WO2015124064A1 - Thiophene as hepatitis c virus inhibitor or variant derivative thereof and use thereof for drug preparation - Google Patents

Abstract

Disclosed is a thiophene series as hepatitis C virus (HCV) inhibitors or variant derivatives thereof and compositions thereof, and the present invention relates to the application thereof in preparing chronic hepatitis C virus infection drugs. Particularly, the present invention relates to a series of compounds used as NS5A inhibitors and compositions thereof and uses thereof for drug preparation.

Description

Thiophene or a variant derivative thereof as a hepatitis C virus inhibitor and its pharmaceutical use Technical field

The present invention relates to thiophene or a variant derivative thereof and a composition thereof as inhibitors of hepatitis C virus (HCV), and to the use thereof for the preparation of a medicament for treating chronic hepatitis C virus infection. In particular, the invention relates to a series of compounds as NS5A inhibitors, as well as to compositions and pharmaceutical uses thereof.

Background technique

HCV is one of the major human pathogens, with an estimated 170 million chronic HCV infections worldwide, five times the number of human immunodeficiency virus type 1 infections. People with chronic HCV infection develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic H CV infection is the leading cause of death in patients worldwide due to liver disease.

Currently, standard chronic HCV infection therapies are a combination of alpha-interferon and ribavirin with one of the direct-acting antiviral (DAA) drugs approved in the last two years. Although the curative effect is significantly improved compared with the previous combination of α-interferon and ribavirin, it is still ineffective for some patients with chronic HCV infection, and the virus can produce drug resistance. In addition, α-interferon and ribavirin have obvious side effects. Therefore, new and effective drugs for the treatment of chronic HCV infection are currently urgently needed.

HCV is a single-stranded positive-strand RNA virus. It belongs to the genus of the Flaviviridae family. All members of the Flaviviridae are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins by translation of a single uninterrupted open reading frame (ORF).

The nucleotides of the HCV genome and the encoded amino acid sequence are quite heterogeneous. At least 6 major genotypes and more than 50 sub-genotypes have been identified. The main genotypes of HCV are distributed globally. Although a large number of genotypes have been studied for pathogenesis and therapeutic effects, the clinical importance of HCV genetic heterogeneity remains unclear.

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

WO2013095275, WO2012122716, CN102863428A and the like each report a series of compounds as HCV inhibitors, and their effects on activity, solubility and the like need to be improved.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

among them,

E ₁ and E ₇ independently represent the structural unit represented by the formula (a),

among them,

R _{1 is} selected from the group consisting of C=O, C=S, S(=O), S(=O) ₂ , and C(R _1a )(R _1b );

R _{3 is} selected from the group consisting of C(R _3a )(R _3b ), C=O, C=S, S(=O), S(=O) ₂ ;

R _{4 is} selected from two or more substituted [chain hydrocarbon groups, hetero chain hydrocarbon groups, chain hydrocarbon hetero groups, cycloalkyl groups, heterocyclic groups, cyclohetero);

R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from H, F, Cl, Br, I, CN or optionally substituted [OH, SH, NH ₂ , PH ₂ , Hydrocarbyl group, heterohydrocarbyl group, hydrocarbyl group, heterohydro group hetero group];

n ₁ or n ₄ are each independently selected from 0 or 1;

n _{2 is} selected from 0, 1, _2, 3, 4, 5 or 6;

n _{3 is} selected from 0, 1, 2, 3, 4, 5 or 6;

n _{5 is} selected from 1, 2, 3 or 4;

When n ₁ , n ₂ , n ₃ or n ₄ is 0, the corresponding structural unit represents a single bond which only serves as a connection;

E ₂ and E ₆ are each independently selected from -C(=O)N(R _6a )C(R _6b )(R _6c ), CH ₂ , single bond, O, S, C=O, C=S, S (=O), S(=O) ₂ or the structural unit shown in formula (b),

R _6a , R _6b , R _6c are each independently selected from H, C _1-6 alkyl or alkoxy;

W ₅ and W ₆ each independently represent C, N, optionally substituted [CH ₂ , CH, NH, CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ;

W ₇ and W ₈ independently represent H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl a base, a heterohydrocarbyl hetero group], optionally between W ₇ and W _{8 ,} between W ₇ and W _{7 , and} between W ₈ and W ₈ to form a ring;

m ₇ and m _{8 are} selected from 0, 1, 2;

E ₃ and E ₅ are each independently selected from the group consisting of CH ₂ , a single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ or a structural unit represented by the formula (c);

L _{1 is} independently selected from C, N, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡ C, O, S, C=O, C=S, S(=O), S(=O) ₂ or a single bond;

L ₂ , L ₃ , L ₄ , L ₅ , L ₈ , L ₉ are each independently selected from C, N, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 ～6-membered hydrocarbon group or 3- to 6-membered heteroalkyl group], C≡C, O, S, C=O, C=S, S(=O), S(=O) ₂ ;

L ₆ and L ₇ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbon Heteroyl, heteroalkylhetero];

p ₁ , p ₆ , p ₇ are each independently selected from the group consisting of 0, ₁ , ₂ , 3, 4, 5 or 6;

E _{4 is} selected from the structural unit represented by formula (d) or (e),

Wherein Z ₁ , Z ₂ , X ₁ , X ₂ are each independently selected from a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [ CH ₂ , NH, PH, hydrocarbyl, heteroalkyl, hydrocarbyl, heteroalkyl hetero]];

Z ₃ , Z ₄ , X ₃ , X ₄ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group, a heterohydrocarbylhetero group], optionally a ring connecting Z ₃ and Z ₄ ;

q ₃ , q ₄ are each independently selected from 0, 1, 2 or 3;

表示单键或双键；

Represents a single or double bond;

中的------ 代表不成键时该结构单元不存在；------ represents a single button, double button or no key, when

------ in the case that the structural unit does not exist when the key is not formed;

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

Preferably, the substructure unit of the above structural unit (b) is as shown in the formula (g),

among them,

T _{1a is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3- to 6-membered hydrocarbon or 3- to 6-membered heteroalkyl), C≡ C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ;

T _2a , T _3a , T _4a are each independently selected from C, N, optionally substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon group or 3-6 yuan Heterohydrocarbyl], C≡C, O, S, C=O, C=S, S(=O), S(=O) ₂ ;

T _{5a is} selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl, heteroalkyl hetero base];

m _{5a is} selected from 0, 1, 2, 3, 4, 5 or 6;

W _5a and W _6a each independently represent C, N, optionally substituted [CH ₂ , NH, CH, CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ;

T _6a and T _7a are each independently selected from O, S, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3- to 6-membered hydrocarbon group or 3- to 6-membered heteroalkyl group] , C≡C, single bond, C=O, C=S, S(=O), S(=O) ₂ ;

T _8a from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heteroalkyl, hydrocarbyl, heteroalkyl hetero ];

m _{6a is} selected from 0, 1, 2 or 3, and when m _6a is 0, the corresponding structural unit represents a single bond which only serves as a linking;

m _{8a is} selected from 0, 1, 2, 3, 4, 5 or 6;

表示单键或双键；

Represents a single or double bond;

中的------代表不成键时该结构单元及其附属结构单元不存在，T_1a、T_2a两侧的------不同时为双键。------ represents a single button, double button or no key, when

The ------ represents that the structural unit and its subsidiary structural unit do not exist when the key is not _formed , and ------ on both sides of T _1a and T _2a are not double keys at the same time.

Preferably, the substructure unit represented by the above formula (g) is selected from the group consisting of:

Preferably, the substructure unit represented by the above formula (g) is selected from the group consisting of:

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

Preferably, the substructure unit of the structural unit represented by the above formula (d) is as shown in the formula (d-1):

among them,

Z ₁ and Z ₂ are each independently selected from a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [CH ₂ , NH, PH, hydrocarbon group , a heteroalkyl group, a hydrocarbyl group, a heterohydro group hetero group];

Z ₅ , Z ₆ , Z ₇ , Z ₈ are each independently selected from optionally substituted [CH ₂ —CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon group or 3-6-membered hetero Hydrocarbyl group, C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ , Z ₅ , Z ₆ , Z ₇ , Z ₈ cannot be four simultaneous Is a single button.

Preferably, the above Z ₁ and Z ₂ are each independently selected from the following groups which are optionally substituted:

联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、 1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基。Phenyl,

Biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, pyrazolyl, 2-pyrazolyl, pyrazolidinyl, imidazole Base, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H -pyranyl, pyridyl, piperidinyl, 1,4-dioxolyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-trithiane , 1,3,5-triazinyl, benzofuranyl, benzothienyl, fluorenyl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolinyl, porphyrin Or quinoxalinyl.

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

Preferably, the substructure unit of the structural unit represented by the above formula (e) is selected from the group consisting of:

Preferably, the above R _{4 is} selected from a 3- to 10-membered cyclic or heterocyclic or cyclohetero group substituted by two or more, and the hetero atom or hetero atom is selected from N, O, S, S (=O) or S(=O) ₂ .

Preferably, the above R _{4 is} selected from the group consisting of two or more of which are substituted:

Preferably, the above R _{4 is} selected from the group consisting of two or more of which are substituted:

More preferably, the above R _{4 is} selected from the group consisting of two or more of which are substituted:

进一步优选地，当R₄选自上述基团时，R₁为C＝O，R₅为H，n₁、n₄和n₅为1，n₂和n₃为0，R₁与R₄形成酰胺键。

Further preferably, when R _{4 is} selected from the above groups, R ₁ is C=O, R ₅ is H, n ₁ , n ₄ and n ₅ are 1, n ₂ and n ₃ are 0, and R ₁ and R _{4 are} An amide bond is formed.

Preferably, the substructure unit represented by the above formula (a) is selected from the group consisting of:

More preferably, the substructure unit represented by the above formula (a) is selected from the group consisting of:

Preferably, R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from the group consisting of H, F, Cl, Br, I, CN, =0, =S, optionally substituted [ OH, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl, heterocyclylcarbonyl, alkane Oxycarbonylamino], said heterocyclic group being selected from the group consisting of furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl or imidazolyl.

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

甲硫基、乙氧羰基、

Preferably, R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from the group consisting of H, F, Cl, Br, I, CN, =0, =S, optionally substituted [ OH, NH ₂ , methyl, isopropyl, cyclopropyl, butyl, tert-butyl, trifluoromethyl, hydroxymethyl, -CH(OH)CH ₃ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ (OH), -CH(OH)CH ₃ , methoxy, methoxymethyl, -CH(CH ₃ )OCH ₃ , -CH ₂ CH ₂ OCH ₃ ,

Methylthio, ethoxycarbonyl,

Preferably, the substituent for the above substitution is selected from the group consisting of F, Cl, Br, I, CN, =0, =S, optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl Base and / or heteroalkyl heterocycle].

Preferably, the compound of formula (I) is selected from the group consisting of:

Preferably, the above hydrocarbon group, heteroalkyl group, hydrocarbyl group, heterohydro group hetero group is selected from optionally substituted [C _1-12 hydrocarbyl group, C _1-12 heterohydrocarbyl group, C _1-12 hydrocarbyl hetero group, C _1-12 Hydrocarbyl C _1-12 hydrocarbyl, -C _1-12 OH, -C _0-12 COOH, -OC _1-12 COOH, -C _1-12 CN, -C _0-12 CONH ₂ , -C _0-12 OC _1-12 , -C _0-12 CO C _1-12 , -C _0-12 COO C _1-12 , -C _0-12 O(O=)C C _1-12 , -C _0-12 S(= O) C _1-12 or -C _0-12 S(=O) ₂ C _1-12 ], wherein the above group itself is an aromatic ring, a heteroaryl ring, an aliphatic ring, a heteroalicyclic ring, a fatty chain and/or The form of a hetero-fat chain exists, and the number of aromatic rings, heteroaromatic rings, aliphatic rings, heteroalicyclic rings, aliphatic chains and/or hetero-fat chains, ring-forming atoms and their numbers, rings and rings or rings and chains or The linkage between the chains and the chains is arbitrary under the premise of being chemically stable, and the heteroatoms or heteroatoms are independently selected from O, S, N, S(=O) and/or S(=O), respectively. ₂ , the number of heteroatoms or heteroatoms is arbitrary under the premise of being chemically stable.

Preferably, the above substituent for substitution is selected from the group consisting of F, Cl, Br, I, CN, =O, =S, OH, SH, NH ₂ , halogenated or hydroxy or amine or unsubstituted C _1-6 An alkyl or heteroalkyl or alkane group, a hetero atom or a hetero atom group, each independently selected from C _1-6 alkane or unsubstituted -CONH-, -CO ₂ -, C _1-6 alkane or not Substituted -NH-, -O-, -S-, C _1-6 alken or unsubstituted -C=NH, -C=O, -C=S, S(=O) and/or S( =O) ₂ , the number of substituents, heteroatoms or heteroatoms is arbitrary under the premise of being chemically stable

Preferably, the substituent for the above substituent is selected from the group consisting of halogen, OH, SH, NH ₂ , PH ₂ , CN, =O, =S, CF ₃ , -OCF _{3 ,} -OCH ₃ .

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or 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 quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, 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, polygalacturon, propionic acid, salicylic acid, hard Fatty acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic 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 containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.

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

Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and after substitution The compound is stable. When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and the kind and number of substituents may be arbitrary on the basis of chemically achievable.

是指

The term "two or more substituted" is used in particular, and a "two or more substituted" group means that the group can be attached to the remainder of the molecule by its own two atoms. For example, two or more are replaced

Refers to

Unless otherwise specified, when any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

表示其可在环己基或者环基二烯上的任意一个位置发生取代。Unless otherwise specified, when a group or a bond of a substituent may be cross-linked to two atoms on a ring, such a group or substituent may be bonded to any atom on the ring. When the recited group or substituent does not indicate which atom is attached to a compound included in the chemical structural formula, but not specifically mentioned, such a group or substituent may be bonded through any of its atoms. Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit

It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic The hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ₎ -C ₁₀ represents 1 to 10 carbons). The hydrocarbon group includes an aliphatic hydrocarbon group including an chain hydrocarbon group and a cyclic hydrocarbon group, and includes, but not limited to, an alkyl group, an alkenyl group, and an alkynyl group, and the aromatic hydrocarbon group includes, but not limited to, a 6-12 member aromatic hydrocarbon group. For example, benzene, naphthalene, and the like. In some embodiments, the term "alkyl" refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent 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). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.

Unless otherwise specified, the heteroalkyl, heterocyclyl, hydrocarbyl, cyclohetero, heteroalkylhetero, heterocyclylhetero group means a hetero atom or a hetero atom group, a hetero atom or a hetero atom group on a specific group. Including but not limited to N, NH, substituted or protected NH, O, S, S (= O), S (= O) ₂ , the so-called heterohydrocarbyl, heterocyclic group is connected to the rest of the molecule through carbon atoms , that is, a hetero atom may be located at any internal position of the group (except that the group is attached to the rest of the molecule); the so-called hydrocarbon heterocycle, cyclohetero is attached to the rest of the molecule through a hetero atom, ie, The atom is located at a position where the group is attached to the rest of the molecule; the so-called heteroalkylhetero, heterocyclyl is attached to the remainder of the molecule through a heteroatom, wherein the heteroatom can be located at any internal position of the group (including This group is attached to the rest of the molecule).

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like), by itself or in combination with another term, means a stable straight chain. A hydrocarbon group of a chain or a combination thereof having a number of carbon atoms and at least one hetero atom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatoms B, O, N and S may 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, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary and are meant to be attached to the molecule through an oxygen, amino or sulfur atom, respectively. The rest of those alkyl groups.

Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", "cyclohetero" or subordinates thereof (such as cycloalkyl, heterocycloalkyl, cycloalkanyl, cycloalkenyl, heterocycloalkenyl) The cyclyl, cycloheteroyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, and the like, by themselves or in conjunction with other terms, denote a cyclized "hydrocarbyl", "heterohydrocarbyl" or "hydrocarbyl", 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 heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

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

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the hetero atom is selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxygenated The nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

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

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted hetero Aryl. The so-called ring includes a fused ring. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, 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 "hetero atom" 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), antimony ( Ge), aluminum (Al) and boron (B).

Unless otherwise specified, the term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom by a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

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

Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C _1-6 alkoxy group includes a C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

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

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which A carbon atom 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 phenyl ring to form a bicyclic ring.

Unless otherwise specified, examples of heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazole , benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH -carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2 ,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, anthracene , 3H-fluorenyl, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, fluorenyl, isoquinolyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl , piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridine Oxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4H-quina Azinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolyl Thienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 , 2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthesis methods, and techniques of the art. Preferred embodiments are well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the invention.

Unless otherwise specified, the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and liquid phase mass spectrometry (LCMS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), internal standard was four. Methyl silane (TMS).

Unless otherwise specified, the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (TLC) adopts the specification of 0.15mm~0.2mm. The specification is 0.4mm to 0.5mm.

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

Unless otherwise specified, the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, TCI, Alfa, Suiyuan Chemical Accela ChemBio Inc., Beijing Coupling and other companies.

Unless otherwise specified, the examples can be carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified in the examples. An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

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

The microwave reaction used a Biotage Initiator 60 microwave reactor unless otherwise specified.

Unless otherwise specified, unless otherwise stated in the examples, the solution means an aqueous solution.

Unless otherwise specified, the examples are not specifically described, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

Unless otherwise specified, the progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system. , C: petroleum ether and ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.

Unless otherwise specified, the column chromatography eluent system and the thin layer chromatography developer system used for the purification of the compound include: A: dichloromethane and methanol systems, B: petroleum ether and ethyl acetate systems, C: In the dichloromethane and acetone systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.

The invention is specifically described by the following examples, which are not intended to limit the invention.

All solvents used in the present invention are commercially available and can be used without further purification unless otherwise specified.

Unless otherwise specified, the invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, etc. CDI stands for carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, an amine protecting group; BOC stands for t-butylcarbonyl is an amine protecting group; HOAc stands for acetic acid; NaCNBH ₃ stands for cyanide Sodium borohydride; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ Represents thionyl chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point.

软件命名，市售化合物采用供应商目录名称。Unless otherwise specified, the compound is either by hand or

Software naming, commercially available compounds using the supplier catalog name.

Compared with the prior art, the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.

detailed description

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Reference Example 1: Fragment BB-1

synthetic route:

Step 1: Synthesis of Compound BB-1-3

Compound BB-1-1 (1.38 g, 5.0 mmol) was dissolved in acetonitrile (15 mL). Compound BB-1-2 (1.08 g, 5.0 mmol) was added, then DIPEA (0.65 g, 5.0 mmol) was gradually added. After the addition was completed, the above reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure on a rotary EtOAc (EtOAc) (EtOAc). The solvent was evaporated under reduced pressure to give the title compound </RTI></RTI> LCMS: m/z, 314.0 (M-100) ⁺

Step 2: Synthesis of Compound BB-1-4

Compound BB-1-3 (2.0 g, 4.82 mmol) was dissolved in toluene (40 mL). After the reaction mixture was cooled, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solvent was removed to give the title compound </RTI></RTI><RTIgt; LCMS: m/z, 394.1 (M+1) ⁺

Step 3: Synthesis of Compound BB-1-5

Compound BB-1-4 (1.8 g, 4.56 mmol) was dissolved in dichloromethane (20 mL), and the solution was cooled to 0 ° C, then trifluoroacetic acid (6 mL) was gradually added dropwise, and the reaction was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure using a rotary evaporator, and the obtained oil was purified (yield: EtOAc (EtOAc) The aqueous solution was dried over anhydrous sodium sulfate. LCMS: m/z, 294.0 (M+1) ⁺

Step 4: Synthesis of compound BB-1-7

Compound BB-1-5 (588 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL). Compound BB-1-6 (382 mg, 2.0 mmol), HATU (912 mg, 2.4 mmol) and DIPEA (309.6 mg, 2.4 mmol), stirred at room temperature for 2 hours. After adding 30 mL of water, the organic phase obtained by layering was washed once with a NaCI solution, and the organic phase was dried over anhydrous sodium sulfate. PE, 3/1) gave the title compound BB-1-7 (510 mg, 55%).

LCMS: m/z, 467.1 (M+1) ⁺

Step 5: Synthesis of Compound BB-1

The compound BB-1-7 (200 mg, 0.428 mmol) was dissolved in DMF (6 mL), then boron ester BB-1-8 (163 mg, 0.642 mmol), KOAc (84 mg, 0.856 mmol) and Pd(dppf)Cl2 ( 15 mg, 0.02 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled, diluted with water (30 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was combined and dried with anhydrous sodium sulfate. EtOAcjjjjjjjjjj 32%).

LCMS: m/z, 515.3 (M+1) ⁺

Reference Example 2: Fragment BB-2

synthetic route:

Step 1: Synthesis of Compound BB-2-3

Compound BB-2-1 (3.74 g, 20 mmol) was dissolved in DMF <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; Stir at room temperature for 5 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL×2). The organic phase was separated and washed with a saturated NaCI solution. The organic phase was dried over anhydrous sodium sulfate. Compound BB-2-3 (6.1 g, 79%). LCMS: m/z, 384.1 (M+1) ⁺

Step 2: Synthesis of Compound BB-2-4

Compound BB-2-3 (6.0 g, 15.63 mmol) was dissolved in acetic acid (40 mL). EtOAc (12 g, 155.6 The above reaction solution was heated to 90 ° C for 3 hours. After the reaction mixture was cooled, it was diluted with 150 mL of water and neutralized with 4N NaOH (pH=8), and extracted with ethyl acetate (50 mL×2). The organic phase obtained twice was combined and dried over anhydrous sodium sulfate The solvent was removed under reduced pressure to give title compound </RTI> LCMS: m/z, 366.1 (M+1) ⁺

Step 3: Synthesis of compound BB-2-5

The compound BB-2-4 (4.5 g, 12.28 mmol) was dissolved in dichloromethane (45 mL), and the solution was cooled to 0 ° C, then trifluoroacetic acid (9 mL) was gradually added dropwise, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure using a rotary evaporator, and the obtained oil was purified (yield: EtOAc) The aqueous solution was dried over anhydrous sodium sulfate. LCMS: m/z, 266.0 (M+1) ⁺

Step 4: Synthesis of Compound BB-2

Compound BB-2-5 (532 mg, 2.0 mmol) was dissolved in dichloromethane (15 mL). Compound BB-2-6 (385 mg, 2.2 mmol), HATU (836 mg, 2.2 mmol) and DIPEA (368 mg, 2.9 Methyl), stirred at room temperature overnight. After adding 20 mL of water, the organic phase obtained by the layering is washed once with a saturated NaCl solution, and the organic phase obtained is separated and dried over anhydrous sodium sulfate, and the filtrate is filtered to remove the solvent concentrate to give an oil. The title compound BB-2 (200 mg, 24%) was obtained. LCMS: m/z, 423.1 (M+1) ⁺

Reference example: Fragment BB-3

synthetic route:

Step 1: Synthesis of Compound BB-3-2

Compound BB-2-5 (532 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL). Compound BB-1-6 (420 mg, 2.2 mmol), HATU (912 mg, 2.4 mmol) and DIPEA (388 mg, 3.0) Methyl), stirred at room temperature overnight. After adding 30 mL of water, the organic phase obtained by the layering is washed once with a saturated NaCl solution, and the organic phase obtained is separated and dried over anhydrous sodium sulfate, and the filtrate is filtered to remove the solvent concentrate to give an oil. The plate was purified by EtOAc (EtOAc/EtOAc) LCMS: m/z, 439.1 (M+1) ⁺

Step 2: Synthesis of Compound BB-3

Compound BB-3-2 (300 mg, 0.68 mmol) was dissolved in 1,4-dioxane (6 mL), then bis-hydrazinyl borate (258 mg, 1.02 mmol), EtOAc (135 mg, 1. And Pd(dppf)Cl ₂ (30 mg, 0.04 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled, it was diluted with water (20 mL), and the mixture was evaporated. The title compound BB-3 (235 mg, 71%).

LCMS: m/z, 487.3 (M+1) ⁺

Reference Example 4: Fragment BB-4

synthetic route:

Step 1: Synthesis of Compound BB-4-2

Compound BB-8 (292 mg, 1.0 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Stir at room temperature overnight. After adding 30 mL of water, the organic phase obtained by the layering was washed once with a saturated NaCl solution, and the obtained organic phase was dried over anhydrous sodium sulfate, and the filtrate was filtered to remove the solvent concentrate to give the title compound BB-4-2 ( 320 mg, 69%). LCMS: m/z, 463.1 (M+1) ⁺

Step 2: Synthesis of Compound BB-4

Compound BB-4-2 (320 mg, 0.69 mmol) was dissolved in DMF (10 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc ₂ (30 mg, 0.04 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled, it was diluted with water (20 mL), and the mixture was evaporated. The title compound BB-4 (260 mg, 74%) was obtained.

LCMS: m/z, 511.3 (M+1) ⁺

Reference Example 5: Fragment BB-5

synthetic route:

Step 1: Synthesis of Compound BB-5-2

Compound BB-1-1 (1.38 g, 5.0 mmol) was dissolved in acetonitrile (15 mL). Compound BB-5-1 (0.95 g, 5.0 mmol) was added, then DIPEA (0.65 g, 5.0 mmol) was gradually added. After the addition was completed, the above reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure on a rotary EtOAc (EtOAc) (EtOAc). The solvent was evaporated under reduced pressure to give the title compound </RTI></RTI><RTIgt; LCMS: m/z, 285.0 (M-100) ⁺

Step 2: Synthesis of Compound BB-5-3

Compound BB-5-2 (1.8 g, 4.66 mmol) was dissolved in toluene (50 mL). After the reaction mixture was cooled, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solvent was removed to give the title compound BB-5-3 (1.6 g, 94%). LCMS: m/z, 366.1 (M+1) ⁺

Step 3: Synthesis of Compound BB-5-4

The compound BB-5-3 (1.6 g, 4.36 mmol) was dissolved in dichloromethane (20 mL), and the solution was cooled to 0 ° C, and then trifluoroacetic acid (6 mL) was gradually added dropwise, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure using a rotary evaporator, and the obtained oil was purified (yield: EtOAc (EtOAc) The aqueous solution was dried over anhydrous sodium sulfate. LCMS: m/z, 266.0 (M+1) ⁺

Step 4: Synthesis of Compound BB-5-5

Compound BB-5-4 (532 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL). Compound BB-1-6 (382 mg, 2.0 mmol), Methyl), stirred at room temperature for 3 hours. After adding 30 mL of water, the organic phase obtained by layering was washed once with a NaCI solution, and the organic phase was dried over anhydrous sodium sulfate. PE, 3/1) gave the title compound BB-5-5 (400 mg, 46%).

LCMS: m/z, 439.1 (M+1) ⁺

Step 5: Synthesis of Compound BB-5

Compound BB-5-5 (400 mg, 0.91 mmol) was dissolved in 1,4-dioxane (20 mL), then bis-hydrazinyl borate (345 mg, 1.36 mmol), EtOAc (178 mg, 1. And Pd(dppf)Cl ₂ (35 mg, 0.047 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (30 mL), EtOAc (EtOAc) The title compound BB-5 (300 mg, 68%) was obtained.

LCMS: m/z, 487.3 (M+1) ⁺

Reference Example 6: Fragment BB-6

synthetic route:

Step 1: Synthesis of Compound BB-6-2

Compound BB-6-1 (4.6 g, 20 mmol) was dissolved in acetonitrile (70 mL). Compound BB-1-1 (5.56 g, 20 mmol) was added, then DIPEA (2.58 g, 20 mmol) was gradually added. After the addition was completed, the above reaction was stirred at room temperature overnight. The reaction mixture was evaporated to dryness with EtOAc (EtOAc m. The solvent was evaporated under reduced pressure to give the title compound </RTI> </RTI> <RTIgt;

LCMS: m/z, 326.0 (M-100) ⁺

Step 2: Synthesis of Compound BB-6-3

Compound BB-6-2 (8.4 g, 19.7 mmol) was dissolved in toluene (120 mL). EtOAc (22.9 g, After the reaction mixture was cooled, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solvent was removed to give the title compound BB-6-3 (7.8 g, 98%). LCMS: m/z, 406.0 (M+1) ⁺

Step 3: Synthesis of Compound BB-6-4

The compound BB-6-3 (7.1 g, 17.5 mmol) was dissolved in dichloromethane (75 mL), and the solution was cooled to 0 ° C, then trifluoroacetic acid (30 mL) was gradually added dropwise, and the reaction was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure using a rotary evaporator, and the obtained oil was purified (yield: EtOAc) The aqueous solution was dried over anhydrous sodium sulfate. LCMS: m/z, 306.0 (M+1) ⁺

Step 4: Synthesis of Compound BB-6-5

Compound BB-6-4 (305 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL). Compound BB-1-6 (191 mg, 1.0 mmol), HATU (456 mg, 1.2 mmol) and DIPEA (258 mg, 2.0 Methyl), stirred at room temperature for 3 hours. After adding 15 mL of water, the organic phase was separated and washed with aq. EtOAc. EtOAc. /PE, 3/1) gave the title compound BB-6-5 (250 mg, 52%).

LCMS: m/z, 479.0 (M+1) ⁺

Step 5: Synthesis of Compound BB-6

Compound BB-6-5 (160 mg, 0.33 mmol) was dissolved in DMF (4 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc ₂ (12 mg, 0.016 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (10 mL), EtOAc (EtOAc)EtOAc. (eluent, EtOAc / EtOAc /EtOAc) LCMS: m/z, 527.2 (M+1) ⁺

Reference Example 7: Fragment BB-7

synthetic route:

Step 1: Synthesis of Compound BB-7-1

Compound BB-6-4 (305 mg, 1.0 mmol) was dissolved in dichloromethane <RTI ID=0.0>(10 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Methyl), stirred at room temperature for 3 hours. After adding 15 mL of water, the organic phase was separated and washed with aq. EtOAc. EtOAc. /PE, 3/1) gave the title compound 7-1 (260 mg, 56%).

LCMS: m/z, 463.0 (M+1) ⁺

Step 2: Synthesis of Compound BB-7

Compound BB-7-1 (160 mg, 0.33 mmol) was dissolved in DMF (4 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc ₂ (12 mg, 0.016 mmol). The air was replaced with nitrogen three times, and the reaction liquid was reacted at 110 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (10 mL), EtOAc (EtOAc)EtOAc. (eluent, EtOAc / EtOAc /EtOAc)

LCMS: m/z, 511.2 (M+1) ⁺

Reference Example 8: Fragment BB-8

synthetic route:

Step 1: Synthesis of Compound BB-8-2

Compound BB-2-2 (2.15 g, 10 mmol) was dissolved in acetonitrile (40 mL). Compound BB-1-1 (2.78 g, 10 mmol) was added, then DIPEA (1.29 g, 10 mmol) was gradually added. After the addition was completed, the above reaction was stirred at room temperature overnight. The reaction mixture was evaporated to dryness with EtOAc (EtOAc m. The solvent was evaporated under reduced pressure to give the title compound </RTI> </RTI>

LCMS: m/z, 312.0 (M-100) ⁺

Step 2: Synthesis of Compound BB-8-3

Compound BB-8-2 (3.9 g, 9.47 mmol) was dissolved in toluene (70 mL), and then ethyl acetate (7.3 g, 94.8 mmol). After the reaction mixture was cooled, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The solvent was removed to give the title compound BB-8-3 (3.2 g, 86%). LCMS: m/z, 392.1 (M+1) ⁺

Step 3: Synthesis of Compound BB-8

The compound BB-8-3 (3.0 g, 7.65 mmol) was dissolved in dichloromethane (60 mL), and the solution was cooled to 0 ° C, then trifluoroacetic acid (20 mL) was gradually added dropwise, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure on a rotary evaporator, and the obtained oil was purified (yield: EtOAc (EtOAc) The aqueous solution was dried over anhydrous sodium sulfate. LCMS: m/z, 292.0 (M+1) ⁺

Reference Example 9: Fragment BB-9

synthetic route:

Step 1: Synthesis of Compound BB-9-2

The compound N-Boc-L-proline (4.30 g, 20 mmol) and potassium carbonate (3.86 g, 27.97 mmol) were suspended in acetonitrile (100 ml), and compound BB-9-1 (3.31 g, 10.75 mmol) was added at room temperature. ). After stirring at room temperature for 4 hours, after completion of the reaction by TLC, the solvent was evaporated to give the title compound BB-9-2 (white solid, 1.26 g, yield 14%). The product was applied directly to 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 (0.80 g, 1.81 mmol) was dissolved in toluene (50 ml), and ammonium acetate (7.67 g, 99.61 mmol) was added. The mixture was warmed to reflux with aq. EtOAc (EtOAc)EtOAc. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 3 (white powder, 0.29 g, yield 38%). MS m/z: 422.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-9-4

Compound BB-9-3 (5.00 g, 11.84 mmol) was added to a hydrogen chloride/ethyl acetate solution (HCl/EA, 4 mol/L, 20 mL), and stirred at room temperature for 2 hr. After completion of the TLC reaction, the solvent was evaporated to give a white solid intermediate BB-9-4. The product is used directly in the next step without purification.

Step 4: Synthesis of Compound BB-9-5

The above white solid intermediate BB-9-4 (0.242 g, 0.67 mmol), N-Moc-L-valine (BB-2-6, 0.18 g, 0.94 mmol), diisopropyl The amine (0.31 g, 2.39 mmol) was dissolved in DMF (3 mL). After stirring at room temperature for 3 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 5 (yellow solid, 0.22 g, yield 68%). MS m/z: 481.0 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-9

Compound BB-9-5 (0.22 g, 0.46 mmol), bis-pinacol borate (0.14 g, 0.55 mmol) was dissolved in dioxane (4 ml) at room temperature, and potassium acetate was added under nitrogen. (0.09 g, 0.93 mmol) and Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol). The reaction was carried out in a microwave at 120 ° C for 45 minutes. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness eluted with silica gel column ( petroleum ether/ethyl acetate=3:2→ethyl acetate) Compound BB-9 (0.17 g, yield 70%). MS m/z: 527.1 [M+H] ⁺ .

Reference Example 10: Fragment BB-10

synthetic route:

Step 1: Synthesis of Compound BB-10-2

Compound BB-10-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). LCMS m/z: 479.1 [M+H] ⁺

Step 2: Synthesis of Compound BB-10

Compound BB-10 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). LCMS m/z: 527.1 [M+H] ⁺

Reference Example 11: Fragment BB-11

synthetic route:

Step 1: Synthesis of Compound BB-11-2

Compound BB-11-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). MS m/z: 465.1 [M+H] ⁺ .

Step 2: Synthesis of Compound BB-11

Compound BB-11 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). MS m/z: 511.3 [M+H] ⁺ .

Reference Example 12: Fragment BB-12

synthetic route:

Step 1: Synthesis of Compound BB-12-2

Compound BB-12-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). LCMS m/z: 464.9 [M+H] ⁺

Step 2: Synthesis of Compound BB-12

Compound BB-12 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). LCMS m/z: 488.0 [M+Na] ⁺

Reference Example 13: Fragment BB-13

synthetic route:

Step 1: Synthesis of Compound BB-13-2

Compound BB-13-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). MS m/z: 485.1 [M+H] ⁺ .

Step 2: Synthesis of Compound BB-13

Compound BB-13 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). MS m/z: 531.2 [M+H] ⁺

Reference Example 14: Fragment BB-14

synthetic route:

Step 1: Synthesis of BB-14

BB-14-1 (600 mg, 1.90 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride / ethyl acetate solution (HCl / EA, 4mol/L, 20mL) was added and stirred at room temperature for 3 hours. After completion of the TLC reaction, the solvent was evaporated to give a white solid intermediate (410 mg). The above white solid intermediate (410 mg, 1.63 mmol), N-Moc-L-valine (BB-2-6, 399 mg, 2.09 mmol), diisopropylethylamine (735 mg, 5.70 mmol) was dissolved in DMF (10 mL), HATU (1.08 g, 2.84 mmol) was added. After stirring at room temperature overnight, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic layer was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated White solid, 306 mg, yield 43.2%). MS m/z: 374.9 [M+H] ⁺ .

Reference Example 15: Fragment BB-15

synthetic route:

Step 1: Synthesis of Compound BB-15

Compound BB-15 can be produced according to Synthesis Step 1 of Reference Example 14 (BB-14). _{^{1 H NMR (CDCl 3, 400MHz}} ): δ6.90 (s, 1H), 5.23-5.22 (m, 1H), 4.58-4.40 (m, 1H), 4.13-3.88 (m, 4H), 3.70 (s, 3H), 3.21-3.20 (m, 2H), 2.88-2.51 (m, 2H), 2.16-2.07 (m, 3H), 1.97-1.79 (m, 2H).

Reference Example 16: Fragment BB-16

synthetic route:

Step 1: Synthesis of Compound BB-16-2

Compound BB-16-1 (4.1 g, 26.2 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and cis-1,2-cyclohexanedicarboxylic anhydride (AA_013-1, 2.0 g, 13.0 mmol). The mixture was stirred at room temperature for 6 hours, and the solvent was evaporated to dryness eluted eluted elution elution The product is used directly in the next step without purification. _{^{1 H NMR (CDCl 3, 400MHz}} ): δ7.78 (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 = 6.4 Hz, 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 (3.5 g, 10.79 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were suspended in DMF (25 mL), and 2,4'-dibromoacetophenone (BB-1-) was added at room temperature. 1,3.1 g, 11.2 mmol). After stirring at room temperature for 2 hours, the reaction was quenched by TLC, and water (20mL) was evaporated to ethylamine. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. (4.8 g, yield 87.8%). MS m/z: 530.7 [M+Na] ⁺ .

Step 3: Synthesis of Compound BB-16

Compound BB-16-3 (1.50 g, 2.96 mmol) was dissolved in toluene (200 mL) at room temperature and ammonium acetate (11.88 g, 154.09 mmol) was added. The mixture was warmed to reflux under a nitrogen atmosphere and stirred overnight. The mixture was evaporated to room temperature after TLC, and then the mixture was evaporated to ethyl ether (50mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, Light yellow powder, 0.95 g, yield 66.0%). MS m/z: 489.3 [M+H] ⁺ .

Reference Example 17: Fragment BB-17

synthetic route:

Step 1: Synthesis of Compound BB-17-2

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

Step 2: Synthesis of Compound BB-17-3

Compound BB-17-2 (5 g 23.8 mmol), triethylamine (4.8 g, 47.6 mmol) was dissolved in tert-butanol (50 mL), and DPPA (9.8 g, 35.6 mmol) was added. The mixture was heated to reflux with EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated, The product is used directly in the next step without purification. _{^{1 H NMR (CDCl 3, 400MHz}} ): δ6.91 (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).

Step 3: Synthesis of Compound BB-17-4

Compound BB-17-3 (5 g, 17.8 mmol) was dissolved in ethyl acetate (30 mL). After completion of the TLC reaction, the solvent was evaporated to give the title compound BB-17-4 (white solid, 3.6 g, yield 93%). The product is used directly in the next step without purification. ¹ H NMR (Methanol-d ₄ 400 MHz): δ 3.10-3.06 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.59-2.56 (m, 5H).

Step 4: Synthesis of Compound BB-17-5

Compound BB-17-4 (2.9 g, 13.32 mmol), isoamyl nitrite (2.3 g, 19.64 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and copper bromide (3.3 g, 14.8 mmol) was added. The mixture was stirred at room temperature for 3 hr under N.sub.2, and the mixture was evaporated to ethyl ether (30mL×4). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated (dark brown solid, 1.6 g, yield 49%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.05 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H) 2.5-2.45 (m, 2H), 2.42 (s, 3H) .

Step 5: Synthesis of Compound BB-17-6

Compound BB-17-5 (1.0 g, 4.08 mmol) was dissolved in glacial acetic acid (10 mL). A solution of bromine (653 mg, 4.09 mmol) in glacial acetic acid (1 mL) was added dropwise. After stirring overnight at room temperature, the reaction was completed by LCMS. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The product is 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 (400 mg, 1.856 mmol) and potassium carbonate (510 mg, 3.7 mmol) were suspended in DMF (5 mL), stirred at room temperature for 10 min, then compound BB-17-6 (600 mg, 1.85) Mm). After stirring at room temperature for 2 hours, ethyl acetate (100 mL) was added and the mixture was washed with water (20 mL×4) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated, evaporated, mjjjjjjjjjjjjjj g, yield 76%). MS m/z: 359.9 [M-Boc+H] ⁺ .

Step 7: Synthesis of Compound BB-17-8

Compound BB-17-7 (650 mg, 1.42 mmol) was dissolved in toluene (50 mL) at room temperature and ammonium acetate (1.1 g, 14.3 mmol) was added. The temperature was raised to 120 ° C under a nitrogen atmosphere, and stirred overnight. After the reaction was completed by TLC, the mixture was cooled to room temperature, and the mixture was stirred with water (30mL), and ethyl acetate (50mL×3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated (light yellow powder, 349 mg, yield 56%). _{^{1 H NMR (CDCl 3, 400MHz}} ): δ6.94 (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] ⁺ .

Step 8: Synthesis of Compound BB-17-9

The compound BB-17-8 (600 mg, 1.37 mmol) was dissolved in ethyl acetate (10 mL), cooled to 0 ° C, and hydrogen chloride / ethyl acetate solution (HCl / EA, 4 mol / L, 10 mL) was added dropwise at 0 ° C Stir under 1 hour. After completion of the TLC reaction, the solvent was evaporated to give the title compound BB-17-9 (yellow solid, 510 mg, yield 99.4%). The product is used directly in the next step without purification. MS m/z: 339.8 [M+H] ⁺ . Step 9: Synthesis of Compound BB-17

Compound BB-17-9 (573 mg, 1.53 mmol), N-Moc-L-valine (BB-2-6, 323 mg, 1.69 mmol), diisopropylethylamine (594 mg, 4.60 mmol) Dissolved in DMF (10 mL) and added HATU (746 mg, 1.96 mmol). After stirring at room temperature overnight, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, Yellow solid, 317 mg, yield 41.9%). MS m/z: 497.1 [M+H] ⁺ .

Reference examples 18 to 20

Table 1: Using the compound BB-17-9 as a starting material, according to the synthesis method of the step 9 in Reference Example 17, the compounds BB-18, BB-19, BB-20 in the following table were respectively obtained.

Reference Example 21: Fragment BB-21

synthetic route:

Step 1: Synthesis of Compound BB-2-6

L-valine (100 g, 751 mmol) was added to a sodium hydroxide solution (2 mol/L, 535 mL). The mixture was cooled to below 5 ° C in an ice-bath, and methyl chloroformate (118.13 g, 1.25 mmol) was added dropwise and stirred at room temperature overnight. After the TLC detection reaction was completed, the ice bath was cooled to 5 ° C or less, and concentrated hydrochloric acid was added dropwise to adjust the pH to about 5, and the precipitated solid was collected, washed with water (100 mL), and dried to give the title compound BB-2-6 (white solid, 141 g, yield 98.2%). The product is used directly in the next step without purification. _{^{1 H NMR (CDCl 3 400MHz)}} : δ5.19 (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 = 7.2 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H).

Step 2: Synthesis of Compound BB-21-1

The ^{EDC. HCl (26.3g, 136.9mmol)} , N-Moc-L- Valine (BB-2-6,17.6g, 92.05mmol), diisopropylethylamine (35.4g, 274.4mmol) was dissolved Anhydrous dichloromethane (500 mL) was stirred at room temperature for 10 min then EtOAc EtOAc (EtOAc, EtOAc (EtOAc) After the TLC reaction was completed, the reaction was quenched by water (20 mL), and the organic phase was washed with 10% hydrochloric acid to pH 5-6, then washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure to give compound BB-21-1 (yield: 36 g, yield: 76%). The product is used directly in the next step without purification. MS m/z: 449.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-21

Compound BB-21-1 (80 g, 178 mmol), bis-pinacol borate (90 g, 354 mmol) was dissolved in dioxane (600 mL) at room temperature, and potassium acetate (35 g, 357 mmol) was added under nitrogen. And Pd(dppf)Cl ₂ (13 g, 1.78 mmol). The reaction solution was heated to 90 ° C under a nitrogen atmosphere and stirred overnight. After the TLC detection reaction was completed, it was cooled to room temperature. After filtration, the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS m/z: 519.1 [M+Na] ⁺ .

Reference Example 22: Fragment BB-22

synthetic route:

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 atmosphere, the reaction system was heated to reflux and stirred 2 hour. After the TLC detection reaction was completed, it was cooled to room temperature. After filtration, the filtrate was evaporated to dryness to give the title compound BB-22-2 (white solid, 3.8 g, yield: 87.8%). The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.82 (brs, 3H), 2.06 (d, J = 1.6 Hz, 3H), 1.85 (s, 3H).

Step 2: Synthesis of Compound BB-22

Compound BB-22-2 (3 g, 23.1 mmol) was dissolved in a mixed solvent of ethyl acetate / glacial acetic acid (30 mL / 3 mL) at room temperature, and platinum oxide (0.3 g) was added under a nitrogen atmosphere. The reaction was carried out at 50 ° C under a hydrogen pressure of 50 psi for 12 hours and cooled to room temperature. After filtration, the filtrate was evaporated to dryness crystals crystals crystals crystals The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.62 (s, 3H), 3.25 (brs, 1H), 1.04 (d, J = 6.4 Hz, 6H).

Reference Example 23: Fragment BB-23

synthetic route:

Step 1: Synthesis of Compound BB-23-2

3-toluenesulfonyltetrahydrofuran (BB-23-1, 3g, 12.4mmol), dibenzylidene glycine methyl ester (1.49g, 5.88mmol) was dissolved in toluene (30mL) at room temperature, slow under nitrogen LiHMDS (1 mol/L in THF, 7.1 mL, 7.1 mmol) was added dropwise. Heat to 100 ° C under nitrogen and stir overnight. After completion of the TLC reaction, the mixture was cooled to room temperature, and then water (20 mL) The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjj Rate 80%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.67-7.65 (m, 2H), 7.48-7.36 (m, 6H), 7.22-7.20 (m, 2H), 4.10 (t, J = 7.6 Hz, 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 (12.2 g, 37.8 mmol) was dissolved in tetrahydrofuran (100 mL), and hydrochloric acid (2 mol/L, 75.5 mL, 151 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 4 hours. After completion of the TLC reaction, the solvent was evaporated and washed with petroleum ether (50 mL×3), sodium hydroxide was added to the system to adjust the pH to 8-9, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness crystals crystals crystals ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.90-3.85 (m, 2H), 3.73-3.68 (m, 5H), 3.37 (dd, J = 20.8, J = 7.2 Hz, 1H), 2.52-2.46 ( m, 1H), 1.99-1.96 (m, 1H), 1.78-1.77 (m, 1H).

Step 3: Synthesis of Compound BB-23-4

Compound BB-23-3 (2.88 g, 18.1 mmol) was dissolved in dichloromethane (50 mL), diisopropylethylamine (7.0 g, 54.3 mmol) was added and then methyl chloroformate was added dropwise. 1.88 g, 19.9 mmol) and stirred at room temperature for 4 hours. After the TLC reaction was completed, the solvent was evaporated under reduced pressure, and the residue was applied to silica gel column chromatography (ethyl ether/ethyl acetate=20:1→2:1) to give the title compound BB-23-4 (yellow oil, 2.8 g, yield The rate is 71.2%). _{^{1 H NMR (CDCl 3, 400MHz}} ): δ5.38 (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).

Step 4: Synthesis of Compound BB-23-5

Compound BB-23-4 (3.25 g, 15.0 mmol) was dissolved in a methanol/water (100 mL / 100 mL) mixed solvent at room temperature, and sodium hydroxide (1.2 g, 30.0 mmol) was added. The reaction system was warmed to 75 ° C, stirred for 3 hours, and after completion of TLC detection, pH was adjusted to 1-2 with 2N hydrochloric acid, and ethyl acetate (200 mL × 2) was extracted. The organic phase was combined and dried over anhydrous sodium sulfate. ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.60 (dd, J = 26.4, J = 8.4 Hz, 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).

Step 5: Synthesis of Compound BB-23-6

Compound BB-23-5 (550 mg, 2.71 mmol), BB-8 (400 mg, 1.37 mmol), diisopropylethylamine (763 mg, 5.91 mmol) was dissolved in DMF (10 mL). 958 mg, 2.52 mmol). After stirring at room temperature for 3 hours, the solvent was evaporated under reduced pressure and the residue was purified to silica gel elute , 540 mg, yield 82.5%). MS m/z: 476.8 [M+H] ⁺

Step 6: Synthesis of Compound BB-23

Compound BB-23 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 525.0 [M+H] ⁺

Reference Example 24: Fragment BB-24

synthetic route:

Step 1: Synthesis of Compound BB-24-2

Compound BB-24-2 can be produced 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 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 539.2 [M+H] ⁺

Reference Example 25: Fragment BB-25

synthetic route:

Step 1: Synthesis of Compound BB-25-2

The compound BB-25-1 (18.0 g, 77.2 mmol) was dissolved in ethyl acetate (50 mL), and ethyl acetate aqueous solution (4 mol/L, 50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Solvent, the title compound BB-25-2 (yellow yellow, 13.0 g, yield 100%) was obtained. The product is used directly in the next step without purification. ^{1 H NMR (400MHz, DMSO-} d6): δ8.37 (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 (12.2 g, 305 mmol) was dissolved in 200 mL of water, cooled to 0 ° C, and compound BB-25-2 (13.0 g, 76.6 mmol) was added. After it was completely dissolved, methyl chloroformate (7.2 g, 76.2 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. After the TLC detection reaction was completed, 1N hydrochloric acid was added to adjust the pH to 3, and ethyl acetate (30 mL × 3). The organic phase was combined, washed with brine and dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The product is used directly in the next step without purification. ^{1 H NMR: (400MHz, DMSO} -d6) δ12.65 (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).

Step 3: Synthesis of Compound BB-25-4

Compound BB-25-4 can be produced according to Synthesis Step 5 of Reference Example 23 (BB-23). MS m/z: 465.0 [M+H] ⁺

Step 4: Synthesis of Compound BB-25

Compound BB-25 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 513.1 [M+H] ⁺

Reference Example 26: Fragment BB-26

synthetic route:

Step 1: Synthesis of Compound BB-26-2

Compound BB-26-2 can be produced 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 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 469.2 [M+H] ⁺

Reference Example 27: Fragment BB-27

synthetic route:

Step 1: Synthesis of Compound BB-27-2

N-Moc-L-proline (BB-2-6, 10 g, 52.3 mmol) was dissolved in THF (200 ml), cooled to -30 ° C, and triethylamine (11.6 g, 114.9 mmol) and Isobutyl chloroformate (9.36 g, 68.1 mmol). After reacting at -30 ° C for 1 hour, L-serine hydrochloride (BB-27-1, 10.6 g, 68.4 mmol) was further added, and the reaction was continued at -30 ° C for 3 hours, then warmed to room temperature and stirred overnight. After the reaction was completed by TLC, the solvent was evaporated to dryness, and the residue was dissolved in ethyl acetate (200mL) and washed with brine (50mL×3). The organic phase was dried over anhydrous sodium sulfate. The product is 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 (20 g, 72.39 mmol), p-toluenesulfonic acid monohydrate (3.64 g, 19.14 mmol) was dissolved in THF (200 mL) and 2,2-dimethoxypropane (37.7) g, 36.22 mmol). The reaction system was warmed to reflux and stirred at reflux overnight. After the TLC detection reaction was completed, ethyl acetate (400 mL) was added, and the mixture was washed successively with saturated sodium hydrogen carbonate solution (50 mL × 2) and saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate (MgSO4). The product is used directly in the next step without purification. MS m/z: 339.1 [M+Na] ⁺

Step 3: Synthesis of Compound BB-27-4

Compound BB-27-3 (1.8 g, 5.69 mmol) was added to a mixed solution of tetrahydrofuran / tert-butanol / water (36 mL / 9 mL / 9 mL), and lithium hydroxide monohydrate (478.38 mg, 11.39 mmol) was added. After stirring at 30 ° C for 2 hours, the reaction was completed by TLC, and then pH was adjusted to 3 with 1N hydrochloric acid, and ethyl acetate (30mL × 3). The organic phase was combined, washed with brine EtOAc EtOAc EtOAc. The above intermediate (1.7 g, 5.62 mmol), 2,4'-dibromoacetophenone (BB-1-1, 1.99 g, 17.15 mmol) was dissolved in acetonitrile (60 mL) and triethylamine (1.49) g, 14.7 mmol). The mixture was stirred at 50 ° C overnight. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. The product is used directly in the next step without purification. MS m/z: 500.9 [M+H] ⁺ Step 4: Synthesis of Compound BB-27-5

Compound BB-27-4 (2.8 g, 5.61 mmol) was dissolved in dioxane (100 mL) and ammonium acetate (8.64 g, 112.2 mmol). The reaction system was heated to 110 ° C under a nitrogen atmosphere and stirred overnight. After the completion of the TLC reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. , yield 44.4%). MS m/z: 481.3 [M+H] ⁺

Step 5: Synthesis of Compound BB-27

Compound BB-27 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 527.3 [M+H] ⁺

Reference Example 28: Fragment BB-28

synthetic route:

Step 1: Synthesis of Compound BB-28-2

N-Moc-L-proline (BB-2-6, 5.0 g, 26.15 mmol) was dissolved in dichloromethane (60 mL), triethylamine (6.07 g, 60.1 mmol) and HATU (10.85) g, 28.54 mmol). After stirring at room temperature for 10 minutes, 4-hydroxyproline methyl formate hydrochloride (BB-28-1, 5.19 g, 28.54 mmol) was added. After stirring at room temperature for 4 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjj 2.0 g, yield 23.2%). MS m/z: 303.0 [M+H] ⁺

Step 2: Synthesis of Compound BB-28-3

Compound BB-28-2 (2.0 g, 6.62 mmol) was dissolved in DCM (50 mL) EtOAc EtOAc. After the TLC reaction was completed, the reaction was quenched with 5% sodium thiosulfate solution (50 mL), and then saturated sodium hydrogen carbonate solution (100 ml) was added, and the mixture was stirred for 10 minutes and then extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjj 1.0 g, yield 50.3%). MS m/z: 301.0 [M+H] ⁺

Step 3: Synthesis of Compound BB-28-4

Compound BB-28-3 (1.0 g, 3.33 mmol), ethylene glycol (2.68 g, 43.28 mmol) was dissolved in toluene (75 mL), and p-toluenesulfonic acid monohydrate (126.15 mg, 660 mmol) was added. The reaction system was heated to reflux under a nitrogen atmosphere, and stirred overnight. After the reaction was completed by TLC, the mixture was cooled to room temperature, ethyl acetate (30 mL) was added, and washed successively with saturated sodium hydrogen carbonate solution (50 mL×3), brine (50 mL) The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered, evaporated, evaporated , yield 78.3%). MS m/z: 344.9 [M+H] ⁺

Step 4: Synthesis of Compound BB-28-5

Compound BB-28-4 (900 mg, 2.62 mmol) was added to a mixed solution of tetrahydrofuran/tert-butanol/water (20 mL/5 mL/5 mL), and lithium hydroxide monohydrate (239.82 g, 5.71 mmol) was added and stirred at room temperature. After overnight, the reaction was completed by TLC, and the pH was adjusted to 3 with 1N hydrochloric acid and extracted with ethyl acetate (20mL×3). The organic layer was combined, washed with EtOAc EtOAc EtOAcjjjjjj The product is used directly in the next step without purification. MS m/z: 352.9 [M+Na] ⁺

Step 5: Synthesis of Compound BB-28-6

Compound BB-28-5 (680 mg, 2.06 mmol), 2,4'dibromoacetophenone (BB-1-1, 685 mg, 2.47 mmol) was dissolved in acetonitrile (30 mL), and triethylamine (385.8 mg) was added at room temperature. , 3.82 mmol). The mixture was stirred at 50 ° C. The organic phase was dried over anhydrous sodium sulfate (MgSO4) The product is 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 (1.02 g, 1.93 mmol) was dissolved in dioxane (20 mL) and ammonium acetate (1.6 g, 21 mmol). The reaction system was heated to 110 ° C under a nitrogen atmosphere, and stirred overnight. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The title compound BB-28-7 (yellow solid, 650 mg, yield 66.3%) was obtained. MS m/z: 508.8 [M+H] ⁺

Step 7: Synthesis of Compound BB-28

Compound BB-28-6 (100 mg, 0.20 mmol), bis-pinacol borate (55.05 mg, 0.22 mmol) was dissolved in dioxane (2 mL) at room temperature and potassium acetate was added under nitrogen. 63.74 mg, 0.65 mmol) and Pd(dppf)Cl ₂ (11 mg, 0.02 mmol). The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 4 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by silica gel column ( petroleum ether / ethyl acetate = 1:1). Compound BB-28 (yellow solid, 45 mg, yield 40.6%). MS m/z: 555.0 [M+H] ⁺

Reference Example 29: Fragment BB-29

synthetic route:

Step 1: Synthesis of Compound BB-29-2

The sodium hydrogen (1.96 g, 48.9 mmol) was suspended in tetrahydrofuran (60 mL), cooled to 0 ° C, and BB-29-1 (8.0 g, 32.6 mmol) was added dropwise under a nitrogen atmosphere, and the addition was completed at 0 ° C. After stirring for 2 hours, iodomethane (8.0 g, 48.9 mmol) was added at 0 ° C, stirring was continued at this temperature for 2.5 hours, and after completion of TLC detection, water (10 mL) was added to quench the reaction, ethyl acetate (80 mL × 3) )extraction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, (Colorless oil, 5.5 g, yield 65.2%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 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 (5.5 g, 21.3 mmol) was dissolved in a mixed solvent of methanol/water (30 mL / 30 mL) at room temperature, and sodium hydroxide (1.7 g, 42.6 mmol) was added. The reaction system was warmed to 60 ° C, stirred for 8 hours. After the TLC detection reaction was completed, most of the solvent was removed under reduced pressure, cooled to 0 ° C, 2N hydrochloric acid was added dropwise to adjust the pH to 3 to 4, and ethyl acetate (80 mL × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. ¹ H NMR (CDCl ₃ , 400 MHz): δ 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).

Step 3: Synthesis of Compound BB-29-4

Compound BB-29-3 (5.0 g, 20.3 mmol) and 2,4'-dibromoacetophenone (BB-1-1, 6.2 g, 22.3 mmol) were dissolved in DMF (50 mL), and potassium carbonate was slowly added. (5.6 g, 40.6 mmol). After stirring overnight at room temperature, the reaction was quenched by TLC, and water (30mL) was then evaporated to ethylamine (100mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. (Red solid, 3.5 g, yield 41.7%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 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).

Step 4: Synthesis of Compound BB-29-5

Compound BB-29-4 (3.5 g, 7.9 mmol) was dissolved in toluene (70 mL) at room temperature and ammonium acetate (6.1 g, 79.1 mmol) was added. The reaction system was heated to 120 ° C under a nitrogen atmosphere and stirred for 6 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, ethyl acetate (50 mL) was added and washed with water (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered and evaporated. Oil, 3.0 g, yield 88.9%). LC/MS m/z: 424.0 [M+H] ⁺

Step 5: Synthesis of Compound BB-29-6

Compound BB-29-5 (2.0 g, 4.7 mmol) was dissolved in ethyl acetate (5 mL), cooled to EtOAc, EtOAc (EtOAc/EtOAc 2 hours. After completion of the TLC reaction, the solvent was removed under reduced pressure at room temperature to afford compound BB-29-6 (green solid, 1.69 g, yield 99.4%); LC/MS m/z: 323.9 [M+3] ⁺ Step 6: Synthesis of Compound BB-29

Compound BB-29-6 (885 mg, 2.96 mmol), N-Moc-L-valine (BB-2-6, 518.2 mg, 2.96 mmol), diisopropylethylamine (954 mg, 7.4 mmol) Dissolved in DMF (10 mL) and added HATU (1.41 g, 3.7 mmol). After stirring at room temperature for 1 hour, the reaction was completed by TLC, water (10 mL) was evaporated, and ethyl acetate (30mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Red oil, 841 mg, yield 71.3%). LC/MS m/z: 480.4 [M+H] ^{+ .} 501.1 [M+Na] ⁺

Reference Example 30: Fragment BB-30

synthetic route:

Step 1: Synthesis of Compound BB-30

Compound BB-29-6 (885 mg, 2.46 mmol), compound BB-1-6 (566 mg, 2.96 mmol), diisopropylethylamine (954 mg, 7.4 mmol), HATU (1.41 g, 3.7 mmol) Starting material, according to the synthesis method of Step 6 of Reference Example 29 (BB-29), Compound BB-30 (1.1 g, yield 90.2%) was obtained. LCMS m/z: 496.4 [M+H] ⁺ .

Reference Example 31: Fragment BB-31

synthetic route:

Step 1: Synthesis of Compound BB-31-1

Compound BB-2-2 (1.40 g, 6.50 mmol) and diisopropylethylamine (1.01 g, 7.81 mmol) were dissolved in acetonitrile (15 mL), cooled to 0 ° C, and slowly added compound AA_108-2 (2.00) g, 7.15 mmol). The mixture was stirred at 0 ° C for 0.5 hr, and the solvent was evaporated to dryness. g, yield 33%). LC/MS m/z: 435.0 [M+Na] ⁺ .

Step 2: Synthesis of Compound BB-31-2

Compound BB-31-1 (1.26 g, 3.04 mmol) was dissolved in toluene (50 mL) at room temperature and ammonium acetate (2.34 g, 30.39 mmol) was added. The reaction mixture was warmed to reflux under a nitrogen atmosphere and stirred overnight. The mixture was evaporated to room temperature after TLC, and ethyl acetate (50 mL) was then taken and washed with water (30mL×2). The organic phase was dried over anhydrous sodium sulfate (MgSO4). White solid, 0.72 g, yield 60%). LC/MS m/z: 394.8 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-31

The compound BB-31-2 (0.72 g, 1.82 mmol) was dissolved in ethyl acetate (10 mL), cooled to 0 ° C, and then evaporated. After completion of the TLC reaction, the solvent was removed under reduced pressure at room temperature to afford a white solid.

The white solid, compound BB-1-6 (0.52 g, 2.73 mmol), diisopropylethylamine (1.06 g, 8.19 mmol) was dissolved in DMF (4 mL) at room temperature, and then added to HATU (1.04 g, 2.73) Mm). After stirring at room temperature for 3 hours, the reaction was completed by TLC, and then the mixture was applied to water (10mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, Yellow solid, 0.85 g, yield 92%). LC/MS m/z: 466.0 [M+H] ⁺ .

Reference Example 32: Fragment BB-32

synthetic route:

Step 1: Synthesis of Compound BB-32-1

Compound BB-2-2 (1.96 g, 9.22 mmol) and diisopropylethylamine (1.43 g, 11.06 mmol) were dissolved in acetonitrile (15 mL), cooled to 0 ° C, and slowly added compound AA_117-2 (3.00) g, 10.14 mmol). The mixture was stirred at 0 ° C for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified to silica gel column chromatography (ethyl ether / ethyl acetate = 2:1) , 3.7 g, yield 94.4%). LC/MS m/z: 329.8 [M-Boc+H] ⁺ .

Step 2: Synthesis of Compound BB-32-2

BB-32-1 (3.93 g, 9.13 mmol), ammonium acetate (7.04 g, 91.34 mmol) was used as a starting material, and according to the synthesis method of Step 2 of Reference Example 31 (BB-31), Compound BB-32-2 (3.0) was obtained. g, yield 85.0%). LCMS m/z: 310.0 [M-Boc+H] ⁺ .

Step 3: Synthesis of Compound BB-32

Compound BB-32-2 (3.0 g, 7.31 mmol), hydrogen chloride / ethyl acetate solution (HCl / EA, 4M, 100 mL), Compound BB-1-6 (566 mg, 2.96 mmol), diisopropylethyl The amine (1.31 g, 10.10 mmol), HATU (1.65 g, 4.33 mmol) was used as a starting material. Compound BB-32 (yellow solid, 0.60 g, yield 43) was obtained according to the procedure of the procedure of Example 31 (BB-31). %). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.49 (dd, J = 8.0 Hz, J = 2.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 5.70 (d, J = 8.0 Hz), 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 = 8.0 Hz, 1H), 0.88 (m, 1H).

Example 1: AL_001

synthetic route:

Step 1: Synthesis of Compound AL_001

Compound BB-17 (40 mg, 0.081 mmol), BB-21 (44.4 mg, 0.090 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (1.5 mL / 1.5 mL / 1.5 mL) at room temperature under nitrogen Sodium carbonate (17.3 mg, 0.163 mmol) and Pd(dppf)Cl ₂ (6 mg, 0.0081 mmol) were added under the protection. The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred overnight. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by high-purity liquid to give the title compound AL_001 (yellow solid, 14.3 mg, yield 22.4%). MS m/z: 785.3 [M+H] ⁺ .

The compounds in the table below were synthesized by referring to the synthesis method of step 1 in AL_001:

Example 20: AL_023

synthetic route:

Step 1: Synthesis of Compound AL_023-2

Compound AL_023-1 (1.5 g, 5.75 mmol), N,O-dimethylhydroxylamine hydrochloride (613 mg, 6.29 mmol), diisopropylethylamine (1.5 g, 11.63 mmol) was dissolved in DMF. (10 mL), HATU (2.4 g, 6.32 mmol) was added. After stirring at room temperature for 1 hour, the reaction was completed by TLC, then water (10 mL) was evaporated and evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjj 1.65 g, yield 94.3%). The above amide intermediate (1.4 g, 4.6 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -20 ° C, and a solution of methyl magnesium bromide in diethyl ether (3 mol/L, 5 mL, 15 mmol) was slowly added dropwise. After stirring at room temperature for 1 hour, the reaction was quenched by TLC, and water (10mL) was then evaporated to ethylamine (50mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, , 0.9 g, yield 75.6%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 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 (2.5 g, 9.65 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 5 ° C or less, and phenyltrimethylammonium bromide (4.3 g, 9.65 mmol) was added. After stirring at room temperature for 12 hours, the reaction was quenched by TLC, and water (10 mL) was then evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. Liquid, 3.3 g, yield 85.3%). MS m/z: 338.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AL_023-4

Compound AL_023-3 (3.3 g, 9.76 mmol) and potassium carbonate (4 g, 28.99 mmol) were suspended in DMF (20 mL). After stirring at room temperature for 1 hour, the reaction was quenched by TLC, and water (10mL) was then evaporated to ethylamine (50mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and evaporated. The above intermediate was dissolved in toluene (100 mL) and ammonium acetate (3.42 g, 44.5 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere and stirred for 12 hrs. After the reaction was completed by TLC, the mixture was cooled to room temperature, and water (30 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Yellow powder, 2.75 g, yield 62.3%). MS m/z: 454.0 [M+H] ⁺ .

Step 4: Synthesis of compound AL_023-5

Compound AL_023-4 (0.25 g, 0.553 mmol) was added to a hydrogen chloride / ethyl acetate solution (HCl / EA, 4 mol / L, 5 mL) and stirred at room temperature for 1 hour. After the completion of the TLC reaction, the solvent was evaporated to give the title compound: Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound The product is used directly in the next step without purification. MS m/z: 353.8 [M+H] ⁺ .

Step 5: Synthesis of compound AL_023-6

Compound AL_023-5 (195 mg, 0.502 mmol), N-Moc-L-valine (BB-2-6, 117 mg, 0.612 mmol), diisopropylethylamine (143 mg, 1.11 mmol) was dissolved in DMF ( 10 mL), HATU (253 mg, 0.661 mmol) was added and stirred at room temperature for 1 hour. After the TLC detection reaction was completed, water (10 mL) was added to quench the reaction, and ethyl acetate (30 mL × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. Yellow powder, 225.6 mg, yield 88.3%). MS m/z: 511.0 [M+H] ⁺ .

Step 6: Synthesis of compound AL_023

Compound AL_023-6 (40 mg, 0.078 mmol), BB-24 (51 mg, 0.094 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (2 ml / 2 mL / 2 mL) at room temperature. sodium (17mg, 0.157mmol) and _{Pd (dppf) Cl 2 (4mg} , 0.005mmol). The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred for 8 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. 36%). MS m/z: 421.5 [M/2+H] ⁺ .

Example 21: AL_031

synthetic route:

Step 1: Synthesis of Compound AL_031-1

Compound AL_031-1 can be prepared according to step 5 of 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 of AL_023. LCMS m/z: 408.5 [M/2+H] ⁺

The compounds in the table below were synthesized by referring to the synthesis method of step 6 in AL_023:

Example 26: AL_029

synthetic route:

Step 1: Synthesis of Compound AL_029

Compound AL_029-1 (100 mg, 0.333 mmol), BB-21 (364 mg, 0.733 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (1.5 mL / 1.5 mL / 1.5 mL) at room temperature under nitrogen. Sodium carbonate (141.3 mg, 1.33 mmol) and Pd(dppf)Cl ₂ (48.8 mg, 0.067 mmol) were added. The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred overnight. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. 4.8%). MS m/z: 880.1 [M+H] ⁺ .

Example 27: AA_239

synthetic route:

Step 1: Synthesis of Compound AA_239-1

Compound AG_075-1 (2g, 5.92mmol), tributyl(1-ethoxyvinyl)tin (2.34g, 5.92mmol) was dissolved in dioxane (20mL) and added to Pd under nitrogen Dppf) Cl ₂ (870 mg, 1.28 mmol) and Pd(PPh ₃ ) ₄ (1370 mg, 1.28 mmol). The temperature was raised to 80 ° C under a nitrogen atmosphere and stirred for 4 hours. After completion of the TLC reaction, the mixture was cooled to room temperature, water (8 mL) was added, and then NBS (4.2 g, 23.67 mmol) was added and stirred at room temperature for 12 hours. After the TLC reaction was completed, water (10 mL) was added, and then ethyl acetate (50 ml×3) was evaporated, and the solvent was evaporated under reduced pressure to give an a-bromo ketone intermediate; The above α-bromo ketone intermediate and potassium carbonate (1.64 g, 11.84 mmol) were suspended in DMF (20 mL), and compound AA_192-2 (2.1 g, 7.7 mmol) was added at room temperature. After stirring at room temperature for 2 hours, water was added (10 mL), and ethyl acetate (50 mL×3) was evaporated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound AA_239-1 (1.1 g, a two-step yield of 36.3%) was obtained from ether/ethyl acetate = 9:1 to 3:2. LCMS m/z: 575.1 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_239-2

Compound AA_239-1 (1 g, 1.74 mmol) was dissolved in toluene (100 mL) at room temperature and ammonium acetate (1.34 g, 17.4 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr. After the reaction was completed by TLC, the mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and washed with saturated brine (30 mL×3). The organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjjjjjj 0.45 g, yield 46.3%). LCMS m/z: 555.1 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_239-3

Compound AA_239-2 (150 mg, 0.27 mmol), bis-pinacol borate (345 mg, 1.37 mmol) was dissolved in dioxane (10 mL) at room temperature, and potassium acetate (213 mg, 2.17) was added under nitrogen. Methyl) and Pd(dppf)Cl ₂ (40 mg, 0.054 mmol). The mixture was heated to 110 ° C under a nitrogen atmosphere, stirred for 2 hours, and after completion of the TLC reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was applied to silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1 → 1 : 4) The title compound AA_239-3 (white solid, 115 mg, yield 70.5%) was obtained. LCMS m/z: 601.1 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_239

Compound AA_239-3 (30 mg, 0.049 mmol), compound BB-14 (23 mg, 0.059 mmol) was dissolved in tetrahydrofuran / ethylene glycol dimethyl ether / water (2 mL / 2 mL / 2 mL) mixed solvent and added under nitrogen Sodium carbonate (11 mg, 0.099 mmol) and Pd(dppf)Cl ₂ (5 mg, 0.0098 mmol). The temperature was raised to 100 ° C under nitrogen atmosphere, and the reaction was carried out for 8 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by HPLC to give the title compound AA 239 (white solid, 8 mg, yield 21.8%). LCMS m/z: 384.2 [M / 2+H] ⁺ .

Example 28: AA_238

synthetic route:

Step 1: Synthesis of Compound AA_238-1

Compound AG_075-1 (15g, 44.38mmol), 1,2- ethanedithiol (5g, 53.26mmol) was dissolved in chloroform (10mL), was added dropwise _{BF 3 .Et 2 O (5.5ml,} 44.38mmol). The mixture was heated to reflux under a nitrogen atmosphere, stirred for 2 hr, and then, after TLC, the reaction was cooled to room temperature, and the mixture was quenched with water (10 mL) and extracted with chloroform (30 mL×3). The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated N-iodosuccinimide (NIS, 13.6 g, 60.36 mmol) was dissolved in dichloromethane (50 mL), cooled to -78 ° C, and pyridine hydrofluoric acid salt (3.6 g, 36.22 ). After stirring at this temperature for 1 hour, a solution of the above-mentioned thione ketone intermediate (5 g, 12.07 mmol) in dichloromethane (5 ml) was added, and stirring was continued at -78 ° C for 1 hour, and after completion of the TLC reaction, water (10 mL) was added. The reaction was quenched and extracted with dichloromethane (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.75 (m, 2H), 7.61 (m, 2H), 7.40 (m, 2H).

Step 2: Synthesis of Compound AA_238-2

Compound AA_238-1 (7.48 g, 20.77 mmol), tributyl(1-ethoxyvinyl)tin (7.5 g, 20.77 mmol) was dissolved in dioxane (100 mL) and Pd was added under nitrogen. Dppf) Cl ₂ (3 g, 4.15 mmol) and Pd(PPh ₃ ) ₄ (4.8 g, 4.15 mmol). The temperature was raised to 80 ° C under a nitrogen atmosphere and stirred for 4 hours. After completion of the TLC reaction, the mixture was cooled to room temperature, water (20 mL) was added, and then NBS (15 g, 83.07 mmol) was added and stirred at room temperature for 12 hours. After the TLC reaction was completed, water (10 mL) was added, and then ethyl acetate (50 ml × 3) was evaporated. The solvent was evaporated under reduced pressure to give an a-bromo ketone intermediate. The above α-bromo ketone intermediate and potassium carbonate (1.5 g, 11.09 mmol) were suspended in DMF (20 mL), and Compound AA-192-2 (1.98 g, 7.21 mmol) was added at room temperature. After stirring at room temperature for 2 hours, water was added (10 mL), and ethyl acetate (50 mL×3) was evaporated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound AA_238-2 (1.3 g, a two-step yield of 46.3%) was obtained from ether/ethyl acetate = 9:1 to 3:2. LCMS m/z: 596.8 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_238-3

Compound AA_238-2 (2.1 g, 4.45 mmol) was dissolved in toluene (100 mL) at room temperature and ammonium acetate (3.42 g, 44.5 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr. After the reaction was completed by TLC, the mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and washed with saturated brine (30 mL×3). The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1.3 g, yield 62.3%). LCMS m/z: 577.1 [M+H] ⁺ .

Step 4: Synthesis of compound AA_238-4

Compound AA_238-3 (150 mg, 0.26 mmol), bis-pinacol borate (331 mg, 1.13 mmol) was dissolved in dioxane (10 mL) at room temperature, and potassium acetate (205 mg, 2.09) was added under nitrogen. Methyl) and Pd(dppf)Cl ₂ (40 mg, 0.052 mmol). The mixture was heated to 110 ° C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was applied to silica gel column chromatography ( petroleum ether / ethyl acetate = 9:1 → 1 : 4) The title compound AA_238-4 (white solid, 105 mg, yield 66%) was obtained. LCMS m/z: 623.3 [M+H] ⁺ .

Step 5: Synthesis of Compound AA_238

Compound AA_238-4 (20 mg, 0.032 mmol), compound BB-14 (15 mg, 0.039 mmol) was dissolved in tetrahydrofuran / ethylene glycol dimethyl ether / water (2 mL / 2 mL / 2 mL) mixed solvent and added under nitrogen sodium carbonate (9mg, 0.064mmol) and _{Pd (dppf) Cl 2 (5mg} , 0.0064mmol). The temperature was raised to 100 ° C under nitrogen atmosphere, and the reaction was carried out for 8 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by high-purity liquid to obtain the title compound AA 238 ( white solid, 8.2 mg, yield The rate is 27.8%). LCMS m / z: 395.2 [M / 2 + H] +.

Example 29: AA_241_A and AA_241_B

synthetic route:

Step 1: Synthesis of Compound AA_241-1

Compound AG_075-1 (1 g, 2.96 mmol) was dissolved in toluene (10 mL), cooled to 0 ° C, and trimethylaluminum (5.92 ml, 11.83 mmol) was added dropwise under nitrogen. After stirring at room temperature for 1 hour, the reaction was completed by TLC, and then cooled to 0° C., and the mixture was evaporated to ethylamine (10mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Liquid, 0.82 g, yield 82.3%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.68 (m, 2H), 7.49 (m, 4H), 1.719 (s, 3H).

Step 2: Synthesis of Compound AA_241-2

Compound AA_241-1 (1 g, 2.84 mmol), tributyl(1-ethoxyvinyl)tin (1.03 g, 2.84 mmol) was dissolved in dioxane (20 mL) and Pd (dppf) was added under nitrogen. Cl ₂ (417 mg, 0.57 mmol) and Pd(PPh ₃ ) ₄ (657 mg, 0.57 mmol). The temperature was raised to 80 ° C under a nitrogen atmosphere and stirred for 4 hours. After completion of the TLC reaction, the mixture was cooled to room temperature, water (4 mL) was added, and then NBS (2 g, 11.36 mmol) was added and stirred at room temperature for 12 hours. After the TLC reaction was completed, water (10 mL) was added, and then ethyl acetate (50 ml × 3) was evaporated. The solvent was evaporated under reduced pressure to give an a-bromo ketone intermediate. The above α-bromo ketone intermediate and potassium carbonate (0.78 g, 5.68 mmol) were suspended in DMF (20 mL), and the compound AA_192-2 (1.01 g, 3.69 mmol) was added at room temperature. After stirring at room temperature for 2 hours, water was added (10 mL), and ethyl acetate (50 mL×3) was evaporated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound AA_241-2 (yellow solid, 0.65 g, yield of 40.3% in two steps) was obtained from ether/ethyl acetate = 9:1:3:2. LCMS m/z: 591.1 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_241-3

Compound AA_241-2 (650 mg, 1.11 mmol) was dissolved in toluene (100 mL) at room temperature and ammonium acetate (853 mg, 11.1 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr. After the reaction was completed by TLC, the mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and washed with saturated brine (30 mL×3). The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjj 320 mg, yield 52.3%). LCMS m/z: 571.1 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_241-4

Compound AA_241-3 (120 mg, 0.21 mmol), bis-pinacol borate (269 mg, 1.06 mmol) was dissolved in dioxane (10 mL) at room temperature, and potassium acetate (166 mg, 1.69) was added under nitrogen. Methyl) and Pd(dppf)Cl ₂ (36 mg, 0.044 mmol). The mixture was heated to 110 ° C under a nitrogen atmosphere, stirred for 2 hours, and after completion of the TLC reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was applied to silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1 → 1 : 4) The title compound AA_241-4 (white solid, 85 mg, yield 66%) was obtained. LCMS m/z: 617.2 [M+H] ⁺ .

Step 5: Synthesis of compound AA_241_A and AA_241_B

Compound AA_241-4 (70 mg, 0.114 mmol), compound BB-14 (213 mg, 0.568 mmol) was dissolved in tetrahydrofuran / ethylene glycol dimethyl ether / water (2 mL / 2 mL / 2 mL) mixed solvent and added under nitrogen sodium carbonate (97mg, 0.911mmol) and _{Pd (dppf) Cl 2 (15mg} , 0.023mmol). The temperature was raised to 100 ° C under nitrogen atmosphere, and the reaction was carried out for 8 hours. After the TLC detection reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by high-performance liquid (Table 3, Method 6) to obtain the target compound AA_241_A ( White solid, 7 mg) and AA_241_B (white solid, 7 mg), yield 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

synthetic route:

Step 1: Synthesis of Compound AG_075

2,7-Dibromo-9-fluorenone (AG_075-1, 0.2 g, 0.59 mmol), bis-pinacol borate (0.6 g, 2.37 mmol) was dissolved in dioxane (10 mL) at room temperature Potassium acetate (350 mg, 3.55 mmol) and Pd(dppf)Cl ₂ (100 mg, 0.12 mmol) were added under a nitrogen atmosphere. The temperature was raised to 110 ° C under a nitrogen atmosphere, and the reaction was carried out for 2 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was subjected to silica gel column chromatography ( petroleum ether / ethyl acetate = 9:1 → 1 : 4) A white solid (0.198 g, yield 77.3%) was obtained. The above white solid (30 mg, 0.069 mmol), compound BB-14 (78 mg, 0.208 mmol) was dissolved in tetrahydrofuran / ethylene glycol dimethyl ether / water (2mL / 2mL / 2mL) mixed solvent, carbonic acid was added under the protection of nitrogen sodium (37mg, 0.35mmol) and _{Pd (dppf) Cl 2 (10mg} , 0.014mmol). The temperature was raised to 100 ° C under nitrogen atmosphere, and the reaction was carried out for 8 hours. After the TLC detection reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by high-performance liquid (Table 3, Method 6) to obtain the target compound AG_075 ( White solid, 14 mg, yield 26.4%). LCMS m/z 83.4 [M / 2+H] ⁺ .

Example 31: AG_082_A and AG_082_B

synthetic route:

Step 1: Synthesis of AG_082-2

9,10-Dihydrophenanthrene (AG_082-1, 5 g, 27.74 mmol) was dissolved in dichloromethane (50 mL), and iron powder (78 mg, 1.39 mmol) was added. After cooling to 0 ° C, liquid bromine (9.8 g, 61.03 mmol) was added dropwise. After stirring at room temperature for 8 hours, the reaction was quenched by TLC, and water (10 mL) was then evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. 6.2 g, yield 65.9%). _{NMR (CDCl 3, 400MHz):} δ7.59-7.57 (m, 2H), 7.46-7.41 (m, 4H), 2.88-2.86 (m, 4H).

Step 2: Synthesis of compound AG_082_A and AG_082_B

Compound AG_082-2 (0.2 g, 0.59 mmol), bis-pinacol borate (0.6 g, 2.37 mmol) was dissolved in dioxane (10 mL) at room temperature, and potassium acetate (350 mg) was added under nitrogen. , 3.55 mmol) and Pd(dppf)Cl ₂ (100 mg, 0.12 mmol). The temperature was raised to 110 ° C under a nitrogen atmosphere, and the reaction was carried out for 2 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was subjected to silica gel column chromatography ( petroleum ether / ethyl acetate = 9:1 → 1 : 4) A white solid (0.198 g, yield 77.34%). The above white solid (40 mg, 0.093 mmol), compound BB-14 (104 mg, 0.278 mmol) was dissolved in tetrahydrofuran / ethylene glycol dimethyl ether / water (2mL / 2mL / 2mL) mixed solvent, carbonic acid was added under the protection of nitrogen sodium (59mg, 0.56mmol) and _{Pd (dppf) Cl 2 (15mg} , 0.018mmol). The temperature was raised to 100 ° C under nitrogen atmosphere, and the reaction was carried out for 8 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by high-purity liquid to give the title compound AG_082_A (white solid, 7 mg) and AG_082_B (white solid, 7 mg), yield 20.8%. AG_082_A: LCMS m/z: 383.4 [M/2+H] ⁺ .AG_082_B: LCMS m/z: 383.4 [M/2+H] ⁺ .

Example 32: AA_112

synthetic route:

Step 1: Synthesis of Compound AA_112-2

2-Acetyl-5-bromothiophene (AA_112-1, 2.5 g, 12.18 mmol) was dissolved in chloroform (5 mL). The ice bath was cooled to below 5 ° C, and liquid bromine (1.95 g, 12.19 mol) was added dropwise. After stirring at room temperature for 3 hours, the reaction was completed by TLC. EtOAc was evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 2.6 g, yield 74.28%). H NMR (CDCl ₃ , 400 MHz): δ 7.55 (d, J = 4 Hz, 1H), 7.14 (d, J = 4 Hz, 1H), 4.28 (s, 2H).

Step 2: Synthesis of compound AA_112-3

Compound AA_091-2 (1.1 g, 3.87 mmol) and potassium carbonate (0.97 g, 7.04 mmol) were suspended in DMF (20 ml), and compound AA_112-2 (1 g, 3.52 mmol) was added at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Solid, 1.4 g, yield 82.3%). LC/MS m/z: 490.9 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_112-4

Compound AA-1132-3 (530 mg, 1.08 mmol) was dissolved in toluene (20 ml), and ammonium acetate (508 mg, 6.5 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr., and then the mixture was evaporated to room temperature, and the mixture was evaporated to ethyl ether (30 ml × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. Solid, 0.38 g, yield 74.8%). LC/MS m/z: 470.9 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_112

Compound AA_112-4 (50 mg, 0.106 mmol), BB-21 (64 mg, 0.128 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (2 ml / 2 ml / 2 ml) at room temperature, and carbonic acid was added under a nitrogen atmosphere. sodium (23mg, 0.213mmol) and _{Pd (dppf) Cl 2 (3mg} , 0.0105mmol). The mixture was heated to 100 ° C under a nitrogen atmosphere, stirred for 8 hours, and after completion of the TLC reaction, it was cooled to room temperature, filtered, and the solvent was evaporated to dryness. The residue was purified by HPLC to give the title compound AA_112 (white powder, 24 mg, yield 29.6%). LC/MS m/z: 380.5 [M / 2+H] ⁺ .

Experimental Example 1: In vitro evaluation

Purpose:

With HCV genotype 1a (HCV-1a) and 1b (HCV-1b) stably transfected replicon (replicon) Cell ₅₀ measured values of the anti-HCV compound EC ₅₀ and CC. The genotype 1a replicon is derived from the H77 clone and contains K1691R, K2040R and S2204I adaptive mutations. The genotype 1b replicon is derived from the Con1 clone and contains E1202G, T1280I and K1846T adaptive mutations.

Background introduction:

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

Experimental Materials:

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

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

Trypsin (Invitrogen, Cat. #25200072).

PBS (Invitrogen, Cat. #10010023).

Trypan Blue (Invitrogen, Cat. #15250061).

Cell Titer-fluor (Promega, Cat. #G6082).

Bright-Glo (Promega, Cat. #E2650).

CO ₂ incubator, Thermo 240I.

Multidrop automatic dispenser, Thermo.

POD 810Plate Assembler fully automated microplate pretreatment system, Labcyte.

Scepter Handheld Automated Cell Counter handheld automatic cell counter, Millipore.

Microplate Spectrophotometer Microplate Spectrophotometer, Molecular Device.

Experimental steps and methods:

a) Compound solution preparation, dilution and loading:

The compound powder was dissolved in 100% DMSO. Compounds were then diluted 5 fold at 5 fold and added to the cell plates using an Echo liquid handler. The final concentration of DMSO was guaranteed to be 0.5%. Each compound is doubled. The highest starting concentration is 100, 10 or 1 nM, 5 times dilution, 6 points.

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

1) Aspirate the culture supernatant of the cell culture and wash the cells with 10 mL of PBS.

2) Add the pre-warmed trypsin to the washed cell culture flask, and rotate the culture flask to evenly cover the bottom of the flask. Placed in 37 ℃, 5% CO ₂ incubator digestion.

3) Each T150 flask was suspended with 10-15 mL of culture medium, and 0.1 mL of the solution was diluted with a trypan blue solution and counted twice.

4) Cells were diluted with culture medium to 8 × 10 ⁴ / mL, automatic dispenser (Thermo Scientific) The diluted cells were added to 96-well plates (Greiner, Cat. # 655090) (100μL / hole-containing compound, 8000cells/hole). The cells were cultured at 37 ° C for 3 days in a 5% CO ₂ incubator.

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

5) Add the chemiluminescent substrate Cell Titer-fluor to the cell wells and incubate for 30 minutes and then detect the signal with the chemiluminescence detection system Envison (Ex at 405 nm and read at 515 nm). Analysis of compounds on HCV replication data Effects The light emitting sub-cellular activity, and value calculation for ₅₀ CC.

6) Then add luciferase luminescent substrate Bright-Glo, incubate for 5 minutes, detect the luciferase activity (wavelength >700nm) with chemiluminescence detection system Envison; analyze the anti-HCV inhibitory activity of the compound according to luciferase data and use Calculate the EC ₅₀ value.

c) Data processing and analysis:

Using GraphPad Prism software percent inhibition (inh%) non-linear data fitting analysis to give ₅₀ or EC ₅₀ value CC.

The experimental results are shown in Table 1:

Table 1 HCV replicon cell EC ₅₀ /CC ₅₀ test results

Note: EC ₅₀ indicates the in vitro anti-hepatitis C virus activity of the molecule, and an EC _{50 of} less than 1 uM means that the compound has in vitro activity. Four intervals were divided according to the size of the activity: A (0.001 nM to 0.1 nM); B (0.101 nM to 1.0 nM); C (1.001 nM to 10.0 nM); D (10.001 nM to 100 nM). The value of CC ₅₀ indicates the magnitude of the in vitro toxicity of the molecule, and the larger the value, the smaller the toxicity.

Conclusion: The compounds of the invention have excellent anti-hepatitis C virus activity in vitro.

Claims (21)

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

among them, E ₁ and E ₇ independently represent the structural unit represented by the formula (a),

among them, R _{1 is} selected from the group consisting of C=O, C=S, S(=O), S(=O) ₂ , and C(R _1a )(R _1b ); R _{3 is} selected from the group consisting of C(R _3a )(R _3b ), C=O, C=S, S(=O), S(=O) ₂ ; R _{4 is} selected from two or more substituted [chain hydrocarbon groups, hetero chain hydrocarbon groups, chain hydrocarbon hetero groups, cycloalkyl groups, heterocyclic groups, cyclohetero); R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from H, F, Cl, Br, I, CN or optionally substituted [OH, SH, NH ₂ , PH ₂ , Hydrocarbyl group, heterohydrocarbyl group, hydrocarbyl group, heterohydro group hetero group]; Optionally, R _1a and R _1b , R _3a and R _3b together form an optionally substituted 3-6 membered cycloalkyl group; n ₁ or n ₄ are each independently selected from 0 or 1; n _{2 is} selected from 0, 1, _2, 3, 4, 5 or 6; n _{3 is} selected from 0, 1, 2, 3, 4, 5 or 6; n _{5 is} selected from 1, 2, 3 or 4; When n ₁ , n ₂ , n ₃ or n ₄ is 0, the corresponding structural unit represents a single bond which only serves as a connection; E ₂ and E ₆ are each independently selected from -C(=O)N(R _6a )C(R _6b )(R _6c ), CH ₂ , single bond, O, S, C=O, C=S, S (=O), S(=O) ₂ or the structural unit shown in formula (b),

R _6a , R _6b , R _6c are each independently selected from H, C _1-6 alkyl or alkoxy; W ₅ and W ₆ each independently represent C, N, optionally substituted [CH ₂ , CH, NH, CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; W ₇ and W ₈ independently represent H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl a base, a heterohydrocarbyl hetero group], optionally between W ₇ and W _{8 ,} between W ₇ and W _{7 , and} between W ₈ and W ₈ to form a ring; m ₇ and m _{8 are} selected from 0, 1, 2; E ₃ and E ₅ are each independently selected from the group consisting of CH ₂ , a single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ or a structural unit represented by the formula (c);

L _{1 is} independently selected from C, N, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡ C, O, S, C=O, C=S, S(=O), S(=O) ₂ or a single bond; L ₂ , L ₃ , L ₄ , L ₅ , L ₈ , L ₉ are each independently selected from C, N, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 ～6-membered hydrocarbon group or 3- to 6-membered heteroalkyl group], C≡C, O, S, C=O, C=S, S(=O), S(=O) ₂ ; L ₆ and L ₇ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbon Heteroyl, heteroalkylhetero]; p ₁ , p ₆ , p ₇ are each independently selected from the group consisting of 0, ₁ , ₂ , 3, 4, 5 or 6; E _{4 is} selected from the structural unit represented by formula (d) or (e),

Wherein Z ₁ , Z ₂ , X ₁ , X ₂ are each independently selected from a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [ CH ₂ , NH, PH, hydrocarbyl, heteroalkyl, hydrocarbyl, heteroalkyl hetero]]; Z ₃ , Z ₄ , X ₃ , X ₄ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group, a heterohydrocarbylhetero group], optionally a ring connecting Z ₃ and Z ₄ ; q ₃ , q ₄ are each independently selected from 0, 1, 2 or 3;

Represents a single or double bond;

Represents a single key, double key, or no key, when

middle

The structural unit does not exist when it represents no key; Optionally, the compound or a pharmaceutically acceptable salt thereof comprises one or more chiral centers. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substructure unit of the structural unit (b) is as shown in the formula (g),

among them, T _{1a is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3- to 6-membered hydrocarbon or 3- to 6-membered heteroalkyl), C≡ C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; T _2a , T _3a , T _4a are each independently selected from C, N, optionally substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon group or 3-6 yuan Heterohydrocarbyl], C≡C, O, S, C=O, C=S, S(=O), S(=O) ₂ ; T _{5a is} selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl, heteroalkyl hetero base]; m _{5a is} selected from 0, 1, 2, 3, 4, 5 or 6; W _5a and W _6a each independently represent C, N, optionally substituted [CH ₂ , NH, CH, CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon group or 3 to 6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; T _6a and T _7a are each independently selected from O, S, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3- to 6-membered hydrocarbon group or 3- to 6-membered heteroalkyl group] , C≡C, single bond, C=O, C=S, S(=O), S(=O) ₂ ; T _8a from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heteroalkyl, hydrocarbyl, heteroalkyl hetero ]; m _{6a is} selected from 0, 1, 2 or 3, and when m _6a is 0, the corresponding structural unit represents a single bond which only serves as a linking; m _{8a is} selected from 0, 1, 2, 3, 4, 5 or 6;

Represents a single or double bond;

Represents a single key, double key, or no key, when

middle

The structural unit and its subsidiary structural unit do not exist when the key is not _formed , and both sides of T _1a and T _2a

It is not a double bond at the same time. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the substructure unit represented by the formula (g) is selected from

Specifically, the substructure unit represented by the formula (g) is selected from the group consisting of:

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

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substructure unit of the structural unit represented by the formula (d) is as shown in the formula (d-1):

among them, Z ₁ and Z ₂ are each independently selected from a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [CH ₂ , NH, PH, hydrocarbon group , a heteroalkyl group, a hydrocarbyl group, a heterohydro group hetero group]; Z ₅ , Z ₆ , Z ₇ , Z ₈ are each independently selected from optionally substituted [CH ₂ —CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon group or 3-6-membered hetero Hydrocarbyl group, C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ , Z ₅ , Z ₆ , Z ₇ , Z ₈ cannot be four simultaneous Is a single button. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Z ₁ and Z ₂ are each independently selected from the group optionally substituted: Phenyl,

Biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, pyrazolyl, 2-pyrazolyl, pyrazolidinyl, imidazole Base, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H -pyranyl, pyridyl, piperidinyl, 1,4-dioxolyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-trithiane , 1,3,5-triazinyl, benzofuranyl, benzothienyl, fluorenyl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolinyl, porphyrin Or quinoxalinyl. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the substructure unit of the structural unit represented by the formula (d-1) is selected from the group consisting of:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substructure unit of the structural unit represented by the formula (e) is selected from the group consisting of:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the R _{4 is} selected from a two or more substituted 3 to 10 membered cyclo or heterocyclic group or a cyclohetero group, or the hetero atom or The hetero atomic group is selected from N, O, S, S(=O) or S(=O) ₂ . The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the R _{4 is} selected from the group consisting of two or more of the following substituted groups:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the R _{4 is} selected from the group consisting of two or more substituted groups:

Specifically; R _{4 is} selected from the group consisting of two or more substituted groups:

The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ₁ is C=O, R ₅ is H, n ₁ , n ₄ and n ₅ are 1, n ₂ and n ₃ are 0, R ₁ forms an amide bond with R ₄ . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substructure unit represented by the formula (a) is selected from the group consisting of:

Specifically, the substructure unit represented by the formula (a) is selected from the group consisting of:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from the group consisting of H, F, Cl, Br, I, CN, optionally substituted [OH, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, An alkoxycarbonyl group, a heterocyclic carbonyl group, an alkoxycarbonylamino group, which is selected from a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group or an imidazolyl group. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, alkylthio group, alkylthioalkyl group The number of carbon atoms in the alkyl moiety of the alkoxycarbonyl and alkoxycarbonylamino groups is 1, 2, 3, 4, 5 or 6, and the number of carbon atoms of the cycloalkyl group is 3, 4, 5 or 6. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein said R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from the group consisting of H, F, Cl, Br, I, CN, =O, =S, optionally substituted [OH, NH ₂ , methyl, isopropyl, cyclopropyl, butyl, tert-butyl, trifluoromethyl, hydroxymethyl, -CH (OH)CH ₃ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ (OH), -CH(OH)CH ₃ , methoxy, methoxymethyl, -CH(CH ₃ )OCH ₃ , -CH ₂ CH ₂ OCH ₃ ,

Methylthio, ethoxycarbonyl,

The compound according to any one of claims 1 to 16, 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, optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl and/or heteroalkyl hetero). The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the hydrocarbyl group, heteroalkyl group, hydrocarbyl group, heteroalkyl group is selected from the group consisting of optionally substituted C _1-12 hydrocarbyl groups, C _{1- 12} heterohydrocarbyl, C _1-12 heteroaryl hydrocarbon group, C _1-12 heteroaryl C _1-12 hydrocarbon _{hydrocarbons, -C 1-12 OH, -C 0-12 COOH} , -OC 1-12 COOH, -C 1- ₁₂ CN,-C _0-12 CONH ₂ , -C _0-12 O C _1-12 , -C _0-12 CO C _1-12 , -C _0-12 COO C _1-12 , -C _0-12 O( O=)CC _1-12 , -C _0-12 S(=O)C _1-12 or -C _0-12 S(=O) ₂ C _1-12 ], wherein the above group itself is an aromatic ring, a heteroaryl ring, an aliphatic ring, a heteroalicyclic ring, a fatty chain, and/or a hetero fatty chain, and the number of the aromatic ring, heteroaryl ring, fatty ring, heteroalicyclic ring, fatty chain, and/or hetero fatty chain , the ring-forming atom and its number, the ring and the ring or the ring and the chain or the chain-to-chain connection is chemically stable, and the hetero atom or hetero atom group is independently selected from O, S. , N, S (= O) and / or S (= O) ₂ , the number of heteroatoms or heteroatoms is arbitrary under the premise of being chemically stable. The compound according to claim 17 or 18, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, =O, =S, OH, SH, NH ₂ , halogen a substituted or hydroxy or amine or unsubstituted C _1-6 alkyl or heteroalkyl or alkano group, a hetero atom or a hetero atom, each independently selected from C _1-6 alkane or unsubstituted -CONH -, -CO ₂ -, C _1-6 alken or unsubstituted -NH-, -O-, -S-, C _1-6 alken or unsubstituted -C=NH, -C=O , -C=S, S(=O) and/or S(=O) ₂ , the number of substituents, heteroatoms or heteroatoms is arbitrary under the premise of being chemically stable. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from the group consisting of halogen, OH, SH, NH ₂ , CN, =O, =S, CF ₃ , -OCF ₃ , -OCH ₃ . A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of: