: AL _031

The synthetic route is as follows:

step 1: synthesis of Compound AL _031-1

Compound AL _031-1 can be prepared according to step 5 in AL _ 023. LCMS M/z 526.8[ M + H ]]⁺

Step 2: synthesis of Compound AL _031

Compound AL _031 can be prepared according to step 6 in AL _ 023. LCMS M/z 408.5[ M/2+ H]⁺

Referring to the synthetic procedure of step 6 in AL _023, the compounds in the following table were synthesized:

example 26: AL _029

The synthetic route is as follows:

step 1: synthesis of Compound AL _029

Compound AL _029-1(100mg,0.333mmol), BB-21(364mg,0.733mmol) was dissolved in DMF/THF/H at room temperature₂O (1.5mL/1.5mL/1.5mL) mixed solvent, sodium carbonate (141.3mg,1.33mmol) and Pd (dppf) Cl were added under nitrogen protection₂(48.8mg,0.067 mmol). Heating to 100 deg.C under nitrogen, stirring overnight, cooling to room temperature after TLC detection, filtering, removing solvent from the filtrate, and separating the residue by HPLC to obtain the desired compound AL _029 (yellow solid, 14.1mg, 4.8% yield). MS M/z 880.1[ M + H ]]⁺.

Example 27: AA _239

The synthetic route is as follows:

step 1: synthesis of Compound AA _239-1

Compound AG _075-1(2g,5.92mmol), tributyl (1-ethoxyvinyl) tin (2.34g,5.92mmol) and dioxane (20mL) were dissolved and Pd (dppf) Cl added under nitrogen₂(870mg,1.28mmol) and Pd (PPh)₃)₄(1370mg,1.28 mmol). The temperature is raised to 80 ℃ under the protection of nitrogen, and the mixture is stirred for 4 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, water (8mL) was added, followed by NBS (4.2g,23.67mmol), and the mixture was stirred at room temperature for 12 hours. After TLC detection reaction is finished, adding water (10mL), then extracting with ethyl acetate (50mL multiplied by 3), and removing the solvent under reduced pressure to obtain an alpha-bromoketone intermediate; without purification, can be directly applied toAnd (5) next step. The above α -bromoketone intermediate and potassium carbonate (1.64g,11.84mmol) were suspended in DMF (20mL) and compound AA _192-2(2.1g,7.7mmol) was added at room temperature. After completion of TLC detection reaction, water (10mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _239-1(1.1g, yield in two steps: 36.3%). LCMS M/z 575.1[ M + H ]]⁺.

Step 2: synthesis of Compound AA _239-2

Compound AA _239-1(1g,1.74mmol) was dissolved in toluene (100mL) at room temperature and ammonium acetate (1.34g,17.4mmol) was added. After completion of the TLC detection reaction, the mixture was cooled to room temperature, and ethyl acetate (100mL) was added thereto, followed by washing with saturated brine (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _239-2 (white solid, 0.45g, yield 46.3%). LCMS M/z 555.1[ M + H ]]⁺.

And step 3: synthesis of Compound AA _239-3

At room temperature, compound AA _239-2(150mg,0.27mmol), bis-pinacolato borate (345mg,1.37mmol) were dissolved in dioxane (10mL), and potassium acetate (213mg,2.17mmol) and Pd (dppf) Cl were added under nitrogen₂(40mg,0.054 mmol). Heating to 110 ℃ under nitrogen protection, stirring for 2 hours, cooling to room temperature after TLC detection reaction is finished, filtering, spin-drying the solvent from the filtrate, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl acetate =2:1 → 1:4) to obtain the target compound AA _239-3 (white solid, 115mg, yield 70.5%). LCMS M/z 601.1[ M + H ]]⁺.

And 4, step 4: synthesis of Compound AA _239

Dissolving compound AA _239-3(30mg,0.049mmol) and compound BB-14(23mg,0.059mmol) in a mixed solvent of tetrahydrofuran/ethylene glycol dimethyl ether/water (2mL/2mL/2mL), and adding under nitrogen protectionSodium carbonate (11mg,0.099mmol) and Pd (dppf) Cl₂(5mg,0.0098 mmol). Heating to 100 ℃ under the protection of nitrogen, reacting for 8 hours, cooling to room temperature after TLC detection reaction is finished, filtering, drying the solvent from the filtrate by spinning, and separating the residue by high performance liquid chromatography to obtain the target compound AA _239 (white solid, 8mg, 21.8% yield). LCMS M/z 384.2[ M/2+ H]⁺.

Example 28: AA _238

The synthetic route is as follows:

step 1: synthesis of Compound AA _238-1

Compound AG _075-1(15g,44.38mmol), 1, 2-ethanedithiol (5g,53.26mmol) in chloroform (10mL) was dissolved and BF was added dropwise₃.Et₂O (5.5ml,44.38 mmol). The mixture was heated to reflux under nitrogen, stirred for 2 hours, cooled to room temperature after completion of the TLC detection reaction, quenched by addition of water (10mL), and extracted with chloroform (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure to give the thioketal intermediate (white solid, 17.5g, 88.3% yield). N-iodosuccinimide (NIS,13.6g,60.36mmol) was dissolved in dichloromethane (50mL), cooled to-78 deg.C and pyridine hydrofluoride (3.6g,36.22mmol) was added under nitrogen. After stirring at this temperature for 1 hour, a solution of the thioketal intermediate (5g,12.07mmol) in methylene chloride (5mL) was added, and stirring was continued at-78 ℃ for 1 hour, and after completion of the TLC detection reaction, water (10mL) was added to quench the reaction, followed by extraction with methylene chloride (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give the objective compound AA _238-1 (brown liquid, 3.2g, yield 78.3%).¹H NMR(CDCl₃,400MHz):7.75(m,2H),7.61(m,2H),7.40(m,2H).

Step 2: synthesis of Compound AA _238-2

The compound AA _238-1(7.48g,20.77mmol) and tributyl (1-ethoxyvinyl) tin (7.5g,20.77mmol) were dissolved in dioxane (100mL) and Pd (dppf) Cl was added under nitrogen protection₂(3g,4.15mmol) and Pd (PPh)₃)₄(4.8g,4.15 mmol). The temperature is raised to 80 ℃ under the protection of nitrogen, and the mixture is stirred for 4 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, water (20mL) was added, followed by NBS (15g,83.07mmol), and the mixture was stirred at room temperature for 12 hours. After TLC detection reaction, adding water (10mL), then extracting with ethyl acetate (50mL × 3), and removing the solvent under reduced pressure to obtain an alpha-bromoketone intermediate; the product was used in the next step without purification. The above α -bromoketone intermediate and potassium carbonate (1.5g,11.09mmol) were suspended in DMF (20mL) and compound AA _192-2(1.98g,7.21mmol) was added at room temperature. After completion of the TLC detection reaction, water (10mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _238-2(1.3g, yield in two steps, 46.3%). LCMS M/z 596.8[ M + H ]]⁺.

And step 3: synthesis of Compound AA _238-3

Compound AA _238-2(2.1g,4.45mmol) was dissolved in toluene (100mL) at room temperature and ammonium acetate (3.42g,44.5mmol) was added. After completion of the TLC detection reaction, the mixture was cooled to room temperature, and ethyl acetate (100mL) was added thereto, followed by washing with saturated brine (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _238-3 (white solid, 1.3g, yield 62.3%). LCMS M/z 577.1[ M + H ]]⁺.

And 4, step 4: synthesis of Compound AA _238-4

At room temperature, the compound is mixedAA-238-3 (150mg,0.26mmol), bis-pinacolato borate (331mg,1.13mmol) were dissolved in dioxane (10mL), and potassium acetate (205mg,2.09mmol) and Pd (dppf) Cl were added under nitrogen₂(40mg,0.052 mmol). Heating to 110 ℃ under nitrogen protection, stirring for 2 hours, cooling to room temperature after TLC detection reaction, filtering, spin-drying the solvent from the filtrate, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 1:4) to obtain the desired compound AA _238-4 (white solid, 105mg, 66% yield). LCMS M/z 623.3[ M + H ]]⁺.

And 5: synthesis of Compound AA _238

Dissolving compound AA _238-4(20mg,0.032mmol) and compound BB-14(15mg,0.039mmol) in a mixed solvent of tetrahydrofuran/ethylene glycol dimethyl ether/water (2mL/2mL/2mL), and adding sodium carbonate (9mg,0.064mmol) and Pd (dppf) Cl under nitrogen protection₂(5mg,0.0064 mmol). Heating to 100 ℃ under the protection of nitrogen, reacting for 8 hours, cooling to room temperature after TLC detection reaction is finished, filtering, drying the solvent from the filtrate by spinning, and separating the residue by high performance liquid chromatography to obtain the target compound AA _238 (white solid, 8.2mg, yield 27.8%). LCMS M/z 395.2[ M/2+ H]⁺.

Example 29: AA _241_ A and AA _241_ B

The synthetic route is as follows:

step 1: synthesis of Compound AA _241-1

Compound AG _075-1(1g,2.96mmol) was dissolved in toluene (10mL), cooled to 0 deg.C and trimethylaluminum (5.92mL,11.83mmol) was added dropwise under nitrogen. Stirring at room temperature for 1 hour, detecting by TLCAfter completion of the reaction, it was cooled to 0 ℃ and quenched by addition of water (10mL) and extracted with dichloromethane (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _241-1 (yellow liquid, 0.82g, yield 82.3%).¹H NMR(CDCl₃,400MHz):7.68(m,2H),7.49(m,4H),1.719(s,3H).

Step 2: synthesis of Compound AA _241-2

The compound AA _241-1(1g,2.84mmol) and tributyl (1-ethoxyvinyl) tin (1.03g,2.84mmol) were dissolved in dioxane (20mL), Pd (dppf) Cl was added under nitrogen protection₂(417mg,0.57mmol) and Pd (PPh)₃)₄(657mg,0.57 mmol). The temperature is raised to 80 ℃ under the protection of nitrogen, and the mixture is stirred for 4 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, water (4mL) was added, followed by NBS (2g,11.36mmol) and stirred at room temperature for 12 hours. After TLC detection reaction, adding water (10mL), then extracting with ethyl acetate (50mL × 3), and removing the solvent under reduced pressure to obtain an alpha-bromoketone intermediate; the product was used in the next step without purification. The above α -bromoketone intermediate and potassium carbonate (0.78g,5.68mmol) were suspended in DMF (20mL) and compound AA _192-2(1.01g,3.69mmol) was added at room temperature. After completion of the TLC detection reaction, water (10mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =9:1 → 3:2) to obtain the objective compound AA _241-2 (yellow solid, 0.65g, two-step yield 40.3%). LCMS M/z 591.1[ M + H ]]⁺.

And step 3: synthesis of Compound AA _241-3

Compound AA _241-2(650mg,1.11mmol) was dissolved in toluene (100mL) at room temperature and ammonium acetate (853mg,11.1mmol) was added. After completion of the TLC detection reaction, the mixture was cooled to room temperature, and ethyl acetate (100mL) was added thereto, followed by washing with saturated brine (30 mL. times.3). Drying the organic phase with anhydrous sodium sulfate, filtering, removing solvent from the filtrate under reduced pressure, and passing the residue through silica gel columnChromatography (petroleum ether/ethyl acetate =9:1 → 1:4) gave the title compound AA _241-3 (white solid, 320mg, 52.3% yield). LCMS M/z 571.1[ M + H ]]⁺.

And 4, step 4: synthesis of Compound AA _241-4

At room temperature, compound AA _241-3(120mg,0.21mmol), bis-pinacolato borate (269mg,1.06mmol) were dissolved in dioxane (10mL), and potassium acetate (166mg,1.69mmol) and Pd (dppf) Cl were added under nitrogen₂(36mg,0.044 mmol). Heating to 110 ℃ under nitrogen protection, stirring for 2 hours, cooling to room temperature after TLC detection reaction, filtering, spin-drying the solvent from the filtrate, and subjecting the residue to silica gel column chromatography (petroleum ether/ethyl acetate =2:1 → 1:4) to obtain the target compound AA _241-4 (white solid, 85mg, 66% yield). LCMS M/z 617.2[ M + H ]]⁺.

And 5: synthesis of Compounds AA _241_ A and AA _241_ B

Dissolving compound AA _241-4(70mg,0.114mmol) and compound BB-14(213mg,0.568mmol) in a mixed solvent of tetrahydrofuran/ethylene glycol dimethyl ether/water (2mL/2mL/2mL), and adding sodium carbonate (97mg,0.911mmol) and Pd (dppf) Cl under the protection of nitrogen₂(15mg,0.023 mmol). The temperature is raised to 100 ℃ under the protection of nitrogen, the reaction is carried out for 8 hours, after the TLC detection reaction is finished, the reaction is cooled to room temperature, the reaction solution is filtered, the solvent is dried by spinning, and the residue is subjected to high performance liquid phase (table 3, method 6) preparation and separation to obtain the target compounds AA _241_ A (white solid, 7mg) and AA _241_ B (white solid, 7mg) with the yield of 17.8%. AA _241_ A LCMS M/z 384.1[ M/2+ H ]]⁺.AA_241_A:LCMS m/z:384.1[M/2+H]⁺.

Example 30: AG _075

The synthetic route is as follows:

step 1: synthesis of Compound AG _075

At room temperature, 2, 7-dibromo-9-fluorenone (AG _075-1,0.2g,0.59mmol) and bis (pinacolato) borate (0.6g,2.37mmol) were dissolved in dioxane (10mL), and potassium acetate (350mg,3.55mmol) and Pd (dppf) Cl were added under nitrogen protection₂(100mg,0.12 mmol). The temperature was raised to 110 ℃ under nitrogen for 2 hours, after completion of the TLC detection, the reaction was cooled to room temperature, filtered, and after the solvent was evaporated from the filtrate, the residue was chromatographed on silica gel (petroleum ether/ethyl acetate =9:1 → 1:4) to give a white solid (0.198g, 77.3% yield). The above white solid (30mg,0.069mmol), compound BB-14(78mg,0.208mmol) was dissolved in a mixed solvent of tetrahydrofuran/ethylene glycol dimethyl ether/water (2mL/2mL/2mL), and sodium carbonate (37mg,0.35mmol) and Pd (dppf) Cl were added under nitrogen protection₂(10mg,0.014 mmol). The reaction was carried out at 100 ℃ under nitrogen for 8 hours, after TLC detection, the reaction was cooled to room temperature, filtered, the solvent was evaporated from the filtrate, and the residue was isolated by HPLC (Table 3, method 6) to give AG _075 as a white solid in 26.4% yield. LCMS M/z83.4[ M/2+ H ]]⁺.

Example 31: AG _082_ a and AG _082_ B

The synthetic route is as follows:

step 1: synthesis of AG _082-2

9, 10-dihydrophenanthrene (AG _082-1,5g,27.74mmol) was dissolved in dichloromethane (50mL) and iron was addedPowder (78mg,1.39 mmol). Cooled to 0 ℃ and liquid bromine (9.8g,61.03mmol) was added dropwise. After stirring at room temperature for 8 hours, TLC detected completion of the reaction, the reaction was quenched by addition of water (10mL) and extracted with dichloromethane (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate =9:1 → 3:2) to give the target AG _082-2 (white solid, 6.2g, 65.9% yield). NMR (CDCl)₃,400MHz):7.59-7.57(m,2H),7.46-7.41(m,4H),2.88-2.86(m,4H).

Step 2: synthesis of Compounds AG _082_ A and AG _082_ B

Compound AG _082-2(0.2g,0.59mmol), bis-pinacolato borate (0.6g,2.37mmol) were dissolved in dioxane (10mL) at room temperature, and potassium acetate (350mg,3.55mmol) and Pd (dppf) Cl were added under nitrogen₂(100mg,0.12 mmol). The temperature was raised to 110 ℃ under nitrogen for 2 hours, after completion of the TLC detection, the reaction was cooled to room temperature, filtered, and after the solvent was evaporated from the filtrate, the residue was chromatographed on silica gel (petroleum ether/ethyl acetate =9:1 → 1:4) to give a white solid (0.198g, 77.34% yield). The above white solid (40mg,0.093mmol), compound BB-14(104mg,0.278mmol) was dissolved in a mixed solvent of tetrahydrofuran/ethylene glycol dimethyl ether/water (2mL/2mL/2mL), and sodium carbonate (59mg,0.56mmol) and Pd (dppf) Cl were added under nitrogen protection₂(15mg,0.018 mmol). Heating to 100 ℃ under the protection of nitrogen, reacting for 8 hours, cooling to room temperature after TLC detection reaction is finished, filtering, drying the solvent from the filtrate by spinning, and separating the residue by high performance liquid chromatography to obtain the target compounds AG _082_ A (white solid, 7mg) and AG _082_ B (white solid, 7mg) with the yield of 20.8%. AG _082_ A LCMS M/z:383.4[ M/2+ H]⁺.AG_082_B:LCMSm/z:383.4[M/2+H]⁺.

Experimental example 1: in vitro evaluation

Purpose of the experiment:

determination of EC against HCV Compounds Using HCV genotypes 1a (HCV-1 a) and 1b (HCV-1 b) Stable replicon (replicon) cells₅₀And CC₅₀The value is obtained. The replicon of the genotype 1a is derived from H77 clone and contains K1691R, K2040R and S2204I adaptationsAnd (4) sexual mutation. Genotype 1b replicon-derived clones were Con1 clones containing E1202G, T1280I and K1846T adaptive mutations.

Introduction of background:

the HCV1a (HCV-1 a) and 1b (HCV-1 b) genotype subgenomic replicon systems contain related HCV gene subtype non-structural protein genes, G418 resistance gene NEO and luciferase gene, so that HCV related proteins and luciferase can be stably expressed in cells. The replication level of the HCV replicon can be determined by detecting the expression level of the luciferase gene. Thus, the system serves as a model for screening in vitro the activity of anti-HCV compounds.

Experimental materials:

HCV replicon cell lines: HCV-1a and HCV-1b cells.

Cell culture solution: DMEM (Invitrogen, Cat. # 11960077) medium, 10% fetal bovine serum (FBS, Sigma, Cat. # 12003C) and 1% diabody (penicillin 5000IU/mL, streptomycin 10mg/mL, Hyclone, Cat. # SV30010) were added.

Pancreatin (Invitrogen, Cat. # 25200072).

PBS(Invitrogen,Cat.#10010023)。

Trypan blue (Invitrogen, Cat. # 15250061).

Cell Titer-fluor(Promega,Cat.＃G6082)。

Bright-Glo（Promega,Cat.#E2650）。

CO₂Incubator, Thermo 240I.

Multidrop automatic dispenser, Thermo.

POD810Plate Assembler full-automatic microplate pretreatment system, Labcyte.

The scanner Handhelded Automated Cell Counter, Millipore.

Microplate Spectrophotometer, Molecular Device.

Experimental procedures and methods:

a) compound solution preparation, dilution and loading:

the compound powders were dissolved in 100% DMSO. The compound was then diluted 5-fold for 6 spots with Echo

A sonic pipetting device (Echo liquid handler) was added to the cell plate. Ensuring that the final concentration of DMSO is 0.5%. Each compound was double-pored. The highest starting concentration was 100, 10 or 1nM, 5-fold dilution, 6 points.

b) Cell culture (HCV-1 a or HCV-1b replicon cells):

1) the culture supernatant of the cell culture was aspirated off, and the cells were washed with 10mL of PBS.

2) Adding preheated pancreatin into the washed cell culture bottle, and rotating the culture bottle to uniformly cover the pancreatin at the bottom of the culture bottle. Put at 37 ℃ and 5% CO₂Digesting in an incubator.

3) Cells were suspended in 10-15 mL of culture medium per T150 flask, and 0.1mL of the suspension was diluted 2-fold with Trypan blue solution and counted.

4) Cells were diluted to 8X 10 with culture medium⁴The diluted cells were added to compound-containing 96-well plates (Greiner, Cat. #655090) (100. mu.L/well, 8000 cells/well) using an automatic dispenser (Thermo Scientific). Standing at 37 deg.C for 5% CO₂The incubator is used for 3 days.

Cell control wells: no compound was added, only 0.5% DMSO.

5) Cell Titer-fluor was added to the wells and after 30 min incubation the signal was detected with the chemiluminescence detection system Envison (Ex at405nm and read at515 nm). Analysis of the effect of compounds on HCV replicon cell activity based on luminescence data and for calculation of CC₅₀The value is obtained.

6) Then adding luciferase luminescent substrate BRight-Glo, incubation 5 min later, detection by the chemiluminescent detection System Envison (wavelength)>700 nm) luciferase activity; anti-HCV inhibitory Activity of Compounds based on luciferase data and used to calculate EC₅₀The value is obtained.

c) Data processing and analysis:

performing nonlinear fitting analysis on inhibition percentage (inh%) data by using GraphPad Prism software to obtain EC₅₀Or CC₅₀The value is obtained.

The results are shown in Table 1:

TABLE 1HCV replicon cell EC₅₀/CC₅₀Test results

Note: EC (EC)₅₀Indicating the in vitro anti-hepatitis C Virus Activity of the molecule, EC₅₀Less than 1uM indicates that the compound has in vitro activity. Four intervals were divided according to the size of the activity: a (0.001 nM-0.1 nM) and B (0.101 nM-1.0 nM); c (1.001nM to 10.0 nM); d (10.001nM to 100 nM). CC (challenge collapsar)₅₀The value of (A) indicates the molecule

The magnitude of in vitro toxicity, the greater the number the less toxic.

And (4) conclusion: the compound of the invention has excellent in vitro anti-hepatitis C virus activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

n₁Or n₄Each independently selected from 0 or 1;

n₂selected from 0, 1,2,3, 4, 5 or 6;

n₃selected from 0, 1,2,3, 4, 5 or 6;

n₅selected from 1,2,3 or 4;

R_6a、R_6b、R_6ceach independently selected from H, C_1-6Alkyl or alkoxy;

W₅、W₆each independently represents C, N, optionally substituted [ CH₂、CH、NH、CH₂-CH₂、CH=CH、3-6 membered hydrocarbon group or 3-6 membered heterohydrocarbon group]C ≡ C, a single bond, O, S, C = O, C = S, S (= O), S (= O) 2;

m₇、m₈selected from 0, 1, 2;

L₂、L₃、L₄、L₅、L₈、L₉each independently selected from C, N, optionally substituted [ NH, CH₂、CH₂-CH₂CH = CH, 3-6 membered hydrocarbyl or 3-6 membered heterohydrocarbyl]、C≡C、O、S、C=O、C=S、S（=O）、S（=O）₂；

L₆、L₇Each independently selected from H, F, Cl, Br, I, CN, = O, = S or optionally substituted [ OH, SH, NH₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

p₁、p₆、p₇Each independently selected from 0, 1,2,3, 4, 5 or 6;

E₄selected from structural units represented by the formula (d) or (e),

q₃、q₄each independently selected from 0, 1,2 or 3;

represents a single bond or a double bond;

2. A compound according to claim 1, wherein the sub-building block of building block (b) is according to formula (g),

wherein,

m_5aSelected from 0, 1,2,3, 4, 5 or 6;

T_8aFrom H, F, Cl, Br, I, CN, = O, = S or optionally substituted [ OH, SH, NH ]₂、PH₂Alkyl, heteroalkyl, hydrocarby, heterohydrocarby]；

m_8aselected from 0, 1,2,3, 4, 5 or 6;

represents a single bond or a double bond;

represents a single bond, a double bond or no bond whenWherein represents the structural unit and its auxiliary structural units are absent when no bond is formed, T_1a、T_2aBoth sides are not simultaneously double bonds.

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the sub-structural unit of formula (g) is selected from:

4. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unit represented by formula (c) is selected from:

5. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a sub-structural unit of the structural unit of formula (d) is represented by formula (d-1):

wherein,

Z₅、Z₆、Z₇、Z₈each independently selected from optionally substitutedIs [ CH ]₂-CH₂、CH=CH、CH₂CH, NH, 3-to 6-membered hydrocarbon group or 3-to 6-membered heterohydrocarbon group]C ≡ C, single bond, O, S, C = O, C = S, S (= O), S (= O)₂，Z₅、Z₆、Z₇、Z₈Not all four of them are simultaneously single bonds.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Z₁、Z₂Each independently selected from the group consisting of optionally substituted:

7. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the sub-structural units of the structural unit represented by formula (d-1) are selected from:or

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the sub-building blocks of the building block of formula (e) are selected from:

9. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said R₄Is selected from more than two substituted 3-10 membered cyclic group or heterocyclic group or cyclohetero group, and the heteroatom or heteroatom group is selected from N, O, S, S (= O) or S (= O)₂。

10. A compound or pharmaceutically acceptable salt thereof according to claim 9, wherein R is₄Selected from the following groups substituted by two or more positions:or

11. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said R₄Selected from the following groups substituted by two or more positions:

or

12. The method of claim 11A compound or a pharmaceutically acceptable salt thereof, wherein R₁Is C = O, R₅Is H, n₁、n₄And n₅Is 1, n₂And n₃Is 0, R₁And R₄Forming an amide bond.

13. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the sub-building block of formula (a) is selected from:

or

14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said R₂、R₅、R_1a、R_1b、R_3a、R_3bEach independently selected from H, F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, NH₂Alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylamino]And the heterocyclic group is selected from furyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, pyrazolyl or imidazolyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein the number of carbon atoms in the alkyl portion of the alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl, and alkoxycarbonylamino is 1,2,3, 4, 5, or6, and the number of carbon atoms in the cycloalkyl is 3,4, 5, or 6.

16. A compound or pharmaceutically acceptable salt thereof according to claim 14, wherein R is₂、R₅、R_1a、R_1b、R_3a、R_3bEach independently selected from H, F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, NH₂Methyl, isopropyl, cyclopropyl, butyl, tert-butyl, trifluoromethyl, hydroxymethyl, -CH (OH) CH₃、-CH₂CH₂OH、-CH₂CH₂（OH）、-CH（OH）CH₃Methoxy, methoxymethyl, -CH (CH)₃）OCH₃、-CH₂CH₂OCH₃、Methylthio group, ethoxycarbonyl group,Or

17. The compound according to any one of claims 1 to 16, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, = O, = S, optionally substituted [ OH, SH, NH, or a pharmaceutically acceptable salt thereof₂、PH₂A hydrocarbon group, a heterohydrocarbon group and/or a heterohydrocarbon group]。

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the hydrocarbyl, heterohydrocarbyl, hydrocarby, heterohydrocarbyl is selected from optionally substituted [ C_1-12Hydrocarbyl radical, C_1-12Heterohydrocarbyl radical, C_1-12Hydrocarbon hetero group, C_1-12Hydrocarbon hetero group C_1-12Hydrocarbyl radical, -C_1-12OH、-C_0-12COOH、-OC_1-12COOH、-C_1-12CN、-C_0-12CONH₂、-C_0-12O C_1-12、-C_0-12CO C_1-12、-C_0-12COO C_1-12、-C_0-12O（O=）C C_1-12、-C_0-12S(=O)C_1-12or-C_0-12S(=O)₂C_1-12]Wherein the above groups are present as aromatic rings, heteroaromatic rings, aliphatic rings, heteroaliphatic rings, aliphatic chains and/or heteroaliphatic chains, and the number of aromatic rings, heteroaromatic rings, aliphatic rings, heteroaliphatic rings, aliphatic chains and/or heteroaliphatic chains, the number of ring-forming atoms and the number thereof, the manner of connection between rings or chains is arbitrary, provided that it is chemically stable, the heteroatoms or heteroatom groups each being independently selected from O, S, N, S (= O) and/or S (= O)₂The number of heteroatoms or groups of heteroatoms is arbitrary provided that it is chemically stable.

19. The compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein the substituent for substitution is selected from the group consisting of F, Cl, Br, I, CN, = O, = S, OH, SH, NH₂Halogen or hydroxy or amino or unsubstituted C_1-6Alkyl or heteroalkyl, heteroatom or heteroatom group each independently selected from C_1-6Alkyl or unsubstituted-CONH-, -CO₂-、C_1-6Alkyl or unsubstituted-NH-, -O-, -S-, C_1-6Alkyl or unsubstituted-C = NH, -C = O, -C = S, S (= O) and/or S (= O)₂The number of substituents, heteroatoms or groups of heteroatoms is arbitrary provided that it is chemically stable.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from the group consisting of halogen, OH, SH, NH₂、PH₂、CN、=O、=S、CF₃、-OCF₃、-OCH₃Protecting groups and/or leaving groups.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the structure having a chiral center is present in the following variants: the chiral centers of which are located at other sites and the number of which is chemically stable to be achieved is arbitrary; alternatively, it is arbitrary provided that it also has other chiral centers and the number thereof is chemically stable to be achieved; alternatively, it does not have a chiral center.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the manufacture of a medicament for the treatment of HCV.