TW201542521A - Hepatitis c virus inhibitors and uses thereof in preparation of drugs - Google Patents

Abstract

A series of hepatitis C virus (HCV) inhibitors and compositions and applications thereof in the preparation of drugs for treating chronic HCV infection. Especially, a series of compounds that are used as NS5A inhibitors, and compositions and uses thereof in the preparation of drugs.

Description

Hepatitis C virus inhibitor and its pharmaceutical use

The present invention relates to hepatitis C virus (HCV) inhibitors and compositions thereof, and to their use in the manufacture of a medicament for the treatment of 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.

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 HCV 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 generally considered 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 subsequent cuts downstream of NS3 were 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.

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

Wherein A ₁ , A ₇ , B ₁ , B ₇ , Q ₁ , Q ₇ , Y ₁ , Y ₇ , D ₁ , D ₇ each independently represent a structural unit represented by the formula (a), Wherein R _{1 is} selected from C=O, C=S, S(=O), S(=O) ₂ , C(R _1a )(R _1b ); and R _{3 is} selected from 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, heterochain hydrocarbon, chain hydrocarbon, cycloalkyl, heterocyclic And a heterocyclic group; 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, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; optionally, R _1a and R _1b , R _3a and R _3b together form an optionally substituted 3-6 ring alkyl group; n ₁ or n ₄ are each independently selected from 0 or. 1; n ₂ is selected from _{n 2a, n 2b, n 2c} , A 1 n ₂ is the n _2a, n _2a, 4, 5 or 6 is selected from In B ₁ , n ₂ is n _2b , n _2b is 0, and A ₇ , B ₇ , Q ₁ , Q ₇ , Y ₁ , Y ₇ , D ₁ , D ₇ , n ₂ is n _2c , and n _{2c 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 , When n ₃ or n ₄ is 0, the corresponding structural unit represents a single bond which only functions as a linkage; A ₂ , A ₆ , B ₆ , Q ₆ , D ₂ , D 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 a structural unit represented by formula (b), W ₁ and W ₂ each independently represent H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl Or a heterohydrocarbylhetero], optionally between W ₁ and W _{2 ,} between W ₁ and W _{1 , and} between W ₂ and W ₂ to form a ring; m ₁ , m _{2 are} selected from 0, ₁ , 2 W _{3 is} selected from optionally substituted NH or a single bond; W _{4 is} selected from optionally substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, NH, 3-6-membered hydrocarbon or 3-6-membered a heterohydrocarbyl group, C≡C, a single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; R _6a , R _6b , R _6c are each independently selected from H , C _1-6 alkyl or alkoxy; W ₅ , W ₆ independently represent C, N, optionally substituted [CH ₂ , CH, NH, CH ₂ -CH ₂ , CH=CH, 3~ 6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; W ₇ and W ₈ respectively Independently representing H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heteroalkyl heteroaryl ], optionally between W ₇ and W _{8 ,} between W ₇ and W _{7 ,} between W ₈ and W ₈ to form a ring; m ₇ , m _{8 are} selected from 0, 1, 2; Y _{2b is} selected from O , S, C=O, C=S, S(=O), S(=O) ₂ , C≡C, optionally substituted [NH, CH ₂ -CH ₂ , CH=CH, 3~6 yuan a hydrocarbon group or a 3-6 membered heteroalkyl group; Y _2a , Y _2c , Y _6a , Y _6b , Y _6c are each independently selected from optionally substituted [CH ₂ , NH, CH ₂ -CH ₂ , CH=CH, 3~6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; Y _2d , Y _6d are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or hetero Hydrocarbylhetero]; A ₃ , A ₅ , B ₃ , B ₅ , Q ₃ , Q ₅ , Y ₃ , Y ₅ , D ₅ are each independently selected from 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 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 ; 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, hydrocarbyl or heterohydrocarbyl]; p ₁ , p ₆ , p ₇ are each independently selected from the group consisting of 0, 1, 2 , 3, 4, 5 or 6; A ₄ , B ₄ , Q ₄ , Y ₄ , D _{4 are} selected from CH ₂ , single bond, O, S, C=O, C=S, S(=O), S (=O) ₂ , aryl or heteroaryl; Represents a single or double key; ------ represents a single key, double key or no key, when Where ------ represents the absence of the structural unit when the bond is not bonded; optionally, the compound or a pharmaceutically acceptable salt thereof comprises one or more chiral centers.

In some aspects of the invention, the structural unit The substructure unit is as shown in equation (f). Wherein T _{1 is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl), C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; T ₂ , T ₃ , T ₄ are independently selected from C, N, and Selected substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], C≡C, O, S, C=O, C= S, S(=O), S(=O) ₂ ; T _{5 is} 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 or a heteroalkyl group; m _{5 is} selected from 0, ₁ , 2, 3, 4, 5 or 6; and T ₆ and T ₇ are each independently selected from O, S, Optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon or 3 to 6-membered heteroalkyl), C≡C, single bond, C=O, C= S, S(=O), S(=O) ₂ ; T ₉ 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 or a heterohydrocarbylhetero group]; m _{6 is} selected from 0, 1, 2 or 3, and when m ₆ is 0, the corresponding structural unit represents a single bond which only serves as a linkage; m ₉ Selected from 0, 1, 2, 3, 4 5 or 6; Represents a single or double key; ------ represents a single key, double key or no key, when The middle ------ means that the structural unit does not exist when the key is not formed, and the ------ on both sides of the T ₂ is not a double key.

In some aspects of the invention, the substructure unit represented by the above formula (f) is selected from the group consisting of:

In some aspects of the invention, the substructure unit represented by the above formula (f) is selected from the group consisting of:

In some aspects of the present invention, the substructure unit of the structural unit (b) is as shown in the formula (g), Wherein T _{1a is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon or 3-6-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, and Selected substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], 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 , a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group or a heterohydro group hetero group]; m _{5a is} selected from 0, 1, 2, 3, 4, 5 or 6; W _5a and W _6a independently represent C, N, and any Selected substituted [CH ₂ , NH, CH, CH ₂ -CH ₂ , CH=CH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], C≡C, single bond, O, S, C=O , C=S, S(=O), S(=O) ₂ ; T _6a , T _7a are each independently selected from O, S, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3~6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, C=O, C=S, S(=O), S(=O) ₂ ; T _8a H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH , SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; m _{6a is} selected from 0, 1, 2 or 3. When m _6a is 0, the corresponding structural unit represents only a link. a single bond of action; m _{8a is} selected from 0, 1, 2, 3, 4, 5 or 6; Represents a single or double key; ------ represents a single key, double key 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.

In some aspects of the invention, the substructure unit represented by the above formula (g) is selected from the group consisting of:

In some aspects of the invention, the substructure unit represented by the above formula (g) is selected from the group consisting of:

In some embodiments of the invention, the above Y _2a is isopropyl.

In some aspects of the invention, the above Y _6b is

In some aspects of the invention, the structural unit The substructure unit is selected from the group consisting of:

In some embodiments of the invention, the structural unit of formula (c) above is selected from the group consisting of:

In some embodiments of the invention, the above A ₄ , B ₄ , Q ₄ , D ₄ or Y ₄ are each independently selected from the structural unit represented by formula (e), optionally substituted benzene or optionally substituted biphenyl. , Wherein X ₁ and X ₂ are each independently selected from the group consisting of a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [CH ₂ , NH, PH a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group or a heterohydrocarbylhetero group; X ₃ and X ₄ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [ OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; q ₃ , q ₄ are each independently selected from 0, 1, 2 or 3.

In some aspects of the invention, the above A ₄ , B ₄ , Q ₄ , D ₄ or Y ₄ are each independently selected from:

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of two or more substituted 3 to 10 membered cyclic or heterocyclic or cyclohetero, and the hetero atom or hetero atom is selected from the group consisting of N, O, S, and S ( =O) or S(=O) ₂ .

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of two or more substituted groups:

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of two or more substituted groups:

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of two or more substituted groups:

In some aspects of the invention, 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 form a guanamine bond.

In some aspects of the invention, the substructure unit represented by the above formula (a) is selected from the group consisting of:

In some aspects of the invention, the substructure unit represented by the above formula (a) is selected from the group consisting of:

In some embodiments of the invention, the above 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, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonyl Amino group], the heterocyclic group 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.

In some embodiments of the invention, the above alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, alkoxycarbonyl, and alkoxycarbonylaminone are alkane The number of carbon atoms in the base moiety is 1, 2, 3, 4, 5 or 6, and the number of carbon atoms of the cycloalkyl group is 3, 4, 5 or 6.

In some embodiments of the invention, the above 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, or ].

In some embodiments of the invention, the substituent for the above substitution is selected from the group consisting of F, Cl, Br, I, CN, =O, =S, optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, hetero Hydrocarbyl, hydrocarbyl and/or heteroalkylhetero].

In some embodiments of the invention, the above hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl hetero group is selected from the group consisting of an optionally substituted [C _1-12 hydrocarbyl group, a C _1-12 heterohydrocarbyl group, a C _1-12 hydrocarbyl 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 COC _1-12 , -C _0-12 COOC _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 in the form of a hetero-fat chain, and the number of aromatic rings, heteroaromatic rings, aliphatic rings, hetero-fat rings, aliphatic chains and/or hetero-fat chains, ring-forming atoms and their numbers, rings and rings or rings The chain or chain-to-chain linkage 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) ₂ , the number of heteroatoms or heteroatoms is arbitrary under the premise of being chemically stable.

In some embodiments of the invention, the substituent substituent 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 a C _1-6 alkyl or heteroalkyl or alkane group, the hetero atom or hetero atom group being independently selected from C _1-6 alkane or unsubstituted -CONH-, -CO ₂ -, C _1-6 alkane 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.

In some embodiments of the invention, the substituent for substitution is selected from the group consisting of halogen, OH, SH, NH ₂ , CN, =O, =S, CF ₃ , -OCF ₃ or -OCH ₃ .

In some embodiments of the invention, the above compound is selected from the group consisting of

Another object of the present invention is to provide a process for the preparation of a compound of the formula (II), comprising the steps of the formula (S1): a structural unit in the compound represented by the formula (II) Substructure unit is

In some embodiments of the present invention, the method for preparing the compound of the above formula (II), comprising the step represented by the formula (S2):

In some embodiments of the present invention, the method for preparing the compound of the above formula (II), comprising the step represented by the formula (S3): The compound represented by (II) is

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

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

Definition and description

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

C _{1-12 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₂ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .

C _1-12 alkyl or heteroalkyl, C _3-12 cyclo or heterocycloalkyl, C _1-12 alkyl or heteroalkyl substituted by C _3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to: C _1-12 alkyl, C _1-12 alkylamino, N,N-di(C _1-12 alkyl)amino, C _1-12 alkoxy, C _1-12 alkyl fluorenyl, C _{1- 12} alkoxycarbonyl, C _1-12 alkylsulfonyl, C _1-12 alkylsulfinyl, C _3-12 cycloalkyl, C _3-12 cycloalkylamino, C _3-12 heterocycloalkane Amino, C _3-12 cycloalkoxy, C _3-12 cycloalkylguanidino, C _3-12 cycloalkyloxycarbonyl, C _3-12 cycloalkylsulfonyl, C _3-12 cycloalkyl Sulfosyl, 5- to 12-membered aryl or heteroaryl, 5- to 12-membered aralkyl or heteroarylalkyl; methyl, ethyl, n-propyl, isopropyl, -CH ₂ C (CH ₃ (CH ₃ )(OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropenyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, A Sulfhydryl, methoxycarbonyl, methanesulfonyl, methylsulfinyl, ethoxy, ethoxylated, ethylsulfonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethyl aminocarbonyl group, _{diethylamino-carbonyl; N (CH 3) 2,} NH (CH 3), - CH 2 CF 3 _{-CH2CH 2 CF 3, -CH 2 CH} 2 F, -CH 2 CH 2 S (= O) 2 CH 3, -CH 2 CH 2 CN, -CH ₂ CH(OH)(CH3) ₂ , -CH ₂ CH(F)(CH ₃ ) ₂ , -CH ₂ CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -S(=O) ₂ CH ₃ , -CH ₂ CH ₂ S(=O) ₂ CH ₃ , And phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, pyrazolyl, 2-pyrazoline Base, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4 -thiadiazolyl, 4 H -pyranyl, pyridyl, piperidinyl, 1,4-dioxolyl, porphyrinyl, indolyl, pyrimidinyl, pyrazinyl, piperazinyl, 1 , 3,5-trithiaalkyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, fluorenyl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl , isoquinolyl, phenyl or quinolinyl; the term "pharmaceutically acceptable" as used herein is used in the context of reliable medical judgment for those compounds, materials, compositions and/or dosage forms. It is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

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 amine 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, a similar acid such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and an amino acid such as arginine Salts such as, 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, "pharmaceutically acceptable salts" are derivatives of the compounds 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-ethyloxybenzoic 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, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid , pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalactosaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, aminosulfonic 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 the use of these compounds in a free acid or base form with a stoichiometric amount of a suitable base in water or an organic solvent or a mixture of the two. Or acid reaction to prepare. 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.

Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the ( R )- and ( S )-enantiomers, diastereomeric a conformation, a ( D )-isomer, a ( L )-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which are It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary groups cleaved to provide a pure Enantiomers are required. Alternatively, when a molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, and then is known in the art. The diastereomeric resolution is carried out by step crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amine from an amine) Carbamate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, vegetables. And minerals, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

For a pharmaceutical or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" means a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition means the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

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 the substituted 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 unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

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.

When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.

The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from one or more of the following groups: -R', -OR', =O, = NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R' , -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) ₂ R', -NR""'-C(NR'R"R'")=NR'''', NR''''C(NR'R")=NR'", -S(O)R', -S (O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluoro (C ₁ -C ₄ ) Alkyl, the number of substituents is 0~(2m'+1), where m' is the total number of carbon atoms in such a group. R', R", R"', R'''' and R''''', each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogens), substituted or unsubstituted An alkyl group, an alkoxy group, a thioalkoxy group or an aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected as if present More than one R', Each of these groups when R", R"', R'''' and R'''''s group. When R' and R" are attached to the same nitrogen atom, they can be bonded to the nitrogen atom. A 5-, 6- or 7-membered ring is formed. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include carbon. a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF ₃ , -CH ₂ CF ₃ ) and a mercapto group (e.g., -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH _{3 ,} etc.).

Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from -R', -OR', -NR'R", -SR', - Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C (O) R', NR'C(O)NR"R"', -NR"C(O)2R', -NR'''''-C(NR'R"R'")=NR'''',NR''''C(NR'R")=NR'",-S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", NR" SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluorine (C ₁ -C ₄ ) alkoxy, and fluorine (C ₁ -C ₄ )alkyl, etc., substituent The number is between 0 and the total number of open valences on the aromatic ring; wherein R', R", R"', R'''' and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each The R groups are independently selected, as are each of these groups when more than one R', R", R"', R'''' and R""' groups are present.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or single bond, r is 1~4 The integer. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, and X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl.

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 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.

Examples of haloalkyl groups 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, bis-butoxy, tert-butoxy, n-pentyloxy, and S -pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "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.

The term "halo" or "halogen" means fluoro, chloro, bromo and iodo.

Unless otherwise specified, the term "hetero" means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and atomic groups containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), antimony (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and -C(=O) optionally substituted N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ring includes a single ring, Joint ring, spiral ring, parallel ring or bridge ring. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5~7-membered ring" means 5~7 atoms arranged around. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Therefore, the "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 a phenyl group. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group. It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridge rings include, but are not limited to: one carbon atom, two carbon atoms, one A nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octyl octyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzodecylphenyl, benzoxazolyl, benzoxazoline , benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4a H -carbazolyl, porphyrin , benzodihydropyranyl, chromene, porphyrin decahydroquinolinyl, 2 H , 6 H -1,5,2-dithiazinyl, dihydrofuro[2,3- b ]tetrahydrofuran , furanyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl, 3 H - Sulfhydryl, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, decyl, isoquinolyl, isothiazolyl, isoxazolyl, Methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolyl, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2 , 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, hydroxymethyl, pyrimidinyl Phenyridinyl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenolzinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, Piperonyl, acridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, indolyl, pyridazole, pyridoimidazole, pyridylthiazole, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4 H -quinazinyl, quinolyl, quinuclidinyl, Tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4 -thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolylthiophenyl, thienyl, thienozolyl, thiophene And thiazolyl, 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 term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrohydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or 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, tert-butyl, isobutyl, secondary butyl, isobutyl, cyclohexyl, (ring Hexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals 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 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 "heteroalkyl", by itself or in conjunction with another term, refers to a stable linear, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. 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 can be located at any internal position of the heterohydrocarbyl group (including 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.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventionally used to mean that they are attached to the remainder of the molecule through an oxygen, amine or sulfur atom, respectively. Those alkyl groups.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) The heterocyclic alkynyl group, etc., by itself or in combination with other terms, respectively represent a cyclized "hydrocarbyl group" or "heterohydrocarbyl group". Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. 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 "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which 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 oxidized, and the nitrogen atom is The ground is 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-isoxazolyl, 4- Isozolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoxazolinyl, 5-isoquinolyl, 2-quinolyl, 5-quinolyl, 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.

For simplicity, 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.

The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction such as 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 Ester and the like; an oxime group such as an ethoxy group, a trifluoroacetoxy group or the like.

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 on the amine nitrogen site. Representative amine protecting groups include, but are not limited to, indenyl; indenyl, for example, alkanealkyl (e.g., ethyl, trichloroethyl or trifluoroethyl); alkoxycarbonyl, such as three Grade butoxycarbonyl (Boc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di- (4'-Methoxyphenyl)methyl; methoxyalkyl, such as trimethylmethanyl (TMS) and tertiary butyl dimethyl methacrylate (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing the side reaction of a hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tertiary butyl groups; fluorenyl groups such as alkane fluorenyl groups (e.g., ethenyl); arylmethyl groups such as benzyl (Bn) , p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); formyl, such as trimethylmethanyl (TMS) And tertiary butyl dimethylformamidine (TBS) and the like.

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 listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI Representative 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 hydrazine; Ethyl acetate; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for tertiary carbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for cyanoborohydride Sodium; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tertiary butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for Barium chloride; CS ₂ stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione ; n -Bu ₄ NF Table tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp mp Representative; Representative LDA lithium diisopropylamide.

Compounds are named by hand or by ChemDraw® software, and commercial compounds are listed under the supplier's catalogue. 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 weight, Equal; 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 dimethylene EtOAc; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents a tertiary carbonyl group is an amine protecting group; HOAc represents acetic acid; NaCNBH ₃ represents Sodium cyanoborohydride; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl butyl carbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine SOCl ₂ represents a hydrazine chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-diketone; n -Bu ₄ NF represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents a melting point. 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, and a specific embodiment thereof is also disclosed. It will be apparent to those skilled in the art that various changes and modifications may be made to the embodiments of the invention.

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) The organic layer was dried over anhydrous sodium 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 NaCl 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

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)Cl ₂ (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. After the reaction mixture was cooled, it was diluted with water (30 mL), and the mixture was evaporated. The title compound BB-1 (70 mg, 32%) was obtained. 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 saturated NaCI. 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. The reaction mixture was cooled, 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 by pressure to give the title compound 2-4 (4.5 g, 79%). 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 organic layer was dried over anhydrous sodium 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 under reduced pressure to remove the solvent concentrate to obtain an oil. The title compound BB-2 (200 mg, 24%) was obtained. LCMS m/z : 423.1 [M+1] ⁺ .

Reference Example 3: 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 under reduced pressure to remove the solvent concentrate to obtain 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%) was obtained. 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) The organic layer was dried over anhydrous sodium 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 NaCl 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. After the reaction mixture was cooled, it was diluted with water (30 mL), and the mixture was evaporated. 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 organic layer was dried over anhydrous sodium 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 obtained by crystallization was washed once with a saturated NaCI solution, and the organic phase was dried over anhydrous sodium sulfate. /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) The title compound BB-6 (90 mg, 52%). 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><RTIID=0.0></RTI></RTI><RTIgt; Methyl), stirred at room temperature for 3 hours. After adding 15 mL of water, the organic phase obtained by crystallization was washed once with a saturated NaCI solution, and the organic phase was dried over anhydrous sodium sulfate. /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) The title compound BB-7 (110 mg, 62%). LCMS: m / z, 511.2 [ M + 1] +.

Reference Example 8: Fragment BB-8

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 using a rotary evaporator, and the obtained oil was purified (yield: EtOAc) The organic layer was dried over anhydrous sodium 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) was added at room temperature. Mm). 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 and evaporated, evaporated, (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-proline acid (BB-2-6, 0.18 g, 0.94 mmol), diisopropyl Ethylamine (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 and evaporated, evaporated, (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 acetic acid was added under nitrogen. potassium (0.09g, 0.93mmol) and _{Pd (dppf) Cl 2 (0.03g} , 0.04mmol). 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. Target 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-proline acid (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 phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, 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}} ): δ 6.90 (s, 1 H), 5.23-5.22 (m, 1 H), 4.58-4.40 (m, 1 H), 4.13-3.88 (m, 4 H), 3.70 (s, 3 H), 3.21-3.20 (m, 2 H), 2.88-2.51 (m, 2 H), 2.16-2.07 (m, 3 H), 1.97-1.79 (m, 2 H).

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) was added under nitrogen. , 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 , 400 MHz): δ 7.78 (s, 1 H), 5.23-5.22 (m, 1 H), 3.47 (s, 2 H), 3.06-3.03 (m, 1 H), 2.78-2. (m, 2 H), 2.08 (brs, 1 H), 1.86 (m, 1 H), 1.65-1.51 (m, 2 H), 1.27-1.23 (m, 4 H), 1.20 (d, J = 6.4 Hz, 6 H), 0.80-0.63 (m, 2 H), 0.58-0.57 (m, 2 H).

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 then filtered, and the solvent was evaporated, and the residue was purified by EtOAc (EtOAc/EtOAc/EtOAc 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 and evaporated, evaporated, evaporated, Yellow powder, 0.95 g, yield 66.0%). MS m/z : 489.3 [M+H] ⁺ .

Reference Example 21: Fragment BB-21

synthetic route:

Step 1: Synthesis of Compound BB-2-6

L-Proline (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 ₃ 400 MHz): δ 5.19 (d, J = 8.8 Hz, 1 H), 4.32 (dd, J = 8.8 Hz, J = 4.4 Hz, 1 H), 3.71 (s, 3 H), 2.26 -2.18 (m, 1 H), 1.01 (d, J = 7.2 Hz, 3 H), 0.94 (d, J = 6.4 Hz, 3 H).

Step 2: Synthesis of Compound BB-21-1

Will EDC ^. HCl (26.3 g, 136.9 mmol), N-Moc-L-proline (BB-2-6, 17.6 g, 92.05 mmol), diisopropylethylamine (35.4 g, 274.4 mmol) dissolved in anhydrous dichloro Methane (500 mL) was stirred at room temperature for 10 min then EtOAc EtOAc (EtOAc m. After the TLC reaction was completed, the reaction was quenched by water (20 mL). The organic phase was washed with 10% hydrochloric acid to pH 5 to 6 and 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: 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) 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 crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 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, 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, 3 H), 2.06 (d, J = 1.6 Hz, 3 H), 1.85 (s, 3 H).

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, 3 H), 3.25 (brs, 1 H), 1.04 (d, J = 6.4 Hz, 6 H).

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 under nitrogen LiHMDS (1 mol/L in THF, 7.1 mL, 7.1 mmol) was slowly 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. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield 80%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.67-7.65 (m, 2 H), 7.48-7.36 (m, 6 H), 7.22-7.20 (m, 2 H), 4.10 (t, J = 7.6 Hz, 1 H), 3.94-3.92 (m, 1 H), 3.79-3.46 (m, 5 H), 3.64-3.46 (m, 1 H), 3.05-3.01 (m, 1 H), 2.07-2.02 (m, 1 H), 1.81-1.61 (m, 1 H).

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, 2 H), 3.73 - 3.68 (m, 5 H), 3.37 (dd, J = 20.8, J = 7.2 Hz, 1 H), 2.52- 2.46 (m, 1 H), 1.99-1.96 (m, 1 H), 1.78-1.77 (m, 1 H).

Step 3: Synthesis of Compound BB-23-4

Compound BB-23-3 (2.88 g, 18.1 mmol) was dissolved in dichloromethane (50 mL) at room temperature, diisopropylethylamine (7.0 g, 54.3 mmol) was added, then methyl chloroformate was added dropwise (1.88 g, 19.9 mmol) and stirred at room temperature for 4 h. After the completion of the TLC reaction, the solvent was evaporated under reduced pressure, and the residue was purified by EtOAc (EtOAc (EtOAc) Yield 71.2%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.38 (brs, 1 H), 4.42-4.38 (m, 1 H), 3.92-3.90 (m, 2 H), 3.78 (s, 3 H), 3.75-3.68 (m, 6 H), 2.71-2.67 (m, 1 H), 2.08-1.81 (m, 2 H).

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 TLC detection, the 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, 1 H), 4.40 (brs, 1 H), 3.99 - 3.89 (m, 2 H), 3.79-3.72 ( m, 5 H), 2.80-2.77 (m, 1 H), 2.13 - 2.07 (m, 1 H), 1.92-1.80 (m, 1 H).

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) at room temperature. (958 mg, 2.52 mmol). The mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl ether/ethyl acetate=10:1→ethyl acetate) Solid, 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), ethyl acetate solution (4 mol/L, 50 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed after TLC. The solvent was removed to give the title compound BB-25-2 (light yellow, 13.0 g, yield 100%). The product is used directly in the next step without purification. ¹ H NMR (400 MHz, DMSO- d6 ): δ 8.37 (brs, 3H), 3.81-3.88 (m, 2H), 3.23 (s, 3H), 1.20 (d, J = 6.4 Hz, 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) δ 12.65 (brs, 1H), 7.02 (d, J = 9.0Hz, 1H), 4.04-4.01 (m, 2H), 3.76-3.74 (m, 1H), 3.51 (s, 3H), 3.81 (s, 3H), 1.96 (s, 3H).

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-seramine hydrochloride (BB-27-1, 10.6 g, 68.4 mmol) was further added, and the reaction was continued at -30 ° C for 3 hours, and then raised to room temperature. Stir 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) at room temperature, 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/tertiary 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 extracted with 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). 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 then 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 warmed 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 solvent was evaporated to dryness. The residue was purified by silica gel chromatography ( petroleum ether / ethyl acetate = 2:1) to afford compound BB-27-5 (yellow solid, 1.2 g, 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) and 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, filtered, evaporated, evaporated, evaporated, evaporated. 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, filtered and evaporated. 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, and ethyl acetate (30 mL) was added thereto, followed by saturated sodium hydrogen carbonate solution (50 mL×3), saturated brine (50 mL) After washing, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. , 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/tertiary butanol/water (20 mL/5 mL/5 mL), and lithium hydroxide monohydrate (239.82 g, 5.71 mmol) was added. After stirring overnight, the reaction was completed by TLC, and then pH was adjusted to 3 with 1N hydrochloric acid, and 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, 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 nitrogen atmosphere, stirred overnight, and after TLC detection, the reaction was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by chromatography ( petroleum ether / ethyl acetate = 1:1 The target 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 chromatography ( petroleum ether / ethyl acetate = 1:1). Target 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, and then filtered and evaporated. Colorless oil, 5.5 g, yield 65.2%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.33-4.25 (m, 1 H), 3.93-3.89 (m, 1 H), 3.70 (s, 3 H), 3.59-3.47 (m, 2 H), 3.44 (s, 3 H), 2.03-1.98 (m, 2 H), 1.43 (s, 9 H).

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, 1 H), 3.99-3.98 (m, 1 H), 3.65-3.53 (m, 2 H), 3.33 (s, 3 H). -2.05 (m, 2 H), 1.47 (s, 9 H).

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 at room temperature overnight, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered and evaporated. Red solid, 3.5 g, yield 41.7%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.79-7.76 (m, 2 H), 7.67-7.65 (m, 2 H), 5.58-5.18 (m, 2 H), 4.55 - 4.50 (m, 1 H), 4.16-4.05 (m, 1 H). 3.67-3.37 (m, 2 H), 3.36 (s, 3 H), 2.50-2.40 (m, 2 H), 1.47 (s, 9 H).

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 completion of the reaction 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.]]]]]]]] 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-proline (BB-2-6, 518.2 mg, 2.96 mmol), diisopropylethylamine (954 mg, 7.4) Methyl) was dissolved in DMF (10 mL). 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 and evaporated, evaporated, evaporated, 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). After stirring at 0 ° C for 0.5 hours, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1) to afford the title compound BB-31-1 (white solid, 1.26) 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 system was warmed 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 (50 mL) was added and washed with water (30mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated, evaporated, mjjjjjjjjjjjjj Solid, 0.72 g, yield 60%). LC/MS m/z : 394.8 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-31

Compound BB-31-2 (0.72 g, 1.82 mmol) was dissolved in ethyl acetate (10 mL), cooled to 0 ° C, EtOAc (EtOAc/EtOAc . 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) 2.73 mmol). 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 and evaporated, evaporated, evaporated 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). After stirring at 0 ° C for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1) to afford title compound BB-32-1 (br. , 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) %). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.49 (dd, J = 8.0 Hz, J = 2.8 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.19(s,1 H), 5.70 (d, J = 8.0 Hz), 5.31 (m, 1 H), 4.58 (m, 1 H), 3.73 (m, 2 H), 3.70 (s, 3 H), 3.27(s,3 H), 2.85 (m, 1 H), 2.22 (m, 1 H), 1.44 (m, 1 H), 1.19 (d, J = 8.0 Hz, 1 H), 0.88 (m, 1) H).

Reference Example 33: Fragment BB-33

synthetic route:

Step 1: Synthesis of Compound BB-33-2

The compound L-proline (300 mg, 2.56 mmol) was dissolved in aqueous sodium hydroxide (1N, 5 mL), and then, after 10 min, compound BB-33-2 (356 mg, 2.82 mmol) Stir for 8 h. After completion of the reaction, hydrochloric acid solution (6 N, 10 mL) was added to adjust to pH = 4, and then lyophilized to give the title compound BB-33-2 (170 mg, 32%). LCMS m/z : 208.1 [M+H] ⁺

Step 2: Synthesis of Compound BB-33

Compound BB-33-2 (170 mg, 0.82 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; ), stirred at room temperature for 2 h. Water (100 mL) was added, and extracted with dichloromethane (3×30 mL). The organic phase was dried over anhydrous sodium sulfate. The title compound BB-33 (350 mg, 89%) was obtained. LCMS m/z : 481.1 [M+H] ⁺

Reference Example 34: Fragment BB-34

synthetic route:

Step 1: Synthesis of Compound BB-34-2

The NaOH (0.7g, 17.5mmol) was dissolved in 20mL water, cooled to 0 deg.] C, was added compound BB-34-1 (2.0g, 16.8mmol) , NaHCO 3 (0.8g, 8.4mmol). After completely dissolved, methyl chloroformate (1.6 g, 16.8 mmol) was added dropwise to the reaction mixture and stirred at room temperature overnight, pH was adjusted to 3 with 1N HCl and extracted with ethyl acetate (30 mL×3) The extract was washed with brine, dried over anhydrous sodium sulfate It was used directly in the next step without purification. ^{1 H NMR (400MHz, DMSO- d} 6): δ: 8.38 (br, 3H), 4.12 (s, 1H), 3.76-3.65 (m, 2H), 3.27 (s, 3H).

Step 2: Synthesis of Compound BB-34-3

Compound BB-8 (1.5 g, 5.1 mmol), compound BB-34-2 (0.9 g, 5.1 mmol) and HATU (2.1 g, 5.6 mmol) were dissolved in dichloromethane (10.0 mL). After triethylamine (1.5 g, 15.3 mmol) was added dropwise, stirring was continued at room temperature overnight, then 20 mL of water was added and then extracted with CH ₂ Cl ₂ (20 mL×3). The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 3 (brown oil, 570.0 mg, yield: 20.5%). LCMS m/z : 453.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-34

Compound BB-34-3 (451.0 mg, 1.0 mmol), potassium acetate (196.0 mg, 2.0 mmol) and bis-colonol borate (280.0 mg, 1.1 mmol) were dissolved in 10 mL of dioxane, and Pd was added. (dppf) Cl ₂ (39.0 mg, 0.05 mmol), heated under reflux for 2 hours under nitrogen. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (15 mL). EtOAc. = 20/1) The title compound BB-34 (light brown liquid, 150.0 mg, yield: 30.0%) was obtained. LCMS m/z : 499.2 [M+H] ⁺ .

Referring to the synthesis method of steps 1 to 2 in BB-34, the following examples are synthesized:

Reference Example 40: Fragment BB-40

synthetic route:

Step 1: Synthesis of Compound BB-40-2

Compound BB-40-1 (10 g, 43.24 mmol) was dissolved in acetonitrile (165 mL), then compound BB-1-1 (12 g, 43.24 mmol) and diisopropylethylamine (5.59 g, 43.24 mmol). Stir at room temperature overnight. The solvent was evaporated to drynessnessnessnessnessnessnessnessnessnessnesssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss LCMS m/z : 330.0 [M - 100 + H] ⁺ .

Step 2: Synthesis of Compound BB-40-3

The compound BB-40-2 (18 g, 42.03 mmol) was dissolved in toluene (350 mL), and then, ethyl acetate (32.4 g, 420.30 mmol) was added, and the reaction mixture was heated to reflux overnight. The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjj ¹ H NMR (400 MHz, Methanol- d ₄ ) δ: 7.61-7.59 (m, 2H), 7.51-7.49 (m, 2H), 7.40-7.38 (m, 1H), 5.01-4.99 (m, 1H), 4.45 (s, 1H), 3.77-3.73 (m, 1H), 3.58-3.55 (m, 1H), 2.37-2.32 (m, 1H), 2.19-2.14 (m, 1H), 1.43 (s, 3H), 1.22 (s, 6H).

Step 3: Synthesis of Compound BB-40-4

Compound BB-40-3 (14g, 34.29mmol) was dissolved in dichloromethane (250mL), was added _{Boc 2 O (8.23g, 37.72mmol)} , triethylamine (10.41g, 102.87mmol) and DMAP (0.208g, 1.71 mmol), the reaction mixture was stirred at room temperature for 3 h. Water (100 mL) was added, and the mixture was extracted with methylene chloride (2×300 mL), and the organic phase was evaporated, and the solvent was evaporated, and the residue was purified by EtOAc (EtOAc:EtOAc -40-4 (11 g, 63%).

Step 4: Synthesis of Compound BB-40-5

Compound BB-40-4 (2 g, 3.93 mmol) was dissolved in dichloromethane (10 mL). 4N EtOAc / EtOAc (EtOAc) The solvent was removed under reduced pressure to give the title compound </RTI></RTI><RTIgt; LCMS m/z : 310.0 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-40-6

Compound BB-40-5 (1.2 g, 3.89 mmol) was dissolved in DMF (30 mL). Compound BB-2-6 (750 mg, 4.28 mmol), HATU (1.77 g, 4.67 mmol) and triethylamine (1.97 g) , 19.47 mmol), and the reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with EtOAc (EtOAc (EtOAc) 6 (1.3 g, 72%). LCMS m/z : 467.1 [M+H] ⁺ .

Step 6: Synthesis of Compound BB-40-7

Compound BB-40-6 (800mg, 1.72mmol) was dissolved in dichloromethane (20mL), was added _{Boc 2 O (394mg, 1.806mmol)} , triethylamine (522mg, 5.16mmol) and DMAP (10mg, 0.086mmol) The reaction solution was stirred at room temperature for 3 h. Water (10 mL) was added, and extracted with dichloromethane (2×20 mL), EtOAc evaporated -40-7 (400 mg, 41%). LCMS m/z : 567.0 [M+H] ⁺ .

Step 7: Synthesis of Compound BB-40-8

Dess-Martin reagent (1125 mg, 2.65 mmol) was dissolved in dichloromethane (20 mL). Compound BB-40-7 (500 mg, 0.884 mmol) The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc) PE) The title compound BB-40-8 (400 mg, 80%) was obtained.

Step 8: Synthesis of Compound BB-40

Compound BB-40-78 (100mg, 0.177mmol) was dissolved in toluene (7mL), was added ethylene glycol (55mg, 0.885mmol) and p -TsOH (7mg, 0.035mmol), the reaction was refluxed overnight. After the reaction mixture was cooled, diluted with ethyl acetate (10 mL), EtOAc (EtOAc)EtOAc. The title compound BB-40 (25 mg, 28%) was obtained. LCMS m/z : 509.0 [M+H] ⁺ .

Referring to the synthesis method of steps 5-8 in BB-40, the following examples are synthesized:

Reference Example 42: Fragment BB-42

synthetic route:

Step 1: Synthesis of Compound BB-41

Compound BB-40-8 (300 mg, 0.532 mmol) was dissolved in toluene (20 mL). Compound BB-41-1 (277 mg, 2.66 mmol) and p- TsOH (10 mg, 0.053 mmol) were added and the reaction mixture was refluxed overnight. After the reaction mixture was cooled, diluted with ethyl acetate (10 mL), EtOAc (EtOAc)EtOAc. The title compound BB-41 (120 mg, 41%) was obtained. LCMS m/z : 551.0 [M+H] ⁺ .

Reference Example 43: Fragment BB-43

synthetic route:

Step 1: Synthesis of Compound BB-43-2

Compound BB-43-1 (9g, 36.69mmol) was dissolved in dichloromethane (200mL), was added Dess-Martin (31g, 73.38mmol) and NaHCO ₃ (6.2g, 73.38mmol), at room temperature and then stirred for 3h. The reaction mixture was quenched with EtOAc (EtOAc (EtOAc)EtOAc. BB-43-2 (8g, 90%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.81-4.69 (m, 1 H), 3.90-3.87 (m, 1 H), 3.75 (s, 3 H), 2.94-2.90 (m, 1 H), 2.62 -2.55 (m, 1 H), 1.51-1.44 (m, 9 H).

Step 2: Synthesis of Compound BB-43-3

Methyltriphenylphosphonium bromide (14.69 g, 41.11 mmol) was dissolved in THF (70 mL). EtOAc (EtOAc m. Compound BB-43-2 (5 g, 20.55 mmol) was then added and the mixture was warmed to room temperature and stirred for 2 h. The mixture was quenched with EtOAc (EtOAc (EtOAc)EtOAc. 43-3 (2.5 g, 50%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 5.01-4.98 (m, 2 H), 4.48-4.37 (m, 1 H), 4.08-4.04 (m, 2 H), 3.71 (s, 3 H), 2.96 - 2.94 3.75 (m, 1 H), 2.63-2.60 (m, 1 H), 1.46-1.41 (m, 9 H).

Step 3: Synthesis of Compound BB-43-4

Compound BB-43-3 (1 g, 4.41 mmol) and tetrabutylammonium bromide (0.027 mg, 0.083 mmol) were dissolved in DCE (10 mL), and sodium tribromoacetate (3.30 g, 10.36 mmol) was added. Heat to 70 ° C under nitrogen for 3 h. After cooling to room temperature, the solvent was evaporated.jjjjjjjjjjjjj _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.65-4.34 (m, 1 H), 3.91-3.84 (m, 1 H), 3.78-3.71 (m, 3 H), 3.53-3.43 (m, 1 H) , 2.65-2.35 (m, 2 H), 2.04-1.75 (m, 2 H), 1.60-1.25 (m, 9 H).

Step 4: Synthesis of Compound BB-43-5

Compound BB-43-4 (2.1g, 5.26mmol) was dissolved in water (25mL), was added _{H 3 PO 2 (3.13g, 47.36mmol} ), triethylamine (5.32g, 52.62mmol), V- 50 (142mg , 0.53 mmol), the reaction solution was heated to 100 ° C, and 0.1 equivalent of V-50 was added every 30 minutes, and a total of 1 equivalent of V-50 was added. The reaction was heated at 100 ° C overnight. The solvent was removed under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The solvent was removed under reduced pressure to give the title compound BB-43-5 (1 g, 79%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.45-4.25 (m, 1 H), 3.37-3.17 (m, 2 H), 2.42-2.20 (m, 1 H), 2.02-2.00 (m, 1 H) , 1.41-1.31 (m, 9 H), 0.57-0.51 (m, 4 H).

Step 5: Synthesis of Compound BB-43-6

Compound BB-43-5 (150 mg, 0.622 mmol) was dissolved in acetonitrile (5 mL), and compound BB-1-1 (173 mg, 0.622 mmol) and diisopropylethylamine (80 mg, 0.622 Stir for 2 h. The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjj LCMS m/z : 340.0 [M - 100 + H] ⁺ .

Step 6: Synthesis of Compound BB-43-7

Compound BB-43-6 (130 mg, 0.297 mmol) was dissolved in toluene (5 mL). The solvent was evaporated to dryness <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The target compound BB-43-7 (110 mg, 81%) was obtained. LCMS m/z : 420.1 [M+H] ⁺ .

Step 7: Synthesis of Compound BB-43-8

Compound BB-43-7 (110 mg, 0.263 mmol) was dissolved in dichloromethane (3 mL). The solvent was removed under reduced pressure, water (3 mL) was evaporated,EtOAcjjjjjjjjjjjj 70mg, 84%). LCMS m/z : 320.1 [M+H] ⁺ .

Step 8: Synthesis of Compound BB-43-9

Compound BB-43-8 (70 mg, 0.220 mmol) was dissolved in dichloromethane (5 mL). Compound BB-1-6 (46 mg, 0.242 mmol), HATU (100 mg, 0.264 mmol) and triethylamine (67 mg, 0.660 mmol), the reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with EtOAc (EtOAc (EtOAc) 9 (90 mg, 83%). LCMS m/z : 491.0 [M+H] ⁺ .

Step 9: Synthesis of Compound BB-43

Compound BB-43-9 (90 mg, 0.183 mmol) and bis-hydrazinol borate (93 mg, 0.366 mmol) were dissolved in DMF (5 mL), and then Pd(dppf)Cl ₂ (10 mg, 0.014 mmol) and Potassium acetate (54 mg, 0.550 mmol), and the reaction mixture was reacted under nitrogen for 8 h at 80-90 °C. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) (EtOAc (EtOAc) Target compound BB-43 (80 mg, 88%). LCMS m/z : 539.2 [M+H] ⁺ .

Referring to the synthesis methods of steps 8-9 in BB-43, the following examples are synthesized:

Reference Example 44: Fragment BB-44

synthetic route:

Step 1: Synthesis of Compound BB-44-3

Compound BB-44-1 (15.0 g, 61.5 mmol) was dissolved in 600 mL of THF and cooled to -78 ° C. LHMDS solution (135 mL, 1M in THF, 135.0 mmol) was slowly added dropwise, and the reaction was continued for 2 hours after the addition was completed. Then slowly warm to room temperature and stir overnight. The reaction solution was re-cooled to -78 ° C, BB-44-2 (130 mmol) was added, then slowly warmed to room temperature and stirred for 3 h. The reaction was quenched by the addition of 10.0 mL EtOAc EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate (Colorless liquid, 6.0 g, yield: 30.3%). LCMS m/z : 669.22 [2M+Na] ⁺ .

Step 2: Synthesis of Compound BB-44-4

Compound BB-44-3 (2.0 g, 6.2 mmol) was dissolved in dichloromethane (120 mL), and then stirred, and then stirred at room temperature for 2 days. The reaction was quenched by the addition of lead acetate and stirred for 2 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssss ). LCMS m/z : 613.3 [2M+Na] ⁺ .

Step 3: Synthesis of Compound BB-44-5

Compound BB-44-4 (2.9 g, 10.0 mmol) was dissolved in a mixed solvent of 15 mL of ethyl acetate and 15 mL of ethanol, and 10% Pd/C (300.0 mg) was added under a nitrogen atmosphere, and replaced with hydrogen three times, then The hydrogen balloon was stirred at room temperature overnight. The reaction was filtered to remove Pd/C, and the solvent was evaporated under reduced pressure to give the title compound BB-44-5 (colorless liquid, 1.6 g, yield: 54.0%). _{^{1 H NMR (400MHz, CDCl 3}} ): δ: 4.54-4.50 (m, 1 H), 3.76 (s, 3 H), 2.26-2.19 (m, 1 H), 2.04-1.93 (m, 3 H), 1.82-1.78 (m, 2 H), 1.66-1.54 (m, 4 H), 1.48 (s, 9 H).

Step 4: Synthesis of Compound BB-44-6

Compound BB-44-5 (0.9 g, 3.0 mmol) was dissolved in 30 mL of THF and cooled to -78 ° C, and a solution of DBAL-H in toluene (1 M, 9.0 mL, 9.0 mmol) was slowly added dropwise. Stir slowly to room temperature and stir for 1 hour. The reaction solution was re-cooled to -78 ° C, quenched by the addition of 10 mL of methanol, stirring was continued for half an hour and then warmed to room temperature. The mixture was extracted with ethyl acetate (30 mL×3). EtOAc was evaporated. /1) The title compound BB-44-6 (colorless liquid, 0.9 g, yield: 90.0%) was obtained.

Step 5: Synthesis of Compound BB-44-7

Compound BB-44-6 (0.8 g, 2.6 mmol) and triethyl decane (0.75 g, 6.5 mmol) were dissolved in 15 mL of dichloromethane and cooled to -78 ° C, and a solution of boron trifluoride diethyl ether (6.5) was slowly added dropwise. After a half hour, 750 mg of triethyldecane and 6.5 mL of boron trifluoride diethyl ether solution were added again. The reaction was stirred at -78 ℃ 2 h, saturated NaHCO ₃ solution was added to quench the reaction, and extracted with dichloromethane (30mL × 3), the organic phase was washed with saturated brine were combined, dried over anhydrous sodium sulfate was added, the solvent was removed under reduced pressure The residue obtained was purified by silica gel column chromatography (eluent: EtOAc/EtOAc: EtOAc: _{^{1 H NMR (400MHz, CDCl 3}} ): δ: 3.84 (t, J = 8.0Hz, 1 H), 3.72 (s, 3 H), 2.90 (d, J = 10.1Hz, 1H), 2.73 (d, J =10.1 Hz, 1 H), 2.08-2.05 (m, 4 H), 1.78 (dd, J = 12.6, 7.1 Hz, 1 H), 1.62-1.53 (m, 6 H).

Step 6: Synthesis of Compound BB-44-8

Compound BB-44-7 (360.0 mg, 2.0 mmol), compound BB-1-6 (410.3 mg, 2.2 mmol) and HATU (1.1 g, 3.0 mmol) were dissolved in dichloromethane (20.0 mL) at room temperature After adding triethylamine (600.7 mg, 6.0 mmol), stirring was continued at room temperature overnight, and after adding 20 mL of water, it was extracted with dichloromethane (20 mL × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. 8 (light brown liquid, 50.0 mg, yield: 71.4%). LCMS m/z : 357.1 [M+H] ⁺ .

Step 7: Synthesis of Compound BB-44-9

Compound BB-44-8 (100.0 mg, 0.28 mmol) was dissolved in EtOH (5.0 mL) ^. H ₂ O (14.2 mg, 0.34 mmol), stirring at room temperature overnight, pH 1 was added with 1N HCl, and extracted with ethyl acetate (10 mL×3). The sodium was dried and the solvent was evaporated under reduced pressure to give crude product BB-44-9 (white solid, 90.0 mg, 93.7%). It was used directly in the next step without purification. LCMS m/z : 343.1 [M+H] ⁺ .

Step 8: Synthesis of Compound BB-44-10

Compound BB-44-9 (90.0 mg, 0.26 mmol), compound BB-1-1 (73.0 mg, 0.26 mmol) and diisopropylethylamine (33.4 mg, 0.26 mmol) were dissolved in acetonitrile (5.0 mL) The mixture was stirred overnight at rt. It was used directly in the next step without purification. LCMS m/z : 539.0 [M+H] ⁺ .

Step 9: Synthesis of Compound BB-44-11

Compound BB-44-10 (90.0 mg, 0.26 mmol) was dissolved in 10 mL of toluene. Ammonium acetate (138.6 mg, 1.8 mmol) was added at room temperature, and the reaction was heated to reflux overnight. The title compound BB-44-11 (light brown liquid, 80.0 mg, yield: 86.0%) was obtained. LCMS m/z : 519.1 [M+H] ⁺ .

Step 10: Synthesis of Compound BB-44

Compound BB-44-11 (50.0 mg, 0.09 mmol), potassium acetate (17.6 mg, 0.18 mmol) and the compound bis-colonol borate (36.6 mg, 0.14 mmol) were dissolved in 10 mL of dioxane and added Pd(dppf)Cl ₂ (3.0 mg, 0.0024 mol) was heated under reflux for 2 hours under nitrogen. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (15 mL). EtOAc. = 20/1) The title compound BB-44 (light brown liquid, 35 mg, yield: 64.8%) was obtained. LCMS m/z : 567.2 [M+H] ⁺ .

Reference Example 46: Fragment BB-46

synthetic route:

Step 1: Synthesis of Compound BB-46-2

Compound BB-46-1 (3.2 g, 15.90 mmol) was dissolved in acetonitrile (60 mL). Compound BB-1-1 (4.42 g, 15.90 mmol) and diisopropylethylamine (2.06 g, 15.90 ), stirred at room temperature for 2 h. The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjj LCMS m/z : 297.9 [M - 100 + H] ⁺ .

Step 2: Synthesis of Compound BB-46-3

Compound BB-46-2 (6.3 g, 15.82 mmol) was dissolved in toluene (350 mL). The solvent was evaporated to dryness <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The target compound BB-46-3 (4.5 g, 75%) was obtained. LCMS m/z : 380.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-46-4

Compound BB-46-3 (0.9 g, 2.38 mmol) was dissolved in dichloromethane (12 mL). Water (10 mL) was added, and the mixture was diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) . LCMS m/z : 280.0 [M+H] ⁺ .

Step 4: Synthesis of Compound BB-46-5

Compound BB-46-4 (600 mg, 2.16 mmol) was dissolved in dichloromethane (30 mL). Compound BB-1-6 (454 mg, 2.37 mmol), HATU (984 mg, 2.59 mmol) and triethylamine (655 mg, 6.47 mmol), the reaction was stirred at room temperature for 1 h. The mixture was quenched with EtOAc (EtOAc m. 5 (900 mg, 92%). LCMS m/z : 453.0 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-46

Compound BB-46-5 (300 mg, 0.665 mmol) and bis-hydrazinol borate (338 mg, 1.33 mmol) were dissolved in 1,4-dioxane (10 mL) and Pd(dppf)Cl ₂ was added sequentially. (30 mg, 0.040 mmol) and potassium acetate (196 mg, 1.99 mmol). The reaction mixture was reacted under nitrogen at 80-90 ° C for 4 h. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The title compound BB-46 (200 mg, 60%) was obtained. LCMS m/z : 499.3 [M+H] ⁺ .

Reference Example 47: Fragment BB-47

synthetic route:

Step 1: Synthesis of Compound BB-47-2

Compound BB-47-1 (50 mg, 0.132 mmol) and triethylamine (20 mg, 0.20 mmol) were dissolved in dichloromethane (3 mL) and trifluoromethanesulfonic anhydride (40.9 mg, 0.145 mmol) Dissolved in dichloromethane (1 mL) and added dropwise to the reaction mixture, and stirred at room temperature for 12 h. Add a saturated solution of ammonium chloride (10 mL), extract with dichloromethane (3×30 mL), dry the organic phase with anhydrous sodium sulfate, and remove the solvent concentrate under reduced pressure for separation by gel column chromatography (eluent: 10% dichloro Methane / MeOH) gave BB-47-2 (24 mg, 36.4%).

Step 2: Synthesis of Compound BB-47-3

The compound BB-47-2 (128 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and the mixture was evaporated. The reaction mixture was diluted with methylene chloride (20 mL), EtOAc (EtOAc) 81.97%). LCMS m/z : 412.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-47

Compound BB-47-3 (47.35 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), then BB-24-1 (25 mg, 0.12 mmol), HATU (53.2 mg, 0.14 mmol) and diisopropyl Ethylamine (31.0 mg, 0.24 mmol) was stirred at room temperature for 12 h. Water (15 mL) was added, and extracted with dichloromethane (3×30 mL). The organic phase was dried over anhydrous sodium sulfate. to give the title compound BB-47 (30mg, 42.7% ) L LCMS m / z:. 611.2 [m + H] +.

Referring to the synthesis method of step 3 in BB-47, each reference example in the following table is synthesized:

Reference Example 48: Fragment BB-48

synthetic route:

Step 1: Synthesis of Compound BB-48-1

Cyclopentene (30 g, 365 mmol) and sodium 4-methylbenzenesulfinate (108 g, 606 mol) were sequentially dissolved in 400 mL of water and 400 mL of dichloromethane in a two-phase solvent, and iodine (92.7 g, 365 mol), stirred at room temperature overnight. After adding 400 mL of dichloromethane, the mixture was washed with saturated aqueous sodium hydrogen sulfate (500 mL), saturated aqueous sodium hydrogen sulfate (50 mL) and brine (50 mL) The title compound BB-48-1 (brown oil, 133 g, yield 100%) was obtained.

Step 2: Synthesis of Compound BB-48-2

Compound BB-48-1 (133 g, 365 mmol) was dissolved in toluene (1000 mL), and DBU (55.6 g, 365 mol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. The solid reaction solution was filtered off, the filtrate was washed successively with 1M hydrochloric acid solution (100 mL), saturated aqueous NaHCO ₃ (200mL), brine (200mL) washed organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give the title compound BB -48-2 (grey solid, 70 g, yield: 81%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.55-7.45 (m, 2 H), 7.35-7.28 (m, 2 H), 7.02 (s, 1 H), 2.48 (s, 3 H), 2.25-2.15 (m, 4 H), 1.65-1.53 (m, 4 H).

Step 3: Synthesis of Compound BB-48-3

A solution of compound BB-48-2 (23 g, 97.3 mmol) and ethyl isocyanoacetate (27.5 g, 243.3 mmol.) in tetrahydrofuran (200 mL) was slowly added dropwise to NaH (9.7 g, 243.3). The suspension of tetrahydrofuran (200 mL) was stirred at 0 ° C for 1 hour, slowly warmed to room temperature and stirring was continued for 2 hours. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The title compound BB-48-3 (white solid, 17 g, yield: 97%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.76 (br, 1 H), 6.63 (s, 1 H), 4.31-4.25 (m, 2 H), 2.82-2.791 (m, 2 H), 2.55-2.52 (m, 2 H), 1.77-1.70 (m, 4 H), 1.33 (m, 3 H).

Step 4: Synthesis of Compound BB-48-4

Compound BB-48-3 (8 g, 41.4 mmol) was dissolved in tetrahydrofuran (100 mL), NIS (11.2 g, 49.77 mmol) was slowly added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to drynesshhhhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 6/1) The title compound BB-48-4 was obtained as a white solid 9.5 g, yield 71%. LCMS m/z : 320.40 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-48-5

Compound BB-48-4 (9.5g, 29.77mmol) was dissolved in dichloromethane (100mL), sequentially added _{Boc 2 O (7.8g, 35.7mmol)} , triethylamine (9.04g, 89.3mmol), at room temperature Stir for 3 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc) (light yellow solid, 10 g, yield 80%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.31-4.25 (q, 2 H), 2.79-2.76 (m, 2 H), 2.45-2.32 (m, 2 H), 1.77-1.70 (m, 4 H) , 1.1.63 (s, 9 H), 1.33 (m, 3 H).

Step 6: Synthesis of Compound BB-48-6

Compound BB-48-5 (7 g, 16.7 mmol) and p-bromobenzeneboronic acid (3.35 g, 16.7 mmol) were dissolved in 1,4-dioxane/water = 5:1 (100 mL) and Pd (dppf) was added sequentially. Cl ₂ (1.38 g, 1.67 mmol) and sodium carbonate (5.31 g, 50.1 mmol) were reacted at 100 ° C for 4 hours under nitrogen. After adding water (30 mL), EtOAc (3 mL, EtOAc) /1) The title compound BB-48-6 (yield of pale yellow solid, 3 g, yield: 40%) was obtained. LCMS: m/z 394.3 [M - 56+H] ⁺ .

Step 7: Synthesis of Compound BB-48-7

KOH (0.63 g, 11.15 mmol) was placed in ethyl acetate (50 mL), and the mixture was refluxed for 1 hour, and then compound BB-48-6 (1 g, 2.23 mmol) was added, and the mixture was heated to reflux for 1 hour. After the reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane (100 mL×3). , yield 81%). LCMS m/z : 278.0 [M+H] ⁺ .

Step 8: Synthesis of Compound BB-48-8

Phosphorus oxychloride (1.39 g, 9.05 mmol) was added dropwise to the compound BB-48-7 (0.5 g, 1.81 mmol) and 2-pyrrolidone (0.77 g, 9.05 mmol) of 1,2- under ice bath. The solution of dichloroethane (50 mL) was reacted for 1 hour in an ice bath, and the reaction was continued to room temperature for 2 hours. The reaction solution was slowly added dropwise to a saturated sodium acetate solution (50 mL), and then adjusted to pH 11 with 10 M KOH solution at 0 ° C, extracted with dichloromethane (3×50 mL), and the organic phase was combined with anhydrous sodium sulfate. Drying and removal of the solvent under reduced vacuo afforded title compound </RTI></RTI><RTIgt; LCMS m/z : 343.0 [M+H] ⁺ .

Step 9: Synthesis of Compound BB-48-9

Compound BB-48-8 (200mg, 0.582mmol) was dissolved in dichloromethane / MeOH (1: 1,20mL), was added NaBH ₄ (220mg, 5.83mmol), the reaction was heated at reflux overnight. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) : 74%). LCMS m/z : 345.1 [M+H] ⁺ .

Step 10: Synthesis of Compound BB-48

Compound BB-48-9 (180 mg, 0.52 mmol) was dissolved in dichloromethane (5 mL). EtOAc EtOAc EtOAc (EtOAc, EtOAc, EtOAc , 1.56 mmol), stirred at room temperature for 2 hours. Water (10 mL) was added, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1) The title compound BB-48 (white-like semi-solid, 150 mg, yield 57%) was obtained. LCMS m/z : 502.1 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of step 10 in BB-48 and HPLC separation:

Reference Example 54: Fragment BB-54

synthetic route:

Step 1: Synthesis of Compound BB-54-1

Cyclopentene (3 g, 44.04 mmol) and sodium 4-methylbenzenesulfinate (13.34 g, 74.87 mmol) were dissolved in 40 mL of water and 40 mL of dichloromethane, respectively, and iodine (11.18 g, 44.04) was added in portions. Methyl), stirred at room temperature overnight. The organic phase was extracted with aq. Filtration and removal of solvent under reduced pressure gave the title compound </RTI>

Step 2: Synthesis of compound BB-54-2.

Compound BB-54-1 (15.42 g, 44.04 mmol) was dissolved in toluene (100 mL), DBU (6.80 g, 44.04 mmol). The solid reaction solution was filtered off, the filtrate was washed successively with 1M HCl solution _{(50mL), NaHCO 3 (50mL} ), saturated brine (50mL) wash the organic phase with anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to give the title compound BB-54-2 (5g, 41%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.78-7.76 (m, 2 H), 7.33-7.31 (m, 2 H), 6.40 (s, 1 H), 2.53-2.50 (m, 4 H), 2.43 (s, 3 H), 2.04-1.97 (m, 2 H).

Step 3: Synthesis of Compound BB-54-3

A solution of compound BB-54-3 (5 g, 22.49 mmol) and ethyl isocyanoacetate (6.42 g, 56.23 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise to NaH (2.25 g, 56.23 mmol). The solution was stirred at 0 °C for 1 h in tetrahydrofuran (50 mL), then stirred at room temperature for 30 min. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.70 (br, 1 H), 6.57 (s, 1 H), 4.30-4.25 (m, 2 H), 2.83-2.80 (m, 2 H), 2.65-2.61 (m, 2 H), 2.38-2.33 (m, 2 H), 1.34-1.31 (m, 3 H).

Step 4: Synthesis of Compound BB-54-4

Compound BB-54-3 (1 g, 5.58 mmol) was dissolved in tetrahydrofuran (20 mL), EtOAc (l. The reaction mixture was washed with saturated brine (2×20 mL), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Compound BB-54-4 (1.57 g, 92%). LCMS m/z : 306.0 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-54-5

Compound BB-54-4 (1.57g, 5.15mmol) was dissolved in dichloromethane (20mL), were successively added _{Boc 2 O (1.24g, 5.66mmol)} , triethylamine (1.56g, 15.44mmol), at room temperature Stir for 3 h. The reaction mixture was concentrated and purified by silica gel column chromatography eluting eluting _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.28-4.22 (m, 2 H), 2.85-2.82 (m, 2 H), 2.54-2.51 (m, 2 H), 2.31-2.27 (m, 2 H) , 1.59 (s, 9 H), 1.32-1.29 (m, 3 H).

Step 6: Synthesis of Compound BB-54-6

Compound BB-54-5 (2 g, 4.94 mmol) and p-bromobenzeneboronic acid (0.99 g, 4.94 mmol) were dissolved in 1,4-dioxane/water = 5:1 (30 mL), then Pd (dppf) Cl ₂ (0.2 g, 0.27 mmol) and sodium carbonate (1.57 g, 14.81 mmol), the reaction mixture was reacted under nitrogen for 10 h at 100 ° C. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. PE), the title compound BB-54-6 (1.3 g, 61%) was obtained. LCMS m/z : 380.0 [M - 56 + H] ⁺ .

Step 7: Synthesis of Compound BB-54-7

Potassium hydroxide (650 mg, 11.51 mmol) was dissolved in EtOAc (50 mL), EtOAc (EtOAc) After adding water, the mixture was extracted with methylene chloride (2×30 mL). LCMS m/z : 262.0 [M+H] ⁺ .

Step 8: Synthesis of Compound BB-54-8

Phosphorus oxychloride (1050 mg, 6.87 mmol) was added dropwise to the compound BB-54-7 (450 mg, 1.72 mmol) and 2-pyrrolidone (584 mg, 6.87 mmol) of 1,2-dichloroethane under ice-cooling. A solution of the alkane (20 mL) was then reacted at room temperature for 2 h. The reaction mixture was poured into a saturated sodium acetate solution, and then the mixture was adjusted to pH 11 with a 10 M aqueous KOH solution at 0 ° C, and extracted with dichloromethane (2×30 mL). Filtration and removal of solvent under reduced pressure gave the title compound </RTI></RTI><RTIgt; _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.48-7.38 (m, 4H), 5.85-5.65 (br, 1H), 3.95-3.82 (m, 2H), 3.41-3.37 (m, 2H), 2.46-2.44 (m, 2H), 2.29-2.27 (m, 2H), 2.18-2.14 (m, 2H), 2.00-1.95 (m, 2H).

Step 9: Synthesis of Compound BB-54-9

Compound BB-54-8 (200mg, 0.607mmol) was dissolved in dichloromethane / MeOH = 1: 1 (20mL ), was added NaBH ₄ (460mg, 12.15mmol), The reaction was heated at reflux for 1h. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) LCMS m/z : 331.0 [M+H] ⁺ .

Step 10: Synthesis of Compound BB-54-10

Compound BB-54-9 (80 mg, 0.242 mmol) was dissolved in dichloromethane (5 mL). Compound BB-2-6 (42 mg, 0.242 mmol), HATU (92 mg, 0.242 mmol) and triethylamine (73 mg) , 0.725 mmol), stirred at room temperature for 1 h. Water was added, and the mixture was extracted with methylene chloride (3×30 mL). EtOAcjjjjjjjjjjjjjjjjjj BB-54-10 (55 mg, 47%).

Step 11: Synthesis of Compound BB-54

Using the compound BB-54-10 as a raw material, the compound BB-54 was synthesized by referring to the synthesis method of the step 3 in BB-34.

The compounds in the following table were synthesized by referring to the synthesis method of Step 10 in BB-54 and HPLC separation:

Reference Example 58: Fragments BB-58-A and BB-58-B

synthetic route:

Step 1: Synthesis of Compound BB-58-3

Compound BB-58-1 (270 mg, 1.22 mmol) and compound BB-58-2 (723 mg, 7.29 mmol) were dissolved in dichloromethane (30 mL), and phosphorus oxychloride (932 mg, 6.08 mmol) was slowly taken in an ice bath. Add and react overnight under nitrogen. The reaction mixture was slowly poured into a saturated aqueous solution of ammonium acetate, and the mixture was quenched with NaOH (10M). The mixture was adjusted to pH 9 to 10, and extracted with dichloromethane (50 mL×3). Filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (50 mL), and sodium hydrogen hydride (399 mg, 10.55 mmol) was slowly added and the mixture was reacted at room temperature for 2 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) , 310 mg, yield 84%). LCMS m/z : 305 [M+H] ⁺ .

Step 2: Synthesis of Compounds BB-58-4A and BB-58-4B

Compound BB-58-3 (310 mg, 1.02 mmol) and compound BB-1-6 (233 mg, 1.22 mmol) and HATU (463 mg, 1.22 mmol) were dissolved in dichloromethane (20 mL). The amine (205 mg, 2.03 mmol) was slowly added and allowed to react overnight under nitrogen. Saturated NaHCO ₃ solution (10 mL) quenched the reaction and extracted with dichloromethane (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative silica gel (eluent: PE: EA = 1:1) to give the title compound BB-58-4A (yellow solid, 110 mg, yield 23%) and BB-58-4B (lavender) Solid, 120 mg, yield 25%). LCMS m/z : 478 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-58-A

Compound BB-58-4A (40 mg, 0.084 mmol), bis-hydrazinol borate (43 mg, 0.084 mmol) was dissolved in a mixed solvent DMF / THF / H ₂ O (2 mL / 2 mL / 2 mL) and then added Pd(dppf)Cl ₂ (6 mg, 0.0084 mmol) and Na ₂ CO ₃ (27 mg, 0.25 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C for 2 hours under N ₂ protection, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude product was purified by preparative HPLC to afford the title compound BB-58-A (white solid, 8 mg, yield 12%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 10.59 (br, 0.4 H), 9.10 (br, 1 H), 7.75-7.50 (m, 8 H), 7.21 (s, 1 H), 6.52-6.48 ( m,1 H), 6.21-6.03 (m, 2 H), 5.82-5.71 (m, 2 H), 5.37-5.05 (m, 2 H), 4.62-4.57 (m, 2 H), 3.84-3.68 ( m, 10 H), 3.39-3.26 (m, 5 H), 3.11-2.73 (m, 2 H), 2.62-2.45 (m, 2 H), 1.87-1.70 (m, 4 H), 1.71-1.42 ( m, 4 H), 1.30-1.14 (m, 6 H); LCMS m/z : 784 [M+H] ⁺ .

Reference Example 59: Fragments BB-59-A and BB-59-B

synthetic route:

Step 1: Synthesis of Compound BB-59-1

1-BOC-2-pyrroleboronic acid (4.2 g, 19.90 mmol) and 1-bromo-4-iodobenzene (6.19 g, 21.89 mmol) in a 250 mL round bottom flask, catalyst Pd(dppf)Cl ₂ (1.45 g) , 1.99 mmol), K ₂ CO ₃ (8.29 g, 59.71 mmol) was dissolved in 150 mL of dioxane and 50 mL of water, and was then filtered with nitrogen and warmed to 80 ° C for 2 hours. After the reaction was completed, 200 mL of water was added and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered and evaporated. (white solid, 620 mg, yield 81%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 7.48-7.44 (m, 2H), 7.34-7.33 (m, 1H), 7.22-7.20 (m, 2H), 6.22-6.17 (m, 2H), 1.39 (s, 9H). LCMS m/z : 754 [M+H] ⁺ .

Step 2: Synthesis of Compound BB-59-2

Compound BB-59-1 (3.3 g, 10.24 mmol) was dissolved in 50 mL each of methanol and tetrahydrofuran, and sodium methoxide (4.43 g, 81.94 mmol) was slowly added, and reacted at room temperature for 3 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)

Step 3: Synthesis of Compound BB-59-3-1

Compound BB-59-2 (2.1 g, 9.46 mmol) and 2-pyrrolidone (5.63 g, 66.19 mmol) were dissolved in dichloromethane (50 mL), and phosphorus oxychloride (7.25 g, 47.28 mmol) was slowly taken in an ice bath. Add and react overnight under nitrogen. The reaction solution was slowly poured into a saturated aqueous solution of ammonium acetate, and the mixture was quenched with NaOH (10M). The mixture was adjusted to pH 9 to 10, and extracted with dichloromethane (100 mL×3). Filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (100 mL), and sodium hydrogen hydride (4.91 g, 129.68 mmol) was slowly added and the mixture was reacted at room temperature for 2 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc m. , 80%). LCMS m/z : 291 [M+H] ⁺ .

Step 4: Synthesis of Compound BB-59-4

Compound BB-59-3 (500 mg, 1.72 mmol) and compound BB-2-6 (361 mg, 2.06 mmol) and HATU (783 mg, 2.06 mmol) were dissolved in dichloromethane (30 mL). The ethyl ethylamine (444 mg, 3.44 mmol) was slowly added and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with ethyl acetate (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: PE: EA = 1:1) to afford the title compound BB-59-4 (yellow solid, 620mg, yield 81%). LCMS m/z : 448 [M+H] ⁺ .

Step 5: Synthesis of Compounds BB-59-A and BB-59-B

Compound BB-59-4 (620 mg, 1.38 mmol), bisindole boronate (527 mg, 2.07 mmol), potassium acetate (541 mg, 5.52 mmol) and Pd(dppf)Cl ₂ (103 mg, 0.14 mmol) The mixture was placed in a 50 mL three-necked flask, N _{2 was} protected, and 1,4-dioxane (20 mL) was poured. The reaction system was heated to 90 ° C overnight, and the heating was stopped and allowed to cool. Filtration, the filter cake was washed twice with ethyl acetate, and the obtained filtrate was evaporated to remove solvent. The crude product was purified by silica gel column chromatography (eluent: PE: EA = 1:1) to give the target compound BB-59-A ( Gray solid, 190 mg, yield 28%) and BB-59-B (yellow solid, 260 mg, yield 38%). LCMS m/z : 495 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis methods of steps 4 to 5 in BB-59-A/B and HPLC separation:

Reference Example 63: Fragments BB-63-A and BB-63-B

synthetic route:

Step 1: Synthesis of Compound BB-63-1

2,5-dihydrofuran (7 g, 99.9 mmol) and sodium 4-methylbenzenesulfinate (18.2 g, 1.1.9 mol) were dissolved in a mixed solvent of 400 mL of water and 400 mL of dichloromethane, batchwise Iodine (25.9 g, 101.9 mol) was added and stirred at room temperature overnight. The organic phase was washed with aq. The solvent was removed under reduced pressure to give the title compound br.

Step 2: Synthesis of Compound BB-63-2

Compound BB-63-1 (35 g, 99.9 mmol) was dissolved in acetonitrile (500 mL), triethylamine (21 mL, 149.8 mol) was added and stirred at room temperature for 2 hr. The solvent was evaporated to drynesshhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The solvent was removed by pressure to give the title compound BB-63-2 (light yellow solid, 15 g, yield: 67%). ^{1 H-NMR (400MHz, CDCl} 3) δ: 7.89-7.82 (m, 2H), 7.35-7.33 (m, 2H), 6.77 (s, 1H), 4.77-4.69 (m, 4H), 2.44 (s, 3H).

Step 3: Synthesis of Compound BB-63-3

A solution of compound BB-63-2 (7 g, 31.2 mmol) and ethyl isocyanoacetate (5.32 g, 46.8 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise to NaH (3.12 g, 78.1 mmol). In a suspension of tetrahydrofuran (100 mL), the mixture was stirred at 0 ° C for 1 hour, and slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with EtOAc (EtOAc (EtOAc)EtOAc. , yield: 35%). LCMS m/z : 182.1 [M+H] ⁺ .

Step 4: Synthesis of Compound BB-63-4

Compound BB-63-3 (2 g, 11 mmol) was dissolved in tetrahydrofuran (50 mL), NIS (2.98 g, 13.3 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. The compound BB-63-4 (light yellow solid, 1.5 g, yield: 44%) was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.87 (s, 2H), 4.52 (s, 2H), 4.1 (t, J = 7.1Hz, 2H), 1.23 (q, J = 6.8Hz, 3H) .LCMS m/z : 308.1 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-63-5

Compound BB-63-4 (1.5g, 4.88mmol) was dissolved in dichloromethane (20mL), were successively added _{Boc 2 O (1.28g, 5.86mmol)} , triethylamine (1.48g, 14.7mmol), at room temperature Stir for 3 hours. The solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS m/z : 353.2 [M+H - 55] ⁺ .

Step 6: Synthesis of Compound BB-63-6

Compound BB-63-5 (1.4 g, 3.44 mmol) and p-bromobenzeneboronic acid (0.76 g, 3.78 mmol) were dissolved in 1,4-dioxane/water = 5/1 (100 mL), and Pd was added sequentially. Dppf)Cl ₂ (0.3 g, 0.344 mmol) and sodium carbonate (1.1 g, 10.3 mmol), and the reaction mixture was reacted at 100 ° C for 4 hours under nitrogen atmosphere. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. 2), the title compound BB-63-6 (yield: white solid, yield: 46%). LCMS m/z : 379.9 [M - 56 + H] ⁺ .

Step 7: Synthesis of Compound BB-63-7

KOH (1.3 g, 22.9 mmol) was dissolved in ethylene glycol (50 mL), and the mixture was refluxed for 1 hour, and then compound BB-63-6 (2 g, 4.58 mmol) was added, and the mixture was heated to reflux for 1 hour. After cooling to room temperature, it was poured into ice-water (100 mL), EtOAc (EtOAc m. 0.5 g, yield 41%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.41 (br, 1H), 7.41-7.39 (m, 2H), 7.05-7.03 (m, 2H), 9.48 (s, 1H), 4.98 (s, 2H), 4.84 (s, 2H). LCMS m/z : 263.9 [M+H] ⁺ .

Step 8: Synthesis of Compound BB-63-8

Phosphorus oxychloride (1.74 g, 11.4 mmol) was added dropwise to the compound BB-63-7 (0.5 g, 1.89 mmol) and 2-pyrrolidone (0.81 g, 9.47 mmol) of 1,2- under ice bath. The solution of dichloroethane (50 mL) was reacted at room temperature for 2 hours. After the reaction was completed, it was poured into a saturated sodium acetate solution (50 mL), and the mixture was adjusted to pH 11 with a 10 M aqueous KOH solution at 0 ° C, and extracted with dichloromethane (3×50 mL). The organic layer was dried (MgSO4). LCMS m/z : 333.0 [M+H] ⁺ .

Step 9: Synthesis of Compound BB-63-9

Compound BB-63-8 (0.3g, 0.91mmol) was dissolved in dichloromethane / MeOH (1: 1,20mL), was added NaBH ₄ (0.34g, 9.06mmol), the reaction was heated at reflux overnight. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. :33%). LCMS m/z : 335.0 [M+H] ⁺ .

Step 10: Synthesis of Compounds BB-63-A and BB-63-B

Compound BB-63-9 (100 mg, 0.3 mmol) was dissolved in dichloromethane <RTI ID=0.0>(5 </RTI><RTIID=0.0></RTI></RTI><RTIgt; 91 mg, 0.9 mmol), stirred at room temperature for 2 hours. Water (20 mL) was added, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3) The objective compound BB-63-A (yellow solid, 50 mg, yield: 34%) and the title compound BB-63-B (light yellow solid, 50 mg, yield: 34%). LCMS m/z : 490.1 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of Step 10 in BB-63-A/B:

Reference Example 65: Fragments BB-65-A and BB-65-B

synthetic route:

Step 1: Synthesis of Compound BB-65-2

Compound BB-65-1 (1 g, 14.27 mmol), sodium 4-methylbenzenesulfinate (10.17 g, 57.07 mmol), KI (2.37 g, 14.27 mmol) were dissolved in acetonitrile (100 mL) Benzene (6.89 g, 21.40 mmol) was stirred at room temperature for 1 h. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc (EtOAc) -65-2 (3g, 60%).

Step 2: Synthesis of Compound BB-65-3

Compound BB-65-2 (3g, 8.52mmol) was dissolved in acetonitrile (40mL), was added DBU (6.07g, 34.08mol), stirred at room temperature 1h, the reaction solution was washed successively with _{1M HCl (50mL), NaHCO 3} (20mL) The mixture was washed with a saturated aqueous solution of EtOAc (EtOAc) (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.75 (d, 2H, J = 8.4 Hz), 7.33-7.31 (d, 2H, J = 8.0 Hz), 7.19-7.18 (m, 1H), 4.62 4.57 (m, 2H), 2.81-2.75 (m, 2H), 2.43 (s, 3H).

Step 3: Synthesis of Compound BB-65-5

The compound BB-65-4-1 (250.0 g, 255.0 mmol) was dissolved in 1.5 L of ethyl acetate. , 287.0 g), without further separation, proceed directly to the next reaction. Phosphorus oxychloride (226.1 g, 1.5 mol) was slowly added dropwise to the compound BB-65-4-2 (287.0 g, 1.3 mmol) and triethylamine (526.2 g, 5.2 mol) in tetrahydrofuran under ice bath. In the solution of 1.5 L), after the dropwise addition of phosphorus oxychloride, the ice bath was removed, and the mixture was stirred at room temperature until the reaction was completed. The reaction mixture was poured into a vigorously stirred ice water, and extracted with dichloromethane (1.0 L×3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate -4 (white solid, 254.8 g), without further separation, directly to the next reaction. Compound BB-65-3 ((1 g, 5.35 mmol) and BB-65-4 (1.57 g, 8.03 mmol) were dissolved in THF (20 mL), and t-BuOK solution (1M in THF was added dropwise at 0 ° C, 16 mL, 16.00 mmol), and stirred at room temperature for 2 h. The reaction was quenched with EtOAc EtOAc (EtOAc) lotion: 20% EtOAc / PE) to give the title compound BB-65-5 (360mg, 25% ) LCMS m / z:. 265.9 [m + H] +.

Step 4: Synthesis of Compound BB-65-6

Phosphorus oxychloride (836 mg, 5.45 mmol) was added dropwise to the compound BB-65-5 (360 mg, 1.36 mmol) and 2-pyrrolidone (580 mg, 6.82 mmol) of 1,2-dichloroethane under ice-cooling. A solution of the alkane (30 mL) was then allowed to react at room temperature for 2 h. The reaction mixture was poured into a saturated sodium acetate solution, and then the mixture was adjusted to pH 11 with a 10 M aqueous KOH solution at 0 ° C, and extracted with dichloromethane (2×30 mL). Filtration and removal of the solvent under reduced pressure gave the title compound br. LCMS m/z : 331.0 [M+H] ⁺ .

Step 5: Synthesis of Compound BB-65-7

Compound BB-65-6 (250mg, 0.755mmol) was dissolved in dichloromethane / MeOH = 1: 1 (20mL ), was added NaBH ₄ (286mg, 7.55mmol), the reaction was heated at reflux for 1h. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)

Step 6: Synthesis of Compounds BB-65-A and BB-65-B

Compound BB-65-7 (250 mg, 0.750 mmol) was dissolved in dichloromethane (10 mL). Compound BB-2-6 (145 mg, 0.825 mmol), HATU (342 mg, 0.900 mmol) and triethylamine (228 mg) , 2.25 mmol), stirred at room temperature for 1 h. Water was added, and the mixture was extracted with methylene chloride (3×30 mL). EtOAcjjjjjjjjjjjjjjjjj BB-65-A (90 mg, 24%) and BB-65-B (90 mg, 24%). LCMS m/z : 492.0 [M+H] ⁺ .

Reference Example 66: Fragments BB-66-A and BB-66-B

synthetic route:

Step 1: Synthesis of Compound BB-66-2

Iodine acetate (4.8 g, 15.0 mmol) was slowly added to a suspension containing sodium p-toluenesulfinate (7.1 g, 40.0 mmol) and potassium iodide (1.6 g, 10.0 mmol) in acetonitrile (40 mL) at room temperature. In the solution, vigorous stirring was continued for 1 hour at room temperature after the addition was completed. Then the reaction was quenched by the addition of a saturated solution of sodium sulfite (100 mL) and neutralized with a saturated sodium bicarbonate solution to weakly basic (pH=8~9), stirring was continued for half an hour and extracted with ethyl acetate (500 mL×3). The combined organic phases were washed with water (100 mL) and brine (100 mL). The obtained crude product was dissolved in 40 mL of acetonitrile, and DBU (6.7 g, 38.0 mol) was added to obtain a brown-black solution. After stirring at this temperature for 2 hours, it was filtered, and the filtrate was diluted with 1 M hydrochloric acid (50 mL), saturated sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL) were washed and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified mjjjjjjjjjjjj 700.0 mg, yield: 30.4%). _{^{1 H NMR (400MHz, CDCl 3}} ): δ: 7.72 (d, 2H, J = 8.0Hz), 7.57 (s, 1H), 7.29 (d, 2H, J = 8.0Hz), 4.05 (t, 2H, J =12.0), 2.41 (s, 3H), 2.15 (t, 2H, J = 12.0), 1.67-1.60 (m, 2H).

Step 2: Synthesis of Compound BB-66-3

A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 12.6 mL, 12.6 mmol) was slowly added dropwise to the compound BB-65-4 (1.0 g, 4.2 mmol) and the compound BB-66-2 (1.2 g). In a solution of 6.3 mmol) in tetrahydrofuran (10 mL), after the dropwise addition of the potassium potassium butoxide solution, the ice bath was removed and stirred at room temperature until the reaction was completed. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The title compound BB-66-3 (yield: EtOAc, EtOAc: EtOAc: LCMS m/z : 278.0 [M+H] ⁺ .

Step 3: Synthesis of Compound BB-66-4

Phosphorus oxychloride (643.8 mg, 4.2 mmol) was slowly added dropwise to the compound BB-66-3 (200.0 mg, 0.7 mmol) and the compound 2-pyrrolidone (306.0 mg, 3.5 mmol) in tetrahydrofuran (5 mL) under ice bath. In the solution, after the dropwise addition of the phosphorus oxychloride is removed, the ice bath is removed, and the mixture is stirred at room temperature until the reaction is completed. The reaction solution was slowly poured into a vigorously stirred 10 mL aqueous sodium acetate solution, and neutralized to pH with a 2N aqueous sodium hydroxide solution. 9. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was dissolved in 10 mL of methanol, and sodium borohydride was slowly added to the solution under ice bath, and then the mixture was heated to reflux overnight. After the reaction was quenched with water, EtOAc EtOAc (EtOAc (EtOAc) Solid, 200.0 mg, yield: 80.6%).

Step 4: Synthesis of Compounds BB-66-A and BB-66-B

Compound BB-66-4 (200.0 mg, 0.5 mmol), compound BB-2-6 (111.0 mg, 0.6 mmol) and HATU (228.0 mg, 0.6 mmol) were dissolved in dichloromethane (10.0 mL) at room temperature After triethylamine (101.2 mg, 8.4 mmol) was added dropwise slowly, stirring was continued at room temperature overnight, and then 20 mL of water was added, and then extracted with dichloromethane (20 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate. -66-A (purple solid, 20.0 mg, yield: 12.0%) and compound BB-66-B (purpury solid, 15.0 mg). LCMS m/z : 506.0 [M+H] ⁺ .

Example 1: AG_015

synthetic route:

Step 1: Synthesis of Compound AG_015

Compound BB-48 (20 mg, 39.8 mmol) and compound BB-21 (47 mg, 0.11 mmol) were dissolved in THF/DMF/H ₂ O = 1:1:1 (6 mL) and Pd(dppf)Cl ₂ 3 mg, 3.98 mmol) and sodium carbonate (12 mg, 119 mmol), and the reaction mixture was reacted at 100 ° C for 4 hours under a nitrogen atmosphere. After adding water (10 mL), EtOAc (EtOAc) (EtOAc) 15%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 10.76 (br, 1H), 9.46 (br, 1H), 9.08 (br, 1H), 7.80-7.33 (m, 9H), 5.51-5.23 (m, 3H), 4.62-4.26 (m, 1 H), 4.18-4.06 (m, 1H), 3.86-3.61 (m, 7H), 3.37-3.30 (m, 1H), 2.77-2.64 (m, 2H), 2.57-2.37 ( m, 2H), 2.17-2.06 (m, 2H), 2.06-1.99 (m, 6 H), 1.81-1.69 (m, 7H), 0.90-0.43 (m, 12H). LCMS m/z : 792.6 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of step 1 in AG_015 and HPLC separation:

Example 11: AG_014

synthetic route:

Step 1: Synthesis of Compound AG_014

Compound BB-54-10 (55 mg, 0.113 mmol) and compound BB-21 (47 mg, 0.113 mmol) were dissolved in THF/DMF/H2O = 1:1:1 (6 mL) and Pd(dppf)Cl ₂ 5 mg, 0.007 mmol) and sodium carbonate (36 mg, 0.338 mmol), and the reaction mixture was reacted at 100 ° C for 4 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.88-7.63 (m, 7H), 7.63-7.53 (m, 1H), 7.49-7.38 (m, 1H), 5.25-5.23 (m, 1H), 4.52-4.42 (m, 2H), 4.22-4.12 (m, 1H), 3.67-3.63 (m, 2H), 3.63-3.61 (m, 7H), 3.50-3.45 (m, 1H), 2.80-2.60 (m, 2H) , 2.57-2.52 (m, 4H), 2.45-2.25 (m, 4H), 2.24-2.01 (m, 6H), 0.99-0.88 (m, 12H). LCMS: m/z, 778.5 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of step 1 in AG_014 and HPLC separation:

Example 65: AG_060

synthetic route:

Step 1: Synthesis of Compound AG_060

Compound BB-63 (mixture of BB-63-A and BB-63-B, 30 mg, 61.2 mmol) and compound BB-21 (37 mg, 73.4 mmol) were dissolved in THF/DMF/H ₂ O = 1:1: 1 (6 mL), Pd(dppf)Cl ₂ (5 mg, 6.12 mmol) and sodium carbonate (20 mg, 183.5 mmol) were successively added, and the reaction mixture was reacted at 100 ° C for 4 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. %). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 10.81 (br, 1H), 10.42 (br, 1H), 10.02 (br, 1H), 7.78-7.71 (m, 1H), 7.58-7.43 (m, 5H), 7.25-7.21 (m, 3H), 5.63-5.59 (m, 2H), 5.46-5.41 (m, 2H), 5.03 (s, 2H), 4.93-4.87 (m, 2H), 4.49-4.41 (m, 2H) ), 3.96-3.49 (m, 8H), 3.11-3.09 (m, 1H), 2.53-2.34 (m, 1H), 2.26-1.90 (m, 8H), 1.11 - 0.87 (m, 12H). LCMS m/z : 780.5 [M+H] ⁺ .

Example 66: AG_060_B

synthetic route:

Step 1: Synthesis of Compound AG_060_B

Compound BB-63-A (30 mg, 61.2 mmol) and compound BB-21 (36 mg, 73.4 mmol) were dissolved in THF/DMF/H ₂ O = 1:1:1 (6 mL) and Pd(dppf)Cl was added in sequence. ₂ (5 mg, 6.1 mmol) and sodium carbonate (19 mg, 183.5 mmol), and the reaction mixture was reacted at 100 ° C for 4 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. %). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 10.79 (br, 1H), 10.41 (br, 1H), 10.01 (br, 1H), 7.78-7.72 (m, 1H), 7.57-7.44 (m, 5H), 7.24-7.20 (m, 3H), 5.64-5.59 (m, 2H), 5.46-5.39 (m, 2H), 5.01 (s, 2H), 4.93-4.86 (m, 2H), 4.47-4.41 (m, 2H) ), 3.94-3.49 (m, 8H), 3.11-3.08 (m, 1H), 2.51-2.34 (m, 1H), 2.27-1.90 (m, 8H), 1.12-0.86 (m, 12H). LCMS m/z : 780.3 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of step 1 in AG_060_B and HPLC separation:

Example 81: AG_122_A

synthetic route:

Step 1: Synthesis of Compound AG_122_A

Compound BB-65-A (30 mg, 0.061 mmol) and compound BB-21 (36 mg, 0.073 mmol) were dissolved in THF/DMF/H2O = 1:1:1 (6 mL), and Pd(dppf)Cl ₂ was added sequentially. 5 mg, 0.007 mmol) and sodium carbonate (19 mg, 0.184 mmol), and the reaction mixture was reacted at 100 ° C for 4 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.14-9.12 (br, 1H), 7.82-7.80 (br, 1H), 7.57-7.51 (m, 5H), 7.40-7.33 (m, 2H), 7.21-7. (m, 2H), 5.49-5.40 (m, 2H), 5.32-5.25 (m, 2H), 4.93-4.89 (m, 2H), 4.33-4.31 (m, 2H), 3.82-3.62 (m, 8H) , 3.50-3.45 (m, 1H), 3.05-2.98 (m, 3H), 2.38-2.22 (m, 2H), 2.18-2.05 (m, 4H), 2.02-1.88 (m, 2H), 1.08-0.98 ( m, 1H), 0.92-0.86 (m, 11H).

Example 82: AG_122_B

synthetic route:

Step 1: Synthesis of Compound AG_122_B

Compound BB-65-B (30mg, 0.061mmol) and Compound BB-21 (36mg, 0.073mmol) was dissolved in THF / DMF / H2O = 1: 1: 1 (6mL), were added Pd (dppf) Cl ₂ ( 5 mg, 0.007 mmol) and sodium carbonate (19 mg, 0.184 mmol), and the reaction mixture was reacted at 100 ° C for 4 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.80-10.70 (br, 1H), 10.40-10.30 (br, 1H), 9.14-9.12 (br, 1H), 7.78-7.68 (m, 1H), 7.58-7.49 (m, 7H), 7.21-7.19 (m, 2H), 5.41-5.38 (m, 2H), 5.28-5.26 (m, 2H), 4.92-4.89 (m, 2H), 4.32-4.25 (m, 2H) , 3.92-3.82 (m, 2H), 3.72-3.68 (m, 3H), 3.59-3.55 (m, 4H), 3.04-2.98 (m, 3H), 2.41-2.28 (m, 2H), 2.12-1.95 ( m, 6H), 1.04-0.84 (m, 12H).

Example 83: AG_114_A

synthetic route:

Step 1: Synthesis of Compound AG_114_A

Compound BB-66-A (15.0 mg, 0.03 mmol), compound BB-21 (14.7 mg, 0.03 mmol), Pd(dppf)Cl ₂ (0.7 mg, 0.001 mmol) and sodium carbonate (9.5 mg, 0.09 mmol) a 50mL round bottom flask, N ₂ protection. THF (1 mL), DMF (1 mL), and H ₂ O (1 mL) were poured, and the reaction system was heated to 90 ° C for 2 hours, the heating was stopped, and the mixture was allowed to cool. 5 mL of water was added to the reaction liquid, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate _{^{1 H NMR (400MHz, CDCl 3}} ): δ: 7.81-7.48 (m, 8H), 7.21 (s, 1H), 5.39-5.14 (m, 4H), 4.35-4.07 (m, 5H), 3.61-3.55 ( m, 8H), 2.72-2.54 (m, 3H), 2.23-1.96 (m, 9H). LCMS m/z : 794.3 [M+H] ⁺ .

Example 84: AG_114_B

synthetic route:

Step 1: Synthesis of Compound AG_114_B

Compound BB-66-B (15.0 mg, 0.03 mmol), compound BB-21 (14.7 mg, 0.03 mmol), Pd(dppf)Cl ₂ (0.7 mg, 0.001 mmol) and sodium carbonate (9.5 mg, 0.09 mmol) a 50mL round bottom flask, N ₂ protection. THF (1 mL), DMF (1 mL), and H ₂ O (1 mL) were poured, and the reaction system was heated to 90 ° C for 2 hours, the heating was stopped, and the mixture was allowed to cool. 5 mL of water was added to the reaction liquid, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate _{^{1 H NMR (400MHz, CDCl 3}} ): δ: 7.68-7.52 (m, 8H), 7.21 (s, 1H), 5.39-5.14 (m, 4H), 4.35-4.07 (m, 5H), 3.61-3.55 ( m, 8H), 2.44-1.96 (m, 12H), 0.95-0.871 (m, 12H). LCMS m/z : 794.3 [M+H] ⁺ .

The compounds in the following table were synthesized by referring to the synthesis method of step 1 in AG_114_A and HPLC separation:

Example 86: AG_095

synthetic route:

Step 1: Synthesis of Compound AG_095-1

Compound BB-59-3 (1.00 g, 3.43 mmol) and compound BB-1-6 (788 mg, 4.12 mmol) and HATU (3.02 g, 4.12 mmol) were dissolved in dichloromethane (30 mL). Isopropylethylamine (885 mg, 6.88 mmol) was slowly added and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (30mLx 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: PE: EA = 1:1) to give the title compound AG_095-1 (yellow solid, 220 mg, yield 14%) LCMS m/z : 464 [M+H ] ⁺ .

Step 2: Synthesis of compounds AG_095-2 and AG_09-3

The compound AG_095-1 (200 mg, 0.43 mmol) was dissolved in 5 mL of DMF, and NCS (63 mg, 0.47 mmol) was slowly added and allowed to react overnight at room temperature. The reaction was quenched with EtOAc (EtOAc (EtOAc) (EtOAc) 20 mg, yield 9%) and AG_095-3 (white solid, 37 mg, yield 17%). ^{AG_095-2: 1 H-NMR (400MHz} , CDCl3): δ 9.75 (s, 1H), 7.48 (s, 4H), 6.00 (d, J = 2.4Hz, 1H), 5.66 (d, J = 8.0Hz, 1H), 5.32-5.29 (m, 1H), 4.52 (t, J = 3.8 Hz, 1H), 3.79-3.52 (m, 6H), 3.16 (s, 3H), 2.24-2.06 (m, 4H), 1.09 (d, J = 6.4 Hz, 3H). ^{AG_095-3: 1 H-NMR (400MHz} , CDCl 3): δ: 9.24 (s, 1H), 7.41 (d, J = 8.4Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 6.32 ( d, J = 3.2 Hz, 1H), 5.63 (d, J = 7.6 Hz, 1H), 5.40 - 5.37 (m, 1H), 4.79 - 4.76 (m, 1H), 3.91-3.88 (m, 1H), 3.82 - 3.79 (m, 1H), 3.70-3.67 (m, 4H), 3.41 (s, 3H), 2.39-2.00 (m, 4H), 1.14 (d, J = 6.4 Hz, 3H).

Step 3: Synthesis of Compound AG_095

Compound AG_095-2 (37 mg, 0.074 mmol), BB-25 (38 mg, 0.074 mmol) was dissolved in mixed solvent DMF / THF / H ₂ O (2 mL / 2 mL / 2 mL), then Pd(dppf)Cl ₂ ( 5 mg, 0.007 mmol), and Na ₂ CO ₃ (24 mg, 0.22 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C for 2 hours under N ₂ protection, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude product was purified by preparative HPLC to afford the title compound AG-095 (white solid, 16 mg, yield 27%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 8.83 (s, 1H), 7.87-7.46 (m, 8H), 7.15 (s, 1H), 6.03 (s, 1H), 5.71-5.66 (m, 2H) , 5.35 (s, 2H), 4.55 (s, 1H), 3.92-3.56 (m, 11H), 3.36-3.19 (m, 5H), 2.77 (s, 1H), 2.31-2.94 (m, 8H), 1.24 -1.13 (m, 6H). LCMS m/z : 804[M+H] ⁺ .

Example 87: AG_094

synthetic route:

Step 1: Synthesis of Compound AG_094

Compound AG_095-3 (20 mg, 0.040 mmol), BB-25 (21 mg, 0.040 mmol) was dissolved in mixed solvent DMF / THF / H ₂ O (2mL / 2mL / 2mL), then Pd(dppf)Cl ₂ ( 3 mg, 0.004 mmol) and Na ₂ CO ₃ (14 mg, 0.12 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C under N ₂ for 2 hours, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude product was purified by preparative HPLC to afford the title compound AG-094 (white solid, 14 mg, yield 44%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 9.74 (br, 1H), 7.54-7.40 (m, 8H), 6.98 (s, 1H), 6.38 (d, J = 2.4Hz, 1H), 5.69-5.66 (m, 1H), 5.33-5.29 (m, 2H), 4.71-4.69 (m, 1H), 4.53-4.50 (m, 1H), 3.92-3.67 (m, 10), 3.45-3.31 (m, 5H) , 2.71-2.69 (m, 1H), 2.31-2.94 (m, 8H), 1.24-1.19 (m, 6H); LCMS m/z : 804 [M+H] ⁺ .

Example 88: AG_087

synthetic route:

Step 1: Synthesis of Compound AG_087-1

Compound BB-59-4 (100 mg, 0.24 mmol) was dissolved in 5 mL DMF, NCS (33 mg, 0.24 mmol) was slowly added and allowed to react overnight at room temperature. The reaction was quenched with EtOAc (EtOAc m. Yield: 24%). ¹ H-NMR (400 MHz, CDCl 3 ): δ: 9.91 (br, 1H), 7.74 - 7.38 (m, 4H), 5.94 (d, J = 2.4 Hz, 1H), 5.23-5.17 (m, 2H), 4.23 - 4.18 (m, 1H), 3.61-3.59 (m, 1H), 3.53-3.51 (m, 2H), 2.15 - 1.88 (m, 6H), 0.95 - 0.80 (m, 6H).

Step 2: Synthesis of Compound AG_087

Compound AG-087-1 (26 mg, 0.054 mmol), BB-21 (27 mg, 0.054 mmol) was dissolved in mixed solvent DMF / THF / H ₂ O (2 mL / 2 mL / 2 mL), then Pd(dppf)Cl was added ₂ (4 mg, 0.0054 mmol), and Na ₂ CO ₃ (17 mg, 0.16 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C under N ₂ for 2 hours, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude product was purified by preparative HPLC to afford the title compound </ RTI></RTI></RTI></RTI></RTI> (white solid, 3 mg, yield: 7%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 10.68 (br, 0.4H), 10.27 (br, 1H), 9.92 (br, 1H), 7.74-7.40 (m, 8H), 7.16 (s, 1H), 5.98(s,1H), 5.35-5.20(m,4H), 4.25-4.23(m,2H), 3.77-3.51(m,9H),3.08-2.93(m,1H),2.27-1.90(m,8H ), 0.95-0.80 (m, 12H); LCMS m/z : 772[M+H] ⁺ .

Example 89: AG_118_B

synthetic route:

Step 1: Synthesis of Compound AG_118_B

The compound AG_118_B was synthesized by referring to the synthesis method of the step 1 in AG_114_A and HPLC separation. ^{1 H-NMR (400MHz, CDCl3} ): δ: 9.79 (br, 0.4H), 9.44 (br, 1H), 7.69-7.43 (m, 8H), 7.22 (s, 1H), 6.52 (s, 1H), 6.29-6.00 (m, 2H), 5.70-5.68 (m, 1H), 5.39-5.37 (m, 1H), 4.56-4.49 (m, 1H), 3.87-3.68 (m, 10H), 3.45-3.27 (m , 6H), 2.91-2.77 (m, 1H), 2.33-1.54 (m, 10H), 1.28-1.16 (m, 6H); LCMS m/z : 784 [M+H] ⁺ .

Example 90: AG_096

synthetic route:

Step 1: Synthesis of Compound AG_096-2-1

Compound AG_096-1 (10 g, 64.03 mmol) was dissolved in 250 mL of THF, and 2.0 M LDA solution (38.42 mL, 76.83 mmol) was slowly added at -78 ° C. After the addition was completed, the reaction was carried out at -78 ° C for 1 hour, and then Tf ₂ O (21.68 g, 76.83 mmol) was slowly added and allowed to warm to room temperature overnight. The mixture was extracted with EtOAc EtOAc (EtOAc m. The solvent was evaporated, and the crude material was purified mjjjjlililililililililililililililililili LCMS m/z : 289 [M+H] ⁺ .

Step 2: Synthesis of Compound AG_096-3

In a 500 mL round bottom flask, compound AG_096-2-1 (13.00 g, 45.10 mmol) and AG_096-2-2 (11.42 g, 70.77 mmol), catalyst Pd(dppf)Cl2 (3.31 g, 4.51 mmol), K ₂ CO ₃ (18.70 g, 135.30 mmol) was dissolved in 200 mL of dioxane and 60 mL of water, protected with nitrogen, and heated to 80 ° C for 2 hours. After completion of the reaction, 200 mL of water was added and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, 3 (yellow solid, 11.5 g, yield 84%). LCMS m/z : 206 [M + H - 100] ⁺ .

Step 3: Synthesis of Compound AG_096-4

Compound AG_096-3 (8.6 g, 28.16 mmol) was dissolved in 150 mL of THF, and 2.0 M LDA solution (28.16 mL, 56.33 mmol) was slowly added at -78 ° C. After the addition was completed, the reaction was carried out at -78 ° C for 1 hour, then Iodine (8.58 g, 33.80 mmol) was naturally warmed to room temperature for 1 hour. The mixture was extracted with EtOAc EtOAc (EtOAc m. The solvent was evaporated, and the crude product was purified and purified eluted eluted eluted elut elut elut elut elut elut elut LCMS m/z : 332 [M + H - 100] ⁺ .

Step 4: Synthesis of Compound AG_096-5

Compound AG_096-4 (4.2 g, 9.74 mmol) was dissolved in 100 mL of ethanol, and a 2.0 M aqueous NaOH solution (24 mL, 48.69 mmol) was slowly added, and the mixture was heated to 90 ° C for 4 hours. The mixture was extracted with aq. EtOAc (EtOAc) (EtOAc) The solvent was evaporated, and the title compound was mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS m/z : 304 [M+H] ⁺ .

Step 5: Synthesis of Compound AG_096-6

Compound AG_096-5-1 (300 mg, 0.99 mol) and compound AG_096-5-2 (107 mg, 0.99 mol) were dissolved in 20 mL of acetonitrile, and DIC (125 mg, 0.99 mol) was slowly added and allowed to react overnight at room temperature. Filtration, and the filtrate was concentrated under reduced pressure to give purified crystals. LCMS m/z : 394 [M+H] ⁺ .

Step 6: Synthesis of Compound AG_096-7

In a 100 mL round bottom flask, compound AG_096-6 (200 mg, 0.51 mmol) and 4-bromo-phenylboronic acid (102 mg, 0.51 mmol), catalyst Pd(dppf)Cl ₂ (37 mg, 0.051 mmol), K ₂ CO ₃ (211 mg, 1.53 mmol) was dissolved in 20 mL of dioxane and 3 mL of water, protected with nitrogen, and heated to 80 ° C for 2 hours. After completion of the reaction, 20 mL of water was added and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, 7 (yellow solid, 140 mg, yield 65%). LCMS m/z : 422 [M+H] ⁺ .

Step 7: Synthesis of Compound AG_096-8

Compound AG_096-7 (160 mg, 0.38 mmol), BB-25 (194 mg, 0.38 mmol) was dissolved in a mixed solvent DMF/THF/H ₂ O (10 mL / 10 mL / 10 mL), then Pd(dppf)Cl ₂ ( 28 mg, 0.038 mmol) and Na ₂ CO ₃ (120 mg, 1.14 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C for 2 hours under N ₂ protection, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude material was purified mjjjjjjj LCMS m/z : 728 [M+H] ⁺ .

Step 8: Synthesis of Compound AG_096

The compound AG_096-8 (110 mg, 0.15 mmol) was dissolved in 5 mL of MeOH and 5 mL of ethyl acetate. The catalyst Pd(OH) ₂ /C (20 mg) was slowly added under argon atmosphere, and H _{2 was} replaced 3 times at room temperature. overnight. Filtration and concentration of the filtrate under reduced pressure afforded crude compound (m.). ^{1 H-NMR (400MHz, CDCl} 3): δ: 9.06 (s, 1H), 8.30-8.27 (m, 1H), 7.78-7.62 (m, 9H), 7.18-7.13 (m, 2H), 6.93-6.91 (m, 1H), 6.42 (s, 1H), 6.01 (s, 1H), 5.81-5.71 (m, 2H), 5.33 (s, 1H), 4.59 (s, 1H), 4.25-4.23 (m, 1H) ), 3.73-3.63 (m, 7H), 3.46-3.24 (m, 5H), 2.89-2.87 (m, 2H), 2.22-1.99 (m, 10H), 1.22-1.13 (m, 3H); LCMS m/ z :, 730 [M+H] ⁺ .

Example 91: AG_103

synthetic route:

Step 1: Synthesis of Compound AG_103-1

The compound 4-bromo-3-fluorobenzoic acid (10 g, 45.66 mmol) and the compound O,N-dimethylhydroxylamine hydrochloride (5.34 g, 54.79 mmol) and HATU (20.85 g, 54.79 mmol) were dissolved in two Methyl chloride (200 mL) was slowly added to diisopropylethylamine (17.67 g, 136.98 mmol) under ice-cooling and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (100mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give the objective compound AG_103-1 as a gray solid (10.3 g, yield 86%). LCMS m/z : 262 [M+H] ⁺ .

Step 2: Synthesis of Compound AG_103-2

Compound AG_103-1 (8.00 g, 30.53 mmol) was dissolved in 250 mL of THF, and methyl Grignard reagent (12.21 mL, 36.63 mmol) was slowly added at -78 ° C, and naturally allowed to react to room temperature for 18 hours. After completion of the reaction, it was quenched with EtOAc (150 mL) The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then evaporated, evaporated, evaporated, evaporated. -2 is a gray solid (4.6 g, yield 69%). LCMS m/z : 217 [M+H] ⁺ .

Step 3: Synthesis of Compound AG_103-3

Compound AG_103-2 (4.6 g, 21.19 mmol), pinacol boron ester (10.76 g, 42.397 mmol), KOAC (8.32 g, 84.78 mmol) and Pd(dppf)Cl ₂ (777 mg, 1.06 mmol) were placed in 250 mL In a three-necked flask, N _{2 was} protected, and 1,4-dioxane (100 mL) was injected, and the reaction system was heated to 90 ° C overnight, and the heating was stopped and naturally cooled. Filtration, the filter cake was washed twice with ethyl acetate, and the obtained filtrate was evaporated to remove solvent. The crude product was purified by chromatography (eluent: petroleum ether: EtOAc = 5:1) Solid (4.2 g, yield 75%). ^{1 H-NMR (400MHz, CDCl} 3): δ: 7.82-7.80 (m, 1H), 7.69-7.68 (m, 1H), 7.58-7.56 (m, 1H), 2.59 (s, 3H), 1.36 (s , 12H).

Step 4: Synthesis of Compound AG_103-4

In a 250 mL round bottom flask, AG_103-3-1 (2.00 g, 7.57 mmol) and AG_103-3-2 (2.371 mg, 7.57 mmol), catalyst Pd(dppf)Cl ₂ (560 mg, 0.76 mmol), K ₂ CO ₃ (3.14 g, 22.7 mmol) was dissolved in 50 mL of dioxane and 10 mL of water, protected with nitrogen, and heated to 80 ° C for 2 hours. After the reaction was completed, 200 mL of water was added and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, evaporated, evaporated It was a gray solid (1.2 g, yield 49%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 7.78-7.68 (m, 2H), 7.43-7.41 (m, 1H), 7.18-7.11 (m, 3H), 3.80 (s, 3H), 2.61 (s, 3H).

Step 5: Synthesis of Compound AG_103-5

Compound AG_103-4 (1.00 g, 3.09 mmol) was dissolved in 50 mL of dichloromethane, and BBr ₃ (1.94 g, 7.74 mmol) was slowly added at -78 ° C, and reacted for 2 hours. After completion of the reaction, it was quenched with EtOAc (30 mL &lt The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give a crude product (yield: petroleum ether: ethyl acetate = 3:1). It was a gray solid (260 mg, yield 27%).

Step 6: Synthesis of Compound AG_103-6

Compound AG_103-5 (30 mg, 0.097 mmol) was dissolved in 5 mL of DMF, K ₂ CO ₃ (67 mg, 0.49 mmol) was added, and the mixture was heated to 120 ° C for 2 hours. After completion of the reaction, 20 mL of water was added and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate LCMS m/z : 289 [M+H] ⁺ .

Step 7: Synthesis of Compound AG_103-7

Compound AG_103-6 (25 mg, 0.086 mmol) was dissolved in 5 mL of dioxane, and Br ₂ (14 mg, 0.086 mmol) was slowly added and allowed to react at room temperature for 2 hours. The reaction mixture was evaporated to dryness crystals crystals crystals

Step 8: Synthesis of compound AG_103-8

Compound AG_103-7 (28 mg, 0.076 mmol) and compound Boc-L-proline (16 mg, 0.076 mmol) were dissolved in dichloromethane (5 mL) and diisopropylethylamine (10 mg, 0.076 mmol) was slowly added. The reaction was carried out overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (10mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound as a brown solid AG_103-8 (35 mg of, yield 92%). LCMS m/z : 402 [M + H - 100] ⁺ .

Step 9: Synthesis of compound AG_103-9

The compound AG_103-8 (35 mg, 0.070 mmol) was dissolved in 10 mL of toluene, and ammonium acetate (54 mg, 0.70 mmol) was added thereto, and the mixture was heated to reflux for 18 hours. The reaction mixture was washed with water and aq. EtOAc. EtOAc. It was a gray solid (27 mg, 80%). LCMS m/z : 482 [M+H] ⁺ .

Step 10: Synthesis of Compound AG_103-10

Compound AG_103-9 (27 mg, 0.056 mmol) was dissolved in 4 mL of dichloromethane, and TFA (1 mL) was slowly added and allowed to react at room temperature for 3 hours. Concentrated under reduced pressure, the resulting residue was dissolved with NaHCO ₃ solution, (10mL x3) and extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a gray solid AG_103-10 (20mg, 93%). LCMS m/z : 382 [M+H] ⁺ .

Step 11: Synthesis of compound AG_103_11

Compound AG_103-10 (20 mg, 0.052 mmol) and compound BB-1-6 (11 mg, 0.056 mmol) and HATU (21 mg, 0.056 mmol) were dissolved in dichloromethane (5 mL) and diisopropyl The amine (13 mg, 0.10 mmol) was slowly added and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (10mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product was purified by preparative plate silica gel (eluent: petroleum ether: acetic acid The title compound AG_103_11 was obtained as a gray solid (25 mg, yield 86%). LCMS m/z : 555 [M+H] ⁺ .

Step 12: Synthesis of Compound AG_103-12

In a 50 mL round bottom flask, 1-BOC-2-pyrroleboronic acid (10 mg, 0.050 mmol) and AG_103-11 (25 mg, 0.045 mmol), catalyst Pd(dppf)Cl ₂ (2 mg, 0.002 mmol), K ₂ CO ₃ (19 mg, 0.14 mmol) was dissolved in 2 mL of dioxane and 0.7 mL of water, protected with nitrogen, and heated to 80 ° C for 2 hours. After completion of the reaction, 20 mL of water was added and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated to dryness to give crude crystals (yield: petroleum ether: ethyl acetate = 1:1). It was a gray solid (24 mg, yield 83%). LCMS m/z : 642 [M+H] ⁺ .

Step 13: Synthesis of Compound AG_103-13

The compound AG_103-12 (24 mg, 0.037 mmol) was dissolved in 2 mL of each of methanol and tetrahydrofuran, and sodium methoxide (16 mg, 0.30 mmol) was slowly added and allowed to react at room temperature for 3 hours. The reaction was quenched with EtOAc EtOAc (EtOAc) LCMS m/z : 542 [M+H] ⁺ .

Step 14: Synthesis of compound AG_103-14

The compound AG_103-13 (18 mg, 0.030 mmol) and 2-pyrrolidone (17 mg, 0.20 mmol) were dissolved in dichloromethane (5 mL), and POCI ₃ (25 mg, 0.17 mmol) was slowly added to the reaction under nitrogen overnight. . The reaction solution was slowly poured into a saturated aqueous solution of ammonium acetate, and the mixture was quenched with NaOH (10M). The mixture was adjusted to pH 9 to 10, and extracted with dichloromethane (10 mL×3). Filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in MeOH (10 mL). EtOAc. The mixture was diluted with EtOAc (EtOAc) (EtOAc m. ). LCMS m/z : 611 [M+H] ⁺ .

Step 15: Synthesis of Compound AG_103

Compound AG_103-14 (15 mg, 0.026 mmol) and compound BB-1-6 (6 mg, 0.029 mmol) and HATU (11 mg, 0.029 mmol) were dissolved in dichloromethane (2 mL) and diisopropyl The amine (6 mg, 049 mmol) was added slowly and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (10mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative HPLC to give the objective compound AG-103 as a gray solid (4 mg, yield 21%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 10.12 (br, 0.5H), 9.97 (br, 0.5H), 7.83-7.48 (m, 6H), 7.29 (s, 1H), 6.47 (d, J = 3.6 Hz, 1H), 6.07 (s, 1H), 5.74-5.67 (m, 2H), 5.43-5.38 (m, 2H), 4.60-4.38 (m, 2H), 3.78-3.66 (m, 12H), 3.40 - 3.23 (m, 6H), 2.89-2.76 (m, 1H), 2.26-2.08 (m, 7H), 1.24-1.13 (m, 6H); LCMS m/z : 784 [M+H] ⁺ .

Example 92: AG_085

synthetic route:

Step 1: Synthesis of Compound AG_085-2

Compound AG_085-1 (3.00 g, 12.24 mol) was dissolved in DMSO (30 mL), KOH (2.75 g, 48.96 mol) was slowly added at 0 ° C, stirred under nitrogen for 1 hour, then CH ₃ I (2.80 g, 34.27) Mol) reaction overnight. The reaction was quenched with EtOAc (EtOAc) (EtOAc). , yield 96%). ^{1 H-NMR (400MHz, CDCl3} ): δ: 8.05-7.97 (m, 2H), 7.76 (d, J = 8.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.60-7.52 (m , 2H), 4.49 (s, 2H), 1.51 (s, 6H).

Step 2: Synthesis of Compound AG_085-4

Compound AG_085-2 (2.30 g, 14.58 mmol) and compound AG_085-3 (3.32 g, 12.15 mmol) were dissolved in dichloromethane (100 mL), and AlCl ₃ (1.94 g, 14.58 mmol) was slowly added and reacted overnight under nitrogen atmosphere. . The reaction was quenched with EtOAc (EtOAc)EtOAc. Ester = 10:1) The title compound AG_085-4 (brown solid, 1.4 g, yield 87%) was isolated. ^{1 H-NMR (400MHz, CDCl3} ): δ: 8.05-7.97 (m, 2H), 7.76 (d, J = 8.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.60-7.52 (m , 2H), 4.49 (s, 2H), 1.51 (s, 6H).

Step 3: Synthesis of Compound AG_085-5

Compound AG_085-4 (1.2 g, 3.04 mmol) and compound Boc-L-proline (655 mg, 3.04 mmol) were dissolved in dichloromethane (20 mL) and diisopropylethylamine (433 mg, 3.35 mmol) ), reacted overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound AG_085-5 (1.4g brown solid, yield Rate 87%). LCMS m/z : 428 [M + H - 100] ⁺ .

Step 4: Synthesis of compound AG_085-6

The compound AG_085-5 (1.4 g, 2.65 mmol) was dissolved in 50 mL of toluene, and ammonium acetate (3.06 g, 39.74 mmol) was added thereto, and the mixture was heated to reflux for 18 hours. The reaction mixture was washed with water and aq. EtOAc. EtOAc (EtOAc m. 6 (grey solid, 800 mg, 59%). LCMS m/z : 508 [M+H] ⁺ .

Step 5: Synthesis of Compound AG_085-7

The compound AG_085-6 (400 mg, 0.79 mmol) was dissolved in 10 mL of dichloromethane, and TFA (3 mL) was slowly added and allowed to react at room temperature for 3 hours. Concentrated under reduced pressure, the resulting residue was dissolved NaHCO ₃ solution, (30mL x3) and extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound AG_085-7 (gray solid, 280 mg of, 87%). LCMS m/z : 408 [M+H] ⁺ .

Step 6: Synthesis of compound AG_085-8

Compound AG_085-7 (200 mg, 0.49 mmol) and compound BB-2-6 (103 mg, 0.59 mmol) and HATU (224 mg, 0.59 mmol) were dissolved in dichloromethane (10 mL) and diisopropyl The amine (127 mg, 0.98 mmol) was slowly added and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (20mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product was purified by preparative plate silica gel (eluent: petroleum ether: acetic acid The title compound AG_085-8 (gray solid, 220 mg, yield: 79%). LCMS m/z : 565 [M+H] ⁺ .

Step 7: Synthesis of Compound AG_085-9

1-BOC-2-pyrroleboronic acid (54 mg, 0.25 mmol) and AG_085-8 (120 mg, 0.21 mmol) in a 50 mL round bottom flask, catalyst Pd(dppf)Cl ₂ (15 mg, 0.021 mmol), K ₂ CO ₃ (87 mg, 0.63 mmol) was dissolved in 10 mL of dioxane and 3 mL of water, protected with nitrogen, and heated to 80 ° C for 2 hours. After completion of the reaction, 20 mL of water was added and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate LCMS m/z : 652 [M+H] ⁺ .

Step 8: Synthesis of compound AG_085-10

The compound AG_085-9 (120 mg, 0.18 mmol) was dissolved in 10 mL of methanol and tetrahydrofuran, and sodium methoxide (80 mg, 1.47 mmol) was slowly added and reacted at room temperature for 3 hours. The reaction was quenched with EtOAc (EtOAc m. LCMS m/z : 552 [M+H] ⁺ .

Step 9: Synthesis of compound AG_085-11

Compound AG_085-10 (90 mg, 0.16 mmol) and 2-pyrrolidone (83 mg, 0.98 mmol) were dissolved in dichloromethane (10 mL), and phosphorus oxychloride (125 mg, 0.82 mmol) was slowly added under nitrogen The reaction was overnight. The reaction solution was slowly poured into a saturated aqueous solution of ammonium acetate, and the mixture was quenched with NaOH (10M). The mixture was adjusted to pH 9 to 10, and extracted with dichloromethane (10 mL×3). Filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in MeOH (10 mL). EtOAc (EtOAc) The mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) ). LCMS m/z : 621 [M+H] ⁺ .

Step 10: Synthesis of Compound AG_085

Compound AG_085-11 (40 mg, 0.063 mmol) and compound BB-1-6 (15 mg, 0.077 mmol) and HATU (29 mg, 0.077 mmol) were dissolved in dichloromethane (5 mL) and diisopropyl The amine (19 mg, 0.13 mmol) was slowly added and allowed to react overnight under nitrogen. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (10mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative HPLC to give the title compound AG-085 as a gray solid (5 mg, yield 10%). ^{1 H-NMR (400MHz, CDCl3} ) δ: 10.69 (br, 0.3H), 10.33 (br, 0.5H), 10.11 (br, 0.5H), 9.87 (br, 0.5H), 7.83-7.63 (m, 3H ), 7.49-7.39 (m, 3H), 7.24 (s, 1H), 6.41 (s, 1H), 6.07 (s, 1H), 5.74-5.67 (m, 1H), 5.42-5.27 (m, 3H), 4.53 (s, 1H), 4.31 (s, 1H), 3.83-3.60 (m, 10H), 3.39-3.20 (m, 5H), 2.89-2.76 (m, 1H), 2.37-2.08 (m, 8H), 1.59 (s, 6H), 1.24 - 0.87 (m, 9H); LCMS m/z : 794 [M+H] ⁺ .

Example 93: AG_081_A and AG_081_B

synthetic route:

Step 1: Synthesis of Compound AG_081-1

Compound BB-22 (180 mg, 1.36 mmol) and oxalyl chloride (200 mg, 0.78 mmol) were dissolved in dichloromethane (10 mL), and diisopropylethylamine (352 mg, 2.78 mmol) was slowly added. The reaction was carried out under nitrogen for 1 hour, then compound BB-59-3 (400 mg, 1.36 mmol) was added to the reaction overnight. Quenched with saturated NaHCO ₃ solution, extracted with dichloromethane (20mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Purification by preparative HPLC to give the crude title compound obtained AG_081-1 (Gray Solid, 130 mg, yield 21%). ¹ H-NMR (400 MHz, CDCl 3 ): δ: 9.91-9.79 (br, 1H), 7.42-7.36 (m, 4H), 6.52-6.43 (br, 1H), 6.36 (m, 1H), 6.03 (s, 1H), 5.18-5.16 (m, 1H), 3.67-3.58 (m, 4H), 3.42-3.40 (m, 1H), 2.28-1.86 (m, 4H), 1.15-1.05 (m, 6H).

Step 2: Synthesis of compounds AG_081_A and AG_081_B

Compound AG_081-1 (50 mg, 0.11 mmol), BB-21 (66 mg, 0.13 mmol) was dissolved in a mixed solvent DMF/THF/H ₂ O (2 mL / 2 mL / 2 mL), then Pd(dppf)Cl ₂ ( 16 mg, 0.022 mmol) and Na ₂ CO ₃ (35 mg, 0.33 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 90 ° C under N ₂ for 2 hours, the heating was stopped, and the mixture was cooled. Water (10 mL) was added, and the mixture was evaporated. The solvent was evaporated, and the crude product was purified by preparative HPLC to afford the title compound AG-081-A (white solid, 6 mg, yield 7%) and AG_081_B (white solid, 5 mg, yield 6%). AG_081_A ¹ H-NMR (400MHz, CDCl3): δ: 9.98-9.84 (br, 1H), 7.82-7.47 (m, 8H), 7.19 (s, 1H), 6.51-6.45 (br, 1H), 6.42 (s ,1H),6.07(s,1H),5.42-5.21(m,3H),4.33-4.31(m,1H),3.82-3.48(m,11H),3.09-2.98(m,1H),2.37-1.88 (m, 8H), 1.16-0.87 ( m, 12H); LCMS: m / z 739 [m + H] + AG_081_B 1 H-NMR (400MHz, CDCl3): & 10.31 (br, 0.5H), 9.88 (br , 0.5H), 7.84-7.37 (m, 8H), 7.21 (s, 1H), 6.53-6.42 (br, 1H), 6.42 (s, 1H), 6.07 (s, 1H), 5.37-5.20 (m, 3H), 4.33-4.31 (m, 1H), 3.80-3.43 (m, 11H), 3.08-3.00 (m, 1H), 2.32-1.93 (m, 8H), 1.15-0.85 (m, 12H); LCMS m /z :739[M+H] ⁺ .

Example 94: AA_007

synthetic route:

Step 1: Synthesis of Compound AA_007-2

1-cyclopentene-1,2-dicarboxylic anhydride (AA_007-1, 690 mg, 5 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and compound BB-22 (660 mg, 5 mmol) was added under nitrogen. After stirring at room temperature for 6 hours, the reaction was completed by TLC, and the solvent was evaporated to give a colorless gum. The above colorless gum was suspended in DMF (20 ml) with potassium carbonate (1.6 g, 11.6 mmol), and 2,4-dibromoacetophenone (BB-1-1, 1.6 g, 5.8 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, and then filtered, and the solvent was evaporated, and the residue was purified by EtOAc EtOAc (EtOAc:EtOAc Powder, 2.0 g, two-step yield 85.6%). LC/MS m/z : 490.8 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_007-3

Compound AA_007-2 (2 g, 4.28 mmol) was dissolved in toluene (20 ml), and ammonium acetate (3.3 g, 42.8 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr., and then the mixture was cooled to room temperature by TLC, and then the mixture was stirred with water (30 ml). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl ether/ethyl acetate=9:1→1:1) to give the title compound AA_007-3 (light yellow) Powder, 1.6 g, yield 83.8%). LC/MS m/z : 448.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_007

Compound AA_007-3 (40 mg, 0.089 mmol), BB-21 (44 mg, 0.088 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether / water (2 ml / 0.2 ml) at room temperature, and added under nitrogen atmosphere. sodium carbonate (20mg, 0.188mmol) and _{Pd (dppf) Cl 2 (6mg} , 0.0081mmol). The mixture was heated to 100 ° C under nitrogen atmosphere, stirred for 8 hours, and after TLC detection, the reaction 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 AA_007 (white powder, 20 mg, yield The rate is 30.6%). LC/MS m/z : 737.2 [M+H] ⁺ .

Example 95: AA_033

synthetic route:

Step 1: Synthesis of Compound AA_033-1

Compound AA_007-3 (300 mg, 0.671 mmol), bis-pinacol borate (255 mg, 1.01 mmol) was dissolved in dioxane (10 ml), and potassium acetate (131 mg, 1.342 mmol) and Pd(dppf)Cl ₂ (50 mg, 0.067 mmol). The reaction was carried out in the microwave at 110 ° C for 2 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 9:1 → 2:1) Compound AA_033-1 (85 mg, yield 25.6%). LC/MS m/z : 495 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_033

Compound AA_007-3 (10 mg, 0.022 mmol), AA_033-1 (10 mg, 0.02 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether/water (2 ml/0.2 ml) at room temperature and added under nitrogen atmosphere. sodium carbonate (4.3mg, 0.0404mmol), and _{Pd (PPh 3) 4 (2mg} , 0.002mmol). The reaction was carried out in a microwave at 100 ° C for 8 hours, and after completion of the reaction 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 AA_033 (white solid, 4.5 mg, yield 30.3%). LC/MS m/z : 735.5 [M+H] ⁺ .

Example 96: AA_008

synthetic route:

Step 1: Synthesis of Compound AA_008

Compound AA_007 (20 mg, 0.027 mmol) was dissolved in methanol (5 mL) and palladium char. The reaction was carried out at 50 ° C under a hydrogen pressure of 50 psi for 12 hours, cooled to room temperature, filtered, and the filtrate was evaporated to dryness. LC/MS m/z : 739.[M+H] ⁺ .

Example 97: AA_138

synthetic route:

Step 1: Synthesis of Compound AA_138-2

3-cyclobutenone (AA_138-1, 30 g, 254.74 mmol), diethyl fumarate (43 g, 249.74 mmol), hydroquinone (0.5 g, 4.5 mmol) in absolute ethanol (45 ml), Placed in a stuffy can. Slowly heat to 125 ° C, stir for 24 hours, TLC detection reaction is completed, cooled to room temperature, the reaction system is a yellow liquid, the reaction solution is slowly added to the sodium carbonate / water (30g, 283mmol / 200ml) solution, stirred at room temperature 10 minutes. Extraction with petroleum ether (100 ml x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and then evaporated. The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ 400 MHz): δ 5.68 (d, J = 2.4 Hz, 2 H), 4.16 - 4.10 (m, 4 H), 2.84 - 2.82 (m, 2 H), 2.44-2.39 (m, 2) H), 2.20-2.17 (m, 2 H), 1.27-1.22 (m, 6 H).

Step 2: Synthesis of Compound AA_138-3

Potassium permanganate (11.2 g, 70.9 mmol) was dissolved in water (60 ml), stirred at room temperature for one hour, cooled in an ice bath, and kept at 10 ° C below the compound AA_138-2 (5 g, 22.1 mmol) of acetone (6 mL) The solution is stirred at room temperature overnight after completion of the dropwise addition. After the reaction is completed by TLC, the reaction is quenched by adding sodium thiosulfate, and the mixture is stirred at room temperature for 20 minutes, then cooled to below 5 ° C in an ice bath, and concentrated hydrochloric acid is added dropwise to adjust the pH to 2, the obtained clarified reaction liquid was extracted three times with a mixed solution of ethyl acetate / tetrahydrofuran (50 mL / 50 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give the title compound AA-138-3 (white Solid, 3.75 g, yield 58.5%). The product is used directly in the next step without purification. ^{1 H NMR (DMSO- d6, 400MHz} ): δ 4.07-4.01 (m, 4 H), 3.01 (d, J = 11.6Hz, 2 H), 2.66-2.59 (m, 2 H), 2.43-2.38 (m , 2 H), 1.15 (t, J = 7.2 Hz, 6 H).

Step 3: Synthesis of Compound AA_138-4

Compound AA-138-3 (3.75 g, 12.9 mmol) was dissolved in acetic anhydride (19 mL). The reaction system was heated to 130 ° C, stirred for 2 hours, sodium acetate (0.94 g, 11.5 mmol) was added in one portion, and stirring was continued at 130 ° C until carbon dioxide was no longer formed, cooled to room temperature, and methanol/water (10 ml/10 ml) was added. The reaction was quenched, stirred at room temperature for 30 min and then extracted with dichloromethane (50ml The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered and evaporated. 2.9 g, 98.6% yield). _{^{1 H NMR (CDCl 3 400MHz)}} : δ 4.19-4.14 (m, 4 H), 3.34-3.31 (m, 2 H), 2.66-2.59 (m, 2 H), 2.59-2.50 (m, 2 H), 1.25 (t, J = 7.6 Hz, 6 H).

Step 4: Synthesis of Compound AA_138-5

Compound AA-138-4 (2.0 g, 8.76 mmol) was dissolved in anhydrous dichloromethane (20 mL). After cooling to 0 ° C, DAST (2.82 g, 17.53 mmol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. After the reaction was completed by TLC, the reaction mixture was poured into ice water (20 ml), and saturated aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to 7-8, and dichloromethane (30 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. The product is used directly in the next step without purification. ¹ H NMR (CDCl 3 , 400 MHz): δ 4.18 (q, J = 7.6 Hz, 4 H), 3.34 - 3.29 (m, 2 H), 2.51-2.34 (m, 4 H), 1.26 (s, d = 7.2 Hz, 6 H).

Step 5: Synthesis of Compound AA_138-6

Sodium hydroxide (959 mg, 23.98 mmol) was dissolved in a mixed solvent of methanol / water (5 ml / 5 ml), and compound AA_138-5 (1.5 g, 5.99 mmol) was added. After stirring at room temperature for 2 hours, the reaction was completed by TLC, and the solvent was evaporated. The residue was dissolved in water (20 ml), and the mixture was adjusted to pH 1-2 with 2M hydrochloric acid and extracted with dichloromethane (20 ml × 3). The organic layer was combined, dried over anhydrous sodium sulfate The milky white solid (912 mg, 5.18 mmol) was dissolved in acetic acid (15 ml), and the reaction system was warmed to reflux and stirred for 3 hr. The black oil (457 mg, 2.59 mmol) was dissolved in tetrahydrofuran (10 ml), BB-22 (343 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction by TLC, the solvent was evaporated to give a viscous oil. (780 mg). The above viscous oil (780 mg, 2.53 mmol) diisopropylethylamine (1.09 g, 5.06 mmol) was dissolved in acetonitrile (5 ml), and 2,4-dibromoacetophenone (BB-1-1, 721.3) Mg, 2.6 mmol). After stirring at room temperature for 3 hours, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether/ethyl acetate=10:1→5:1). , 0.6 g, total yield in four steps of 19.8%). LC/MS m/z : 528.9 [M+Na] ⁺ .

Step 6: Synthesis of Compound AA_138-7

Compound AA_138-6 (600 mg, 1.19 mmol) was dissolved in toluene (10 ml) and EtOAc ( EtOAc, EtOAc (EtOAc) The mixture was heated to reflux with aq. EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated , 90 mg, yield 16%). LC/MS m/z : 487.0 [M+H] ⁺ .

Step 7: Synthesis of Compound AA_138

Using the compound AA_138-7, BB-21 as a raw material, the compound AA_138 was obtained by referring to the synthesis method of the step 3 in AA_00. LC/MS m/z : 775.5 [M+H] ⁺ .

Example 98: AA_160

synthetic route:

Step 1: Synthesis of Compound AA_160-2

Monoethyl fumarate (AA_160-1, 50 g, 347.2 mmol) and potassium carbonate (95.89 g, 693.8 mmol) were suspended in DMF (1500 ml), and benzyl bromide (59.34 g, 346.9 mmol) was added dropwise at room temperature. . After stirring at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (2 L), and washed with water (100 mL×4) and brine (200 mL). The organic layer was combined, dried over anhydrous sodium The product is used directly in the next step without purification. ^{1 H NMR (CDCl3,400MHz): δ} 7.38-7.37 (m, 5 H), 6.90 (s, 2 H), 5.24 (s, 2 H), 4.26 (q, J = 6.8Hz, 2 H), 1.31 (t, J = 6.8 Hz, 3 H).

Step 2: Synthesis of Compound AA_160-3

3-cyclobutyrene (AA_138-1, 15.43g, 130.6mmol), AA_160-2 (30g, 128mmol), hydroquinone (0.24g, 2.18mmol) as raw material, according to the synthesis method of AA_138 step 1, The compound AA_160-3 (36 g, yield 97.5%) was obtained. ^{1 H NMR (CDCl3,400MHz): δ} 7.36-7.31 (m, 5 H), 5.71-5.66 (m, 2 H), 5.19-5.08 (m, 2 H), 4.13-4.07 (m, 2 H), 2.94-2.86 (m, 2 H), 2.43 - 2.42 (m, 2 H), 2.22 - 2.19 (m, 2 H), 1.20 (t, d = 2.8 Hz, 3 H).

Step 3: Synthesis of Compound AA_160-4

The compound AA_160-3 (38 g, 132 mmol), potassium permanganate (64.5 g, 409 mmol) was used as a raw material, water (330 mL) was used as a solvent, and the compound AA_160-4 (44 g, yield 95) was obtained according to the procedure of AA_138 Step 2. %). ¹ H NMR (DMSO_ d ₆ , 400 MHz) δ 7.36-7.31 (m, 5 H), 5.07 (s, 2 H), 4.02-3.98 (m, 2 H), 3.11-3.05 (m, 2 H), 2.66 - 2.62 (m, 2 H), 2.42 - 2.37 (m, 2 H), 1.12 (t, J = 7.2 Hz, 3 H).

Step 4: Synthesis of Compound AA_160-5

Compound AA_160-4 (13.5g, 38.3mmol), acetic anhydride (67.5mL), sodium acetate (2.7g, 33.7mmol) as raw material, according to the synthesis method of AA_138 step 3, to obtain compound AA_160-5 (7.0g, produced The rate is 63.1%). ^{1 H NMR (CDCl3,400MHz) δ 7.36-7.32} (m, 5 H), 5.17 (s, 2 H), 4.14-4.10 (m, 2 H), 3.44-3.36 (m, 2 H), 2.68-2.61 (m, 2 H), 2.56-2.49 (m, 2 H), 1.19 (t, d = 7.2 Hz, 3 H).

Step 5: Synthesis of Compound AA_160-6

Compound AA_160-5 (5.0 g, 17.2 mmol), ethylene glycol (10.6 g, 172 mmol) was dissolved in toluene (150 ml), and p-toluenesulfonic acid monohydrate (163 mg, 0.86 mmol) was added. The reaction system was heated to reflux under a nitrogen atmosphere, and stirred overnight. After completion of TLC, the mixture was cooled to room temperature, washed with water (30 ml × 3) and brine (30 ml). The title compound AA_160-6 (yellow solid, 3.2 g, yield 55%) was obtained after dry solvent. The product is used directly in the next step without purification. ^{1 H NMR (CDCl3,400MHz): δ} 7.35-7.31 (m, 5 H), 5.17-5.11 (m, 2 H), 4.11 (q, J = 2.0Hz, 2 H), 3.91-3.88 (m, 4 H), 3.34 - 3.27 (m, 2 H), 2.25-2.23 (m, 2 H), 2.22 - 2.09 (m, 2 H), 1.19 (t, d = 6.8 Hz, 3 H).

Step 6: Synthesis of Compound AA_160-7

Compound AA_160-6 (3.9 g, 11.7 mmol) was dissolved in ethanol (40 ml) at room temperature and 10% palladium charcoal (0.5 g) was added under nitrogen. The reaction was carried out for 3 hours at 50 ° C under a hydrogen pressure of 1 atm, cooled to room temperature, filtered, and the solvent was evaporated to dryness to give the title compound AA-160-7 (yellow oil, 2.7 g, yield 94.7%); In the next step. ¹ H NMR (CDCl 3 , 400 MHz): δ 4.20 - 4.15 (m, 2 H), 3.94 - 3.90 (m, 4 H), 3.33 - 3.24 (m, 2 H), 2.26-2.23 (m, 2 H), 2.23-2.09 (m, 2 H), 1.27-1.23 (m, 3 H).

Step 7: Synthesis of Compound AA_160-8

Compound AA_160-7 (356 mg, 1.46 mmol) was dissolved in dichloromethane (2 mL), EtOAc (EtOAc (EtOAc) The mixture was stirred at room temperature for 2 hours, and after completion of the reaction by TLC, the solvent was evaporated to give the chlorobenzene intermediate. The above chloro-organic intermediate was dissolved in dichloromethane (5 ml), cooled to below 5 ° C in an ice bath, BB-22 (192.6 mg, 1.46 mmol) was added, and then triethylamine (884 mg, 8.76 mmol) was added dropwise. After stirring at room temperature, the solvent was evaporated under reduced pressure. The yield in two steps was 76%). ^{1 H NMR (CDCl3,400MHz): δ} : 4.77-4.75 (m, 1 H), 4.15-4.04 (m, 2 H), 3.86-3.84 (m, 3 H), 3.72-3.65 (m, 4 H) , 3.48-3.53 (m, 2 H), 2.75-2.25 (m, 2 H), 2.25-2.20 (m, 2 H), 1.20-1.17 (m, 3 H), 1.04-0.97 (m, 6 H) .

Step 8: Synthesis of compound AA_160-9

Compound AA_160-8 (670 mg, 1.87 mmol) was dissolved in a mixed solvent of methanol/water (2.5 ml / 2.5 ml) at room temperature, and lithium hydroxide monohydrate (307 mg, 7.5 mmol) was added. After stirring at 60 ° C for 6 hours, the reaction was completed by TLC, and then cooled to room temperature. The pH was adjusted to 2 to 3 by dropwise addition of 1M hydrochloric acid, and extracted with dichloromethane (50ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated The above carboxylic acid intermediate (210 mg) and potassium carbonate (178 mg, 1.28 mmol) were suspended in DMF (5 ml), and 2,4-dibromoacetophenone (BB-1-1, 177.92 mg, 0.64 mmol) was added at room temperature. ). After stirring at room temperature for 2 hours, the reaction mixture was poured into water (20 ml), and ethyl acetate (50 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and then filtered, evaporated, evaporated. Yield, 700 mg, yield 71%). </RTI>^< / RTI>^<RTIID=0.0></^RTI>

Step 9: Synthesis of Compound AA_160-10

Compound AA-160-9 (70 mg, 0.133 mmol) was dissolved in toluene (20 ml), and ammonium acetate (204 mg, 2.65 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, , 40 mg, yield 60%). LC/MS m/z : 507.1 [M+H] ⁺ .

Step 10: Synthesis of Compound AA_160

Starting from the compound AA_160-10, BB-21, the compound AA_160 was synthesized by referring to the synthesis step 3 of AA_007. LC/MS m/z : 797.5 [M+H] ⁺ .

Example 99: AA_014

synthetic route:

Step 1: Synthesis of Compound AA_014-2

Compound BB-22 (0.5 g, 3.8 mmol) was dissolved in tetrahydrofuran (10 ml), and 1-cyclohexene-1,2-dicarboxylic anhydride (AA_014-1, 0.88 g, 5.78 mmol) was added at 10 °C. After stirring at 10 ° C for 14 hours, the solvent was evaporated to dryness eluted elution elution The above colorless gum was suspended in DMF (15 ml) with potassium carbonate (1.3 g, 9.2 mmol), and 2,4-dibromoacetophenone (BB-1-1, 1.3 g, 4.6 mmol) was added at room temperature. . After stirring at 10 ° C for 12 hours, the reaction was quenched by TLC, and water (10 ml) was then evaporated to ethylamine. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. The yield in two steps was 35.9%). LC / MS (ESI) m / z 482.9 [M + H] +.

Step 2: Synthesis of compound AA_014-3

Compound AA_014-2 (1 g, 2.1 mmol) was dissolved in toluene (60 ml) at room temperature and ammonium acetate (10 g, 130 mmol) was added. The mixture 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, and then the mixture was stirred with water (50 ml), and ethyl acetate (100 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by silica gel chromatography ( petroleum ether / ethyl acetate = 10:1 → 1:1) to give the title compound AA_014-3 (0.2 g) , yield 20%). LC / MS (ESI) m / z 460.9 [M + H] +.

Step 3: Synthesis of Compound AA_014

Compound AA_014-3 (50 mg, 0.11 mmol), BB-21 (54 mg, 0.11 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether / water (2 ml / 0.5 ml) at room temperature, and carbonic acid was added under the protection of nitrogen. sodium (35mg, 0.33mmol) and _{Pd (PPh 3) 4 (13mg} , 0.011mmol). The reaction was carried out in the microwave at 120 ° C for 10 minutes. 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 AA_014 (4.7 mg, yield 6%). LC / MS (ESI) m / z 751.2 [M + H] +. 1 H NMR (400MHz, CD 3 OD) δ 7.84-7.74 (m, 8 H), 7.69-7.67 (m, 2 H), 5.21- 5.18 (m, 1 H), 4.63 (brs, 1 H), 4.26-4.24 (m, 1 H), 4.02-3.99 (m, 1 H), 3.92 (m, 1 H), 3.80 (s, 3 H) ), 3.68 (s, 3 H), 2.40-2.19 (m, 2 H), 2.08 (m, 3 H), 1.82 (m, 3 H), 1.31 (brs, 1 H), 1.21-1.20 (m, 4 H), 1.02-0.92 (m, 12 H).

Example 100: AA_013_A and AA_013_B

synthetic route:

Step 1: Synthesis of Compound AA_013-2

Compound BB-22 (1 g, 7.6 mmol) was dissolved in tetrahydrofuran (10 ml), and cis-1,2-cyclohexanedicarboxylic anhydride (AA_013-1, 1 g, 6.5 mmol) was added at 10 °C. After stirring at 10 ° C for 14 hours, the solvent was evaporated to dryness eluted eluted eluted elution The above colorless gum was suspended in DMF (20 ml) with potassium carbonate (2 g, 14.0 mmol), and 2,4-dibromoacetophenone (BB-1-1, 2 g, 7.0 mmol) was added at 10 °C. After stirring at 10 ° C 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, The yield in two steps was 31.9%). LC/MS m/z 482.8 [M+H] ⁺ .

Step 2: Synthesis of compound AA_013-3

Compound AA_013-2 (1 g, 2.1 mmol) was dissolved in toluene (40 ml), and ammonium acetate (7 g, 91 mmol) was added. The mixture 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, and water (30 ml) was added to quench the reaction, and ethyl acetate (50 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by silica gel column ( petroleum ether / ethyl acetate = 10:1 → 1:1) to give the title compound AA_013-3 (0.4 g) , yield 41.7%). LC/MS m/z 464.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_013

Compound AA_013-3 (300 mg, 0.65 mmol), BB-21 (330 mg, 0.65 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether/water (3 ml/0.5 ml) at room temperature and added under nitrogen atmosphere. sodium carbonate (210mg, 1.95mmol), and _{Pd (PPh 3) 4 (150mg} , 0.13mmol). The reaction was carried out in a microwave at 120 ° C for 10 minutes, and after completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness, and the residue was purified by high-purity liquid to give the title compound AA_013 (53 mg, yield 11%). ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ 0.79-1.35 (m, 14 H) 1.43-2.13 (m, 10 H) 2.17 (br.s., 5 H) 3.03-3.26 (m, 2 H) 3.67 (br.s., 5 H) 3.82 (d, J = 15.31 Hz, 5 H) 4.25 (d, J = 7.03 Hz, 1 H) 4.49 - 4.73 (m, 1 H) 5.19 (br.s., 1 H) 7.33 (br.s., 2 H) 7.68 (br.s., 8 H)

Step 4: Synthesis of AA_013_A and AA_013_B

The compound AA_013 (40 mg, 0.05 mmol) was isolated by chiral SFC to afford the title compound AA_013_A (16.5 mg) and AA_013_B (14.5 mg). ^{AA_013_A: 1 H NMR (400MHz,} CD 3 OD) δ 7.81-7.67 (m, 8 H), 7.34 (brs, 2 H), 5.21-5.18 (m, 1 H), 4.26-4.24 (m, 1 H) , 4.03-3.89 (m, 2 H), 3.85-3.81 (m, 2 H), 3.67 (s, 3 H), 3.52 (brs, 1 H), 3.37 (s, 3 H), 3.25-3.09 (m , 2 H), 2.37-2.20 (m, 2 H), 2.12-1.91 (m, 5 H), 1.51-1.49 (m, 2 H), 1.10-0.92 (m, 14 H), 0.80 (m, 2) H).AA_013_B: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.78-7.68 (m, 8 H), 7.36-7.33 (m, 2 H), 5.19 (m, 1 H), 4.26 - 4.24 (m, 1 H), 4.05-3.91 (m, 2 H), 3.84-3.80 (m, 2 H), 3.67 (s, 3 H), 3.52 (brs, 1 H), 3.37-3.10 (m, 5 H), 2.37-2.29 (m, 2 H), 2.06-1.93 (m, 5 H), 1.51 (m, 2 H), 1.09-0.92 (m, 14 H), 0.79 (m, 2 H).

Example 101: AA_090_A and AA_090_B

synthetic route:

Step 1: Synthesis of Compound AA_090-2

Compound BB-14 (303 mg, 0.814 mmol), AA_090-1 (200 mg, 0.74 mmol) was dissolved in a mixed solvent of DMF / THF / H ₂ O (2 mL / 2 ml / 2 mL) at room temperature under nitrogen atmosphere sodium carbonate (156mg, 1.48mmol) and _{Pd (dppf) Cl 2 (15.7mg} , 0.02mmol). The mixture was heated to 110 ° C under a nitrogen atmosphere, stirred for 2 hours, and after completion of TLC detection, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was purified by chromatography ( petroleum ether / ethyl acetate = 1:2) The title compound AA_090-2 (220 mg, yield 68%) was obtained. LC/MS m/z : 437.0 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_090-3

Compound AA-090-2 (220 mg, 0.504 mmol), N-phenylbis(trifluoromethylsulfonyl)imide (197 mg, 0.55 mmol) was dissolved in tetrahydrofuran (10 ml), and potassium carbonate (104 mg, 0.75 mmol). After stirring at 30 ° C for 5 hours, the reaction was quenched by TLC, and water (10 mL) was then evaporated to ethylamine (50mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. ). LC/MS m/z : 570.0 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_090-4

Compound AA_090-3 (88 mg, 0.154 mmol), bis-pinacol borate (58 mg, 0.232 mmol) was dissolved in dioxane (3 mL) at room temperature, and potassium acetate (29.4 mg) was added under nitrogen. , 0.3 mmol) and Pd(dppf)Cl ₂ (10.9 mg, 0.015 mmol). The mixture was heated to 90 ° C under nitrogen atmosphere, stirred for 4 hours, and after completion of TLC detection, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was subjected to silica gel chromatography ( petroleum ether / ethyl acetate = 9:1 → 1:4) The title compound AA_090-4 (60 mg, yield 70.8%) was obtained. LC/MS m/z : 547.1 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_090

The compound AA_090-4 (10 mg, 0.110 mmol), AA_013-3 (61 mg, 0.132 mmol) was used as a starting material, and the compound AA_090_A (10 mg) and AA_090_B (9 mg) were isolated by a chiral SFC. AA_090_A: LC/MS m/z : 803.6 [M+H] ⁺ .AA_090_B: LC/MS m/z : 804.3 [M+H] ⁺ .

Example 102: AA_029

synthetic route:

Step 1: Synthesis of Compound AA_029-1

Compound AA_013-3 (50 mg, 0.11 mmol), bis-pinacol borate (56 mg, 0.22 mmol) was dissolved in tetrahydrofuran (1 ml) and potassium acetate (33 mg, 0.33 mmol) And Pd(dppf)Cl ₂ (10 mg, 0.011 mmol). The reaction was carried out in a microwave at 100 ° C for 60 minutes, and after completion of the reaction by TLC, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 10:1 → 1:1). Compound AA_029-1 (50 mg, yield 89%). LC/MS m/z 511.1 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_029

Compound AA_013-3 (50 mg, 0.11 mmol), AA_029-1 (50 mg, 0.097 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (0.5 ml / 0.5 ml / 0.5 ml) at room temperature under nitrogen Sodium carbonate (25 mg, 0.22 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.011 mmol) were added under the protection. The reaction was carried out in a microwave at 100 ° C for 30 minutes, and after completion of the reaction 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 AA 029 (7.5 mg, yield 9%). _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.69-7.65 (m, 8 H), 7.56-7.55 (m, 2 H), 4.57-4.45 (m, 2 H), 3.72-3.63 (m, 6 H) , 3.34 (m, 1 H), 3.11 (m, 1 H), 2.12 (m, 1 H), 1.95-1.76 (m, 7 H), 1.65-1.38 (m, 5 H), 7.47-7.75 (m) , 6 H), 0.99-0.92 (m, 18 H), 0.68 (m, 1 H). LC/MS m/z 767.3 [M+H] ⁺ .

Example 103: AA_100

synthetic route:

Step 1: Synthesis of Compound AA_100

Using the compounds AA_029-1, AG_014_10-A as raw materials, the compound AA_100 was prepared by the synthesis method of the step 2 in AA_029. LC/MS m / z 792.5 [M+H] ⁺ .

Example 104: AA_108

synthetic route:

Step 1: Synthesis of Compound AA_108-2

5-Ethyl-2-bromopyridine (AA_108-1, 2.00 g, 10.00 mmol) was dissolved in glacial acetic acid (30 mL). Bromine (1.60 g, 10.01 mmol) was added dropwise, followed by dropwise addition of bromic acid (0.68 mL, 6.00 mmol). After stirring at room temperature for 4 hours, the reaction mixture was evaporated to dryness eluted elution elution The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.88 (s, 1 H), 8.13 (m, 1 H), 7.71 (m, 1 H), 7.63 (m, 1 H), 4.56 (m, 2 H) .

Step 2: Synthesis of Compound AA_108-3

Compound BB-22 (6.5 g, 48.65 mmol) was dissolved in tetrahydrofuran (100 ml), and cis-1,2-cyclohexanedicarboxylic acid anhydride (AA_013-1, 5 g, 32.43 mmol) was added. The mixture was stirred at room temperature for 6 hr. The above-mentioned colorless gum (0.50 g, 1.75 mmol) and diisopropylethylamine (0.27 g, 2.10 mmol) were dissolved in DMF (7 ml), cooled to 0 ° C, and compound AA_108-2 (0.63 g, 1.75 mmol). After stirring at 0 ° C for 2 hours, the reaction was quenched by TLC, and water (20 ml) was evaporated to ethylamine. The organic phase was combined, dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield in two steps was 13%). LC/MS m/z : 485.9 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_108-4

Compound AA_108-3 (0.11 g, 0.19 mmol) was dissolved in toluene (50 ml), and ammonium acetate (0.81 g, 10.51 mmol) was added. The mixture was heated to reflux with aq. EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, Solid, 0.10 g, yield 70%). LC/MS m/z : 466.0 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_108

The compound AA_108 was prepared by using the compound AA_108-4, BB-21 as a raw material, and referring to the synthesis method of the step 3 in AA_013_A. LC/MS m/z : 754.6 [M+H] ⁺ .

Example 105: AA_072

synthetic route:

Step 1: Synthesis of Compound AA_072-2

6-Bromo-2-naphthoic acid (AA_072-1, 10 g, 39.83 mmol), N,O-dimethylhydroxylamine hydrochloride (5.05 g, 51.76 mmol), diisopropylethylamine 15.44 g, 119.49 mmol) was dissolved in DMF (100 mL) and EtOAc (23 g, 59.7 mmol). After stirring at room temperature for 4 hours, after the TLC reaction was completed, methyl tributyl butyl ether (300 ml) was added and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered and evaporated to ethylamine. The product is used directly in the next step without purification. The above Weinreb decylamine (5.8 g, 35.9 mmol) was dissolved in tetrahydrofuran (25 ml), cooled to 0 ° C, and a solution of methyl magnesium bromide in diethyl ether (3 mol / L, 7.9 mL, 23.7 mmol) was slowly added dropwise. After stirring at room temperature for 2 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate and filtered and evaporated The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.43 (s, 1 H), 8.067.85-7.80 (m, 2 H), 7.85-7.80 (m, 2 H), 7.65 (d, J = 2.0 Hz, 1 H).

Step 2: Synthesis of Compound AA_072-3

The compound AA_072-2 (3.5 g, 14.06 mmol) was dissolved in glacial acetic acid (30 mL), and liquid bromine (2.2 g, 14.06 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour, and water was added after TLC detection. (80 mL). The solid was collected by filtration to give the title compound AA_072-3 (white solid, 1.74 g, yield 37.82%). The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.12 - 8.05 (m, 2 H), 7.78 - 7.85 (m, 3 H), 7.83 - 7.68 (m, 1 H), 4.56 (s, 2 H).

Step 3: Synthesis of Compound AA_072-4

Compound BB-22 (1 g, 7.6 mmol) was dissolved in tetrahydrofuran (10 ml), and cis-1,2-cyclohexanedicarboxylic anhydride (AA_013-1, 1 g, 6.5 mmol) was added at 10 °C. After stirring at 10 ° C for 14 hours, the solvent was evaporated to dryness eluted elution elution The above-mentioned colorless gum (1.8 g, 6.3 mmol), and EtOAc (EtOAc, EtOAc, 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 and evaporated. The above yellow oil (2 g, 4.28 mmol) was dissolved in toluene (100 ml), and ammonium acetate (4.9 g, 63 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere and stirred for 15 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, and water (100 ml) was added to quench the reaction, and ethyl acetate (300 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, , 1.0 g, yield 30.3%). LC/MS m/z : 514.8 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_072-5

Compound AA_072-4 (500 mg, 0.97 mmol), bis-pinacol borate (371 mg, 1.46 mmol) was dissolved in dioxane (10 ml) at room temperature, and potassium acetate (191 mg) was added under nitrogen. , 1.95 mmol) and Pd(dppf)Cl ₂ (71.2 mg, 0.097 mmol). The mixture was heated to 100 ° C under a nitrogen atmosphere, stirred for 2 hours, and after completion of the TLC reaction, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was subjected to silica gel chromatography ( petroleum ether / ethyl acetate = 20:1 → 2:1) The title compound AA_072-5 (yellow solid, 395 mg, yield 72.5%) was obtained. ¹ H NMR (CDCl ₃ , 400 MHz): δ : 8.43 - 8.31 (m, 1 H), 8.19 (brs, 1 H), 7.89-7.81 (m, 4 H), 7.34 (m, 1 H), 3.86 ( s, 3 H), 3.22 (m, 1 H), 1.89 (m, 1 H), 1.52-1.50 (m, 1 H), 1.39 (s, 6 H), 1.27-1.23 (m, 12 H), 1.11-1.10 (m, 4 H), 0.88 (m, 2 H), 0.56 (brs, 2 H).

Step 5: Synthesis of AA_072

AA_072-5 (40 mg, 0.071 mmol), BB-27-5 (31 mg, 0.065 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. was added sodium carbonate (14mg, 0.13mmol) and _{Pd (dppf) Cl 2 (5mg} , 0.0065mmol) under nitrogen. 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 HPLC to give the title compound AA_072 (white solid, 4 mg, yield 7.4%). LC/MS ( m/z) 436.[M+H] ⁺ .

The compound in the following table was synthesized by using the compound AA_072-5 as a raw material and referring to the synthesis method of the step 5 in AA_072.

Example 115: AA_096

synthetic route:

Step 1: Synthesis of Compound AA_096-2

Compound BB-22 (6.5 g, 49.24 mmol) was dissolved in tetrahydrofuran (100 ml), and cis-1,2-cyclohexanedicarboxylic acid anhydride (AA_013-1, 5 g, 32.43 mmol) was added. The mixture was stirred at room temperature for 6 hr. The above colorless gum (528 mg, 1.86 mmol), (R)-4-bromo-A-methylbenzylamine (AA_096-1, 385 mg, 1.92 mmol) and diisopropylethylamine (452 mg, 3.5 mmol) Dissolved in DMF (5 ml) and added HATU (730 mg, 1.92 mmol). 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 and evaporated, evaporated, Solid, 0.65 g, two-step yield 75.3%). LC/MS m/z : 469.8 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_096

Compound AA_096-2 (40 mg, 0.0854 mmol), BB-21 (51 mg, 0.102 mmol) was dissolved in a mixed solvent of DMF / THF / H ₂ O (2 ml / 2 ml / 2 ml) and added under nitrogen atmosphere sodium carbonate (18mg, 0.171mmol) and _{Pd (dppf) Cl 2 (3mg} , 0.0041mmol). 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 filtrate was evaporated to dryness. The residue was purified by high-purity liquid to give the title compound AA_096 (white solid, 14 mg. The rate is 21.6%). LC/MS m/z : 380.0 [M / 2+H] ⁺ .

Example 116: AA_097

synthetic route:

Step 1: Synthesis of Compound AA_097-2

Compound AA_097-2 can be prepared according to the synthetic method of Step 1 of AA_096. LC/MS m/z : 469.8 [M+H] ⁺ .

Step 2: Synthesis of AA_097

Compound AA_097 can be prepared according to the synthetic method of Step 2 of AA_096. LC/MS m/z : 379.9 [M / 2+H] ⁺ .

Example 117: AA_106 and AA_107

synthetic route:

Step 1: Synthesis of Compound AA_106-2

Maleic anhydride (AA_106-1, 4.00 g, 40.79 mmol) was mixed with furan (4.00 g, 58.76 mmol). The reaction was carried out in a microwave at 65 ° C for 10 minutes, and after completion of the reaction by TLC, the mixture was cooled to room temperature, and the solid was finely ground, washed with a mixture of petroleum ether/acetone (6 ml / 24 ml), and the solid was collected and dried to give AA_106-2 (white powder, 6.57 g). , yield 96.9%). ¹ H NMR (CDCl ₃ 400 MHz): δ 6.37 (s, 2 H), 5.45 (s, 2 H), 3.18 (s, 2 H).

Step 2: Synthesis of Compound AA_106-3

Compound AA_106-2 (3 g of 18.06 mmol) was dissolved in tetrahydrofuran (50 ml) and 10% palladium charcoal (1.89 g) was added under nitrogen. The reaction was carried out for 5 hours at room temperature under a hydrogen pressure of 1 atm. After the reaction was completed by TLC, filtered, and the solvent was evaporated to give the title compound AA-106-3 (white solid, 2.99 g, yield 98%). The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.02 (m, 2 H), 3.16 (s, 2 H), 1.87 (m, 2 H), 1.61 (m, 2 H).

Step 3: Synthesis of Compound AA_106-4

Compound BB-22 (0.79 g, 5.95 mmol) was dissolved in tetrahydrofuran (15 ml), and compound AA_106-3 (1.00 g, 5.95 mmol) was added. The mixture was stirred at room temperature for 2 hr. The product is used directly in the next step without purification. The above colorless gum was suspended in DMF (10 ml) with potassium carbonate (1.65 g, 11.92 mmol), and 2,4-dibromoacetophenone (BB-1-1, 1.66 g, 5.96 mmol) was added at room temperature. ). After stirring at room temperature for 2 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, , 1.56 g, 53% yield in two steps). LC/MS m/z : 499.1 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_106-5

Compound AA_106-4 (1.56 g, 3.14 mmol) was dissolved in toluene (100 ml), and ammonium acetate (10.54 g, 172.52 mmol) was added. The mixture was heated to reflux with aq. EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, Solid, 0.83 g, yield 55%). LC/MS m/z : 478.7 [M+H] ⁺ .

Step 5: Synthesis of AA_106 and AA_107

Using the compounds AA_106-5, AA_090-4 as raw materials, referring to the synthesis method of the step 5 in AA_072, the compounds AA_106 and AA_107 were isolated by high performance liquid phase separation. AA_106: LCMS m / z: 817.6 [M + H] + .AA_107: LCMS m / z: 817.6 [M + H] +.

Example 118: AA_089

synthetic route:

Step 1: Synthesis of Compound AA_089-2

4-Fluorobenzaldehyde (AA_089-1, 2g, 16.11mmol) was dissolved in hydrazine chloride (20ml) at room temperature. The reaction system was heated to reflux and stirred for 2 hours. After TLC detection, the solvent was evaporated and dried. Target compound AA_089-2 (light yellow solid, 2.7 g, yield 93.75%). The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.59 (m, 2 H), 7.12 (m, 2 H), 6.73 (s, 1 H).

Step 2: Synthesis of Compound AA_089-4

Compound AA_089-2 (2g, 6.2mmol), cesium carbonate (10g, 31mmol) was suspended in DMF (50ml), and compound AA_089-3 (2.8g, 12.4mmol) was added to the reaction system to warm up to 100 ° C, stirring After 3 hours, the reaction was completed by TLC, and then cooled to room temperature, and the mixture was evaporated to ethyl ether (100 ml × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. 1.4 g, yield 54%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.66 (s, 1 H), 7.65 (m, 1 H), 7.22 (m, 2 H), 7.05 (m, 6 H), 7.00 (s, 1 H) , 6.86 (m, 1 H).

Step 3: Synthesis of Compound AA_089-5

Compound AA_089-4 (1.4 g, 3.27 mmol), bis-pinacol borate (1.3 g, 4.89 mmol) was dissolved in dioxane (10 ml) at room temperature, and potassium acetate was added under nitrogen ( 960 mg, 9.81 mmol) and Pd(dppf)Cl ₂ (24 mg, 0.327 mmol). Heat to 110 ° C under nitrogen atmosphere, stir for 2 hours, TLC detection reaction was completed, cooled to room temperature, filtered, the filtrate was spun dry solvent, the residue was chromatographed by column chromatography (petroleum ether / ethyl acetate = 9:1 → 2:1) The title compound AA_089-5 (solid, 1.3 g, yield 83.8%) was obtained. LC/MS m/z : 475.8 [M+H] ⁺ .

Step 4: Synthesis of AA_089-6

Compound AA_089-5 (800 mg, 1.68 mmol), BB-14 (753 mg, 2.02 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (2 ml / 2 ml / 2 ml) at room temperature and added under nitrogen atmosphere. sodium carbonate (356mg, 3.36mmol) and _{Pd (dppf) Cl 2 (123mg} , 0.168mmol). The mixture was heated to 100 ° C under nitrogen atmosphere, stirred for 8 hours, and after completion of TLC detection, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was subjected to silica gel chromatography ( petroleum ether / ethyl acetate = 4:1 → 2:3) The title compound AA_089-6 (white solid, 0.5 g, yield 51.3%) was obtained. LC/MS m/z : 6421. [M+H] ⁺ .

Step 5: Synthesis of AA_089-7

Compound AA_089-6 (0.5 g, 0.778 mmol), bis-pinacol borate (0.24 g, 0.934 mmol) was dissolved in dioxane (10 ml) at room temperature and potassium acetate was added under nitrogen ( 153 mg, 1.6 mmol), Pd ₂ (dba) ₃ (32 mg, 0.0343 mmol) and X-phos (32 mg, 0.0686 mmol). Heat to 110 ° C under nitrogen atmosphere, stir for 2 hours, TLC detection reaction was completed, cooled to room temperature, filtered, the filtrate was spun dry solvent, the residue was chromatographed by column chromatography (petroleum ether / ethyl acetate = 9:1 → 1:4) The title compound AA_089-7 was obtained as a yellow solid (0.48 g, yield 72.3%). LC/MS m/z : 734.2 [M+H] ⁺ .

Step 6: Synthesis of Compound AA_089

Using the compound AA_089-7, AA_029-1 as a starting material, the compound AA_089 (11 mg, yield 23.8%) was obtained by the synthetic procedure of Step 3 in AA_013. LCMS m/z : 496.1 [M / 2+H] ⁺ .

Example 119: AA_091_A and AA_091_B

synthetic route:

Step 1: Synthesis of Compound AA_091-2

Compound BB-22 (0.17 g, 1.3 mmol) was dissolved in tetrahydrofuran (5 ml), and trans-1,2-cyclohexanedicarboxylic anhydride (AA_091-1, 0.1 g, 0.65 mmol) was added. The mixture was stirred at room temperature overnight. The product is used directly in the next step without purification. LC/MS m/z : 286.9 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_091-3

Compound AA_091-2 (0.25 g, 0.87 mmol) and potassium carbonate (0.24 g, 1.75 mmol) were suspended in DMF (5 ml) at room temperature, and 2,4-dibromoacetophenone (BB) was added at room temperature. -1-1, 0.243 g, 0.87 mmol). After stirring at room temperature for 3 hours, the reaction was quenched by EtOAc (3 mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The product is used directly in the next step without purification. LC/MS m/z : 484.8 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_091-4

Compound AA_091-3 (0.3 g, 0.62 mmol) was dissolved in toluene (50 ml) at room temperature and ammonium acetate (7.2 g, 93.6 mmol) was added. The mixture was heated to 120 ° C under a nitrogen atmosphere, and stirred for 4 hours. After the reaction was completed by TLC, the mixture was cooled to room temperature, and then the mixture was evaporated to ethyl acetate (100 ml × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and then filtered, evaporated, evaporated. Solid, 0.15 g, yield 52.3%). LC/MS m/z : 464.7 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_091-5

Compound AA_091-4 (0.15 g, 0.32 mmol), bis-pinacol borate (0.12 g, 0.48 mmol) was dissolved in dioxane (10 ml) at room temperature, and potassium acetate was added under nitrogen ( 0.06 g, 0.65 mmol) and Pd(dppf)Cl ₂ (0.03 g, 0.032 mmol). The mixture was heated to 100 ° C under a nitrogen atmosphere, stirred for 2 hours, and after completion of the TLC reaction, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was subjected to silica gel chromatography ( petroleum ether / ethyl acetate = 20:1 → 2:1) The title compound AA_091-5 (0.10 g, yield 60.6%) was obtained. LC/MS m/z : 5121. [M+H] ⁺ .

Step 5: Synthesis of Compound AA_091

Compound AA_091-5 (0.03 g, 0.065 mmol) and BB-21 (0.035 g, 0.071 mmol) were 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 was added sodium carbonate (0.014g, 0.13mmol) and _{Pd (dppf) Cl 2 (0.005g} , 0.0065mmol). 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 HPLC to give the title compound AA_091 (white solid, 0.018 g, yield The rate is 37.0%). LC/MS m/z : 753.5 [M+H] ⁺ .

Step 6: Preparation of AA_091_A and AA_091_B

The title compound AA_091_A (0.5 mg) and AA_091_B (4 mg) were isolated by preparative </RTI><RTIgt; AA_091_A: LC/MS m/z: 753.5 [M+H] ⁺ .AA_091_B: LC/MS m/z : 753.5 [M+H] ⁺ .

The compound in the following table was synthesized by using the compound AA_091-5 as a raw material and referring to the synthesis method of the step 5 in AA_091:

Example 123: AA_117

synthetic route:

Step 1: Synthesis of Compound AA_117-2

3-Fluoro-4-bromoacetophenone (AA_117-1, 2.00 g, 9.22 mmol) was dissolved in glacial acetic acid (15 mL). Bromine (0.47 mL, 9.22 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated to dryness to afford the title compound AA_117-2 (yellow brown solid, 2.73 g). The product is used directly in the next step without purification. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.75-7.66 (m, 3 H), 4.39 (s, 2 H).

Step 2: Synthesis of Compound AA_117-3

Compound AA_091-2 (0.50 g, 1.75 mmol) and diisopropylethylamine (0.27 g, 2.10 mmol) were dissolved in DMF (7 ml), cooled to 0 ° C, and compound AA_117-2 (0.57 g, 1.92) Mm). After stirring at 0 ° C for 0.5 hour, the reaction was quenched by TLC, and water (20 mL) was evaporated to ethylamine. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield in two steps was 36.2%). LC/MS m/z : 524.8 [M+Na] ⁺ .

Step 3: Synthesis of Compound AA_117-4

Compound AA_117-3 (0.68 g, 1.36 mmol) was dissolved in toluene (70 ml), and ammonium acetate (5.75 g, 74.60 mmol) was added. The mixture was heated to reflux with aq. EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, Solid, 0.49 g, yield 76%). LC/MS m/z : 482.8 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_117

Starting from the compound AA_117-4 and the compound BB-21, the compound AA_117 was prepared by referring to the synthesis method of the step 5 in AA_091. LC/MS m/z : 771.5 [M+H] ⁺ .

Example 124: AA_118

synthetic route:

Step 1: Synthesis of Compound AA_118-2

Compound AA_118-2 can be prepared according to the synthetic method of Step 1 in AA_117. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.91-7.85 (m, 1 H), 7.48-7.40 (m, 2 H), 4.50 (d, J = 2.0 Hz, 2 H).

Step 2: Synthesis of Compound AA_118-3

Compound AA_118-3 can be prepared according to the synthetic method of Step 2 of AA_117. LC/MS m/z : 500.9 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_118-4

Compound AA_118-4 can be prepared according to the synthetic method of Step 3 in AA_117. LC/MS m/z : 480.9 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_118

Starting from the compound AA_118-4 and the compound BB-21, the compound AA-118 was prepared by referring to the synthesis method of the step 5 in AA_091. LCMS m/z : 771.5 [M+H] ⁺ .

Example 125: AA_127

synthetic route:

Step 1: Synthesis of AA_127-2

AA_091-2 (2.7 g, 9.43 mmol) and potassium carbonate (1.8 g, 13.5 mmol) were suspended in DMF (20 ml), and compound AA_127-1 (3.7 g, 10.8 mmol) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with anhydrous sodium s The above yellow oily intermediate was dissolved in toluene (50 ml) and ammonium acetate (6.9 g, 90 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr., and then the mixture was cooled to room temperature by TLC, and then the mixture was stirred with water (30 ml). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, , yield 54%). LC/MS m/z : 545.0 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_127

Starting from the compound AA_127-2 and the compound BB-21, the compound AA_127 was prepared by referring to the synthesis method of the step 5 in AA_091. LC/MS m/z : 833.5 [M+H] ⁺ .

Example 126: AL_003

synthetic route:

Step 1: Synthesis of Compound AL_003

Compound AG_036-2 (20 mg, 0.038 mmol), AA_091-5 (21.2 mg, 0.042 mmol) was dissolved in a mixed solvent DMF/THF/H ₂ O (2 ml / 2 ml / 2 ml), then Pd(dppf)Cl _{2 was added} (2.8 mg, 0.004 mmol) and Na ₂ CO ₃ (8 mg, 0.075 mmol), N _{2 was} replaced 3 times, and the mixture was heated to 100 ° C under N ₂ protection overnight, the heating was stopped, and the mixture was cooled. After filtration, the filtrate was evaporated to dryness. The solvent was distilled off, the crude product isolated was purified by preparative HPLC to give the title compound AL_003 (white solid, 7.8 mg, yield 25.2%) LC / MS m / z:. 834.4 [M + H] +.

Example 127: AA_032

synthetic route:

Step 1: Synthesis of Compound AA_032-2

Compound BB-22 (0.5 g, 3.78 mmol) was dissolved in tetrahydrofuran (10 ml), and compound AA_032-1 (0.4 g, 2.44 mmol) was added at 10 °C. After stirring at 10 ° C for 14 hours, the reaction was completed by TLC, and then the solvent was evaporated to give the crystals. The product is used directly in the next step without purification. The above colorless colloidal intermediate was suspended in DMF (10 ml) with potassium carbonate (1 g, 7.25 mmol), and 2,4-dibromoacetophenone (BB-1-1, 0.9 g, 3.24 mmol) was added at room temperature. ). After stirring at 10 ° C for 12 hours, the reaction was quenched by TLC, and water (10 mL) was then evaporated to ethylamine (10mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by silica gel column ( petroleum ether / ethyl acetate = 10:1 → 3:1) to give the title compound AA_032-2 (0.9 g) , two-step yield 74.81%).

Step 2: Synthesis of Compound AA_032-3

Compound AA_032-2 (0.5 g, 1.01 mmol) was dissolved in toluene (50 ml) and ammonium acetate (0.8 g, 10.1 mmol) was added. The mixture was heated to 120 ° C under a nitrogen atmosphere, and stirred for 6 hours. After completion of the reaction by TLC, the mixture was cooled to room temperature, and then the mixture was stirred with water (50 mL), and ethyl acetate (100 mL×3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated, , yield 64%). LC/MS m/z 474.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_032

Compound AA_032-3 (100 mg, 0.21 mmol), BB-21 (120 mg, 0.25 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether/water (2 ml/0.5 ml) at room temperature and added under nitrogen atmosphere. sodium carbonate (45mg, 0.42mmol) and _{Pd (PPh 3) 4 (15mg} , 0.021mmol). The reaction was carried out in a microwave at 120 ° C for 10 minutes, and after completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness, and the residue was purified by HPLC to give the title compound AA_032 (5 mg, yield 3.1%). LC/MS m/z 763.3 [M+H] ⁺ .

Example 128: AA_034

synthetic route:

Step 1: Synthesis of Compound AA_034-1

Compound AA_032-3 (100 mg, 0.21 mmol), bis-pinacol borate (80 mg, 0.32 mmol) was dissolved in tetrahydrofuran (1 ml), and potassium acetate (60 mg, 0.63 mmol) was added under nitrogen. And Pd(dppf)Cl ₂ (15 mg, 0.021 mmol). The reaction was carried out in a microwave at 100 ° C for 30 minutes, and after completion of the TLC reaction, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness, and the residue was subjected to silica gel chromatography ( petroleum ether / ethyl acetate = 10:1 → 1:1) to obtain the target. Compound AA_034-1 (80 mg, yield 73%). LC/MS m/z 520.8 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_034

Compound AA_032-3 (40 mg, 0.085 mmol), AA_034-1 (40 mg, 0.077 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (0.5 ml / 0.5 ml / 0.5 ml) at room temperature under nitrogen Sodium carbonate (20 mg, 0.17 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.0085 mmol) were added under the protection. The reaction was carried out in a microwave at 100 ° C for 30 minutes, and after completion of the reaction 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_034 (1 mg, yield 1.5%). _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.69-7.67 (m, 8 H), 7.28 (brs., 2 H), 6.82 (m, 3 H), 6.35 (m, 1 H), 4.13-4.11 ( m, 2 H), 3.85 (s, 6 H), 3.60-3.56 (m, 2 H), 3.17-3.14 (m, 6 H), 1.61 (s, 6 H), 1.31 (m, 2 H), 0.98-0.96 (m, 8 H).

Example 129: AA_016

synthetic route:

Step 1: Synthesis of Compound AA_016

Compound AA_032 (30 mg, 0.04 mmol) was dissolved in ethanol (5 ml) at room temperature and palladium charcoal (10 mg) was added under nitrogen. The reaction was carried out for 12 hours at 20 ° C under a hydrogen pressure of 1 atm, filtered, and the solvent was evaporated to dryness. The residue was purified by HPLC to afford title compound AA_016 (white solid, 21 mg, yield 70%). LC/MS m/z : 765.3 [M+H] ⁺ .

Example 130: AA_095

synthetic route:

Step 1: Synthesis of AA_095

Using the compound AA_106-5, BB-21 as a starting material, the target compound AA_095 was obtained according to the synthesis method of AA_091 Step 5. LC/MS m/z : 767.4 [M+H] ⁺ .

Example 131: AA_190_A and AA_190_B

synthetic route:

Step 1: Synthesis of Compound AA_190-1

Monoethyl maleate (AA_160-1, 50g, 346.92mmol) and potassium carbonate (47.9g, 347.1mmol) were suspended in DMF (1L), cooled to 0 ° C, benzyl bromide (57.3g, 346.92) Mm). After stirring at room temperature for 10 hours, the reaction mixture was diluted with ethyl acetate (1.5 L), and washed with saturated brine (500 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered and evaporated The above yellow oily intermediate was dissolved in toluene (800 ml), cyclopentadiene (45.7 g, 693.8 mmol) was added dropwise, heated to 90 ° C under nitrogen atmosphere, stirred for 10 hours, and the solvent was removed under reduced pressure after TLC. The residue was subjected to silica gel column chromatography (purified petroleum ether: petroleum ether / ethyl acetate = 9:1) to afford the title compound AA 190-1 (75 g, yield 72.1%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.38-7.34 (m, 5 H), 6.89 (s, 1 H), 6.01-5.94 (m, 1 H), 5.24 (s, 1 H), 5.16-5. (m, 2 H), 4.26 (q, J = 3.2 Hz, 1 H), 4.18-4.09 (m, 1 H), 3.28-3.13 (m, 1 H), 2.79-2.71 (m, 1 H), 1.47-1.44 (m, 1 H), 1.33-1.23 (m, 3 H).

Step 2: Synthesis of Compound AA_190-2

Compound AA_190-1 (75 g, 250 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature and 10% palladium charcoal (7.5 g) was added under nitrogen. The reaction was carried out for 12 hours at room temperature under a hydrogen pressure of 1 atm, and after the reaction was completed by TLC, filtered, and the solvent was evaporated to give the title compound AA-190-2 (white solid, 45.3 g, yield: 85.5%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.17 - 4.15 (m, 2 H), 2.69 - 2.62 (m, 4 H), 1.48-1.25 (m, 9 H).

Step 3: Synthesis of Compound AA_190-3

Compound AA_190-2 (10 g, 47.1 mmol) was dissolved in dichloromethane (100 mL), EtOAc (EtOAc:EtOAc) After stirring at room temperature for 1 hour, the reaction was completed by TLC, and then the solvent was evaporated to give a yellow oil. The above yellow oily intermediate was dissolved in tetrahydrofuran (100 ml), cooled to below 5 ° C in an ice bath, and compound BB-22 (6.8 g, 51.8 mmol) was added, followed by dropwise addition of diisopropylethylamine (18.2 g, 141.3) Mm). After stirring at room temperature for 10 hours, ethyl acetate (100 mL) was added and the mixture was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. Analysis (petroleum ether / ethyl acetate = 5:1) affordedyiel The above yellow oily intermediate (7.6 g, 23.3 mmol) was dissolved in tetrahydrofuran / methanol / water (30 ml / 30 ml / 30 ml), and lithium hydroxide monohydrate (5.5 g, 233 mmol) was added. After stirring at 60 ° C for 10 hours, the reaction was completed by TLC, and then cooled to room temperature. The pH was adjusted to 3 to 4 by dropwise addition of 1M hydrochloric acid, and extracted with ethyl acetate (100 ml × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give the title compound AA-190-3 (2.7 g, yield 19.3%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.77 (s, 3 H), 2.63 - 2.59 (m, 3 H), 1.60-1.56 (m, 4 H), 1.31-1.06 (m, 10 H).

Step 4: Synthesis of Compound AA_190-4

Compound AA_190-3 (2.7 g, 9.0 mmol) and potassium carbonate (1.86 g, 13.5 mmol) were suspended in DMF (20 ml) at room temperature, and 2,4-dibromoacetophenone (BB) was added at room temperature. -1-1, 2.97 g, 10.8 mmol). The mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated to dryness. The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated. The above yellow oily intermediate was dissolved in toluene (50 ml) and ammonium acetate (6.9 g, 90 mmol) was added. The mixture was heated to reflux under a nitrogen atmosphere, and stirred for 12 hr., and then the mixture was cooled to room temperature by TLC, and then the mixture was stirred with water (30 ml). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated. , two-step yield 53.9%). LC/MS m/z : 475.0 [M+H] ⁺ .

Step 5: Synthesis of compound AA_190_A and AA_190_B

Compound AA_190-4 (40 mg, 0.084 mmol), compound BB-10 (55.0 mg, 0.105 mmol), sodium carbonate (18.5 mg, 0.174 mmol), Pd(dppf)Cl ₂ (6.4 mg, 0.0087 mmol), In the mixed solvent of DMF/THF/H ₂ O (1.5 ml/1.5 ml/1.5 ml), the target compound AA_190_A (17.4 mg, yield 26.4%) and AA_190_B were isolated according to the synthesis method of AA_091 steps 5-6. 17.2 mg, yield 26.3%). AA_190_A: LC/MS m/z : 795.6 [M+H] ⁺ .AA_190_B: LC/MS m/z : 398.4 [M/2+H] ⁺ .

Using the compound AA_190-4 as a raw material, refer to the synthesis method of steps 5 to 6 in AA_091 to synthesize the compounds in the following table:

Example 141: AA_158

synthetic route:

Step 1: Synthesis of Compound AA_158-2

Compound AA_190-2 (10 g, 47.1 mmol) was dissolved in dichloromethane (100 ml) at room temperature, then added to DMF (0.1 ml) to catalyze the reaction, cooled to 0 ° C, and added dropwise chlorobenzene (1.48 g, 116.6 mmol) . The mixture was stirred at room temperature for 1 hr. The above yellow oily intermediate (10.8 g, 47.1 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to below 5 ° C in an ice bath, and compound AA-158-1 (9.03 g, 51.8 mmol) was added, followed by dropwise addition of diisopropyl Amine (18.2 g, 141.3 mmol). After stirring at room temperature for 10 hours, ethyl acetate (100 mL) was added and the mixture was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. Analysis (petroleum ether / ethyl acetate = 5:1) gave Compound AA-158-2 (6.9 g, yield 40%).

Step 2: Synthesis of Compound AA_158-3

The title compound AA_158-3 (2.2 g, a two-step yield of 22.9%) was obtained from the title compound (A). LC/MS m/z : 539.0 [M+Na] ⁺ .

Step 3: Synthesis of Compound AA_158

Using the compound AA_158-3, BB-21 as a starting material, the target compound AA_158 was obtained according to the synthesis method of AA_091 Step 5. LC/MS m/z : 807.3 [M+H] ⁺ .

Example 142: AA_027

synthetic route:

Step 1: Synthesis of Compound AA_027-2

Using 1-cyclopentene-1,2-dicarboxylic anhydride (AA_007-1,500 mg, 3.623 mmol), isopropylamine (214 mg, 3.623 mmol) as a starting material, according to the synthesis method of Step 1 of AA_007, the target compound AA_027-2 was obtained ( 1.1 g, two-step yield 73.8%). LC/MS m/z : 394[M+H] ⁺ .

Step 2: Synthesis of Compound AA_027-3

Starting from compound AA_027-2 (1 g, 2.54 mmol), ammonium acetate (1.95 g, 25.4 mmol), the title compound AA_027-3 (yellow powder, 0.78 g, yield 82.8%) was obtained according to the procedure of AA_007 Step 2. . LC/MS m/z : 375.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_027

Compound AA_027-3 (100 mg, 0.267 mmol), BB-21 (160 mg, 0.321 mmol), sodium carbonate (45 mg, 0.534 mmol) and Pd(dppf)Cl ₂ (20 mg, 0.0267 mmol) were used as raw materials, according to AA_007 Step 3 The synthetic method gave the title compound AA_027 (white powder, 86 mg, yield 43.8%). LC/MS m/z : 664.1 [M+H] ⁺ .

Example 143: AA_047

synthetic route:

Step 1: Synthesis of Compound AA_047-2

Using 1-cyclopentene-1,2-dicarboxylic anhydride (AA_007-1, 50 mg, 0.362 mmol), AA_047-1 (48 mg, 0.362 mmol) as the starting material, according to the synthesis method of Step 1 of AA_007, the target compound AA_047- 2 (138 mg, a two-step yield of 83.8%). LC/MS m/z : 465.8 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_047-3

Compound AA_047-2 (138 mg, 0.296 mmol), ammonium acetate (228 mg, 2.96 mmol) was used as the starting material, and the title compound AA_047-3 (yellow powder, 100 mg, yield 73.8%) was obtained according to the procedure of AA_007 Step 2. LC/MS m/z : 447.7 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_047

Starting from compound AA_047-3 (50 mg, 0.112 mmol), BB-21 (66 mg, 0.135 mmol), sodium carbonate (24 mg, 0.224 mmol) and Pd(dppf)Cl ₂ (8 mg, 0.0112 mmol), according to AA_007 Step 3 The title compound AA_047 (white powder, 20 mg, yield 23.8%) LC/MS m/z : 722.2 [M+H] ⁺ .

Example 144: AA_064

synthetic route:

Step 1: Synthesis of Compound AA_064

Compound AA_047 (20 mg, 0.0277 mmol), cyclopropylamine (8 mg, 0.0305 mmol), diisopropylethylamine (10 mg, 0.0554 mmol) was dissolved in DMF (2 mL). ). 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, and then evaporated. LC / MS MS m / z: 761.8 [M + H] +.

Example 145: AA_065

synthetic route:

Step 1: Synthesis of Compound AA_065

Compound AA_065 (white powder, 11 mg, yield 25.8%) was obtained according to the procedure of AA_064 Step 1 using compound AA_047, methylamine. LCMS m/z : 368.4 [M / 2+H] ⁺ .

Example 146: AA_028

synthetic route:

Step 1: Synthesis of AA_028

Using the compound AA_027 (20 mg, 0.0301 mmol) as a starting material and palladium on carbon (2 mg) as a catalyst, the title compound AA_028 (white powder, 8 mg, yield 33.8%) was obtained according to the procedure of AA_016 Step 1. LC/MS m/z : 666.2 [M+H] ⁺ .

Example 147: AA_054

synthetic route:

Step 1: Synthesis of Compound AA_054-2

Compound AA_054-1 (500 mg, 2.7 mmol) was dissolved in ethanol (10 mL) and palladium charcoal (200 mg) was added. The reaction was carried out for 5 hours at 20 ° C under a hydrogen pressure of 1 atm, filtered, and the solvent was evaporated to dryness to give crystals (yield: The yellow oily intermediate was suspended in DMF (15 ml) with potassium carbonate (0.8 g, 5.4 mmol), and 2,4-dibromoacetophenone (BB-1-1, 0.9 g, 3.2) was added at 10 °C. Mm). After stirring at 10 ° C for 12 hours, the reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. The yield in two steps was 95%). LC/MS m/z : 404.6 [M+Na] ⁺ .

Step 2: Synthesis of Compound AA_054-3

Compound AA_054-2 (1 g, 2.6 mmol) was dissolved in toluene (60 ml), and ammonium acetate (10 g, 130 mmol) was added. The mixture 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, and water (30 ml) was added to quench the reaction, and ethyl acetate (50 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated, Powder, 0.6 g, yield 70%). LC/MS m/z : 364.6 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_054-4

Compound AA_054-3 (300 mg, 0.83 mmol), BB-21 (500 mg, 1 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (4 ml / 4 ml / 4 ml) at room temperature, and carbonic acid was added under nitrogen atmosphere. potassium (300mg, 2.2mmol) and _{Pd (dppf) Cl 2 (60mg} , 0.083mmol). The reaction was carried out in a microwave at 100 ° C for 3 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 AA_054-4 (white powder, 300 mg, yield 40%). LC/MS m/z : 639.1.[M+H] ⁺ .

Step 4: Synthesis of Compound AA_054

Compound AA_054-4 (50 mg, 0.078 mmol), 2-piperazinone (15 mg, 0.15 mmol), diisopropylethylamine (25 mg, 0.4 mmol) was dissolved in DMF (1 mL) (50 mg, 0.15 mmol). 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, and evaporated. ^{1 H NMR (400MHz, METHANOL-} d4) δ 0.92-1.00 (m, 6 H) 1.31-2.37 (m, 20 H) 3.19-4.75 (m, 12 H) 5.18-5.22 (m, 1 H) 7.33 (s , 2 H) 7.60-7.80 (m, 8 H).

The compound in the following table was synthesized by using the compound AA_054-4 as a raw material and referring to the synthesis method of the steps 5 to 6 in AA_091:

Example 155: AA_063

synthetic route:

Step 1: Synthesis of Compound AA_063-1

Compound AA_047-1 (0.5 g, 3.2 mmol) was dissolved in tetrahydrofuran (10 ml), and cis-1,2-cyclohexanedicarboxylic anhydride (AA_013-1, 0.5 g, 3.9 mmol) was added at 10 °C. After stirring at 10 ° C for 14 hours, the reaction was completed by TLC. The above colorless colloidal intermediate (1 g, 3.2 mmol) and potassium carbonate (1 g, 7.2 mmol) were suspended in DMF (10 ml), and 2,4-dibromoacetophenone (BB-1-1) was added at 10 °C. , 1 g, 3.6 mmol). After stirring at 10 ° C for 2 hours, the reaction was quenched by TLC, then water (10 ml) The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by EtOAc (EtOAc (EtOAc) , two-step yield 40%). LC/MS m/z : 484.0 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_063-2

Compound AA_063-1 (0.3 g, 0.62 mmol) was dissolved in toluene (60 mL) at room temperature and ammonium acetate (3 g, 50 mmol) was added. The mixture 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, and water (30 ml) was added to quench the reaction, and ethyl acetate (50 ml × 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and filtered, and the solvent was evaporated, and the residue was purified by silica gel chromatography ( petroleum ether / ethyl acetate = 10:1 → 1:1) to give the target compound AA_063-2 (0.2 g) , yield 70%). LC/MS m/z : 463.8 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_063

Compound AA_063-2 (50 mg, 0.11 mmol), BB-21 (54 mg, 0.11 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (0.5 ml / 0.5 ml / 0.5 ml) at room temperature under nitrogen Sodium hydrogencarbonate (20 mg, 0.22 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.011 mmol) were added under the protection. The reaction was carried out in a microwave at 80 ° C for 5 minutes, and after completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, and the solvent was evaporated to dryness to give the title compound AA_063 (white powder, 10.5 mg, yield 13%). ^{1 H NMR (400MHz, METHANOL-} d4) δ 0.92-1.31 (m, 16 H) 1.75-2.75 (m, 11 H) 3.50-3.93 (m, 14 H) 4.24-5.21 (m, 5 H) 7.35-7.81 (m, 10 H) 8.47 (br.s., 2 H).

Example 156: AA_237_A and AA_237_B

synthetic route:

Step 1: Synthesis of Compound AA_237-1

Compound AA_190-2 (19 g, 90 mmol) and potassium carbonate (5.1 g, 135 mmol) were suspended in DMF (300 mL), and 2,4'-dibromoacetophenone (BB-1-1, 37 g, 108 mmol). After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure, and ethyl acetate (500 mL) was added to the residue, and the mixture was washed with saturated brine (100 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and filtered and evaporated. The yellow oily intermediate was dissolved in toluene (500 mL) at room temperature and ammonium acetate (69.3 g, 900 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 (1 L) was added and washed with brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered and evaporated. 22.6 g, yield 65%). LCMS m/z : 391.1 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_237-2

Compound AA_237-1 (3.9 g, 10.8 mmol), compound BB-21 (5.35 g, 10.8 mmol), sodium carbonate (2.28 g, 21.6 mmol) and Pd(dppf)Cl ₂ (394 mg, 0.54 mmol) were used as starting materials. In a mixed solvent of DMF/THF/H ₂ O (30 mL / 30 mL / 30 mL), Compound AA_237-2 (3.7 g, yield 51.0%) was obtained according to the procedure of AA_091 Step 5. LCMS m/z : 680.4 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_237-3

Compound AA_237_2 (2 g, 2.8 mmol) was dissolved in tetrahydrofuran / methanol / water (5 mL / 5 mL / 5 mL) mixed solvent, and lithium hydroxide monohydrate (0.694 g, 28 mmol) was added. After stirring at 50 ° C for 10 hours, the reaction was completed by TLC, then cooled to room temperature, extracted with ethyl acetate (5 mL×2), and the aqueous phase was added dropwise with 1N hydrochloric acid to adjust the pH to 3 to 4, and the precipitated solid was collected and dried to obtain Target compound AA_237-3 (1.33 g, yield 68.0%). LCMS m/z : 651.3 [M+H] ⁺ .

Step 4: Synthesis of compounds AA_237_A and AA_237_B

Compound AA_237-3 (30 mg, 0.046 mmol), aniline (6.4 mg, 0.069 mmol) was dissolved in tetrahydrofuran (2 mL) and DMTM (19.1 mg, 0.069 mmol) was added. The reaction system was warmed to 90 ° C, stirred overnight, and the solvent was evaporated to dryness after TLC detection. The residue was purified by high-performance liquid to obtain the target AA_237_A (1.8 mg yield: 10%) and compound AA_237_B (2.2 mg, yield 12%). . AA_237_A: LC / MS m / z : 726.0 [M + H] + .AA_237_B: LC / MS m / z: 726.2 [M / 2 + H] +.

The compound in the following table was synthesized by using the compound AA_237-3 as a raw material and referring to the synthesis method of the step 4 in AA_237:

Example 220: AA_226

synthetic route:

Step 1: Synthesis of Compound AA_226-2

Starting from compound AA_237-1 (3.9 g, 10.8 mmol), compound BB-25 (5.59 g, 10.8 mmol), sodium carbonate (2.28 g, 21.6 mmol) and Pd(dppf)Cl ₂ (394 mg, 0.54 mmol), In a mixed solvent of DMF / THF / H ₂ O (30 mL / 30 mL / 30 mL), the crude oily intermediate (3.5 g, yield 46.6%). The above yellow oily intermediate (2 g, 2.8 mmol) was dissolved in tetrahydrofuran/methanol/water (5mL/5mL/5mL) mixed solvent, and lithium hydroxide monohydrate (0.694 g, 28 mmol) was added. After stirring at 50 ° C for 10 hours, the reaction was completed by TLC, then cooled to room temperature, extracted with ethyl acetate (5 mL×2), and the aqueous phase was added dropwise with 1N hydrochloric acid to adjust the pH to 3 to 4, and the precipitated solid was collected and dried to obtain Target compound AA_226-2 (1.33 g, yield 68.0%). LCMS m/z : 667.2 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_226

Compound AA_226-2 (30 mg, 0.046 mmol), aniline (8.2 mg, 0.069 mmol) was dissolved in tetrahydrofuran (2 mL), and DMTMM (19.1 mg, 0.069 mmol) was added. The reaction system was warmed to 60 ° C and stirred overnight. After the reaction was completed by TLC, the solvent was evaporated, and the residue was purified by high-purity liquid to give the title compound AA 226 (1.0 mg, yield: 2.9%). LC/MS MS m/z : 386.3 [M / 2+H] ⁺ .

The compound in the following table was synthesized by using the compound AA_226-2 as a raw material and referring to the synthesis method of the step 2 in AA_226:

Example 276: AA_192_A and AA_192_B

synthetic route:

Step 1: Synthesis of Compound AA_192-1

Compound AA_190-2 (10 g, 47.1 mmol) was dissolved in dichloromethane (100 mL) at room temperature, then added to DMF (0.1 mL) to catalyze the reaction, cooled to 0 ° C, and added with dichloromethane (1.48 g, 116.6 mmol) . After stirring at room temperature for 1 hour, the reaction was completed by TLC, and the solvent was evaporated to give an intermediate. The above chloro-organic intermediate was dissolved in tetrahydrofuran (100 mL), cooled to below 5 ° C in an ice bath, 3-aminomethylpyridine (5.59 g, 51.8 mmol) was added, then diisopropylethylamine (18.2 g, 141.3 mmol). The mixture was stirred at room temperature for 10 hours, and the mixture was filtered and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solvent was removed under reduced pressure and the residue was applied to mjjjjjjjjjjjjjjj LCMS m/z : 302.9 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_192-2

Compound AA_192-1 (7.8 g, 25.8 mmol) was dissolved in a mixed solvent of tetrahydrofuran/methanol/water (30 mL / 30 mL / 30 mL), and lithium hydroxide monohydrate (6.19 g, 258 mmol) was added. After stirring at 60 ° C for 10 hours, most of the organic solvent was removed under reduced pressure after TLC detection. The residual mixture was extracted with ethyl acetate (5 mL×2). The aqueous phase was added dropwise with 1N hydrochloric acid to adjust the pH to 3-4. The ester (20 mL × 3) was extracted, and the organic layer was combined, dried over anhydrous sodium sulfate, and filtered, and the solvent was evaporated to give the title compound AA_192-2 (2.8 g, yield 40%). LCMS m/z : 274.9 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_192-3

Compound AA_192-2 (2.8 g, 10.2 mmol) and potassium carbonate (0.51 g, 13.5 mmol) were suspended in DMF (30 mL), and 2,4'-dibromoacetophenone (BB-1-1) was added at room temperature. , 2.97 g, 10.8 mmol). The mixture was stirred at room temperature for 2 hr. EtOAc was evaporated. The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated to ethylamine. The product is used directly in the next step without purification. LCMS m/z : 470.9 [M+H] ⁺ .

Step 4: Synthesis of compound AA_192-4

Compound AA_192-3 (4.7 g, 99.7 mmol) was dissolved in toluene (50 mL) at room temperature and then ammonium sulfate (7.85 g, 102 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, filtered, and then filtered, evaporated, evaporated. . LCMS m/z : 450.9 [M+H] ⁺ .

Step 5: Synthesis of compound AA_192_A and compound AA_192_B

Starting from compound AA_192-4 (26.0 mg, 0.057 mmol), compound BB-28 (35 mg, 0.063 mmol), sodium carbonate (12.2 mg, 0.115 mmol) and Pd(dppf)Cl ₂ (4.2 mg, 0.0057 mmol), In the mixed solvent of DMF/THF/H ₂ O (1.5 mL/1.5 mL/1.5 mL), the synthesis method of AA_091 steps 5-6 was separated by high performance liquid phase separation to obtain the target compound AA_192_A (4.8 mg) and compound AA_192_B ( 5.6 mg), yield 22.6%. AA_192_A: LC / MS m / z : 799.6 [M + H] + .AA_192_B: LC / MS m / z: 799.5 [M + H] +.

The compound in the following table was synthesized by using the compound AA_192-4 as a raw material and referring to the synthesis method of the step 5 in AA_192:

Example 291: AA_162_ENDOA2

synthetic route:

Step 1: Synthesis of Compound AA_162-2

(R)-2-(o-methyl)benzene-CBS-oxazolborane (4.11 g, 11.63 mmol) was dissolved in toluene (23 mL), cooled to -25 ° C, and bis trifluoromethyl was added dropwise under nitrogen. A 1 M toluene solution (11.63 mL) of sulfonimide (3.27 g, 11.63 mmol) was stirred at -25 °C for 30 min. After cooling to -60 ° C, diethyl fumarate (10.0 g, 54.18 mmol) was added and stirred for 5 min. Then, a toluene solution (10 mL) of cyclopentadiene (19.2 g, 291 mmol) was added dropwise at -60 ° C, and the mixture was stirred for 16 hours. After completion of the TLC reaction, the solvent was evaporated and the residue was chromatographed. Petroleum ether / ethyl acetate = 2:1 → 1:4) The title compound AA_162-2 (yellow liquid, 10.0 g, yield 72%) was obtained. ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.31-6.28 (m, 1 H), 6.09-6.07 (m, 1 H), 4.21-4.10 (m, 4 H), 3.40-3.38 (m, 1 H) , 3.28 (s, 1 H), 3.13 (s, 1 H), 2.70-2.68 (m, 1 H), 1.63 (d, J = 8.8 Hz, 1 H), 1.47 (d, J = 8.8 Hz, 1 H), 1.31-1.23 (m, 6 H).

Step 2: Synthesis of Compound AA_162-3

Compound AA_162-2 (12 g, 50.36 mmol) was dissolved in a mixed solvent of DMSO / water (100 mL / 1000 mL), cooled to 0 ° C, 0.25 M aqueous potassium hydroxide solution (343 mL, 85.61 mmol) was added dropwise and stirred at 0 ° C After 3 hours, after the TLC reaction was completed, 1N hydrochloric acid was added at 0 ° C to adjust the pH to 3, which was saturated with sodium chloride and then extracted with ethyl acetate (200 mL × 3). After filtration, the filtrate was evaporated to dryness to give the title compound AA_162-3 (10.4 g, yield 92.4%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.31-6.29 (m, 1 H), 6.10-6.08 (m, 1 H), 4.11 (q, J = 3.2 Hz, 2 H), 3.38-3.36 (m, 1 H), 3.29 (m, 1 H), 3.23-3.20 (m, 1 H), 2.74-2.72 (m, 1 H), 1.63-1.61 (m, 1 H), 2.74-2.72 (m, 1 H) ), 1.49-1.47 (m, 1 H), 1.24 (t, J = 3.2 Hz, 3 H).

Step 3: Synthesis of Compound AA_162-4

Compound AA_162-3 (10.46 g, 43.91 mmol) was dissolved in ethanol (100 mL) at room temperature and 10% palladium charcoal (0.5 g) was added under nitrogen. The reaction was carried out for 12 hours at room temperature under a hydrogen pressure of 25 psi, filtered, and the solvent was evaporated to dryness to give the title compound AA 162-4 (yellow oil, 9.0 g, yield: 87.5%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.17-4.10 (m, 2 H), 2.65-2.62 (m, 4 H), 1.59-1.53 (m, 2 H), 1.36-1.22 (m, 7 H) .

Step 4: Synthesis of Compound AA_162-5

Compound AA_162-4 (2 g, 9.42 mmol) and potassium carbonate (2.6 g, 18.85 mmol) were suspended in DMF (10 mL), and 2,4'-dibromoacetophenone (BB-1-1, 3.2 g, 11.31 mmol). After stirring at room temperature for 1 hour, the reaction was quenched by TLC, then water (30mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, Powder, 3.4 g, two-step yield 78.8%). LC/MS m/z : 409[M+H] ⁺ .

Step 5: Synthesis of Compound AA_162-6

Compound AA_162-5 (3.4 g, 8.31 mmol) was dissolved in toluene (100 mL) at room temperature and ammonium acetate (5.2 g, 66.55 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 water (30 mL) was added to quench the reaction, and ethyl acetate (50 mL×3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and then filtered, and the solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl ether / ethyl acetate = 9:1 → 1:1) to give the title compound AA 162-6 (light yellow) Powder, 2.88 g, yield 88.8%). LC/MS m/z : 389.0 [M+H] ⁺ .

Step 6: Synthesis of compound AA_162-7

Compound AA_162-6 (300 mg, 0.771 mmol) was dissolved in tetrahydrofuran / methanol / water (2 mL / 2 mL / 2 mL). After stirring for 8 hours at room temperature, most of the organic solvent was removed under reduced pressure after TLC detection. The mixture was cooled to 0 ° C, and 1N hydrochloric acid was added dropwise to adjust the pH to 6 and the solid was collected by filtration to give the title compound AA_162-7 (yellow powder, 250 mg, yield 89.8%). LC/MS m/z : 360.9 [M+H] ⁺ .

Step 7: Synthesis of Compound AA_162-8

Compound AA_162-7 (150 mg, 0.415 mmol), 3-aminomethylpyridine (54 mg, 0.498 mmol), diisopropylethylamine (107 mg, 0.830 mmol) was dissolved in DMF (2 mL). HATU (190 mg, 0.498 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, and then filtered, evaporated, evaporated. Powder, 135 mg, yield 72.8%). LC/MS m/z : 453.0 [M+H] ⁺ .

Step 8: Synthesis of compound AA_162_ENDOA2

Starting from the compounds AA_162-8 and BB-21, the synthesis method AA_162_ENDOA2 was obtained by referring to the synthesis method of Step 5 in AA_192. LC/MS m/z : 741.3 [M+H] ⁺ .

Example 292: AA_273_ENDOA2

synthetic route:

Step 1: Synthesis of Compound AA_273-1

Using the compounds AA_162-6 and BB-21 as raw materials, referring to the synthesis method of the steps 2 to 3 in AA_237, the compound AA_273-1 was obtained. LC/MS m/z : 651.3 [M+H] ⁺ .

Step 2: Synthesis of compound AA_273_ENDOA2

Compound AA_273-1 (30 mg, 0.046 mmol), AA_273-2 (9.3 mg, 0.069 mmol) was dissolved in tetrahydrofuran (2 mL) and DMTMM (19.1 mg, 0.069 mmol) was added. The reaction system was warmed to 90 ° C, stirred overnight, and the solvent was evaporated to dryness after TLC detection. The residue was purified by high-purity liquid to obtain the target AA_273_ENDOA2 (2.8 mg, yield 7.9%). LC/MS m/z : 767.3 [M+H] ⁺ .

The compound in the following table was synthesized by using the compound AA_273-1 as a raw material and referring to the synthesis method of the step 2 in AA_273_ENDOA2:

Example 330: 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 extracted with ethyl acetate (50 mL×3), 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), filtered,jjjjjjjjjjjjjjjjjjjj 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 mmol) and Pd(dppf)Cl ₂ (40 mg, 0.054 mmol). Heat to 110 ° C under nitrogen atmosphere, stir for 2 hours, after TLC detection reaction was completed, cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by 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 (11mg, 0.099mmol) and _{Pd (dppf) Cl 2 (5mg} , 0.0098mmol). 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 239 (white solid, 8 mg, yield The rate is 21.8%). LCMS m/z : 384.2 [M / 2+H] ⁺ .

Example 331: AA_238

synthetic route:

Step 1: Synthesis of Compound AA_238-1

Compound AG_075-1 (15 g, 44.38 mmol), 1,2-ethanedithiol (5 g, 53.26 mmol) was dissolved in chloroform (10 mL), and BF ₃ ‧Et ₂ O (5.5 ml, 44.38 mmol) was added dropwise. 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-iodobutylidene imide (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 mmol ). 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, 2 H), 7.61 (m, 2 H), 7.40 (m, 2 H).

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 extracted with ethyl acetate (50 mL×3), 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, filtered, and then filtered, evaporated, evaporated, m.jjjjjjjjjjjjjjjjjj 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), and potassium acetate (205 mg, 2.09 mmol) and Pd(dppf)Cl ₂ (40 mg, 0.052 mmol). Heat to 110 ° C under nitrogen atmosphere, stir for 2 hours, TLC detection reaction was completed, cooled to room temperature, filtered, the filtrate was spun dry solvent, the residue was chromatographed by 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 a 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 238 ( white solid, 8.2 mg, Yield 27.8%). LCMS m/z : 395.2 [M / 2+H] ⁺ .

Example 332: 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, and then filtered and evaporated. , 0.82 g, yield 82.3%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.68 (m, 2 H), 7.49 (m, 4 H), 1.19 (s, 3 H).

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 extracted with ethyl acetate (50 mL×3), 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, filtered, and then filtered, evaporated, evaporated,,,,,,,,,,,, , 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 mmol) and Pd(dppf)Cl ₂ (36 mg, 0.044 mmol). Heat to 110 ° C under nitrogen atmosphere, stir for 2 hours, after TLC detection reaction was completed, cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was purified by 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 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_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 333: AA_242

synthetic route:

Step 1: Synthesis of Compound AA_242-1

Compound AA_162_6 (1.0 g, 2.57 mmol) was dissolved in tetrahydrofuran / ethanol / water (5 mL / 5 mL / 5 mL) mixed solvent, and lithium hydroxide monohydrate (0.215 g, 5.14 mmol) was added. After stirring at 50 ° C for 10 hours, the reaction was completed by TLC, cooled to room temperature, extracted with ethyl acetate (10 mL×2), and the aqueous phase was added dropwise with 1N hydrochloric acid to adjust the pH to 3 to 4, and the precipitated solid was collected and dried to obtain Target compound AA_242-1 (0.65 g, yield 70.0%). LCMS m/z : 362.9 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_242-3

Compound AA_242-1 (178 mg, 0.49 mmol) and diisopropylethylamine (191.1 g, 1.48 mmol) were dissolved in acetonitrile (5 mL) and 3-(2-bromoethyl)pyridine was added at room temperature. AA_242-2, 128.1 mg, 0.64 mmol). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure by TLC, and the residue was purified by silica gel chromatography ( petroleum ether / ethyl acetate = 1:1 → ethyl acetate) to give the object compound AA_242-3 (red oily liquid) , 50 mg, yield 21.1%). LCMS m/z : 480.0 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_242-4

The compound AA_242-3 (20 mg, 0.021 mmol) and ammonium acetate (32 g, 0.42 mmol) were dissolved in toluene (10 mL) in a mixed solvent, and the mixture was stirred and refluxed at 120 ° C for 10 hours. The solvent and the residue were subjected to EtOAc EtOAcjjjjjjjj LCMS m/z : 462.0 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_242

Starting from compound AA_242-4 (20 mg, 0.0434 mmol), compound BB-21 (25.9 mg, 0.052 mmol), sodium carbonate (9.2 mg, 0.087 mmol) and Pd(dppf)Cl ₂ (3.2 mg, 0.00434 mmol), In a mixed solvent of DMF/THF/H ₂ O (1.5 mL / 1.5 mL / 1.5 mL), compound AA-242 (2.5 g, yield 7.7%) was obtained according to the procedure of AA_238 Step: 4 . LCMS m/z : 750.2 [M+H] ⁺ .

Example 334: AA_150_A and AA_150_B

synthetic route:

Step 1: Synthesis of Compound AA_150-1

The compound AA_091-1 (2g, 12.97mmol) was suspended in methanol (30mL), cooled to 0 ° C, slowly added potassium carbonate (3.59g, 25.95mmol), stirred at room temperature for 2 hours, after TLC detection, cooled to 0 Concentrated hydrochloric acid was added dropwise to pH EtOAc (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and filtered and evaporated. The above white solid intermediate and potassium carbonate (3.59 g, 25.95 mmol) were suspended in acetonitrile (40 ml), and 2,4-dibromoacetophenone (BB-1-1, 3.61 g, 12.97 mmol) was added. After stirring at room temperature for 12 hours, the solvent was evaporated under reduced pressure, and then evaporated to ethyl ether (EtOAc) The combined organic phases were dried with EtOAc EtOAc EtOAc. The above yellow oily intermediate was dissolved in toluene (100 mL) and ammonium acetate (10.0 g, 129.7 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, and ethyl acetate (150 mL) was added and washed with brine (40 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered, evaporated, evaporated, evaporated, The step yield was 22.7%). LCMS m/z : 364.9 [M+H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.67-7.65 (m, 2 H), 7.52-7.48 (m, 3 H), 3.49 (s, 3 H) ), 3.90-2.86 (m, 1 H), 3.08 (m, 1 H), 1.79-1.77 (m, 2 H), 1.57 (m, 2 H), 1.41-1.34 (m, 4 H).

Step 2: Synthesis of Compound AA_150-2

Compound AA 150-1 (1.07 g, 3.0 mmol), compound BB-21 (1.64 g, 3.3 mmol), sodium carbonate (0.64 g, 6.0 mmol) and Pd(dppf)Cl ₂ (220 mg, 0.3 mmol) were used as starting materials. In a mixed solvent of DMF/THF/H ₂ O (2 mL / 2 mL / 2 mL), compound AA-150-2 (yellow solid, 0.7 g, yield 36. LCMS m/z : 653.3 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_150-3

Compound AA-150-2 (700 mg, 1.07 mmol) was dissolved in tetrahydrofuran / methanol / water (4 mL / 4 mL / 4 mL). After stirring at room temperature overnight, the reaction was completed under reduced pressure of TLC. Water (5 mL) was evaporated under reduced pressure, and 1N hydrochloric acid was added dropwise to adjust the pH to 3 to 4, and the precipitated solid was collected to give the title compound AA_150-3 (385 mg, yield 60.7%). LCMS m/z : 639.22 [M+H] ⁺ .

Step 4: Synthesis of compounds AA_150_A and AA_150_B

Compound AA-150-3 (30 mg, 0.046 mmol), 3-aminomethylpyridine (6.1 mg, 0.056 mmol) was dissolved in tetrahydrofuran (2 mL), and DMTMM (15.5 mg, 0.056 mmol) was added. The reaction system was warmed to 90 ° C, stirred overnight, and the solvent was dissolved by TLC. The residue was purified by high-purity liquid to obtain the target AA_150_A (2.0 mg) and AA_150_B (3.2 mg), yield 15.2%. AA_150_A: LC / MS m / z : 729.3 [M + H] + .AA_150_B: LC / MS m / z: 729.3 [M + H] +.

The compound in the following table was synthesized by using the compound AA_150-3 as a raw material and referring to the synthesis method of the step 4 in AA_150:

Example 338: AA_286

synthetic route:

Step 1: Synthesis of Compound AA_286-1

Compound AA_242-1 (1.6 g, 4.43 mmol), triethylamine (0.896 g, 8.86 mmol) was dissolved in tris-butanol (100 mL), and DPPA (1.83 g, 6.64 mmol) was slowly added. It was heated to reflux under a nitrogen atmosphere and stirred overnight. EtOAc was evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. %). LC/MS m/z : 434.2 [M+H] ⁺ .

Step 2: Synthesis of Compound AA_286-2

The compound AA_286-1 (150 mg, 0.46 mmol), BB-21 (276 mg, 0.56 mmol) was dissolved in a mixed solvent of DMF/THF/H ₂ O (5 ml / 5 ml / 5 ml), and sodium carbonate (74 mg) was added under a nitrogen atmosphere. , 0.93 mmol) and Pd(dppf)Cl ₂ (40 mg, 0.046 mmol). The mixture was heated to reflux under a nitrogen atmosphere and stirred overnight. After TLC, the reaction mixture was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column ( petroleum ether / ethyl acetate = 5:1 → 1: 1) The title compound AA_286-2 (196 mg, yield 56%) was obtained. LC/MS m/z : 723.4 [M+H] ⁺ .

Step 3: Synthesis of Compound AA_286-3

The compound AA_286-2 (200 mg, 0.48 mmol) was dissolved in ethyl acetate (5 mL), cooled to EtOAc, EtOAc (EtOAc/EtOAc After completion of the TLC reaction, the solvent was removed under reduced pressure at room temperature to afford compound AA-286-3 (white solid, 171 mg, yield 99.4%); LC/MS m/z : 622.4 [M+H] ⁺ .

Step 4: Synthesis of Compound AA_286

Compound AA_286-3 (173 mg, 0.28 mmol), N-Moc-proline (BB-2-6, 58 mg, 0.33 mmol), diisopropylethylamine (72 mg, 0.56 mmol) To DMF (10 mL) was added HATU (130 mg, 0.34 mmol). After stirring at room temperature for 2 hours, the reaction was quenched by TLC, and water (10 mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. The rate is 56.2%). LC/MS m/z : 779.4 [M+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 cell line and contains K1691R, K2040R and S2204I adaptive mutations. The genotype 1b replicon is derived from the Con1 cell line 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 gene, G418 resistance gene NEO and luciferase gene, making HCV-related proteins and fluorescein Photozymes 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 240 I.

Multidrop automatic dispenser, Thermo.

POD 810 Plate 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. The compound was then diluted 6 times at 5 fold and added to the cell dish using an Echo liquid handler. Ensure a final DMSO concentration of 0.5%. Each compound is doubled. The highest initial concentration is 100, 10 or 1 nM, 5 times diluted, 6 times.

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. The cells were incubated at 37 ° C in a 5% CO ₂ incubator.

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) Dilute the cells to 8 × 10 ⁴ /mL with the culture solution, and add the diluted cells to a compound-containing 96-well plate (Greiner, Cat. # 655090) (100 μL/well, using an automatic liquid separator (Thermo Scientific). 8000cells/hole). The cells were cultured at 37 ° C for 3 days in a 5% CO ₂ incubator. Cell control plate: no compound, only 0.5% DMSO.

5) Add the chemiluminescent substrate Cell Titer-fluor to the cell well, and after 30 minutes of incubation, use the chemiluminescence detection system Envison (Ex at 405 nm and read at 515 nm) to detect the signal. 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 used to calculate the EC ₅₀ value.

c) Data processing and analysis:

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

The experimental results are shown in Table 1:

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

Claims (29)

a compound of the formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, Wherein A ₁ , A ₇ , B ₁ , B ₇ , Q ₁ , Q ₇ , Y ₁ , Y ₇ , D ₁ , D ₇ each independently represent a structural unit represented by the formula (a), Wherein R _{1 is} selected from C=O, C=S, S(=O), S(=O) ₂ , C(R _1a )(R _1b ); and R _{3 is} selected from 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, heterochain hydrocarbon, chain hydrocarbon, cycloalkyl, heterocyclic And a heterocyclic group; 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, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; optionally, R _1a and R _1b , R _3a and R _3b together form an optionally substituted 3-6 ring alkyl group; n ₁ or n ₄ are each independently selected from 0 or. 1; n ₂ is selected from _{n 2a, n 2b, n 2c} , A 1 n ₂ is the n _2a, n _2a, 4, 5 or 6 is selected from In B ₁ , n ₂ is n _2b , n _2b is 0, and A ₇ , B ₇ , Q ₁ , Q ₇ , Y ₁ , Y ₇ , D ₁ , D ₇ , n ₂ is n _2c , and n _{2c 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 , When n ₃ or n ₄ is 0, the corresponding structural unit represents a single bond which only functions as a linkage; A ₂ , A ₆ , B ₆ , Q ₆ , D ₂ , D 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 a structural unit represented by formula (b), W ₁ and W ₂ each independently represent H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl Or a heterohydrocarbylhetero], optionally between W ₁ and W _{2 ,} between W ₁ and W _{1 , and} between W ₂ and W ₂ to form a ring; m ₁ , m _{2 are} selected from 0, ₁ , 2 W _{3 is} selected from optionally substituted NH or a single bond; W _{4 is} selected from optionally substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, NH, 3-6-membered hydrocarbon or 3-6-membered a heterohydrocarbyl group, C≡C, a single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; R _6a , R _6b , R _6c are each independently selected from H , C _1-6 alkyl or alkoxy; W ₅ , W ₆ independently represent C, N, optionally substituted [CH ₂ , CH, NH, CH ₂ -CH ₂ , CH=CH, 3~ 6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; W ₇ and W ₈ respectively Independently representing H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heteroalkyl heteroaryl ], optionally between W ₇ and W _{8 ,} between W ₇ and W _{7 ,} between W ₈ and W ₈ to form a ring; m ₇ , m _{8 are} selected from 0, 1, 2; Y _{2b is} selected from O , S, C=O, C=S, S(=O), S(=O) ₂ , C≡C, optionally substituted [NH, CH ₂ -CH ₂ , CH=CH, 3~6 yuan a hydrocarbon group or a 3-6 membered heteroalkyl group; Y _2a , Y _2c , Y _6a , Y _6b , Y _6c are each independently selected from optionally substituted [CH ₂ , NH, CH ₂ -CH ₂ , CH=CH, 3~6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; Y _2d , Y _6d are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or hetero Hydrocarbylhetero]; A ₃ , A ₅ , B ₃ , B ₅ , Q ₃ , Q ₅ , Y ₃ , Y ₅ , D ₅ are each independently selected from 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 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 ; 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, hydrocarbyl or heterohydrocarbyl]; p ₁ , p ₆ , p ₇ are each independently selected from the group consisting of 0, 1, 2 , 3, 4, 5 or 6; A ₄ , B ₄ , Q ₄ , Y ₄ , D _{4 are} selected from CH ₂ , single bond, O, S, C=O, C=S, S(=O), S (=O) ₂ , aryl or heteroaryl; Represents a single or double key; ------ represents a single key, double key or no key, when Where ------ represents the absence of the structural unit when the bond is not bonded; optionally, the compound or a pharmaceutically acceptable salt thereof comprises one or more chiral centers. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The substructure unit is as shown in equation (f). Wherein T _{1 is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl), C≡C, single bond, O, S, C=O, C=S, S(=O), S(=O) ₂ ; T ₂ , T ₃ , T ₄ are independently selected from C, N, and Selected substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], C≡C, O, S, C=O, C= S, S(=O), S(=O) ₂ ; T _{5 is} 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 or a heteroalkyl group; m _{5 is} selected from 0, ₁ , 2, 3, 4, 5 or 6; and T ₆ and T ₇ are each independently selected from O, S, Optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3 to 6-membered hydrocarbon or 3 to 6-membered heteroalkyl), C≡C, single bond, C=O, C= S, S(=O), S(=O) ₂ ; T ₉ 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 or a heterohydrocarbylhetero group]; m _{6 is} selected from 0, 1, 2 or 3, and when m ₆ is 0, the corresponding structural unit represents a single bond which only serves as a linkage; m ₉ Selected from 0, 1, 2, 3, 4 5 or 6; Represents a single or double key; ------ represents a single key, double key or no key, when The middle ------ means that the structural unit does not exist when the key is not formed, and the ------ on both sides of the T ₂ is not a double key. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the substructure unit represented by formula (f) is selected from the group consisting of: Specifically, the substructure unit represented by the formula (f) is selected from the group consisting of: The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the substructure unit of the structural unit (b) is as shown in the formula (g), Wherein T _{1a is} independently selected from C, N, optionally substituted [CH ₂ -CH ₂ , CH=CH, CH ₂ , CH, NH, 3-6-membered hydrocarbon or 3-6-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, and Selected substituted [CH ₂ , CH ₂ -CH ₂ , CH=CH, CH, NH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], 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 , a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group or a heterohydrocarbyl hetero group]; m _{5a is} selected from 0, 1, 2, 3, 4, 5 or 6; W _5a and W _6a independently represent C, N, and any Selected substituted [CH ₂ , NH, CH, CH ₂ -CH ₂ , CH=CH, 3-6-membered hydrocarbon or 3-6-membered heteroalkyl], C≡C, single bond, O, S, C=O , C=S, S(=O), S(=O) ₂ ; T _6a , T _7a are each independently selected from O, S, optionally substituted [NH, CH, CH ₂ , CH ₂ -CH ₂ , CH=CH, 3~6-membered hydrocarbon group or 3~6-membered heteroalkyl group], C≡C, single bond, C=O, C=S, S(=O), S(=O) ₂ ; T _8a H, F, Cl, Br, I, CN, =O, =S or optionally substituted [OH , SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; m _{6a is} selected from 0, 1, 2 or 3. When m _6a is 0, the corresponding structural unit represents only a link. a single bond of action; m _{8a is} selected from 0, 1, 2, 3, 4, 5 or 6; Represents a single or double key; ------ represents a single key, double key 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. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the sub-structural unit represented by formula (g) is selected from the group consisting of: Specifically, the substructure unit represented by the formula (g) is selected from the group consisting of: The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y _2a is isopropyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y _6b is The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unit The substructure unit is selected from the group consisting of: The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit represented by formula (c) is selected from the group consisting of: The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A ₄ , B ₄ , Q ₄ , D ₄ or Y ₄ are each independently selected from the structural unit represented by formula (e), Selecting substituted benzene or optionally substituted biphenyl, Wherein X ₁ and X ₂ are each independently selected from the group consisting of a single bond, O, S, C=O, C=S, S=O, S(=O) ₂ or optionally substituted [CH ₂ , NH, PH a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group or a heterohydrocarbylhetero group; X ₃ and X ₄ are each independently selected from H, F, Cl, Br, I, CN, =O, =S or optionally substituted [ OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl]; q ₃ , q ₄ are each independently selected from 0, 1, 2 or 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A ₄ , B ₄ , Q ₄ , D ₄ or Y ₄ are each independently selected from the group consisting of: The compound of 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, the hetero atom Or the hetero atomic group is selected from N, O, S, S(=O) or S(=O) ₂ . The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the R _{4 is} selected from the group consisting of two or more substituted groups: The compound of 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 of claim 14, 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 and R ₄ form a guanamine bond. The compound of 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 of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from H, F, Cl, Br, I, CN, optionally substituted [OH, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl a group, an alkoxycarbonyl group, a heterocyclic carbonyl group or 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 of claim 17, or a pharmaceutically acceptable salt thereof, wherein the alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, alkylthio group, alkylthio group The number of carbon atoms of the alkyl moiety in the alkyl group, the alkoxycarbonyl group and the alkoxycarbonylamino group 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 of claim 17, or a pharmaceutically acceptable salt thereof, wherein R ₂ , R ₅ , R _1a , R _1b , R _3a , R _3b are each independently selected from 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, or ]. The compound of any one of claims 1 to 19, 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, The substituted [OH, SH, NH ₂ , PH ₂ , hydrocarbyl, heterohydrocarbyl, hydrocarbyl and/or heterohydrocarbyl] groups are selected. The compound of claim 20, wherein the hydrocarbyl, heterohydrocarbyl, hydrocarbyl or heterohydrocarbyl hetero group is selected from the group consisting of optionally substituted [C _1-12 hydrocarbyl, C, or a pharmaceutically acceptable salt thereof. _1-12 heteroalkyl, C _1-12 hydrocarbyl, 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=)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 aromatic a ring, a heteroaryl ring, an aliphatic ring, a heteroalicyclic ring, a fatty chain, and/or a hetero fatty chain, and the aromatic ring, heteroaryl ring, fatty ring, heteroalicyclic ring, fatty chain, and/or hetero fatty chain The number, the ring-forming atom and its number, the ring-to-ring or the ring-to-chain or the chain-to-chain connection are arbitrary under the premise of chemically stable implementation, and the heteroatoms or heteroatoms are independently selected from O, S, respectively. , N, S (=O) and / or S (= O) ₂ , the number of heteroatoms or heteroatoms is arbitrary under the premise of chemically stable implementation. The compound of any one of claims 20 or 21, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, =O, =S, OH, or a pharmaceutically acceptable salt thereof. SH, NH ₂ , halogenated or hydroxy or amine or unsubstituted C _1-6 alkyl or heteroalkyl or alkylene, heteroatoms or heteroatoms are 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 of claim 22 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from the group consisting of halogen, OH, SH, NH ₂ , CN, =0, =S, CF ₃ , -OCF ₃ Or -OCH ₃ . The compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising: A process for the preparation of a compound of the formula (II) according to any one of claims 1 to 24, which comprises the step of the formula (S1): a structural unit in the compound represented by the formula (II) Substructure unit is A method for preparing a compound of the formula (II) as described in claim 25, which comprises the step represented by the formula (S2): A method for preparing a compound of the formula (II) as described in claim 26, which comprises the step of the formula (S3): The compound represented by (II) is A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for the preparation of a medicament for the treatment of HCV.