TW201439060A - Bridged ring compounds as HCV inhibitors, pharmaceutical compositions and uses thereof - Google Patents

Abstract

Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.

Description

Bridged ring compound as hepatitis C inhibitor and pharmaceutical composition and use thereof

The present invention is in the field of medicine and relates to compounds for the treatment of hepatitis C virus (HCV) infection, compositions of said compounds, and uses and methods of use thereof. In particular, the compounds described herein are bridged ring compounds that can act as NS5A inhibitors. More specifically, the present invention relates to a compound which can inhibit the function of the NS5A protein encoded by the hepatitis C virus, a pharmaceutical composition of the compound, and a method for inhibiting the function of the NS5A protein.

HCV is the major human pathogen, with an estimated global infection of approximately 170 million people, five times the number of human immunodeficiency virus type 1 infections. Most of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection will be the leading cause of premature death from liver disease worldwide.

Currently, the most effective HCV therapy is a combination of alpha-interferon and ribavirin that produces sustained efficacy in 40% of patients. Recent clinical results indicate that PEGylated alpha-interferon is superior to unmodified alpha-interferon as a monotherapy. However, even with experimental treatment regimens including a combination of pegylated alpha-interferon and ribavirin, most patients are unable to consistently reduce viral load, and many patients are often accompanied by some side effects that cannot be treated for long periods of time. . Therefore, new and effective methods for treating HCV infection are currently urgently needed.

HCV is a positive strand RNA virus. Based on a comparison of the deduced amino acid sequence and the broad similarity of the 5' untranslated region, HCV is classified into a separate 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 in the entire HCV genome and the encoded amino acid sequence memory are quite heterogeneous. At least 7 major genotypes have been identified and more than 50 subtypes have been disclosed. In HCV-infected cells, viral RNA is translated into polyproteins and split into 10 individual proteins. At the amino terminus is a structural protein, followed by E1 and E2. In addition, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a very important role in the HCV life cycle (see, for example, Lindenbach, BD and CMRice, Nature.436 , 933-938, 2005 ).

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 single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame encoding a single large 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 is believed to be a metalloproteinase that cleaves at the NS2-NS3 junction; the second is a serine protease comprising the N-terminal region of NS3 (also referred to herein as the NS3 protease), which mediates all subsequent cleavage downstream of NS3. The NS3-NS4A cleavage site is cis, and the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NA5B sites are trans. The NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease and may assist in membrane localization of NS3 and other viral replicase components. The formation of the NS3 protein with the NS4A complex appears to be a processing event necessary to increase proteolytic efficiency at all sites. The NS3 protein also showed nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.

The compounds of the invention are useful for treating HCV infection in a patient which selectively inhibits replication of the HCV virus. In particular, the compounds of the invention are compounds which are effective in inhibiting the function of the NS5A protein. For HCV NS5A proteins see, for example, Tan, S.-L., Katzel, MG, Virology 2001 , 284 , 1-12; and Park, K.-J.; Choi, S.-H, J. Biological Chemistry , 2003 .

The present invention relates to novel bridged ring compounds and methods of combating HCV infection. The compounds or pharmaceutical compositions of the invention have a good inhibitory effect on HCV infection, particularly on the HCV NS5A protein.

In one aspect, the invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a compound of formula (I) or a compound of formula (I), Solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein each of A and A' is independently a bond, an alkylene group, an alkenylene group, a cycloalkylene group, a heterocycloalkylene group, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ ) -C(=O)-O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Wherein each X ¹ , X ¹ or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; Is a carbocyclic or heterocyclic group; W ₂ is a fused bicyclic group or a fused heterobicyclic group; each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b - Each of a and b is independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0, 1, 2 or 3; each p is independent Ground is 0, 1, 2 or 3; each r is independently 0, 1 or 2; each f and f' is independently 0, 1, 2, 3 or 4; e is 0, 1, 2, 3 or 4 Each X and X' is independently N or CR ⁷ ; each Y and Y' is independently H, oxime, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl An optical, alpha-amino acid group or an optical isomer of an a-amino acid group, or each Y and Y' is independently the structural unit: -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )- (CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² Or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ^12; each U is independently -C (= O) -, - C (= S) -, - S (= O) - or -S (= O) ₂ -; each t is independently 2, 3 or 4; each k is independently 0, 1 or 2; each R ^1, R ^2, R ³ and R ⁴ are independently H, deuterium, alkyl, heteroalkyl, aralkyl group , cycloalkyl, heterocyclyl, heteroaryl or aryl; or R ¹ , R ² and X-CH arbitrarily form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; or R ³ , R ⁴ and X'-CH optionally form a 3-8 membered heterocyclic ring or 3-8 members. a carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; each R ^{5 is} independently H, hydrazine, hydroxy, alkyl, Heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=O)-, alkyl-C(=O)-, carbamidine group, an alkyl group -OS (= O) _r, an alkyl group -S (= O) _r O-, alkyl -S (= O) _r - sulfo or amino acyl; each R ^5a and R ^{5a 'is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O) NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ¹³ , -N(R ¹³ ) C(=O)-R ¹³ , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC( =O)-Alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, Alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, hetero Arylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl Sulfhydryl, alkyl decyloxy, alkoxy fluorenyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy a heterocyclylamino or aryloxy group; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)- , R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ ^{-, R 13 S (= O} ) 2 -, aliphatic, halogenated aliphatic, aliphatic hydroxyl, aliphatic amino group, an aliphatic alkoxy Alkylamino aliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclic aliphatic,cycloalkylaliphatic,aryloxyaliphatic,heterocyclicoxyaliphatic,cycloalkane a hydroxy-aliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; wherein the aliphatic of the group is an alkane Each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S (=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, hetero Cyclo, cycloalkyl, decyl, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamine , heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, Alkyl fluorenyl, alkyl decyloxy, alkoxy fluorenyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfin Alkoxy, heterocyclylalkylamino or aryloxy; each R ⁷ and R ^{7a are} independently H, hydrazine, F, Cl, Br, I, aliphatic, heteroalkyl, halogenated aliphatic, hydroxyaliphatic , amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclic aliphatic, cycloalkyl aliphatic, aryloxy aliphatic , heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl Wherein the aliphatic group of the group is an alkyl group; each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, ring Alkyl, heterocyclic, aryl, Aryl, aralkyl, alkoxy, alkyl -OC (= O) -, group -C (= O) -, carbamoyl acyl, alkyl -OS (= O) _r -, alkyl - S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl; each R ⁹ , R ^9a , R ¹⁰ and R ^{11 are} independently H, hydrazine, alkyl, heteroalkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl; each R ¹² independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC( =O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N( R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; or R ¹¹ , R ¹² and the atoms attached thereto may form 4 a -7 membered ring; and each of R ¹³ and R ^{13a is} independently H, hydrazine, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; when R ¹³ and R ^13a attached to the same nitrogen atom, R ^13, R ^13a, and nitrogen The substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring may be optionally formed; each of the following groups: an alkylene group, an alkenylene group, a cycloalkylene group, a heterocycloalkylene group, (CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C (=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² , -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² , NR ⁶ , CR ⁷ R ^7a , CR ⁷ , -( CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b -, -(CH ₂ ) _a -O-(CH _{2 b} -, R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a ) -, R ¹³ OS(=O) ₂ -, alkyl-OC(=O)-, alkyl-C(=O)-, alkyl-OS(=O) _r -, alkyl-S(=O _r O-, alkyl-S(=O) _r -, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ^13a R ¹³ N -alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, α-amino acid group, C _5-12 fused bicyclic, C _5-12 fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclo, alkoxy, aliphatic, halogenated aliphatic, hydroxyaliphatic, aminoaliphatic , alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, Aryl aliphatic, heteroaryl aliphatic, heterocyclic aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, Heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroaryl Alkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino or aryloxy may optionally be one Or a plurality selected from the group consisting of hydrazine, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, fluorenyl, nitro Alkyl, aryloxy, heteroaryloxy, oxo (=O), carboxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, Alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ - or carboxyalkane Substituted by a substituent of an oxy group.

In some of these embodiments, wherein Is a C _3-8 carbocyclic group or a C _2-10 heterocyclic group; and W ₂ is a C _5-12 fused bicyclic group or a C _5-12 fused heterocyclic group.

In some of these embodiments, wherein The structural unit is the following substructure: The structural unit is the following substructure: Wherein each X ^{3 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ⁴ and X ^{5 is} independently O, S, NR ⁶ , C(=O) Or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each Q ^{3 is} independently N or CR ⁷ ; e is 0, 1, 2, 3 or 4; each i is independently 0, 1, 2, 3 or 4; each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, Cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(= O) NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorene , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyl acyl group, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl group, -CF _3, -OCF _3, mercapto, nitro, C _1-6 alkyl Group, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ is independently hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkane , C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy Alkyl C _1-6 alkyl, C _{2-10heterocyclyloxy} C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 Alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2 a -10} heterocyclic group or a C _3-10 carbocyclic group; each of R ⁷ and R ^{7a is} independently H, fluorene, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _{6- 10} aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkane , C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _{6 -10} arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _{1 a -9heteroaryl} group, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heteroalkyl , C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^13a attached to the same nitrogen atom, R ^13, R ^13a, and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, fused bicyclic or spiro bicyclic.

In some of these embodiments, wherein The structural unit is the following substructure: Independently the following substructures: Wherein each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CH; each f is independently 0, ¹ , ² , 3 or 4; each R ^5a and R ^{5a' is} independently H,氘, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C( =O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl Mercapto, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl, C _1-6 alkyl sulfonyl, C _1-6 alkoxy sulfonyl, C _1-6 alkyl Sulfosyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl a group, -CF ₃ , -OCF ₃ , fluorenyl, nitro or C _1-6 alkylamino; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O) -, R ¹³ C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkane group, C _1-6 alkoxy C _1-6 alkyl group C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _{1- a 6} alkyl group, a C _2-10 heterocyclic group C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 Alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _{1 -6} alkyl; or when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclo or fused bicyclic ring.

In some of these embodiments, wherein each A and A' is independently a bond, C _1-6 alkylene, C _2-6 alkenylene, C _3-8 cycloalkylene, C _2-10 hetero Cycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -( CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )- (CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-( CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-O-(CR ⁸ R ^8a ) _p -, or each of A and A' independently is the following Group: Wherein each X ¹ , X ¹ or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; t is 0, 1, 2, 3 or 4; each Y ¹ and Y ^{2 is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b -; each a and b are independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0, 1, 2 or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl , C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS (=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently hydrogen , 氘, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O) -, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 Alkyl, C _{1-9heteroaryl} C _1-6 alkyl, C _{2-10heterocyclyl} C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryl Oxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _{1- 6} alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2-10heterocyclyl} or C _3-10 carbocyclyl; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ NC _1-6 alkyl, R ¹³ S(=O)-C _1-6 alkyl, R ¹³ R ^13a NC(= O)-C _1-6 alkyl, R ^13a R ¹³ NC _1-6 alkoxy, R ¹³ S(=O)-C _1-6 alkoxy, R ¹³ R ^13a NC(=O)-C _{1 -6} alkoxy, C _6-10 aryl, C _1-9 heteroaryl, C _1-6 alkoxy, C _1-6 alkyl Group, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl group, a mercapto group, a nitro group , C _6-10 aryl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino or C _6-10 aryloxy; each R ⁷ and R ^{7a are} independently H, 氘, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1- 6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl , C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclic Oxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 An alkyl group, a C _3-10 cycloalkylamino C _1-6 alkyl group, a C _6-10 aryl group, a C _1-9 heteroaryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; R ¹³ and R ^{13a are} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1-9heteroaryl} or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and a nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; and each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F , Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 Aryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O) -,carbamoyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - sulfo or amino acyl; in some of these embodiments, each of a and a ^'are independently a _{bond, -CH 2 -, - (CH} 2) 2 -, - CH = CH -, - CH = CH -CH ₂ -, -N(R ⁵ )-, -C(=O)-, -C(=S)-, -C(=O)-O-, -C(=O)N(R ⁵ ) -, -OC(=O)N(R ⁵ )-, -OC(=O)O-, -N(R ⁵ )C(=O)N(R ⁵ )-, -(R ⁵ )NS(= O) ₂ -, -S(=O) ₂ -, -OS(=O) ₂ -, -(R ⁵ )NS(=O)-, -S(=O)-, -OS(=O)- , or each of A and A ^' independently of the following groups: Wherein X ¹ is O or S; Y ¹ is N or CH; t is 0, 1, 2 or 3; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 hetero Alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS (=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently hydrogen, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _{2 a -10} heterocyclic group or a C _3-8 carbocyclic group; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, fluorenyl or nitro And each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and the nitrogen atom A substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring may be optionally formed.

In some embodiments thereof, wherein each R ¹ , R ² , R ³ and R ^{4 are} independently H, C _1-8 alkyl, C _1-8 heteroalkyl, C _6-10 aryl C _{1- 6} alkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _1-9 heteroaryl or C _6-10 aryl, or R ¹ , R ² and X-CH are optionally formed 3-8 a heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; R ³ , R ⁴ and X '-CH optionally forms a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclic ring or a C _5-12 spiro bicyclo ring. .

In other embodiments, wherein R ¹ , R ² and X-CH, or R ³ , R ⁴ and X′-CH may optionally form a 3-8 membered heterocyclic ring, a C _5-12 fused bicyclic ring, C _{5 - 12} fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclo.

In other embodiments, the heterocyclic or fused ring or spiro ring system formed by R ¹ , R ² and YX-CH is selected from the group consisting of the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _6-10 aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4.

In other embodiments, the heterocyclic or fused ring or spiro ring system formed by R ³ , R ⁴ and Y′-X′-CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _6-10 aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4.

In some of these embodiments, it has the structure shown in formula (II): among them, The structural unit is the following substructure: Independently for the following substructure: Each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; each Q ^{3 is} independently N and CH; each X ^{3 is} independently O, S , NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ^{1 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; e is 0, 1, 2, 3 or 4; Independently 0, 1, 2, 3 or 4; each f and f' is independently 0, 1, 2, 3 or 4, X ⁴ and X ^{5 are} independently O, S, NR ⁶ , C (= O Or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each A and A' is independently a bond, C _1-6 alkylene, C _{2 -6} alkenylene, C _3-8 cycloalkylene, C _2-10 heterocycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O) -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)- O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl- C(=O)-, carbamethyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl- S(=O) _r - or aminosulfonyl; each R ^5a , R ^{5a '} and R ^{6a are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyanide Base, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O )NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S (=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkane Isosulfonyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl, -CF ₃ , -OCF ₃ , fluorenyl, nitro, C _1-6 alkylamino, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ Site hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C (= O) -, R 13 R 13a NS (= O) -, R 13 OS ( =O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 Aliphatic, C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _1-9 heteroaryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; wherein the aliphatic group of the group is an alkyl group, and the alkyl group may be, but not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group. And isobutyl; each R ⁷ and R ^{7a are} independently H, hydrazine, F, Cl, Br, I, C _1-6 aliphatic, C _2-6 heteroalkyl, C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 a cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl or C _3-10 carbocyclyl; wherein the aliphatic group of the group is Alkyl, alkyl may be, but not limited to, methyl, ethyl, propyl, isopropyl Base, butyl and isobutyl; each R ⁸ and R ^{8a are} independently H, hydrazine, hydroxy, cyano, nitro, F, Cl, Br, I, C _1-6 alkyl, C _2-6 Alkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS (=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ¹³ and R ^{13a are} independently H, Anthracene, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _{6 -10} aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclo or a fused bicyclic ring; each n is independently 0, 1, 2 or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; t is 0, 1, 2, 3 Or 4; and each of Y ₄ and Y ₄ 'is independently a bond, O, S, -(CH ₂ ) _n -, -CH=CH-, -S(=O) _r -, -CH ₂ O-, -CH ₂ S-, -CF ₂ -, -CHR ^5a -, -CR ^5a R ^6a , -CH ₂ S(=O) _r or -CH ₂ N(R ⁶ )-.

In other embodiments, it has the structure shown in formula (III): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each X ³ and X ^{5 is} independently O, S , NR ⁶ , C (=O) or (CR ⁷ R ^7a ) _e ; and each of i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (IV): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or ( CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; and each i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (V): Wherein each of Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; each X ³ and X ^{5 is} independently O, S, NR ⁶ , C (=O) Or (CR ⁷ R ^7a ) _e ; and each i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (VI): Wherein Q ⁴ is O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ Is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; and each i and e are independently 0, 1, 2, 3 or 4.

In some of these embodiments, wherein each Y and Y' is independently an a-amino acid group.

In other embodiments, wherein the alpha-amino acid group is selected from the group consisting of isoleucine, bright Amino acid, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, aspartame, aspartic acid, glutamic acid, glutamine, guanidine Acid, serine, tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N,N-dimethylglycine, homoserine, norvaline, norleucine, A group formed by ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline.

In other embodiments, wherein the alpha-amino acid of the alpha-amino acid group is in the D configuration.

In other embodiments, wherein the alpha-amino acid of the alpha-amino acid group is in the L configuration.

In some of these embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U- (CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -C( =O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -C(=O) -(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=O) -R ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-R ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=O) -OR ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-OR ¹³ .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -C(=O) -(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-R ¹² , wherein R ¹¹ , R ^{12 are} attached thereto The atoms can form a 4-7 membered ring.

In still other embodiments, wherein each R ⁹ , R ^9a , R ¹⁰ and R ^{11 are} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl , C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxy alkane a C _1-9 heteroaryl C _1-6 alkyl group, a C _2-10 heterocyclic C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; each R ^{12 is} independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(= O) NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ ) C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 a heteroaryl group or a C _6-10 aryl C _1-6 alkyl group; or R ¹¹ , R ¹² and an atom attached thereto may form a 4-7 membered ring; each of R ¹³ and R ^{13a is} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 Aryl C _1-6 alkyl; when R ¹³ and R ^{13a is} attached to the same nitrogen atom, and R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; each t is independently 0, 1, 2 3 or 4; and each k is independently 0, 1, or 2.

In still other embodiments, wherein each R ⁹ , R ^9a , R ¹⁰ and R ^{11 are,} independently, H, hydrazine, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl; ¹² independently -C(=O)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , methyl, ethyl, propyl, phenyl, cyclohexyl, a phenyl or a pyridinyl group; or R ¹¹ , R ¹² and an atom attached thereto may form a 4-7 membered ring; and each of R ¹³ and R ^{13a is} independently H, hydrazine, methyl, ethyl, propyl, Phenyl, cyclohexyl, morpholinyl or acridinyl.

In other embodiments, it has the structure shown in formula (VII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl , C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 An alkyl group, a C _2-10 heterocyclic C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 Aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl C _1-6 alkyl It may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In other embodiments, it has the structure shown in formula (VIII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, three Fluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl; wherein said C _1-3 hydroxy Alkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazine The group, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In some of these embodiments, it has the structure shown in formula (IX): Wherein each of Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; i is 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independent The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{2 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group.

In some of these embodiments, it has the structure shown in formula (X): Wherein each of Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; i is 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independent The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{1 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group.

In some of these embodiments, it has the structure shown in formula (XI): Wherein each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), benzyl, C _1-4 alkyl, F, Cl, Br or I; each R ¹⁴ and R ^{14a are} independently H, 氘, C _1-4 alkyl, C _6-10 aryl, C _2-10 heterocyclyl or C _3-8 cycloalkyl; each R ¹⁶ and R ^{16a are} independently hydroxy, C _1-4 alkane a oxy group, a C _6-10 aryloxy group, a C _2-10 heterocyclic group or a C _3-8 cycloalkyl group; wherein the benzyl group, the C _1-4 alkyl group, the C _6-10 aryl group, C _2-10 heterocyclyl, C _1-4 alkyloxy, C _3-8 cycloalkyl, C _6-10 aryloxy may be optionally selected from one or more selected from the group consisting of ruthenium, F, Cl, Substituted by a substituent of Br, a hydroxyl group or a cyano group; The structural unit is of the following substructure: Independently the following groups: Each A and A' is independently the following group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In still other embodiments, wherein each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br, or I; each R ¹⁴ and R ^{14a is} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each of R ¹⁶ and R ^{16a is} independently hydroxy, methoxy Ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In some of these embodiments, it has the structure shown in formula (XII): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; each f and f′ is independently 0, 1, 2, 3 or 4 Each X ³ and X ^{5 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; e is 0, 1, 2, 3 or 4; each R ^5a and R ^5a' Independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, Phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each of R ¹⁶ and R ^{16a is} independently hydroxy, methoxy, ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently a group : A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In some of these embodiments, it has the structure shown in formula (XIII): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl , phenyl or cyclohexyl; each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, oxo (=O), benzyl, ethyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' are} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each i and e are independently 0, 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each R ¹⁶ and R ^16a independently Is a hydroxyl group, a methoxy group, an ethoxy group, a phenoxy group, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In another aspect, the invention provides a pharmaceutical composition comprising any one of the compounds described above.

In some of these embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

In some of these embodiments, it further comprises other anti-HCV drugs.

In other embodiments, the anti-HCV drug is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes a type 1 helper T cell response, interfering RNA, antisense RNA , imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavi infliximab (Bavituximab), Civacir ^TM, boceprevir (of boceprevir), for Lari Telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT -267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vaniprevir (MK-7009), Faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032), sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054 , IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PS I-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222 ), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof.

In other embodiments, wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon , interferon gamma or a combination thereof.

In some of these embodiments, it further comprises at least one HCV inhibitor for inhibiting at least one of an HCV replication process and inhibiting HCV viral protein function; the HCV replication process is selected from the group consisting of HCV entry, The complete viral cycle of HCV that is shelled, translated, replicated, assembled or released. The HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

In another aspect, the compound or pharmaceutical composition of the invention is for use in inhibiting at least one of an HCV replication process and a HCV viral protein function; the HCV replication process is selected from the group consisting of HCV entry, husking, translation, replication, assembly Or release the complete viral cycle of HCV. The HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a hepatitis C disease in a patient, comprising administering to the patient an effective amount of a compound or a compound according to the invention The pharmaceutical composition of the invention.

Another aspect of the invention relates to formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) A method of preparing, isolating and purifying a compound contained in (XII) or (XIII).

The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.

Detailed description of the invention Definitions and general terms

The present invention will detail the documents corresponding to the specific content of the determination. The examples are accompanied by illustrations of structural formulas and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to those described herein, which can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or contradict the application of the present invention, including but not limited to the definition of terms, the use of terms, the techniques described, or the scope as controlled by the present application.

The invention will apply the following definitions unless otherwise indicated. The object of the present invention, the chemical elements according to the Periodic Table, CAS version Handbook of Physics and Chemistry, 75 ^th Ed., 1994 is defined. In addition, the general principles of organic chemistry can be found in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito, 1999 and "March's Advanced Organic Chemistry ", Michael B. Smith and Jerry March, John Wiley & Sons, New York, 2007 , all of the above. References are incorporated herein by reference.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or as specific examples, subclasses, and inclusions of the invention. A class of compounds. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" whether preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently. The substituents described therein may be, but are not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkyne. , heterocyclic, fluorenyl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkane -C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S (=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The term "aliphatic" or "aliphatic" as used herein, denotes a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon group that is fully saturated or contains one or more degrees of unsaturation. Unless otherwise specified, the aliphatic group contains from 1 to 20 carbon atoms, some embodiments of which the aliphatic group contains from 1 to 10 carbon atoms, and in other embodiments, the aliphatic group contains from 1 to 8 carbon atoms. In other embodiments, the aliphatic group contains 1-6 carbon atoms, and in other embodiments, the aliphatic group contains 1-4 carbon atoms, and in other embodiments, the aliphatic group contains 1-3 carbon atoms. . Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like.

The term "haloaliphatic" or "haloaliphatic" means that the aliphatic group is substituted by one or more of the same or different halogen atoms, wherein the aliphatic group has the meaning as described herein, and the halogen atom is fluorine. Examples of chlorine, bromine or iodine include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl and the like.

The term "hydroxyaliphatic" or "hydroxyaliphatic" means that the aliphatic group is substituted by one or more hydroxyl groups, wherein the aliphatic group has the meaning as described herein, such examples include, but are not limited to, Hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.

The term "aminoaliphatic" or "aminoaliphatic" means that the aliphatic group is substituted by one or more amino groups, wherein the aliphatic group has the meaning as described herein, such examples include, but are not limited to, Aminomethyl, 2-aminoethyl, 2-aminoisopropyl, and the like.

The term "alkyl" denotes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 A saturated linear or branched monovalent hydrocarbon group of a carbon atom wherein the alkyl group can be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), Isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH) ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH) ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2 -butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2- Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl-2- Group _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3), n-heptyl, n-octyl Base and so on. The term "alkyl" and its first "alkane" are used herein to encompass both straight-chain and branched saturated carbon chains. The term "alkylene" is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , isopropylidene and so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one of which The position is an unsaturated state, i.e., one CC is a sp ² double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including the group having "reverse", The positioning of cis" or "E", "Z", wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and the like .

The term "alkynyl" means a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one of which The position is an unsaturated state, that is, one CC is a sp triple bond, wherein the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention, wherein specific examples of alkynyl groups include, but Not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), and the like.

The term "hydroxy substituted alkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein the alkyl group has the meanings indicated herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

The term "haloalkyl" denotes an alkyl group substituted by one or more of the same or different halo atoms, wherein the alkyl group has the meaning as defined herein, and the halo atom is fluoro, chloro, bromo or iodo. Examples include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl, and the like.

The term "hydroxyalkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, hydroxyethyl, 2 - hydroxypropyl, hydroxymethyl, and the like.

The term "aminoalkyl" denotes an alkyl group substituted by one or more amino groups, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, aminomethyl, 2 - aminoethyl, 2-aminoisopropyl and the like.

The term "alkylene" means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group. And the alkylene group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro or aryloxy. Such examples include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -), isopropylidene (-CH ₂ -CH(CH ₃ )-), Ethane-1,1-diyl, 2-methoxypropane-1,1-diyl, 2-hydroxypropane-1,1-diyl, 2-methyl-2-hydroxypropane-1,1- Second base and so on.

The term "alkenylene" means an alkene group derived by removing two hydrogen atoms from a linear or branched olefin. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro or aryloxy. Such examples include, but are not limited to, vinylidene (-CH=CH-), isopropylidene (-C(CH ₃ )=CH-), 3-methoxypropene-1,1-diyl , 2-methylbutene-1,1-diyl and the like.

The term "carbocyclylene" ("cycloalkylene") denotes a saturated divalent hydrocarbon ring obtained by removing a single ring of 3 to 12 carbon atoms or a double ring of 7 to 12 carbon atoms by removing two hydrogen atoms. Wherein carbocyclyl or cycloalkyl has the meaning as described herein, such examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-ene Alkenyl, 1-cyclopent-2-enyl and the like.

The term "heterocyclylene" means a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms on the ring are independently selected from heteroatoms and may be fully saturated or contain one or more unsaturations, but not It belongs to the class of aromatics and has two points of attachment to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein. Such examples include, but are not limited to, acridine-1,4-diyl, pyridazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, aza Cyclobutane-1,3-diyl, pyrrolidine-1,3-diyl and the like.

The term "heterocyclylenealkyl" denotes a group obtained by the removal of two hydrogen atoms of a heterocyclylalkyl group, wherein the heterocyclylalkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, morpholin-4-methylmethylene, acridine-N-methylmethylene, and the like.

The term "haloalkylene" means that the haloalkyl moiety has two points of attachment to the rest of the molecule. Wherein the alkylene group has the meaning as described in the present invention, such examples include, but are not limited to, difluoromethylene (-CF ₂ -) and the like.

The term "arylene" means that the aryl system has two points of attachment to the rest of the molecule. Wherein the aryl group has the meaning as described herein, such examples include, but are not limited to, phenylene, p-fluorophenyl, and the like.

The term "aralkylene" means that the aralkyl system has two points of attachment to the rest of the molecule, wherein the aralkyl group has the meaning as described herein. Such examples include, but are not limited to, benzamidine, phenylethylene, and the like.

The term "heteroarylene" means that the heteroaryl system has two points of attachment to the rest of the molecule. Wherein the heteroaryl group has the meaning as described herein, such examples include, but are not limited to, pyridinylene, pyridylene, thiazolyl, imidazolyl, and the like.

The term "heteroarylenealkyl" means that the heteroarylalkyl system has two points of attachment to the rest of the molecule, wherein the heteroarylalkyl has the meaning as described herein, such examples include, but are not It is limited to pyridine-2-ethylene, thiazole-2-methylene, imidazole-2-ethylene, pyrimidine-2-methylene and the like.

The term "subfused bisbicyclic" means that the fused bicyclic system has two points of attachment to the rest of the molecule, wherein the fused bicyclic group has the meaning as described herein. Such examples include, but are not limited to, bicyclo [3.1.0]hexane-3,6-diyl and the like.

The term "sub-fused heterobicyclic" means that the fused heterobicyclic system has two points of attachment to the rest of the molecule. Such examples include, but are not limited to, 3-azabicyclo[3.1.0]hexane-3,6-diyl and the like.

The term "subfused bisbicycloalkyl" means that the fused bicyclic alkyl group has two points of attachment to the rest of the molecule, wherein the fused bicyclic alkyl group has the meaning as described herein.

The term "sub-fused heterobicycloalkyl" means that the fused heterobicycloalkyl has two points of attachment to the rest of the molecule, wherein the fused heterobicycloalkyl has the meaning as described herein.

The term "spirabicyclo" means that the spirobicyclic system has two points of attachment to the rest of the molecule, wherein the spirobicyclic group has the meaning as described herein. Such examples include, but are not limited to, 5-spiro[2.4]heptane-5,7-diyl, spiro[4.4]nonane-2,7-diyl, and the like.

The term "aspynbicyclo" means that the spirobicyclic ring system has two points of attachment to the rest of the molecule, wherein the spiroheterobicyclic group has the meaning as described herein. Such examples include, but are not limited to, 5-azaspiro[2.4]heptane-5,7-diyl, 2-azaspiro[4.4]nonane-2,7-diyl, and the like.

The term "spirabicycloalkyl" means that the spirobicycloalkyl system has two points of attachment to the rest of the molecule, wherein the spirobicycloalkyl has the meaning as described herein.

The term "aspynbicycloalkyl" means that the spirobicycloalkyl system has two points of attachment to the rest of the molecule, wherein the spirobicycloalkyl has the meaning as described herein.

The term "heteroalkyl" denotes the insertion of one or more heteroatoms in the alkyl chain, wherein the alkyl group and heteroatom have the meaning as described herein. Unless otherwise specified, a heteroalkyl group contains from 1 to 10 carbon atoms, and in other embodiments, a heteroalkyl group contains from 1 to 8 carbon atoms. In still other embodiments, a heteroalkyl group contains 1 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms. Such examples include, but are not limited to, CH ₃ OCH ₂ -, CH ₃ CH ₂ OCH ₂ -, CH ₃ SCH ₂ -, (CH ₃ ) ₂ NCH ₂ -, (CH ₃ ) ₂ CH ₂ OCH ₂ -, CH ₃ OCH ₂ CH ₂ -, CH ₃ CH ₂ OCH ₂ CH ₂ -, and the like.

The terms "alicyclic", "alicyclic", "cyclic aliphatic", "carbocyclic", "carbocyclyl" or "cycloalkyl" mean monovalent or multivalent, non-aromatic, A saturated or partially unsaturated ring, and does not contain a hetero atom, including a single ring of 3 to 12 carbon atoms or a bicyclic ring of 7 to 12 carbon atoms. A bicyclic carbocyclic ring having 7 to 12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and a bicyclic carbocyclic ring having 9 or 10 atoms. It may be a bicyclo[5,6] or [6,6] system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of the cyclic aliphatic group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptane Base, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. And the "cyclic aliphatic group" or "carbocyclic ring", "carbocyclic group", "cycloalkyl group" may be substituted or unsubstituted, wherein the substituent may be, but not limited to, hydrazine, hydroxyl group, Amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, Hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl- S(=O)-, a hydroxy-substituted alkyl-S(=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl or carbocyclyl group, as defined herein, attached to an oxygen atom, and attached to the remaining molecule by an oxygen atom. Examples of such include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.

The term "cycloalkylamino" denotes that the amino group is substituted by one or two optionally substituted cycloalkyl groups, wherein cycloalkyl has the meaning as described herein, such examples include, but are not limited to, Cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, and the like.

The term "carbocyclyloxyalkoxy" denotes that alkoxy is substituted by one or more carbocyclyloxy groups, wherein alkoxy and carbocyclyloxy groups have the meanings as described herein Such examples include, but are not limited to, cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl- 3-oxyethoxy group and the like.

The term "cycloalkyloxyaliphatic" or "cycloalkyloxyaliphatic" means that the aliphatic group is substituted by one or more optionally substituted cycloalkyloxy groups, wherein the aliphatic group and the ring The alkyloxy group has the meaning as described herein, and such examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyl Alkoxyethyl, cyclohexyloxyethyl, halocyclopropyloxyethyl and the like.

The term "cycloalkylaminoaliphatic" or "cycloalkylaminoaliphatic" means that the aliphatic group is substituted by one or more optionally substituted cycloalkylamino groups, wherein the aliphatic group and the cycloalkylamino group are substituted. The group has the meaning as described herein, and such examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexyl. Aminoethyl, halocyclopropylaminoethyl and the like.

The term "cycloalkylaliphatic" or "cycloalkylaliphatic" means that the aliphatic group may be substituted by one or more cycloalkyl groups, wherein the cycloalkyl and aliphatic groups have the same according to the invention By way of example, such examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.

The term "cycloalkylalkoxy" ("carbocyclylalkoxy") denotes an alkoxy group substituted by one or more cycloalkyl ("carbocyclyl") groups, wherein cycloalkyl ( "Carbocyclyl" group and alkoxy group have the meanings as described herein, such examples include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentyl Oxyl, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy and the like.

The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring system in which one or more The carbon atoms are independently and optionally substituted by a hetero atom having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but are by no means aromatic, only A connection point is connected to other molecules. The hydrogen atoms on one or more of the rings are independently and optionally substituted by one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered ring of a monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, wherein S or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO ₂ , PO, PO ₂ when When the ring is a three-membered ring, there is only one hetero atom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, here S Or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO ₂ , PO, PO ₂ ).

The heterocyclic group may be a carbon group or a hetero atom group. "Heterocyclyl" also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, Morpholinyl, thiomorpholinyl, thiamethane, thiazolidinyl, oxazolidinyl, pyridazinyl, oxazinyl, azetidinyl, oxetanyl, thioheterobutyl , homoacridinyl, epoxypropyl, azepanyl, oxetanyl, thiaheptyl, 4-methoxy-acridin-1-yl, 1,2,3,6- Tetrahydropyridin-1-yl, oxazepine, diazepine, thiazepine, pyrrolin-1-yl, 2-pyrroline, 3-pyrroline, indanyl , 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyridyl Azolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinidine 1,1-dioxo-2-yl, 4- Hydroxy-1,4-azaphosphazene 4-oxide-1-yl, 2-hydroxy-1-(pyridazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6 -dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4-yl, 5,6-dihydro -4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridine-1(2H)-yl)ethanone-4-yl, 3-aza Bicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1, 2,4]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazole [4,3-c]pyridin-5-yl, 3H-fluorenyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridyl Urea. Examples of the heterocyclic group further include a 1,1-dioxothiomorpholinyl group and a pyrimidinedione group in which two carbon atoms on the ring are substituted by an oxygen atom. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, oxo (=O), a hydroxyl group, an amino group, a halogen, a cyano group, a heteroaryl group, an alkoxy group. , alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C (=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O ₂ - a carboxyl-substituted alkoxy group or the like.

The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy wherein the oxygen atom is attached to the remainder of the molecule; the term "heterocycle" The alkylamino group" includes a heterocyclic group-substituted alkylamino group in which a nitrogen atom is bonded to the remainder of the molecule. Wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein, examples of which include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, Polin-4-ylethoxy, pyridazin-4-ylethoxy, acridin-4-ylethylamino and the like.

The term "heterocyclyl aliphatic" or "heterocyclyl aliphatic" denotes a heterocyclic substituted aliphatic group, wherein the heterocyclic group and the aliphatic group have the meanings as described herein, such examples include, but It is not limited to pyrrole-2-methyl, acridine-2-ethyl, pyridazine-2-ethyl, acridine-2-methyl and the like.

The term "heterocyclyloxy" includes optionally substituted heterocyclyl, as defined herein, attached to an oxygen atom wherein the oxygen atom is attached to the remainder of the molecule, examples of which include, but are not limited to, pyrrole -2-oxy, pyrrole-3-oxy, acridine-2-oxy, acridine-3-oxy, pyridazin-2-oxy, acridine-4-yl and the like.

The term "heterocyclylamino" denotes an amino group substituted by one or two heterocyclyl groups, wherein the nitrogen atom is attached to the remainder of the molecule, and the heterocyclyl has the meaning as described herein, such an example Including, but not limited to, pyrrole-2-amino, pyrrole-3-amino, acridine-2-amino, acridine-3-amino, acridine-4-amino, pyridazin-2-amino, dipyrrole- 2-Amino and the like.

The term "heterocyclyloxyalkoxy" denotes that alkoxy is substituted by one or more heterocyclyloxy groups, wherein alkoxy and heterocyclyloxy groups have the meanings as described herein Such examples include, but are not limited to, pyrrole-2-oxymethoxy, pyrrole-3-oxyethoxy, acridine-2-oxyethoxy, acridine-3-oxyethyl Oxyl, pyridazine-2-oxymethoxy, acridine-4-oxyethoxy, and the like.

The term "heterocyclyloxyaliphatic" or "heterocyclyloxyaliphatic" means that the aliphatic group is substituted by one or more heterocyclyloxy groups, wherein the aliphatic and heterocyclic oxy groups The group has the meaning as described in the present invention, such examples include, but are not limited to, pyrrole-2-oxymethyl, pyridazin-3-oxyethyl, pyridazine-2-oxyethyl, Morpholine-2-oxymethyl, acridine-2-oxyethyl and the like.

The term "heterocyclylaminoaliphatic" or "heterocyclylaminoaliphatic" means that the aliphatic group is substituted by one or more heterocyclylamino groups, wherein the aliphatic and heterocyclylamino groups have Meanings of the invention, such examples include, but are not limited to, pyrrole-2-aminomethyl, pyridazine-3-aminoethyl, pyridazine-2-aminoethyl, acridinium-2-aminoethyl , morpholin-2-aminomethyl and the like.

The term "heteroatom" denotes one or more of the O, S, N, P and Si atoms, including the form of any of the oxidation states of N, S and P; the form of primary, secondary, tertiary and quaternary ammonium salts; a form in which a hydrogen atom on a nitrogen atom is substituted, for example, N (for example, N in a 3,4-dihydro-2H-pyrrolyl group), NH (for example) For example, NH) or NR in a pyrrolidinyl group (for example, NR in an N-substituted pyrrolidinyl group).

The term "halogen" means F, Cl, Br or I.

The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.

The term "alkoxy" as used in the present invention relates to an alkyl group, as defined in the present invention, attached to the main carbon chain through an oxygen atom, examples of which include, but are not limited to, methoxy, ethoxy Base, propoxy, butoxy, and the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, fluorenyl , nitro, etc.

The term "hydroxy substituted alkoxy" denotes that the alkoxy group is substituted by one or more hydroxy groups, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, hydroxymethyl Oxyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, and the like.

The term "aminoalkoxy" denotes that the alkoxy group is substituted by one or more amino groups, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, aminomethoxy 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy and the like.

The term "azidoalkoxy" denotes that the alkoxy group is substituted by one or more azido groups, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, 2- Azidoethoxy, 3-azidopropoxy, 2-azidopropoxy, and the like.

The term "alkoxyalkoxy" denotes that the alkoxy group is substituted by one or more alkoxy groups, wherein the alkoxy group has the meaning as described herein, such examples include, but It is not limited to methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy and the like.

The term "alkoxy aliphatic" or "alkoxy aliphatic" means that the aliphatic group is substituted by one or more alkoxy groups, wherein the aliphatic and alkoxy groups have the same according to the invention By way of example, such examples include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl, and the like.

The term "alkylaminoaliphatic" or "alkylaminoaliphatic" means that the aliphatic group is substituted by one or more alkylamino groups, wherein the aliphatic and alkylamino groups have the meanings as described herein, such that Examples include, but are not limited to, dimethylaminoethyl, methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like.

The term "alkylthioaliphatic" or "alkylthioaliphatic" means that the aliphatic group is substituted by one or more alkylthio groups, wherein the aliphatic and alkylthio groups have the same according to the invention By way of example, such examples include, but are not limited to, methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl, and the like.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy which may be substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, 2-chloro-vinyl, trifluoromethoxy, and the like.

The term "aryl" may be used alone or as a large part of "aralkyl", "aralkyloxy" or "aryloxyalkyl", meaning monocyclic, bicyclic and tertiary containing a 6-14 membered ring. A cyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", and the aromatic ring may include phenyl, naphthyl and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkane Alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)- , alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, carboxyl Substituted alkoxy groups and the like.

The term "arylaliphatic" or "arylaliphatic" means that the aliphatic group is substituted by one or more optionally substituted aryl groups, wherein the aliphatic and aryl groups have the same according to the invention By way of example, such examples include, but are not limited to, phenethyl, benzyl, p-tolylethyl, styryl, and the like.

The term "aryloxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, wherein the aryl group has the meaning as described herein. Examples of such include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like.

The term "arylamino" denotes that the amino group is substituted by one or two optionally substituted aryl groups, wherein the aryl group has the meaning as described herein, such examples include, but are not limited to, phenylamino, P-fluorophenylamino, diphenylamino, xylylamino, di-p-tolylamino and the like.

The term "aryloxyalkoxy" denotes an alkoxy group which is optionally substituted by one or more Substituted by an aryloxy group, wherein the alkoxy and aryloxy groups have the meanings as described herein, such examples include, but are not limited to, phenoxymethoxy, phenoxyethoxy, Phenoxypropoxy group and the like.

The term "aryloxy aliphatic" or "aryloxy aliphatic" means that the aliphatic group is substituted by one or more optionally substituted aryloxy groups, wherein the aryloxy group and the aliphatic group have the invention By way of example, such examples include, but are not limited to, phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl, and the like.

The term "arylaminoaliphatic" or "arylaminoaliphatic" means that the aliphatic group is substituted by one or more optionally substituted arylamino groups, wherein the arylamino group and the aliphatic group have the same according to the invention Meaning, such examples include, but are not limited to, phenylaminomethyl, phenylaminoethyl, toluidine aminoethyl, phenylaminopropyl, phenylaminoallyl, and the like.

The term "arylalkoxy" denotes that the alkoxy group is substituted by one or more optionally substituted aryl groups, wherein aryl and alkoxy have the meanings described herein, such examples include, but It is not limited to phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy or the like.

The term "arylalkylamino" denotes an alkylamino group substituted by one or more optionally substituted aryl groups, wherein aryl and alkylamino have the meanings described herein, such examples include, but are not It is limited to phenylmethylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino and the like.

The term "heteroaryl" may be used alone or as a large part of "heteroarylalkyl" or "heteroarylalkoxy", meaning monocyclic, bicyclic and tricyclic systems which together contain a 5-14 membered ring. Wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms wherein the heteroatoms have the meanings described herein, wherein each ring system comprises a 3-7 membered ring and only one attachment The point is connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, Alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O) -, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, A carboxy substituted alkoxy group or the like.

In other embodiments, the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4- Methyl isoxazole-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, Pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-Triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4- Thiodidiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-tri Zinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuran Benzo, benzothienyl, fluorenyl (such as 2-indenyl), fluorenyl, quinolinyl (such as 2-quinolyl, 3-quinolinyl, 4-quinolinyl) and isoquinolyl (eg 1-isoquinolyl, 3-isoquinolinyl or 4-isoquinolinyl).

The term "heteroaryloxy" includes an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, wherein the heteroaryl group has the invention By way of example, such examples include, but are not limited to, pyridin-2-yloxy, thiazol-2-oxy, imidazol-2-oxy, pyrimidin-2-oxy, and the like.

The term "heteroaryloxyaliphatic" or "heteroaryloxyaliphatic" means that the aliphatic group is substituted by one or more optionally substituted heteroaryloxy groups, wherein the aliphatic group and the hetero group The aryloxy group has the meaning as described herein, and such examples include, but are not limited to, pyridin-2-oxyethyl, thiazol-2-oxymethyl, imidazolium-2-oxyethyl , pyrimidine-2-oxypropyl and the like.

The term "sulfo acyl", whether used alone or with other terms such as "alkylsulfonyl group" used in conjunction, respectively divalent radicals -SO ₂ -.

The term "alkylsulfonyl" refers to an alkyl-substituted sulfonyl group forming an alkylsulfonyl group (-SO ₂ alkyl group such as -SO ₂ CH ₃ ).

The terms "ammoxime", "aminosulfonyl" and "aminosulfonyl" refer to an amino-substituted sulfonyl group to form a sulfonyl group (-SO ₂ NH ₂ ).

The term "carboxy", whether used alone or in conjunction with other terms (such as "carboxyalkyl"), means -CO ₂ H; the term "carbonyl", whether used alone or in conjunction with other terms (eg "aminocarbonyl" or "醯oxy"), which means -(C=O)-.

The term "carboxy substituted alkoxy" denotes that the alkoxy group is substituted by one or more carboxy groups, wherein the alkoxy and carboxy groups have the meanings as described herein, such Examples include, but are not limited to, carboxymethoxy, carboxyethoxy, and the like.

The term "aralkyl" includes aryl substituted alkyl groups. In some embodiments, an aralkyl group refers to a "lower aralkyl" group, ie, an aryl group is attached to a _C1-6 alkyl group. In other embodiments, an aralkyl group refers to a "phenylene support" comprising a _C1-3 alkyl group. Specific examples thereof include a benzyl group, a diphenylmethyl group, and a phenethyl group. The aryl group on the aralkyl group may be further substituted with a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, and a halogenated alkoxy group.

The term "alkylthio" includes a _C1-10 straight or branched alkyl group attached to a divalent sulfur atom. In some embodiments, the alkylthio group is a lower C _1-3 alkylthio group, examples of which include, but are not limited to, methylthio (CH ₃ S-).

The term "haloalkylthio" includes a C _1-10 haloalkyl group attached to a divalent sulfur atom. In some embodiments, the haloalkylthio group is a lower C _1-3 haloalkylthio group, examples of which include, but are not limited to, trifluoromethylthio.

The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is a lower alkylamino group having one or two _C1-6 alkyl groups attached to the nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of _C1-3 . Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N - Diethylamino and the like.

The term "alkylaminohaloalkoxy" denotes that haloalkoxy is substituted by one or more alkylamino groups, wherein haloalkoxy and alkylamino groups have the meanings as described herein, such examples include, but are not It is limited to methylaminodifluoromethoxy, ethylaminotrifluoromethoxy and the like.

The term "heteroarylamino" denotes an amino group substituted by one or two heteroaryl groups, wherein the heteroaryl group has the meanings described herein, such examples include, but are not limited to, N-thienylamino and the like. In some embodiments, the heteroaryl ring on the heteroarylamino group can be further substituted.

The term "heteroarylaliphatic" or "heteroarylaliphatic" means that the aliphatic group is substituted by one or more heteroaryl groups, wherein the heteroaryl and aliphatic groups have the meanings described herein, such Examples include, but are not limited to, thiophen-2-propenyl, pyridin-4-ethyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.

The term "heteroarylalkyl" means that the alkyl group is taken from one or more heteroaryl groups. And wherein the heteroaryl and alkyl groups have the meanings described herein, such examples include, but are not limited to, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like. .

The term "heteroarylalkylamino" includes a heteroarylalkyl group containing a nitrogen atom attached to the other group through a nitrogen atom, wherein the heteroarylalkyl group has the meaning as described herein, such examples include However, it is not limited to pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.

The term "aminoalkyl" includes _C1-10 straight or branched alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a _C1-6 "lower aminoalkyl group" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl.

The term "alkylaminoalkyl" includes alkyl groups substituted with alkylamino groups. In some embodiments, the alkylaminoalkyl group is a _C1-6 lower alkylaminoalkyl group. In other embodiments, the alkylaminoalkyl group is a _C1-3 lower alkylaminoalkyl group. Suitable alkylaminoalkyl groups may be monoalkyl or dialkyl substituted, examples of which include, but are not limited to, N-methylaminomethyl, N,N-dimethylaminoethyl, N , N-diethylaminomethyl and the like.

The term "carboxyalkyl" includes _C1-10 straight or branched alkyl groups which may be substituted by one or more carboxy groups, examples of which include, but are not limited to, carboxymethyl, carboxypropyl and the like.

The term "aryloxy" includes an optionally substituted aryl group, attached to an oxygen atom as defined herein, and attached to the remainder of the molecule by an oxygen atom, examples of which include, but are not limited to, phenoxy groups, etc. .

The term "heteroarylalkoxy" includes a heteroarylalkyl group containing an oxygen atom attached to the other group through an oxygen atom, wherein the heteroarylalkyl group has the meaning as described herein, such examples include , but not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, etc. .

The term "cycloalkylalkyl" denotes an optionally substituted cycloalkyl substituted alkyl group, examples of which include, but are not limited to, cyclohexylmethyl. The cycloalkyl group may be further substituted with hydrazine, a halogen, an alkyl group, an alkoxy group and a hydroxyl group.

The terms "fused bicyclic", "fused ring", "fused bicyclic", "fused ring" mean a saturated or unsaturated, heterocyclic or bridged ring system involving a non-aromatic, heterocyclic or bridged ring system, As shown in the formula (a1), the ring A1 and the ring A2 share a bond, an alkyl chain or a heteroalkyl chain, wherein j is 0, 1, 2, 3 or 4. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). Each of the fused bicyclic rings is either a carbocyclic ring or a heteroalicyclic ring, and such examples include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4 , 7,7a-hexahydro-1H-indole, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, bicyclo[2.2 .1] heptane, 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, all of which are contained in a ring or bridged ring system within. And the fused bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl , alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, Alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl- S(=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The term "fused heterobicyclic" means a saturated or unsaturated, heterocyclic or bridged ring system involving a non-aromatic, heterocyclic or bridged ring system. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, ie 1-3 heteroatoms comprising 1-6 carbon atoms and selected from N, O, P, S Wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO ₂ , PO, PO ₂ , such examples include, but are not limited to, hexahydro-furan [3.2- b] furan, 6-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.1.0]heptane, 3-azabicyclo[3.1.0]heptane, 7-azabicyclo[2.3 .0] heptane, 2-azabicyclo[2.2.1]heptane, and the like. And the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl Alkyl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)- , alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl -S(=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The terms "spirocyclyl", "spirocyclic", "spirobicyclo", "spirobicyclic" mean that one ring originates from a particular cyclic carbon on the other ring. For example, Ring A and Ring B share a single carbon atom in two saturated ring systems and are referred to as "spiro rings." Each ring in the spiral ring is either a carbon ring or a heteroalicyclic ring. Such examples include, but are not limited to, 2,7-diazaspiro[4.4]decane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-aza Spiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptanyl, snail [4.4] Mercaptoalkyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl and the like. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl, Alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkane -C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S (=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The term "spirabicyclo" refers to a spirobicyclic radical system having two points of attachment to the rest of the molecule, wherein the spirobicyclo group has the meaning as described herein.

The term "spirobicyclo" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, Ring A and Ring B share a carbon atom in two saturated ring systems and are referred to as "spirocycles". And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, ie 1-3 heteroatoms comprising 1-6 carbon atoms and selected from N, O, P, S Wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO ₂ , PO, PO ₂ , such examples include, but are not limited to, 4-azaspiro[2.4] Heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptane Alk-5-yl, 5-azaspiro[2.4]heptane-6-yl, 1,4-dioxo-7-azaspiro[4.4]decane-8-yl and the like. And the spiroheterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl , alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, Alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl- S(=O) ₂ -, a carboxy-substituted alkoxy group, and the like.

The α-amino acid group of the present invention is a group formed by removing a hydroxyl group from a carboxyl group of an α-amino acid, which is linked to X or X′, and the α-amino acid group may be optionally selected by one or more Substituted from a substituent of hydrazine, F, Cl, Br, I, hydroxy or cyano. E.g:

As described in the present invention, a ring system in which a substituent is bonded to a central ring (as shown in formula (a)) represents that the substituent (R ^5a ) _f can be substituted at any substitutable position on the ring. . For example, formula (a) represents a position on the W1 ring, W2 ring or W ring that may be substituted.

As described in the present invention, two points of attachment in the ring system are attached to other groups, as shown in formula (b), indicating that both the E and E' ends of ring W3 can be attached to other groups, and In the invention, the groups attached to both ends of E and E' are interchangeable.

As described herein, the dashed line within the ring system represents a double bond or a single bond. For example, the structure of the formula (c) represents any structure selected from the formula (d).

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)): for example, containing asymmetric centers The R, S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers thereof, or mixtures of geometric isomers (or conformational isomers) are within the scope of the invention.

In addition, it should be noted that, unless otherwise explicitly indicated, the descriptions used throughout the text are "individually", "independently" and "...independently "Alternatively, it should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or can be expressed in the same group, between the same symbols. The specific options expressed do not affect each other, taking R ⁹ as an example, the structural formula "-U-(CR ⁹ R ^9a ) _t -R ¹² " and the structural formula "-[U-(CR ⁹ R ^9a ) _t - N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² ′ between R ⁹ The specific options are not affected by each other, and at the same time, in the same chemical formula "-[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a Within _t - N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² ", the specific options of a plurality of R ⁹ are not affected by each other.

The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C _1-24 ) ester, a decyloxymethyl ester, or a carbonate. Carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be deuterated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press , 1987 , J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery , 2008 , 7 , 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51 , 2328-2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, hydrazine, deamination, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

The use of the definitions and conventions of stereochemistry in the present invention is generally referred to the following documents: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms ( 1984 ) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , " Stereochemistry of Organic Compounds ", Joln Wiley & Sons, Inc., New York, 1994 . The compounds of the invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the invention . Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing an optically active compound, the first code D, L or R, S is used to indicate the absolute configuration of the molecular chiral center. The first code d, l or (+), (-) is used to name the symbol of the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the first code (+) or d means that the compound is right-handed. . The chemical structures of these stereoisomers are the same, but their stereostructures are different. A particular stereoisomer can be an enantiomer, a mixture of isomers, commonly referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lack optical activity.

The term "tautomer" or "tautomeric form" means that the isomers of the structure of different energies can be converted into each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. The valence (valence) tautomer includes the interconversion of recombination bond electrons.

The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences , 66 , 1-19, 1977 . Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and Organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods such as ion exchange to obtain these salts by the literature. . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphorate , camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate , gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-benzene Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate hydrazine include salts of alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 alkyl) ₄ . The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C _{1- 8} sulfonate and aromatic sulfonate.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl hydrazine, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

The term "protecting group" or "Pg" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" refers to a substituent which is bonded to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include ethenyl, trifluoroethylidene, tert-butyl Oxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group. Suitable protecting groups include ethenyl and carbaryl. "Carboxyl protecting group" refers to a carboxy substituent group that blocks or protects the carboxy functionality, typically carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethyl Silane Ethyl, 2-(trimethyldecyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(di) Phenylphosphino)ethyl, nitroethyl and the like. General description of protecting groups may Reference: TWGreene, Protective Groups in Organic Synthesis , John Wiley wSons, New York, 1991; and PJKocienski, Protecting Groups, Thieme, Stuttgart , 2005.

It should be noted that the term "inhibiting HCV viral proteins" in the present invention should be understood broadly, and includes both inhibition of the expression level of HCV viral proteins, as well as inhibition of the activity level of HCV viral proteins, and assembly and release levels of viruses. Among them, HCV protein expression levels include, but are not limited to, the translation level of the viral protein gene, the post-translational modification level of the protein, the replication level of the progeny genetic material, and the like.

Description of the compounds of the invention

The bridged ring compound and the pharmaceutical preparation thereof according to the present invention can effectively inhibit HCV infection, and particularly inhibit the activity of the HCV NS5A protein.

In one aspect, the invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a compound of formula (I) or a compound of formula (I), Solvates, metabolites, pharmaceutically acceptable salts or prodrugs: Wherein each of A and A' is independently a bond, an alkylene group, an alkenylene group, a cycloalkylene group, a heterocycloalkylene group, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ ) -C(=O)-O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Wherein each X ¹ , X ^{1 '} or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; Is a carbocyclic or heterocyclic group; W ₂ is a fused bicyclic group or a fused heterobicyclic group; each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b - Each of a and b is independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0, 1, 2 or 3; each p is independent Ground is 0, 1, 2 or 3; each r is independently 0, 1 or 2; each f and f' is independently 0, 1, 2, 3 or 4; e is 0, 1, 2, 3 or 4 Each X and X' is independently N or CR ⁷ ; each Y and Y' is independently H, oxime, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl An optical, alpha-amino acid group or an optical isomer of an a-amino acid group, or each Y and Y' is independently the structural unit: -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )- (CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² Or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ^12; each U is independently -C (= O) -, - C (= S) -, - S (= O) - or -S (= O) ₂ -; each t is independently 2, 3 or 4; each k is independently 0, 1 or 2; each R ^1, R ^2, R ³ and R ⁴ are independently H, deuterium, alkyl, heteroalkyl, aralkyl group , cycloalkyl, heterocyclyl, heteroaryl or aryl; or R ¹ , R ² and X-CH arbitrarily form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; or R ³ , R ⁴ and X'-CH optionally form a 3-8 membered heterocyclic ring or 3-8 members. a carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; each R ^{5 is} independently H, hydrazine, hydroxy, alkyl, Heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=O)-, alkyl-C(=O)-, carbamidine group, an alkyl group -OS (= O) _r, an alkyl group -S (= O) _r O-, alkyl -S (= O) _r - sulfo or amino acyl; each R ^5a and R ^{5a 'is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O) NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ¹³ , -N(R ¹³ ) C(=O)-R ¹³ , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC( =O)-Alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, Alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, hetero Arylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl Sulfhydryl, alkyl decyloxy, alkoxy fluorenyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy a heterocyclylamino or aryloxy group; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)- , R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ ^{-, R 13 S (= O} ) 2 -, aliphatic, halogenated aliphatic, aliphatic hydroxyl, aliphatic amino group, an aliphatic alkoxy Alkylamino aliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclic aliphatic,cycloalkylaliphatic,aryloxyaliphatic,heterocyclicoxyaliphatic,cycloalkane Alkoxy aliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; each R ^{6a is} independently H, hydrazine, Hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O )-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl , R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, nitro, Aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy Heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylalkyl, alkyloxy, alkoxy Alkyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylamino or aryloxy Each of R ⁷ and R ^{7a is} independently H, hydrazine, F, Cl, Br, I, aliphatic, heteroalkyl, halogenated aliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylamino Aliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclylaliphatic,cycloalkylaliphatic,aryloxyaliphatic,heterocyclyloxyaliphatic,cycloalkyloxy a base aliphatic, an arylamino aliphatic, a heterocyclic amino aliphatic, a cycloalkylaminoaliphatic, an aryl, a heteroaryl, a heterocyclic or a carbocyclic group; each of R ⁸ and R ^{8a is} independently H, 氘, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl - OC(=O)-, alkyl-C(=O)-, carbachol Alkyl group -OS (= O) _r -, alkyl -S (= O) _r O-, alkyl -S (= O) _r - sulfo or amino acyl; each of R ^9, R ^9a, R ¹⁰ and R ¹¹ independently H, anthracene, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclyl An alkyl or cycloalkylalkyl group; each R ^{12 is} independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N( R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; R ¹¹ , R ¹² and the atom to which it is attached may form a 4-7 membered ring; and each of R ¹³ and R ^{13a is} independently H, oxime, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl a heteroaryl or aralkyl group; when R ¹³ and R ^13a are bonded to the same nitrogen atom, R ¹³ , R ^13a and a nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a thick Double ring Wherein each of the following groups: alkylene, alkenylene, cycloalkylene, ^{heterocycloalkylene, - (CR 8 R 8a)} n -O- (CR 8 R 8a) p -, - (CR 8 R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O )-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O) -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(= S)-(CR ⁸ R ^8a ) _p -, -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t - N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² , -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-( CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² , NR ⁶ , CR ⁷ R ^7a , CR ⁷ , -(CH ₂ ) _a - , -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b -, -(CH ₂ ) _a -O-(CH ₂ ) _b -, R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, alkyl-OC(=O)-, alkyl-C(=O)-, alkyl-OS(=O) _r -, alkyl-S (= O) _r O-, alkyl-S(=O) _r -, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ^13a R ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy , R ¹³ R ^13a NC(=O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a-amino acid group, C _5-12 fused bicyclic, C _5-12 fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclo, alkoxy, aliphatic, halogenated aliphatic, hydroxyaliphatic, amino fat Group, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclic aliphatic, cycloalkyl aliphatic, aromatic Oxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic,cycloalkylaminoaliphatic,haloalkyl,alkenyl,alkynyl,aryl Amino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, hetero A cycloalkoxy group, a heterocyclylamino group, a heterocyclylalkylamino group or an aryloxy group may be optionally selected from one or more selected from the group consisting of hydrazine, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkane. Oxyl, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy substituted alkane Oxyl, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy substituted Substituted by a substituent of an alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ - or carboxyalkoxy group.

In some of these embodiments, wherein Is a C _3-8 carbocyclic group or a C _2-10 heterocyclic group; and W ₂ is a C _5-12 fused bicyclic group or a C _5-12 fused heterocyclic group.

In some of these embodiments, wherein The structural unit is the following substructure: The structural unit is the following substructure: Wherein each X ^{3 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ⁴ and X ^{5 is} independently O, S, NR ⁶ , C(=O) Or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each Q ^{3 is} independently N or CR ⁷ ; e is 0, 1, 2, 3 or 4; each i is independently 0, 1, 2, 3 or 4; each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, Cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(= O) NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorene , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyl acyl group, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl group, -CF _3, -OCF _3, mercapto, nitro, C _1-6 alkyl Group, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ is independently hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkane , C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy Alkyl C _1-6 alkyl, C _{2-10heterocyclyloxy} C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 Alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2 a -10} heterocyclic group or a C _3-10 carbocyclic group; each of R ⁷ and R ^{7a is} independently H, fluorene, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _{6 -10} aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 Alkyl, C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _{a 1-9heteroaryl} group, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heterocycloalkane a C _3-10 cycloalkyl group, a C _2-10 heterocyclic group, a C _6-10 aryl group, a C _1-9 heteroaryl group or a C _6-10 aryl C _1-6 alkyl group; when R ¹³ and R ^{13a is} attached to the same nitrogen atom, and R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring.

In some of these embodiments, wherein The structural unit is the following substructure: Independently the following substructures: Wherein each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CH; each f is independently 0, ¹ , ² , 3 or 4; each R ^5a and R ^{5a' is} independently H,氘, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C( ^{= O) -R 13a, R 13} R 13a NS (= O) 2 -, R 13 S (= O) 2 -, R 13 S (= O) 2 N (R 13a) -, C 1-6 alkyl Mercapto, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl, C _1-6 alkyl sulfonyl, C _1-6 alkoxy sulfonyl, C _1-6 alkyl Sulfosyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl a group, -CF ₃ , -OCF ₃ , fluorenyl, nitro or C _1-6 alkylamino; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O) -, R ¹³ C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkane group, C _1-6 alkoxy C _1-6 alkyl group C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _{1- a 6} alkyl group, a C _2-10 heterocyclic group C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 Alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _{1 -6} alkyl; or a 3-8 membered ring when R ¹³ and R ^13a attached to the same nitrogen atom, R ^13, R ^13a, and the nitrogen atom optionally form a substituted or unsubstituted, fused bicyclic or spiro bicyclic.

In some of these embodiments, wherein each A and A' is independently a bond, C _1-6 alkylene, C _2-6 alkenylene, C _3-8 cycloalkylene, C _2-10 hetero Cycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -( CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )- (CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-( CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-O-(CR ⁸ R ^8a ) _p -, or each of A and A' independently is the following Group: Wherein each X ¹ , X ^{1 '} or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; t is 0, 1, 2, 3 or 4; each Y ¹ and Y ^{2 is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b -; each a and b are independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0 , 1, 2 or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkane , C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl- OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently Hydrogen, hydrazine, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O )-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 Alkyl, C _{1-9heteroaryl} C _1-6 alkyl, C _{2-10heterocyclyl} C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryl Oxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _{1- 6} alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2-10heterocyclyl} or C _3-10 carbocyclyl; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ NC _1-6 alkyl, R ¹³ S(=O)-C _1-6 alkyl, R ¹³ R ^13a NC(= O)-C _1-6 alkyl, R ^13a R ¹³ NC _1-6 alkoxy, R ¹³ S(=O)-C _1-6 alkoxy, R ¹³ R ^13a NC(=O)-C _{1 -6} alkoxy, C _6-10 aryl, C _1-9 heteroaryl, C _1-6 alkoxy, C _1-6 alkyl Group, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl group, a mercapto group, a nitro group , C _6-10 aryl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino or C _6-10 aryloxy; each R ⁷ and R ^{7a are} independently H, 氘, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1- 6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl , C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclic Oxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 An alkyl group, a C _3-10 cycloalkylamino C _1-6 alkyl group, a C _6-10 aryl group, a C _1-9 heteroaryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; R ¹³ and R ^{13a are} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1-9heteroaryl} or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and a nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; and each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F , Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 Aryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O) -,carbamoyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - sulfo or amino acyl; in some of these embodiments, each of a and a ^'are independently a _{bond, -CH 2 -, - (CH} 2) 2 -, - CH = CH -, - CH = CH -CH ₂ -, -N(R ⁵ )-, -C(=O)-, -C(=S)-, -C(=O)-O-, -C(=O)N(R ⁵ ) -, -OC(=O)N(R ⁵ )-, -OC(=O)O-, -N(R ⁵ )C(=O)N(R ⁵ )-, -(R ⁵ )NS(= O) ₂ -, -S(-O) ₂ -, -OS(=O) ₂ -, -(R ⁵ )NS(=O)-, -S(=O)-, -OS(=O)- , or each of A and A ^' independently of the following groups: Wherein X ¹ is O or S; Y ¹ is N or CH; t is 0, 1, 2 or 3; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 hetero Alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS (=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently hydrogen, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _{2 a -10} heterocyclic group or a C _3-8 carbocyclic group; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, fluorenyl or nitro And each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and the nitrogen atom A substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring may be optionally formed.

In some embodiments thereof, wherein each R ¹ , R ² , R ³ and R ^{4 are} independently H, C _1-8 alkyl, C _1-8 heteroalkyl, C _6-10 aryl C _{1- 6} alkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _1-9 heteroaryl or C _6-10 aryl, or R ¹ , R ² and X-CH are optionally formed 3-8 a heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; R ³ , R ⁴ and X '-CH optionally forms a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclic ring or a C _5-12 spiro bicyclo ring. .

In other embodiments, wherein R ¹ , R ² and X-CH, or R ³ , R ⁴ and X′-CH may optionally form a 3-8 membered heterocyclic ring, a C _5-12 fused bicyclic ring, C _{5 - 12} fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclo.

In other embodiments, the heterocyclic or fused ring or spiro ring system formed by R ¹ , R ² and YX-CH is selected from the group consisting of the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _6-10 aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4.

In other embodiments, the heterocyclic or fused ring or spiro ring system formed by R ³ , R ⁴ and Y′-X′-CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _6-10 aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4.

In some of these embodiments, it has the structure shown in formula (II): among them, The structural unit is the following substructure: Independently for the following substructure: Each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; each Q ^{3 is} independently N and CH; each X ^{3 is} independently O, S , NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ^{1 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; e is 0, 1, 2, 3 or 4; Independently 0, 1, 2, 3 or 4; each f and f' is independently 0, 1, 2, 3 or 4; each X ⁴ and X ^{5 is} independently O, S, NR ⁶ , C (= O) or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each A and A' is independently a bond, C _1-6 alkylene, C _2-6 alkenylene, C _3-8 cycloalkylene, C _2-10 heterocycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O )-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O) -O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl- C(=O)-, carbamethyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl- S(=O) _r - or aminosulfonyl; each R ^5a , R ^{5a '} and R ^{6a are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyanide Base, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O )NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S (=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkane Isosulfonyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl, -CF ₃ , -OCF ₃ , fluorenyl, nitro, C _1-6 alkylamino, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ Site hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C (= O) -, R 13 R 13a NS (= O) -, R 13 OS ( =O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 Aliphatic, C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _1-9 heteroaryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; each of R ⁷ and R ^{7a is} independently H, 氘, F, Cl, Br, I, C _1-6 aliphatic, C _2-6 heterocycloalkane , C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclic or C _3-10 carbocyclyl Each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 ring Alkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkyl-OC ( =O)-, C _1-6 alkyl-C(=O)-, carbamethyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ¹³ and R ^{13a are} independently H, 氘, C _1-6 alkyl, C _2-6 hetero Alkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl; when R ¹³ And R ^13a are bonded to the same nitrogen atom, and R ¹³ , R ^13a and the nitrogen atom are arbitrarily formed as a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; each n is independently 0, 1, 2 Or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; t is 0, 1, 2, 3 or 4; and each Y ₄ and Y ₄ 'is independently a bond, O, S, -(CH ₂ ) _n -, -CH=CH-, -S(=O) _r -, -CH ₂ O-, -CH ₂ S-, -CF ₂ -, -CHR ^5a -, -CR ^5a R ^6a , -CH ₂ S(=O) _r or -CH ₂ N(R ⁶ )-.

In other embodiments, it has the structure shown in formula (III): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each X ³ and X ^{5 is} independently O, S , NR ⁶ , C (=O) or (CR ⁷ R ^7a ) _e ; and each of i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (IV): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or ( CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; and each i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (V):

Wherein each of Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; each X ³ and X ^{5 is} independently O, S, NR ⁶ , C (=O) Or (CR ⁷ R ^7a ) _e ; and each i and e are independently 0, 1, 2, 3 or 4.

In other embodiments, it has the structure shown in formula (VI): Wherein Q ⁴ is O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ Is O, S, NR ⁶ , C(=O) or CR ⁷ R7 ^a ; and each i and e are independently 0, 1, 2, 3 or 4.

In some of these embodiments, wherein each Y and Y' is independently an alpha amino acid Group.

In other embodiments, wherein the alpha-amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine , aspartame, aspartic acid, glutamic acid, glutamine, valine, serine, tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N , N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine Or a group formed by hydroxyproline.

In other embodiments, wherein the alpha-amino acid of the alpha-amino acid group is in the D configuration.

In other embodiments, wherein the alpha-amino acid of the alpha-amino acid group is in the L configuration.

In some of these embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U- (CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -C( =O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -C(=O) -(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=O) -R ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-R ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=O) -OR ¹³ .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-OR ¹³ .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -C(=O) -(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² .

In other embodiments, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-R ¹² , wherein R ¹¹ , R ^{12 are} attached thereto The atoms can form a 4-7 membered ring.

In still other embodiments, wherein each R ⁹ , R ^9a , R ¹⁰ and R ^{11 are} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl , C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxy alkane a C _1-9 heteroaryl C _1-6 alkyl group, a C _2-10 heterocyclic C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; each R ^{12 is} independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(= O) NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ ) C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, or C _6-10 aryl C _1-6 alkyl; or R ^11, R ¹² and the atoms they are attached to form a 4-7 membered ring; each R ¹³ and R ^13a are independently H, deuterium, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl group; when R ¹³ R ^13a attached to the same nitrogen atom, R ^13, R ^13a, and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, fused bicyclic or spiro bicyclic; each t is independently 0, 1, 3 or 4; and each k is independently 0, 1, or 2.

In still other embodiments, wherein each R ⁹ , R ^9a , R ¹⁰ and R ^{11 are,} independently, H, hydrazine, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl; ¹² independently -C(=O)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , methyl, ethyl, propyl, phenyl, cyclohexyl, a phenyl or a pyridinyl group; or R ¹¹ , R ¹² and an atom attached thereto may form a 4-7 membered ring; and each of R ¹³ and R ^{13a is} independently H, hydrazine, methyl, ethyl, propyl, Phenyl, cyclohexyl, morpholinyl or acridinyl.

In other embodiments, it has the structure shown in formula (VII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl , C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 An alkyl group, a C _2-10 heterocyclic group C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; wherein the C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl-C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl C _1-6 alkyl It may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In other embodiments, it has the structure shown in formula (VIII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, three Fluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl; wherein said C _1-3 hydroxy Alkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazine The group, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In some of these embodiments, it has the structure shown in formula (IX): Wherein each of Q ¹ and Q ² are independently a ^{bond, NR 6, O, S,} C (= O) or (CH _{2) i; i,} 2, 3 or 4; R ¹⁴ and R ^14a each independently The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{2 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group.

In some of these embodiments, it has the structure shown in formula (X):

Wherein each of Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; i is 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independent The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{1 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group.

In some of these embodiments, it has the structure shown in formula (XI): Wherein each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), benzyl, C _1-4 alkyl, F, Cl, Br or I; each R ¹⁴ and R ^{14a are} independently H, 氘, C _1-4 alkyl, C _6-10 aryl, C _2-10 heterocyclyl or C _3-8 cycloalkyl; each R ¹⁶ and R ^{16a are} independently hydroxy, C _1-4 alkane a oxy group, a C _6-10 aryloxy group, a C _2-10 heterocyclic group or a C _3-8 cycloalkyl group; wherein the benzyl group, the C _1-4 alkyl group, the C _6-10 aryl group, C _2-10 heterocyclyl, C _1-4 alkyloxy, C _3-8 cycloalkyl, C _6-10 aryloxy may be optionally selected from one or more selected from the group consisting of ruthenium, F, Cl, Substituted by a substituent of Br, a hydroxyl group or a cyano group; The structural unit is of the following substructure: Independently the following groups: Each A and A' is independently the following group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In still other embodiments, wherein each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br, or I; each R ¹⁴ and R ^{14a is} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each of R ¹⁶ and R ^{16a is} independently hydroxy, methoxy Ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano.

In some of these embodiments, it has the structure shown in formula (XII): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; each f and f′ is independently 0, 1, 2, 3 or 4 Each X ³ and X ^{5 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; e is 0, 1, 2, 3 or 4; each R ^5a and R ^5a' Independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, Phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each of R ¹⁶ and R ^{16a is} independently hydroxy, methoxy, ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently a group : A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In some of these embodiments, it has the structure shown in formula (XIII): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl , phenyl or cyclohexyl; each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, oxo (=O), benzyl, ethyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' are} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each i and e are independently 0, 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each R ¹⁶ and R ^16a independently Is a hydroxyl group, a methoxy group, an ethoxy group, a phenoxy group, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures:

In some of these embodiments, it has a structure of one of the following: Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate or pharmaceutically acceptable salt thereof.

Compounds of the invention (herein, in the manner described) "Compounds of formula (I) and stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates and pharmaceutically acceptable salts thereof And prodrugs, which may be collectively referred to as "compounds of the invention", may be used in the manufacture of pharmaceutical products for the treatment of acute and chronic HCV infection, including those described herein. Further, the compounds of the invention can be used to produce articles resistant to HCV. Thus, the compounds of the invention can be used to produce a medicament for the alleviation, prevention, management or treatment of conditions mediated by HCV, particularly HCV NS5A protein mediated diseases. Thus, the compound of the present invention can be used as an active ingredient of a pharmaceutical composition, which may include a compound represented by the formula (I), and may further comprise at least one pharmaceutically acceptable carrier, adjuvant or diluent. .

In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition employed must be compatible chemically or toxicologically to the other components of the formulation and to the mammal being treated. One skilled in the art can specifically select a "pharmaceutically acceptable" substance or composition depending on the other components employed and the article being treated, such as a human.

Salts of the compounds of the invention also include the intermediates used to prepare or purify the compounds of formula (I) or the isolated enantiomers of formula (I), but are not necessarily pharmaceutically acceptable salt.

If the compound of the invention is basic, the desired salt can be used in the literature. Any suitable method is provided, for example, using a mineral acid or an organic acid. Among them, examples of the inorganic acid include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid; pyranoic acids such as glucuronic acid and Galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid and ethyl sulfonate Acid and so on.

If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic hydrazine or an organic hydrazine such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), an alkali metal hydroxide or an alkaline earth. Metal hydroxide, and so on. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as acridine, morpholine and pyridazine Etc., and obtaining inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Composition, formulation and administration of a compound of the invention

The pharmaceutical composition comprises any one of the compounds of the invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. The pharmaceutical composition can be used for the treatment of hepatitis C virus (HCV) infection or hepatitis C disease, in particular, it has a good inhibitory effect on the HCV NS5A protein.

The pharmaceutical composition further comprises a drug that is resistant to HCV. The anti-HCV drug may be any other known anti-HCV drug different from the compound of the present invention. For example, it may be interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes a type 1 helper T cell response, interfering RNA, antisense RNA, imiquimod, inosine 5'- Monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, CivacirTM, boceprevir, telaprevir, erlotinib , daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816 , samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS -650032), sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP -013420), VBY-376, TMC-649128, mericitabine (R-7128), Sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH -222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT- 109, Gl-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof.

Wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or combination. The pharmaceutical composition further comprising at least one HCV inhibitor for inhibiting at least one of an HCV replication process and an HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, uncoating, The complete viral cycle of translation, replication, assembly, and release of HCV; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point required for HCV viral replication ( IRES) and inosine monophosphate dehydrogenase (IMPDH).

When useful in therapy, a therapeutically effective amount of a compound of the invention, especially a compound of formula (I), and pharmaceutically acceptable salts thereof, can be administered as a raw chemical, and as an active ingredient in a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, especially a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, Diluent or excipient. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit, such as a reduction in viral load. When administered alone as a separate active ingredient, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of the active ingredient which results in a therapeutic effect, whether administered sequentially or simultaneously. The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to a further aspect of the invention, there is also provided a process for the preparation of a pharmaceutical formulation which comprises reacting a compound of the invention, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable Mix the carrier, diluent or excipient. The term "pharmaceutically acceptable" as used in the present invention means a compound, a raw material, a composition and/or a dosage form which, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without excessive toxicity or irritation. , allergies or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended use.

The pharmaceutical preparations may be in unit dosage form, each unit dose containing a predetermined amount of active ingredient Minute. The dosage level of the compound of the present invention is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, preferably between about 0.05 mg/kg body weight/day and about 100 mg/day. Between kg body weight/day, monotherapy is often used to prevent or treat HCV-mediated diseases. The pharmaceutical compositions of the present invention can generally be administered from about 1 to about 5 times per day or as a continuous infusion. Such administration can be used as a long-term or short-term therapy. The amount of active ingredient to be combined with the carrier materials to produce a single dosage form will vary depending on the condition to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound employed, the time of treatment, and the age, sex, weight and condition of the patient And change. Preferred unit dosage forms are unit dosage forms containing a daily or divided dose, or a suitable fraction thereof, of the above-described active ingredients herein. Treatment can be initiated with a small dose that is clearly below the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best results are achieved in this case. In general, the level of concentration of the compound to be administered optimally is generally such that it provides effective results in terms of antiviral effects without causing any harmful or toxic side effects.

When a composition of the present invention comprises a combination of a compound of the present invention and one or more other therapeutic or prophylactic agents, the dosage levels of the compound and the additional drug are typically in a monotherapy regimen of about 10 of the normal administered dose. -150%, preferably about 10-80% of the normal administered dose. The pharmaceutical preparations are suitable for administration by any suitable route, for example by oral administration (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, Intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion). Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with carriers or excipients. It is preferably administered orally or by injection.

Pharmaceutical preparations suitable for oral administration are provided in separate units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foam preparations or foaming preparations (whip ); or an oil-in-water emulsion or a water-in-oil emulsion.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be mixed with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible sugar such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present.

A capsule is prepared by preparing a powdery mixture as described above and filling it into a shaped gelatin shell. Glidants and lubricants such as colloidal cerium oxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. Can also join the service A disintegrating or solubilizing agent (for example, agar, calcium carbonate or sodium carbonate) which improves the availability of the drug when the capsule is applied.

Suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture as needed or desired. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, Polyethylene glycol and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. For example, a tablet is prepared by preparing a powdery mixture, granulating or pre-compacting, adding a lubricant and a disintegrating agent, and compressing into a tablet. Suitably comminuted compound with a diluent or binder as described above, optionally with a binder (for example carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), absorption An accelerator (quaternary salt) and/or an absorbent (for example, bentonite, kaolin or dicalcium phosphate) are mixed to prepare a powdery mixture. The powdered mixture may be granulated by wetting with a binder such as syrup, starch syrup, acadiamucilage or a cellulosic material or a solution of polymeric material. An alternative to granulation is that the powdered mixture can be passed through a tablet press, with the result that poorly formed agglomerates are broken down into granules. The granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the die of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier which can be compressed into tablets without the need for granulation or pre-tabletting steps. A protective or coating material consisting of a shellac seal coat, a sugar coating or a polymeric material coat and a polish coating of wax may be provided. Dyes can be added to these coating materials to distinguish between different unit doses.

Oral liquid preparations such as solutions, syrups and elixirs may be prepared in dosage unit form such that a predetermined amount of the compound is contained in a given amount. A syrup can be prepared by dissolving the compound in a suitably flavored aqueous solution, and the elixirs can be prepared by using a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), etc. may also be added. .

Dosage unit formulations for oral administration can be microencapsulated, if appropriate. The formulations may also be formulated for extended or sustained release, for example by coating or embedding in particulate materials such as polymers, waxes and the like.

The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, can also be administered in liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be composed of a variety of phospholipids, such as cholesterol, octadecylamine or phospholipid choline.

The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, can also be delivered by the use of monoclonal antibodies as separate carriers to which the compound molecules are coupled. The compound can also be coupled to a soluble polymer that is a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide, polyhydroxyethylaspartamide or polyoxyethylene polylysine substituted with palmitoyl residues. . In addition, the compounds can be coupled to a class of biodegradable polymers for controlled release of such polymers, such as polylactic acid, polyε-caprolactone, polyhydroxybutyrate, polyorthoesters, polycondensation A crosslinked copolymer or an amphiphilic block copolymer of an aldehyde, a polydihydropyran, a polycyanoacrylate, and a hydrogel.

Pharmaceutical formulations suitable for transdermal administration can be used as a discrete patch to maintain intimate contact with the recipient's epidermis over a prolonged period of time. For example, the active ingredient can be delivered by an iontophoretic patch, generally see Pharmaceutical Research 1986 , 3(6) , 318.

Pharmaceutical preparations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches. .

Pharmaceutical preparations suitable for rectal administration can be presented as a suppository or as an enemas.

A pharmaceutical preparation suitable for nasal administration wherein the carrier is a solid comprises a coarse powder having a particle size of, for example, 20 to 500 micrometers, which is administered by nasal inhalation, i.e., through a nasal passage from a coarse powder container close to the nose. Inhalation. Suitable formulations wherein the carrier is a liquid, suitable for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient.

Pharmaceutical preparations suitable for administration by inhalation include fine particle dust or mist, which can be delivered by various types of metered dose compressed aerosols, nebulizers, insufflators or the like. Prepared in the device.

Pharmaceutical preparations suitable for vaginal administration may be presented as pessaries, pessaries, creams, creams, gels, pastes, foams or sprays.

Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions, aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, bacteriostatic agents and agents The solute of the formulation isotonic with the blood of the recipient, aqueous and non-aqueous sterile suspensions may include suspending and thickening agents. The formulations may be presented in unit or multi-dose containers, such as sealed Ankai and vials, and may be stored under lyophilized (lyophilized) conditions by the addition of a sterile liquid carrier, such as water for injection, just prior to use. Injectable solutions and suspensions for constitutional use may be prepared from sterile powders, granules and tablets.

It will be appreciated that in addition to the ingredients specifically mentioned above, the formulations also include other ingredients commonly used in the art in connection with the type of formulation, such as those suitable for oral administration, which may include flavoring agents.

Use of the compounds and pharmaceutical compositions of the invention

The invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for use in inhibiting at least one of an HCV replication process and inhibition of HCV viral protein function. The HCV replication process is selected from the complete viral cycle of HCV entry, husking, translation, replication, assembly or release of HCV. The HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any of the compounds or pharmaceutical compositions of the present invention can be used for the treatment of hepatitis C virus (HCV) infection or hepatitis C disease, in particular, it has a good inhibitory effect on the HCV NS5A protein.

A method of treatment comprising administration of a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional HCV drug, whereby the compound of the invention may be administered in combination with other anti-HCV agents, wherein the anti-HCV drug is Interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote type 1 helper T cell response, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenation enzyme inhibitors, amantadine, rimantadine, Bavi infliximab (Bavituximab), Civacir ^TM, boceprevir (of boceprevir), telaprevir (of telaprevir), erlotinib (erlotinib), daclatasvir, Simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir ( IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032) , Sovaprevir (ACH-1625), ACH-1095, VX-9 85, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128 ), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof.

Wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or a combination thereof .

And a method of treatment comprising administration of a compound or pharmaceutical composition of the invention, further comprising administration of another anti-HCV drug, wherein the other anti-HCV drug can be administered in combination with a compound of the invention or a pharmaceutical composition thereof, a compound or drug of the invention The composition is presented as a single dosage form, or as a separate compound or pharmaceutical composition as part of a multiple dosage form. Other anti-HCV drugs can be administered simultaneously or not at the same time as the compounds of the invention. In the latter case, the administration can be carried out by staggering, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

An "effective amount" or "effective amount" of a compound or pharmaceutically acceptable composition of the invention refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein. In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and in any route of administration effective to treat or reduce the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific factors, mode of administration, and the like. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.

General synthetic process

In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I). The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. The company, and Qingdao Ocean Chemical Plant purchased it.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

The column is a silicone column. Silicone rubber (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectrum was determined by using CDCl ₃ , d ⁶ -DMSO, CD ₃ OD or d ⁶ -acetone as a solvent (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, doublet), t (triplet, triplet), q (quartet, quadruple), m (multiplet, Multiple peaks), br (broadened, broad peaks), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data was determined by a spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS. The G1329A autosampler and G1315B DAD detector were used. For analysis, the ESI source was applied to an LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data were measured with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 °C) Agilent 6120 Series LC-MS spectrometer, G1329A autosampler and G1315D DAD detector for analysis The ESI source was applied to an LC-MS spectrometer.

Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 μm. The injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B). The gradient elution conditions are shown in Table 1:

Compound purification was evaluated by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, size 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min 5-95% (0.1% formic acid in acetonitrile) (0.1% aqueous formic acid), the column temperature was kept at 40 °C.

The following abbreviations are used throughout the invention:

HOAc acetic acid

MeCN, CH ₃ CN acetonitrile

NH ₃ ammonia

NH ₄ Cl ammonia chloride

BBr ₃ boron tribromide

BSA bovine serum albumin

Br ₂ bromine

BOC, Boc tert-butoxycarbonyl

Cs ₂ CO ₃ strontium carbonate

CHCl ₃ chloroform

CDCl ₃ deuterated chloroform

Cu copper

CuI cuprous iodide

Et ₂ O ether

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Dppa diphenyl phosphate

EtOAc ethyl acetate

EA ethyl acetate

HBr hydrobromic acid

HCl hydrochloric acid

HOAt, HOAT 1-hydroxy-7-azabenzotriazole

HOBT 1-hydroxybenzotriazole

H ₂ hydrogen

H ₂ O ₂ hydrogen peroxide

Fe iron

LDA diisopropylamino potassium

MCPBA m-chloroperoxybenzoic acid

MgSO ₄ magnesium sulfate

MeOH, CH ₃ OH methanol

MeI methyl iodide

CH ₂ Cl ₂ , DCM dichloromethane

NMP N-methylpyrrolidone

mL, m ml

N ₂ nitrogen

Pd/C palladium/carbon

PE petroleum ether (60-90 ° C)

PBS phosphate buffered saline

POCl ₃ phosphorus oxychloride

Pd(PPh ₃ ) ₄ tetraphenylphosphine palladium

Pd(dppf)Cl ₂ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

K ₂ CO ₃ potassium carbonate

KOH potassium hydroxide

RT, rt room temperature

Rt retention time

NaHCO ₃ sodium bicarbonate

NaBH ₄ sodium borohydride

NaBH ₃ CN sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOH sodium hydroxide

NaClO ₂ sodium chlorite

NaCl sodium chloride

NaH ₂ PO ₄ sodium dihydrogen phosphate

NaH sodium hydride

NaI sodium iodide

Na ₂ SO ₄ sodium sulfate

TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate

THF tetrahydrofuran

Et ₃ N, TEA triethylamine

TFA trifluoroacetic acid

P(t-bu) ₃ tri(tert-butyl)phosphine

NBS N-bromobutanediimine

TBAI tetrabutylammonium iodide

H ₂ O water

TEAF triethylamine

PPA polyphosphoric acid

Tf ₂ O trifluoromethanesulfonic anhydride

HCl.EA ethyl acetate

DIPEA diisopropylethylamine

DME ethylene glycol dimethyl ether

HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

NIS N-iodobutanediamine

TFAA trifluoroacetic anhydride

SEMCl 2-(trimethyldecyl)ethoxymethyl chloride

Dess-Martin (Dyss-Martin Oxidant) (1,1,1-Triethoxycarbonyl)-1,1-dihydro-1,2-phenyliodonium-3(1H)-one

TsOH p-toluenesulfonic acid

TMSA trimethyldecyl acetylene

McDonald's 2,2-dimethyl-1,3-dioxane-4,6-dione

BAST bis(2-methoxyethyl)amino sulfur trifluoride

SbCl ₃ antimony trichloride

SmCl ₃ barium chloride

LiHMDS hexamethyldidecylamine lithium

TMSCl trimethylchlorodecane

PhNTf ₂ N-phenyl bis(trifluoromethanesulfonate) imine

TBDMSOTf tert-butyldimethyl p-toluenesulfonate decane

Et ₂ NSF ₃ diethylamine sulfur trifluoride

MTBE methyl tert-butyl ether

LiN(SiMe ₃ ) ₂ bis(trimethylhydrazine) lithium amide

PPh ₃ MeBr bromomethyltriphenylphosphine

Lawesson’s Reagent 2,4-bis(4-methoxyphenyl)-1,3-disulfide-2,4-phosphane-2,4-disulfide

MTBE methyl tert-butyl ether

TEBAC benzyl triethyl ammonium chloride

I ₂ iodine

DAST diethylaminosulfur trifluoride

IPA isopropanol

TCCA trichloroisocyanuric acid

TEMPO 2,2,6,6-tetramethyl acridine-nitrogen-oxide

IMPDH inosine monophosphate dehydrogenase

IRES internal ribosome entry point

resolve resolution Synthesis method 1

Compound 17 can be produced by the synthesis method 1, wherein each of X ⁷ and X ^{8 is} independently a leaving group such as F, Cl, Br, I, OTf, and each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , R ¹⁴ and R ¹⁶ have the meanings as defined in the present invention, and Pg is an amino protecting group such as Boc, Fmoc, Cbz et al. Compound 1 is reduced by Pd/C hydrogen to obtain compound 2 , compound 2 is halogenated to obtain compound 3 , compound 3 is demethylated to obtain compound 4 , and compound 4 is reacted with p-boronic acid pinacol ester under the catalysis of palladium. compound 5, compound 4 and compound 5 'coupling reaction under palladium catalysis to give compound 6. compound 6 is reacted with trifluoromethanesulfonic anhydride to give compound 7 under basic conditions, with boronic acid compound 7 in frequency and Pd catalyst The alcohol ester reacts to give compound 8 . Compound 9 under the action of a borane reduction reaction to give compound 10, followed by Dess - Martin oxidation to give the compound at 11, compound 11 12 compound cyclization under the action of ammonia and glyoxal, compound 12 with NIS the reaction to obtain compound 13, compound 13 removed in the reaction system of a sulfite to obtain an iodine compound 14. Compound 8 and compound 14 coupling reaction under palladium catalysis to give compound 15, compound 15 after deprotection to give compound 16, compound 16 with the condensation reaction of the compound 16-1 to give the title compound 17.

Synthesis method 2

Compound 35 can be produced by the synthesis method 2. Wherein each of A ¹ , A ² and A ^{3 is} independently selected from N or CR ⁷ , and X ⁷ is a leaving group such as F, Cl, Br, I, OTf, and each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{2 '} , X ³ , e, w, Y ₄ , R ¹⁴ , R ¹⁶ , Y ₄ ^' , R ^14a and R ^16a have the meanings as described in the present invention, Pg is an amino group Protecting groups such as Boc, Fmoc, Cbz, etc. Compound 18 is halogenated to give compound 19 , compound 19 is demethylated to obtain compound 20 , and compound 20 is reacted with trifluoromethanesulfonic anhydride under basic conditions to obtain compound 21 , and compound 21 and compound 5 are subjected to palladium catalysis. The coupling reaction gave compound 22 . Compound 14 is deprotected to give compound 23, compound 24 to give a condensation reaction with the compound 16-1 Compound 23, Compound 24 with Pd catalysis with boronic acid pinacol ester to give compound 25. Compound 26 is condensed with compound 9-1 to give a mixture of compounds 27 and 28 , followed by heating and cyclization in an acetic acid system to give compound 29 , compound 29 is deprotected to give compound 30 , and further condensed with compound 16-2 to give compound 31 . Compound 31 is reacted with pinacol borate under the catalysis of palladium to give compound 32 . Compound 25 is reacted with compound 22 under the catalysis of palladium to obtain compound 33. Compound 33 is reacted with trifluoromethanesulfonic anhydride under basic conditions to obtain compound 34 , and compound 34 and compound 32 are coupled under palladium catalysis. The target compound 35 was obtained.

Synthesis method 3

Compound 44 can be produced by Synthetic Method 3, wherein X ⁷ is a leaving group such as F, Cl, Br, I, OTf, and each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , Y ₄ ^' , R ^6a , R ^14a and R ^16a have the meanings as defined in the present invention, and Pg is an amino protecting group such as Boc, Fmoc , Cbz, etc. Compound 7 is reacted with compound 36 under the catalysis of palladium to give compound 37 . Compound 9-1 and compound 38 undergo condensation reaction under the action of hydrazine to obtain compound 39 , and compound 39 is heated and cyclized in ammonium acetate system to obtain compound 40 , and compound 40 is reacted with boronic acid pinacol ester to obtain a compound under the catalysis of palladium. 41 , compound 41 and compound 7 are subjected to a coupling reaction under the catalysis of palladium to obtain compound 42 , and compound 42 is deprotected to obtain compound 43 , and compound 43 is further subjected to condensation reaction with compound 16-2 to obtain target compound 44 .

Synthesis method 4

Compound 48 can be produced by Synthetic Method 4, wherein each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , Y ₄ ^' , R ¹⁴ and R ¹⁶ have the meanings as described in the present invention. Compound 7 is reacted with compound 25 under the catalysis of palladium to give compound 45 . Compound 24-1 is reacted with TMSA under the catalysis of palladium to obtain compound 46. Compound 46 is deprotected by the action of hydrazine to obtain compound 47 , and compound 47 is reacted with compound 45 under the catalysis of palladium to obtain the target compound 48 .

Synthesis method 5

Compound 53 can be produced by the synthesis method 5, wherein each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , Y ₄ ^' , R ¹⁴ , R ¹⁶ , R ^14a and R ^16a have the meanings as defined in the present invention, and Pg is an amino protecting group such as Boc, Fmoc, Cbz and the like. Compound 49 is deprotected to give compound 50 , and compound 50 is further subjected to condensation reaction with compound 16-2 to give compound 51 . Compound 51 is reacted with pinacol borate to catalyze palladium to give compound 52. Compound 52 is further coupled with compound 45 under the catalysis of palladium to give the target compound 53 .

Synthesis method 6

Compound 61 can be produced by the synthesis method 6, wherein X ⁷ is a leaving group such as F, Cl, Br, I, OTf, and each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , Y ₄ ^' , R ¹⁴ , R ¹⁶ , R ^14a and R ^16a have the meanings as described herein. Compound 54 to give compound 55 under alkali action, followed by the CDI, conditions of the system of ammonia in the reaction to give compound 56, compound 56 Compound 57 condensation reaction with compound 58, compound 58 under the action of alkali cyclization to give compound 59 Compound 59 is reacted with p-boronic acid pinacol ester under the catalysis of palladium to obtain compound 60 , and compound 60 and compound 45 are further subjected to coupling reaction under palladium catalysis to obtain target compound 61 .

Synthesis method 7

Compound 71 can be produced by the synthesis method 7, wherein X ⁷ is a leaving group such as F, Cl, Br, I, OTf, and each R ^5a , R ^{5a '} , f, f', Y ¹ , Y ² , Y ^{1 '} , Y ^{2 '} , X ³ , X ⁵ , e, Y ₄ , Y ₄ ^' , R ¹⁴ , R ¹⁶ , R ^14a and R ^16a have the meanings as defined in the present invention, and Pg is an amino-protecting group, such as Boc, Fmoc, Cbz, etc. Compound 62 is reacted under the action of sodium sulfite to obtain compound 63 , and then compound 64 is obtained in a reaction system of dichlorohydrazine and ammonia water, and compound 64 is reacted under the action of HI to obtain compound 65 , and compound 65 and compound 66 are acted upon by hydrazine. The reaction gives compound 67 , compound 67 is deprotected to obtain compound 68 , and compound 68 is condensed with amino acid to obtain compound 69. Compound 69 is reacted with p-boronic acid pinacol ester under the catalysis of palladium to obtain compound 70 , compound 70 and compound 45 in palladium. The coupling reaction is carried out under the catalysis to obtain the target compound 71 .

Synthesis method 8

The object compound 77 can be produced by the synthesis method 8, wherein X ⁷ is a leaving group such as F, Cl, Br, I, OTf, and each of Y ² , R ^6a , Y ₄ , R ^14a and R ^16a has the same The meaning of the present invention means that Pg is an amino protecting group such as Boc, Fmoc, Cbz and the like. Compound 9 is condensed with compound 72 to obtain compound 73 , and then compound 73 is heated and cyclized in an ammonium acetate system to obtain compound 74. Compound 74 is deprotected to obtain compound 75 , and further condensation reaction with compound 16-2 is carried out to obtain compound 76 . Compound 76 is reacted with pinacol borate under the catalysis of palladium to give the target compound 77 .

Example 1

synthetic route

Step 1) Synthesis of Compound 1-2

Under N ₂ protection, n-butyllithium (5.0 mL, 7.93 mmol, 1.6 M n-hexane solution) was dissolved in freshly distilled THF (20 mL), and at -70 ° C, compound 1-1 (1.0 g, 7.93 mmol) of THF solution (10 mL) and I ₂ (2.32 g, 9.12 mmol) in THF (15 mL), dropwise, and the temperature was slowly reacted for 20 minutes, then slowly warmed up, and when the temperature was raised to -60 ° C, sodium thiosulfate was added. Aqueous solution (3.0 mL, 10%). After completion of the reaction, the reaction was quenched by slowly adding aqueous ammonium chloride (10 mL) to remove THF. The aqueous phase was extracted with n-hexane (50mL×3), and the organic phase was combined and washed with 10% aqueous sodium thiosulfate solution and water. Na ₂ SO _{4 was} dried, concentrated and purified by column chromatography (eluent: EtOAc (EtOAc/EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 6.79,6.77,6.75 (d, dd, d, 1H), 6.63,6.62,6.60,6.58 (s, d, d, s, 1H), 6.53-6.52,6.51 -6.50 (m, m, 1 H) ppm.

Step 2) Synthesis of Compound 1-3

Magnesium strips (0.15 g, 6.35 mmol) were added to a reaction flask under N ₂ protection, and a solution of compound 1-2 (1.6 g, 6.35 mmol) in THF (20 mL) and freshly distilled cyclopentadiene (0.71) g, 10.8 mmol), after completion, reflux reaction for 5 h. After completion of the reaction, the reaction was quenched with EtOAc EtOAc EtOAc (EtOAc) , dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v ) = 15/1) to give an oil 0.75g, yield: 69%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.10-7.09,7.08-7.07 (m, m, 1H), 6.97,6.95,6.93 (s, d, s, 1H), 6.76,6.74 (m, m, 1H ), 6.72-6.66 (m, 2H), 4.31-4.27 (m, 1H), 3.84-3.81 (m, 1H), 3.80 (s, 3H), 2.29-2.25, 2.22-2.18 (m, m, 2H) Ppm.

Step 3) Synthesis of Compound 1-4

Compound 1-3 (0.75 g, 4.36 mmol) and Pd/C (75 mg) were suspended in methanol (10 mL), and then reacted under H ₂ and reacted at 50 ° C for 4.0 hours. After completion of the reaction, methanol was removed, water (20mL), (25mL × 3 ) and extracted with DCM, the combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE / EtOAc (v / v) = 15 / 1) gave a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17, 7.15, 7.13 (s, d, s, 1H), 6.74-6.73, 6.72-6.71 (m, m, 1H), 6.58-6.57, 6.56-6.55 (m) ,m,1H),3.88(s,3H),3.56-3.53(m,1H),3.33-3.30(m,1H),1.97-1.86(m,2H),1.80-1.76(m,1H),1.57 -1.53 (m, 1H), 1.24-1.13 (m, 2H) ppm.

Step 4) Synthesis of Compound 1-5

Compound 1-4 (0.65 g, 3.7 mmol), NIS (0.92 g, 4.07 mmol) was suspended in acetonitrile (10 mL) and allowed to react at 50 ° C overnight. After completion of the reaction, the acetonitrile was removed, water (20 mL), and extracted with DCM (25mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE) gave a colorless liquid of 0.83 g, yield: 75%.

MS (ESI, pos.) m / z : 301.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.46, 7.44 (s, s, 1H), 6.38, 6.36 (m, m, 1H), 3.87 (s, 3H), 3.69-3.66 (m, 1H), 3.45-3.42 (m, 1H), 1.99-1.90 (m, 2H), 1.87-1.83 (m, 1H), 1.64-1.60 ( m, 1H), 1.26-1.16 (m, 2H) ppm.

Step 5) Synthesis of Compound 1-6

The compound 1-5 (0.83 g, 2.77 mmol) was dissolved in DCM (20 mL), and then, toluene, and then, BBr ₃ (0.36 mL, 3.88 mmol) was slowly added dropwise thereto, and the mixture was reacted at room temperature for 1.0 hour. After the reaction was completed, the reaction mixture was poured into ice water (20 mL), the aqueous layer was extracted with DCM (20 mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ : PE / EtOAc (v / v) = 12 / 1) gave a colorless liquid 0.79 g, yield: 100%.

MS (ESI, pos.) m / z : 287.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.39, 7.37 (s, s, 1H), 6.31, 6.28 (s, s, 1H), 5.77 (brs, 1H), 3.52-3.46 (m, 2H), 2.05-1.99 (m, 1H), 1.96-1.90 (m, 1H), 1.88-1.84 (m, 1H), 1.65-1.61 ( m, 1H), 1.32-1.26 (m, 1H), 1.23-1.17 (m, 1H) ppm.

Step 6) Synthesis of Compound 1-7

Compound 1-6 (0.5g, 1.75mmol), compound 1-6-2 (0.49g, 1.92mmol) and Pd (dppf) Cl _2. CH ₂ Cl ₂ (72 mg, 0.087 mmol) and anhydrous potassium acetate (0.43 g, 4.37 mmol) were placed in a reaction flask under N ₂ and then poured in anhydrous DMF (5.0 mL) and reacted at 90 ° C for 2.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL), and the mixture was filtered, and then filtered, washed with water (20 mL × 3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE /EtOAc (v / v) = 10/1) afforded white solid.

MS (ESI, pos.) m / z : 397.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.00, 7.98 (s, s, 1H), 6.94, 6.92 (s, s, 1H), 5.77 (brs, 1H), 3.58-3.55 (m, 1H), 3.49-3.46 (m, 1H), 1.99-1.93 (m, 1H), 1.82-1.76 (m, 2H), 1.59-1.55 ( m, 1H), 1.32 (q, 6H), 1.29 (q, 6H), 1.26-1.20 (m, 1H), 1.09-1.03 (m, 1H) ppm.

Step 7) Synthesis of Compound 1-8

Compound 1-7 (0.45 g, 1.14 mmol), Compound 1-6 (0.36 g, 1.25 mmol), potassium carbonate (0.39 g, 2.84 mmol) and Pd(PPh ₃ ) ₄ (65.7 mg, 0.057 mmol) were placed. DME (8.0 mL) and water (2.0 mL) were separately injected into a reaction flask under N ₂ and reacted at 90 ° C for 12 hours. After completion of the reaction, was cooled to room temperature, EtOAc (50mL) After the reaction mixture was diluted, washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 8/1) 0.29 g of a white solid was obtained, yield: 80%.

MS (ESI, pos.) m / z : 319.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.10, 7.08 (s, s, 2H), 6.55, 6.53 (s, s, 2H), 5.77 (brs, 2H), 3.59-3.54 (m, 2H), 3.47-3.43 (m, 2H), 1.99-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.59-1.55 ( m, 2H), 1.26-1.19 (m, 4H) ppm.

Step 8) Synthesis of Compound 1-9

Triethylamine (0.57 mL, 4.09 mmol) and Compound 1-8 (0.26 g, 0.82 mmol) were dissolved in DCM (10 mL) at 0 ° C, stirred for 10 min, then trifluoromethanesulfonic anhydride (0.39) mL, 2.29 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, ice-water was added (25mL) The reaction was quenched, the aqueous layer was extracted with DCM (25mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, purified by column chromatography and concentrated (eluent: PE) gave 0.43 g of a colorless oily product, yield: 90%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.10, 7.08 (s, s, 1H), 6.55, 6.53 (s, s, 1H), 5.77 (brs, 2H), 3.59-3.54 (m, 2H), 3.47 -3.43 (m, 2H), 1.99-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.59-1.55 (m, 2H), 1.26-1.19 (m, 4H) ppm.

Step 9) Synthesis of Compound 1-10

Compound 1-9 (0.4g, 0.69mmol), compound 1-6-2 (0.37g, 1.44mmol) and pd (dppf) Cl _2. CH ₂ Cl ₂ (28 mg, 0.034 mmol) and potassium acetate (0.17 g, 1.72 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (5.0 mL) and then reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL), and the mixture was filtered, and then filtered and washed with water (25 mL×3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE / EtOAc (v/v) = 50/1) afforded 0.26 g of white solid.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.61,7.59 (s, s, 2H), 7.44,7.42 (s, s, 2H), 3.76-3.73 (m, 2H), 3.69-3.66 (m, 2H) , 1.96-1.90 (m, 2H), 1.80- 1.74 (m, 4H), 1.57-1.53 (m, 2H), 1.32, 1.29 (q, q, 24H), 1.23-1.17 (m, 2H), 1.07- 1.01 (m, 2H) ppm.

Step 10) Synthesis of Compound 1-12

Compound 1-11 (10.0 g, 46.6 mmol) was dissolved in THF (100 mL), and borane (100 mL, 1 M in THF) was slowly added dropwise to the reaction flask under nitrogen at 0 ° C. 3.0 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc) Rate: 75.2%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 3.99-3.87 (br, 1H), 3.68-3.51 (m, 2H), 3.48-3.39 (m, 1H), 3.34-3.25 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.71 (m, 2H), 1.45 (s, 9H) ppm.

Step 11) Synthesis of Compound 1-13

Compound 1-12 (7.0 g, 34.8 mmol) was dissolved in DCM (250 mL). EtOAc (20.7 g, 48.8 mmol) oxidant was added portionwise to the reaction flask at 0 ° C. Reaction for 2.0 hours. After the completion of the reaction, the reaction mixture was diluted with water (250 mL), filtered, and the filtrate was evaporated. v/v) = 3 / 2) gave 3.5 g of colorless oil, yield: 50.7%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.46 (d, 1H, J = 2.8Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 2.01-1.93 (m, 2H), 1.91-1.84 (m, 2H), 1.43 (s, 9H) ppm.

Step 12) Synthesis of Compound 1-14

Compound 1-13 (3.5 g, 17.6 mmol) and aqueous ammonia (13 mL) were dissolved in methanol (30 mL), and an aqueous solution of glyoxal (40%, 8 mL) was slowly dropped into the reaction flask at 0 ° C. After completion, the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was evaporated. mjjjjlilililililililililililili

MS (ESI, pos.ion) m / z: 238.2 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 6.96 (s, 1H), 4.94 (dd, 1H, J = 7.68Hz, 2.40 Hz), 3.38 (t, 2H, J = 6.24 Hz), 2.17-2.03 (m, 2H), 1.99-1.91 (m, 2H), 1.48 (s, 9H) ppm.

Step 13) Synthesis of Compound 1-15

Compound 1-14 (2.0 g, 8.4 mmol) was dissolved in DCM (60 mL), and N-iodobutanediamine (3.8 g, 16.8 mmol) was added portionwise to the reaction flask at 0 ° C. hour. After the completion of the reaction, the reaction mixture was washed with EtOAc EtOAc. Rate: 63.1%.

MS (ESI, pos.) m / z : 490.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.89 (dd, 1H, J = 7.64 Hz, 2.52 Hz), 3.36 (t, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H) ppm.

Step 14) Synthesis of Compound 1-16

Compound 1-15 (1.6 g, 3.27 mmol) was suspended in a mixed solvent (50 mL) of ethanol and water (v/v = 3/7), and sodium sulfate (3.7 g, 29 mmol) was added to the mixture and refluxed for 17 hours. After the completion of the reaction, the ethanol was removed, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Agent: PE / EtOAc (v / v) = 3/2).

MS (ESI, pos.) m / z : 364.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.04 (d, 1H, J = 1.84 Hz), 4.89 (dd, 1H, J = 7.72 Hz, 2.56 Hz), 3.36 (t, 2H), 2.18-2.03 (m, 2H), 1.97-1.82 (m, 2H), 1.47 (s, 9H) ppm.

Step 15) Synthesis of Compound 1-17

Compound 1-10 (0.24 g, 0.45 mmol), compound 1-16 (0.34 g, 0.94 mmol), anhydrous potassium carbonate (0.15 g, 1.12 mmol) and Pd(PPh ₃ ) ₄ (25.8 mg, 0.023 mmol) DME (12 mL) and water (3.0 mL) were separately poured into a reaction flask under N ₂ and reacted at 90 ° C for 3.0 hours. After cooling to room temperature, EtOAc (20mL) was diluted mixture was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc (v / v ) = 1/2) 0.25 g of a white solid was obtained, yield: 75%.

MS (ESI, pos.ion) m / z: 379.4 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.90 (s, 2H), 7.39,7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.05-5.00 (m, 2H), 3.77-3.73 (m, 4H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H), 2.47-2.38 (m, 2H), 2.28-2.17 (m, 2H), 2.10 - 1.97 (m, 6H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H) , 1.41 (s, 18H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

Step 16) Synthesis of Compound 1-18

Compound 1-17 (0.24 g, 0.317 mmol) was dissolved in DCM (5.0 mL). After the reaction was completed, the mixture was evaporated. mjjjjjjjjj

MS (ESI, pos.) m / z : 557 [M+H] ⁺ .

Step 17) Synthesis of Compound 1-19

Compound 1-18 (0.2 g, 0.29 mmol), Compound 1-18-2 (115 mg, 0.60 mmol) and EDCI (0.27 g, 1.42 mmol) were dissolved in DCM (5.0 mL). DIPEA (0.76 mL, 4.27 mmol) was added dropwise, and the mixture was reacted at room temperature for 3.0 hours. The reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 60 /1) A white solid 173 mg was obtained, yield: 70%.

MS (ESI, pos.ion) m / z: 436.5 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.81 (s, 2H), 7.39,7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.56, 5.55 (d, d, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 2H), 4.41-4.37 (m, 1H) , 4.34-4.30 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.73 (m, 4H), 3.66 (s, 6H), 3.65-3.61 (m, 2H), 2.30-2.16 (m, 6H), 2.13-1.89 (m, 8H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 2

synthetic route:

Step 1) Synthesis of Compound 2-1

At room temperature, hydrogen chloride in ethyl acetate solution (5mL, 4M) was added dropwise to compound 1-16 (1.50g, 4.13mmol) in EtOAc (10mL) solution, dropwise, to react overnight. After the reaction was completed, it was filtered to give a solid (1 g,yield: 86.5%). Used directly in the next step.

MS (ESI, pos.) m / z : 264.1 [M+H] ⁺ .

Step 2) Synthesis of Compound 2-2

Compound 2-1 (1.2 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) were suspended in DCM (20 mL) and stirred at 0 ° C for 5 min. DIPEA (2.38 mL, 14.4 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL), EtOAc (EtOAc) 1/2) gave 1.31 g of a pale yellow foam solid, yield: 86.8%.

MS (ESI, pos.) m/z: 421.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35 (s, 1H), 5.32, 5.29 (brs, brs, 1H), 5.20 -5.15 (m, 1H), 4.41-4.37 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 2.28-2.17 (m, 3H) , 2.11-1.96 (m, 2H), 0.97-0.95 (m, 3H), 0.91 - 0.89 (m, 3H) ppm.

Step 3) Synthesis of Compound 2-3

The compound 2-3-0 (30 g, 107.9 mmol) and the compound 1-11 (25.5 g, 118.7 mmol) were dissolved in DCM (250 mL), and then slowly dropped to DIPEA (21.4 mL, 129.5 mmol) at 0 ° C After completion, the reaction was carried out at room temperature for 3.0 hours. After completion of the reaction, ice-water (100 mL) to quench the reaction, the aqueous layer was extracted with EtOAc (100mL × 3), drying the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluting Detachment: PE/EtOAc (v/v) = 10/1) gave 40.

MS (ESI, pos.) m / z : 412.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 5.53 -5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H) ppm.

Step 4) Synthesis of Compound 2-4

Compound 2-3 (15 g, 36.4 mmol) and ammonium acetate (42 g, 54.6 mmol) were suspended in toluene (150 mL) and reacted at 110 ° C for 5.0 hours. After completion of the reaction, was cooled to room temperature, water (100 mL) to quench the reaction, the aqueous layer was extracted with EtOAc (100mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na-SO _4, concentrated in vacuo purified by column Purification by chromatography (eluent: PE /EtOAc (v / v) = 5 / 1)

MS (ESI, pos.) m / z : 392.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 7.21. -7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H) ppm.

Step 5) Synthesis of Compound 2-5

Compound 2-4 (10 g, 25.5 mmol) was dissolved in EtOAc (50 mL). After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjjj

MS (ESI, pos.) m / z : 292.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H), 7.21. -7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m, 1H), 3.49-3.39 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1 H) ppm.

Step 6) Synthesis of Compound 2-6

Compound 2-5 (7.01 g, 19.26 mmol), compound 1-18-2 (5.06 g, 28.88 mmol), and EDCI (5.56 g, 28.88 mmol) were dissolved in DCM (100 mL) at 0 ° C and slowly dropped into DIPEA After (21 mL, 127 mmol), it was reacted at room temperature for 3.0 hours. After the reaction was completed, water (100 mL) was added, the aqueous layer was extracted with DCM (100 mL×3), and the organic phase was combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ : PE / EtOAc (v / v) = 1/2) gave 7.6 g,yield: 88%.

MS (ESI, pos.) m/z: 450.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22 -7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H) , 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34 - 2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H) ppm.

Step 7) Synthesis of Compound 2-7

Compound 2-6 (4.99g, 11.13mmol), compound 1-6-2 (4.24g, 16.7mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.91 g, 1.11 mmol) and KOAc (3.30 g, 33.4 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (50 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (200 mL). The mixture was filtered, and then filtered, washed with water (100 mL×3) and brine, dried over anhydrous sodium sulfate Purification (eluent: PE / EtOAc (v/v) = 1/2) gave m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.5-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.32-1.45 (m, 12H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H) ppm.

Step 8) Synthesis of Compound 2-8

Compound 1-9 (0.58 g, 1.0 mmol), compound 2-7 (0.5 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) DME (10 mL) and pure water (2 mL) were separately injected into the reaction flask, and the reaction was carried out at 90 ° C for 5.0 hours under N ₂ protection. After completion of the reaction, was cooled to room temperature, water (15mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (15mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 100/1) afforded 0.52 g of pale yellow foam, yield: 65%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62-7.61,7.60-7.59 (m, m, 3H), 7.56-7.55,7.53-7.52 (m, m, 2H), 7.42,7.40 (s, s, 1H ), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 ( m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 2H), 3.69-3.64 (m, 1H), 3.63(s,3H), 3.45-3.42(m,1H), 2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.78(m,2H),1.61-1.55(m,2H ), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 9) Synthesis of Compound 2-9

Compound 2-8 (0.8g, 1.0mmol), compound 1-6-2 (0.28g, 1.1mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (81.7 mg, 0.1 mmol) and KOAc (0.25 g, 2.5 mmol) were placed in a reaction flask, and DME (3.0 mL) was poured, and the mixture was reacted under N ₂ and reacted at 90 ° C for 5.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (30 mL). The mixture was filtered, and then filtered and washed with water (20 mL×3) and brine, dried over Na ₂ SO ₄ The fraction was purified by chromatography (EtOAc/EtOAc (EtOAc)

MS (ESI, pos.) m / z : 781.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 ( m, m, 4H), 7.58, 7.56 (s, s, 1H), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.75-3.71 (m, 2H), 3.69-3.64(m,1H), 3.63(s,3H), 2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.74(m,3H),1.61-1.53(m,2H ), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 10) Synthesis of Compound 2-10

Compound 2-9 (0.78 g, 1.0 mmol), compound 2-2 (0.43 g, 1.02 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, EtOH (10 mL) and pure water (2 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.52 g of pale yellow solid.

MS (ESI, pos.) m / z : 474.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H) ), 7.26, 7.24 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 4.34-4.30 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.71 (m, 3H), 3.69- 3.66(m,2H), 3.65(s,3H), 3.63(s,3H), 2.30-2.16(m,6H),2.13-1.89(m,8H),1.87-1.80(m,2H),1.64- 1.57 (m, 2H), 1.30-1.16 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90 , 0.89 (m, m, 3H) ppm.

Example 3

synthetic route:

Step 1) Synthesis of Compound 3-1

Compound 2-2 (4.2g, 10mmol), compound 1-6-2 (2.59g, 10.2mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.82 g, 1.0 mmol) and KOAc (2.45 g, 25 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (20 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (200 mL). The mixture was filtered, and then filtered, washed with water (100 mL×3) and brine, dried over anhydrous sodium sulfate Purification (eluent: PE / EtOAc (v / v) = 1/2)

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (s, 1H), 5.55-5.51 (m, 1H), 5.32, 5.29 (d,d,1H), 4.41-4.37 (m,1H), 3.78-3.72 (m, 1H), 3.63 (s, 3H), 3.61-3.54 (m, 1H), 2.25-1.87 (m, 5H), 1.39, 1.36 (q, q, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 2) Synthesis of Compound 3-3

Aluminum trichloride (90 g, 676 mmol) and sodium chloride (25 g, 432 mmol) were placed in a reaction flask, and the temperature was raised to 150 ° C. After the mixture was molten, the compound 3-2 (20 g, 135 mmol) was slowly added dropwise. After the dropwise addition, the temperature was raised to 200 ° C, and the reaction was carried out at a constant temperature for 1.0 hour. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was poured into ice water (500 mL). After filtration, the filter cake was purified by methanol to give a pale solid 19 g.

MS (ESI, pos.) m / z : 149.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80 - 6.79, 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H) ppm.

Step 3) Synthesis of Compound 3-4

Compound 3-3 (5.0 g, 33.7 mmol) and K ₂ CO ₃ (23.4 g, 168.5 mmol) were suspended in acetone (50 mL). Reaction for 5.0 hours. After the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. , dried over anhydrous Na ₂ SO _4, concentrated in vacuo. purification by column chromatography (eluent: PE / EtOAc (v / v ) = 10/1) to give 2.46 g yellow solid, yield: 45%.

MS (ESI, pos.) m / z : 163.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.51-7.48 (m, 1H), 7.30-7.26 (m, 1H), 6.91 - 6.87 (m, 1H), 3.90 (s, 3H), 3.08-3.05 (m, 2H), 2.70-2.67 (m, 2H) ppm.

Step 4) Synthesis of Compound 3-5

Compound 3-4 (20.0 g, 123.3 mmol) was suspended in methanol (250 mL), and NaBH ₄ (2.8 g, 74.0 mmol) was added portionwise at 0 ° C. After completion of the reaction, methanol was removed, the residue was added EtOAc (400mL) was dissolved, washed with water (100mL × 2) and saturated brine (100 mL), dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE/EtOAc (v/v) = 5/1).

MS (ESI, pos.) m / z : 165.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.13-7.09 (m, 1H), 7.08-7.05 (m, 1H), 6.75 -6.72 (m, 1H), 5.29-5.25 (m, 1H), 3.84 (d, 3H), 3.70 (brs, 1H), 2.84-2.80 (m, 2H), 2.49-2.40 (m, 1H), 1.96 -1.88 (m, 1 H) ppm.

Step 5) Synthesis of Compound 3-6

Compound 3-5 (2.0g, 12.2mmol) was dissolved in THF (20mL), the at 0 deg.] C, was added p -TSA (1.0g, 6.1mmol), After the addition, the reaction was refluxed for 3.0 hours. After the reaction was completed, the THF was evaporated, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Colorless liquid 1.23 g, yield: 69%.

MS (ESI, pos.) m / z : 147.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29 (t, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 7.4 Hz), 6.90-6.86 (m, 1H), 6.77 (d, 1H, J = 8.0 Hz), 6.61-6.57 (m, 1H), 3.92 (s, 3H), 3.39 (s, 2H) ppm.

Step 6) Synthesis of Compound 3-7

Compound 3-6 (5.0 g, 34.2 mmol) was dissolved in anhydrous diethyl ether (35 mL), activated zinc powder (2.5 g, 37.6 mmol) was added, and after stirring for 10 minutes, under N ₂ protection, trichloroacetate was slowly added dropwise. Chlorine (4.0 mL, 35.9 mmol) and phosphorus oxychloride (3.3 mL, 35.9 mmol) in diethyl ether (35 mL). After the reaction was completed, the mixture was filtered. EtOAcjjjjjjjjjjjjjj 6.5 g of a pale yellow solid were obtained, yield: 74%.

MS (ESI, pos.) m / z : 257.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28 (t, 1H, J = 7.8 Hz), 7.02 (d, 1H, J =7.6 Hz), 6.79 (d, 1H, J = 8.0 Hz), 4.53-4.45 (m, 2H), 3.82 (s, 3H), 3.36 (d, 1H, J = 17.2 Hz), 3.09-3.00 (m) , 1H) ppm.

Step 7) Synthesis of Compound 3-8

Compound 3-7 (6.45g, 25.2mmol) was dissolved in methanol (80 mL) was added zinc powder (8.2g, 126mmol) and ammonium chloride (6.7g, 126mmol), under N _2, 45 deg.] C overnight. After the reaction was completed, the celite was filtered, and the filtrate was evaporated. EtOAcjjjjjjjjjjjjjjjjjj Separate and purified (eluent: EtOAc/EtOAc (v/v) = 60/1)

MS (ESI, pos.) m / z : 189.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.22 (t, 1H, J = 7.8 Hz), 6.89 (d, 1H, J =7.6 Hz), 6.71 (d, 1H, J = 8.0 Hz), 4.11-3.99 (m, 2H), 3.82 (s, 3H), 3.63-3.52 (m, 1H), 3.27 (d, 1H, J = 17.2 Hz), 3.03-2.93 (m, 1 H), 2.92-2.84 (m, 1 H) ppm.

Step 8) Synthesis of Compound 3-9

Compound 3-8 (2.3 g, 12.2 mmol) was dissolved in triethylene glycol (30 mL), KOH (2.1 g, 36.7 mmol) and hydrazine hydrate (4.8 mL, 97.8 mmol) were added and reacted at 130 ° C for 20 min. Add a water separator and heat up to 200 ° C for 50 minutes. After the reaction was completed, it was cooled to room temperature, and the mixture was poured with water (100 mL), and extracted with PE (150 mL×3). The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Detachment: PE) gave 1.42 g of a colorless liquid, yield: 67%.

MS (ESI, pos.) m / z : 175.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19 (t, 1H, J = 7.7 Hz), 6.84 (d, 1H, J = 7.5 Hz), 6.71 (d, 1H, J = 8.0 Hz), 3.84 (s, 3H), 3.78-3.70 (m, 1H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H) , 2.80-2.70 (m, 1H), 2.60-2.46 (m, 1H), 2.30-2.17 (m, 1H), 1.86-1.70 (m, 2H) ppm.

Step 9) Synthesis of Compound 3-10

The compound 3-9 (9.92 g, 57.0 mmol) was dissolved in THF (80 mL) and acetonitrile (40 mL), NIS (14.2 g, 63.0 mmol) was added, and after stirring for 10 minutes, a catalytic amount of trifluoroacetic acid was added dropwise. The reaction was carried out at room temperature for 5.0 hours. After completion of the reaction, the reaction solution was concentrated, the residue was added EtOAc (200mL), with saturated sodium sulfite solution (50mL × 3) was washed, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE) A colorless liquid of 12.8 g was obtained in a yield: 75%.

MS (ESI, pos.) m / z : 301.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (d, 1H, J = 8.4 Hz), 6.49 (d, 1H, J = 8.4 Hz), 3.81 (s, 3H), 3.70-3.62 (m, 1H), 3.17-3.08 (m, 1H), 3.08-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.60- 2.48 (m, 1H), 2.32-2.20 (m, 1H), 1.94-1.84 (m, 1H), 1.82-1.68 (m, 1 H) ppm.

Step 10) Synthesis of Compound 3-11

Compound 3-10 (2.16 g, 7.2 mmol) was dissolved in DCM (20 mL), and the mixture was slowly dropped into BBr ₃ (2.7 mL, 28.8 mmol) at -78 ° C, and the reaction was continued for 10 minutes at room temperature. 4.0 hours. After the reaction was completed, the reaction mixture was poured into ice water (100 mL), the aqueous layer was extracted with DCM (50mL×3), and the organic phase was combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ Separation and purification (eluent: PE / EtOAc (v / v) = 20/1) afforded 1.85 g of colorless liquid.

MS (ESI, pos.ion) m / z: 287.1 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.43 (d, 1H, J = 8.3Hz), 6.46 (d, 1H, J = 8.3 Hz), 5.05 (s, 1H), 3.70-3.62 (m, 1H), 3.17-3.08 (m, 1H), 3.08-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.60- 2.48 (m, 1H), 2.32-2.20 (m, 1H), 1.94-1.84 (m, 1H), 1.82-1.68 (m, 1 H) ppm.

Step 11) Synthesis of Compound 3-12

Compound 3-11 (1.55 g, 5.4 mmol) was dissolved in DCM (20 mL), and pyridine (1.1 mL, 13.5 mmol) was slowly added dropwise at 0 ° C. After stirring at constant temperature for 10 minutes, Tf ₂ O was slowly added dropwise. 1.4 mL, 8.1 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, ice-water was added (50mL) The reaction was quenched, the aqueous layer was extracted with DCM (50mL × 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography ( Eluent: PE) gave 2.21 g of a colorless liquid, yield: 98%.

MS (ESI, pos.) m / z : 419.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (d, 1H, J = 8.5 Hz), 6.86 (d, 1H, J = 8.5 Hz), 3.76-3.67 (m, 1H), 3.30-3.14 (m, 2H), 3.12-3.00 (m, 1H), 2.65-2.50 (m, 1H), 2.35-2.23 (m, 1H), 1.94-1.84 (m, 1H), 1.83-1.72 (m, 1H) ppm.

Step 12) Synthesis of Compound 3-13

Compound 1-7 (0.27 g, 0.96 mmol), compound 3-12 (0.40 g, 0.96 mmol), potassium carbonate (0.33 g, 2.4 mmol) and Pd(PPh ₃ ) ₄ (55.5 mg, 0.048 mmol) were placed In a reaction flask, DME (8 mL) and water (2 mL) were separately injected under N ₂ and reacted at 90 ° C for 12 hours. After completion of the reaction, after addition of EtOAc (50mL) diluted with the reaction solution, washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc (v / v ) = 8 /1) 0.19 g of a colorless liquid was obtained, yield: 45%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26,7.24 (s, s, 1H), 7.07 (m, 2H), 6.75,6.72 (s, s, 1H), 5.77 (brs, 1H), 4.03-3.96 (m, 1H), 3.58-3.54 (m, 1H), 3.50-3.46 (m, 1H), 3.08-2.97 (m, 1H), 2.81, 2.79, 2.76, 2.74 (m, m, m, m, 1H) ), 2.56-2.46 (m, 1H), 2.43, 2.41, 2.39, 2.37 (m, m, m, m, 1H), 2.18-2.02 (m, 2H), 1.99-1.92 (m, 2H), 1.82- 1.78 (m, 1H), 1.61-1.52 (m, 2H), 1.26-1.19 (m, 2H) ppm.

Step 13) Synthesis of Compound 3-14

Compound 3-13 (0.45 g, 1.0 mmol), compound 3-1 (0.43 g, 1.02 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 100/1) afforded 0.3 g of pale yellow solid.

MS (ESI, pos.ion) m / z: 595.7 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.59 (s, 1H), 7.39,7.37 (s, s, 1H), 7.38 , 7.36 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 6.75, 6.72 (s, s, 1H), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.58-3.54(m,1H),3.50-3.46(m,1H),3.24-3.12(m,1H) ), 2.70-2.57 (m, 2H), 2.30 - 1.92 (m, 10H), 1.82-1.78 (m, 1H), 1.66-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 14) Synthesis of Compound 3-15

Pyridine (0.16 mL, 2.0 mmol) was added dropwise to a solution of compound 3-14 (0.3 g, 0.5 mmol) in DCM (5OmL), and, after stirring for 10 min, trifluoromethanesulfonic anhydride (0.17 mL) , 1.0 mmol) was dropped into a reaction flask, and the mixture was dropped, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Agent: PE/EtOAc (v/v) = 10/1) afforded 0.35 g of colourless oil.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.59 (s, 1H), 7.38,7.35 (t, t, 1H), 7.26,7.24 (s, s, 1H), 7.22,7.21 (s, s, 1H) , 7.20, 7.19 (s, s, 1H), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.88-3.78 (m, 2H), 3.69-3.64 (m, 1H), 3.63 ( s, 3H), 3.47-3.44 (m, 1H), 3.24 - 3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.30 - 1.92 (m, 10H), 1.82-1.78 (m, 1H), 1.66-1.55 (m, 2H), 1.30-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 15) Synthesis of Compound 3-16

DIPEA (19.5 mL, 118 mmol) was added to a solution of compound 1-11 (23 g, 107 mmol) and compound HATU (48.82 g, 128.4 mmol) in THF (250 mL). Compound 3-16-0 (22.1 g, 119 mmol) was reacted at room temperature for 4.0 hours. After the reaction was completed, the mixture was evaporated. The product obtained above was dissolved in glacial acetic acid (100 mL) and reacted at 40 ° C overnight. After the reaction was completed, the reaction mixture was evaporated, evaporated, mjjjjjjjjjjjjj /v) = 1/2) The product obtained was 31.6 g, yield: 81%.

MS (ESI, pos.) m / z : 367.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H) , 1.49 (s, 9H) ppm.

Step 16) Synthesis of Compound 3-17

Compound 3-16 (4.11g, 11.27mmol), compound 1-6-2 (4.29g, 16.9mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.65 g, 0.8 mmol) and KOAc (2.76 g, 28.17 mmol) were placed in a reaction flask under N ₂ and then DMF (30 mL) was added and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (200 mL). The mixture was filtered and evaporated. (Eluent: PE / EtOAc (v / v) = 1/2).

MS (ESI, pos.) m / z : 414.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (s, 1H), 7.45-7.43 (m, 1H), 7.32-7.30 (m, 1H), 5.12-5.10 (m, 1H), 3.45-3.43 (m, 2H), 2.95-2.94 (m, 1H), 2.25-2.22 (m, 2H), 2.01-1.91 (m, 1H) , 1.49 (s, 9H), 1.35 (s, 12H) ppm.

Step 17) Synthesis of Compound 3-18

Compound 3-17 (0.58 g, 1.4 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj

MS (ESI, pos.ion) m / z: 314.2 [M + H] +.

Step 18) Synthesis of Compound 3-19

Compound 3-18 (1.0 g, 2.6 mmol), compound 3-18-2 (0.59 g, 3.1 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.35 g, 2.6 mmol). DIPEA (1.72 mL, 10.4 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc. ) = 1/2) 1.71 g of a white solid was obtained, yield: 93%.

MS (ESI, pos.) m/z: 485.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.62 (brs, 1H), 8.22 (m, 1H), 7.73-7.65 (m) , 2H), 5.72 (d, 1H, J = 8.0 Hz), 5.43 (d, 1H, J = 8.0 Hz), 4.35-4.31 (m, 1H), 3.95-3.88 (m, 1H), 3.78-3.75 ( m,1H), 3.69-3.67 (m, 4H), 3.08-3.04 (m, 1H), 2.43-2.37 (m, 1H), 2.25-2.15 (m, 2H), 1.91 (s, 1H), 1.74 1.72 (m, 1H), 1.52-1.50 (m, 1H), 1.35 (s, 12H), 1.24 (t, 2H, J = 8.0 Hz), 1.12-1.10 (m, 1H), 0.93-0.88 (m, 1H) ppm.

Step 19) Synthesis of Compound 3-20

Compound 3-19 (0.48 g, 1.0 mmol), compound 3-15 (0.53 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Isolation and purification (eluent: DCM / MeOH (v/v) = 50/1)

MS (ESI, pos.) m / z : 468.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.59 (s, 1H), 7.48, 7.46 (s, s, 1H), 7.41, 7.40 (t, t, 1H), 7.23, 7.21 (d, d, 1H), 7.20, 7.19 (s, s, 1H), 5.39, 5.36 (d, d, 1H), 5.32-5.28 (m, 2H), 5.13-5.09 (m, 1H), 4.46-4.30 (m, 3H), 3.93-3.90 (m, 1H), 3.85-3.76 (m, 3H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.24 - 3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.42 -2.34(m,1H),2.30-1.86(m,14H),1.84-1.80(m,1H),1.66-1.49(m,3H),1.27-1.10(m,3H),0.98-0.95(m, 6H), 0.92-0.89 (m, 6H) ppm.

Example 4

synthetic route:

Step 1) Synthesis of Compound 4-2

Dichlorohydrazine (5.5 mL, 75.8 mmol) was slowly added dropwise to a solution of the compound 4-1 (10 g, 77.5 mmol) in MeOH (50 mL) at 0 ° C. After completion of the reaction, NaHCO ₃ solution was added (50mL) The reaction was quenched and extracted with DCM (35mL × 3) removing the methanol, the residue was combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, and concentrated by column Purification by chromatography (eluent: EtOAc) afforded 7.5 g, m.

MS (ESI, pos.) m / z : 144.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38 (br, 1H), 4.20 - 4.16 (m, 1H), 3.67 (s) , 3H), 2.39-2.23 (m, 3H), 2.14 - 2.07 (m, 1 H) ppm.

Step 2) Synthesis of Compound 4-3

DMAP (0.55 g, 4.5 mmol) was added to a solution of compound 4-2 (6.45 g, 45.06 mmol) in MeCN (30 mL) at 0 ° C. After stirring for 10 min, di-tert-butyl dicarbonate (10.82) was added dropwise. g, 49.56 mmol), after completion of the reaction, the reaction was allowed to stand at room temperature for 30 minutes, and then reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was purified and purified (jjjjjjjj

MS (ESI, pos. ion) m / z : 144.2 [M-BOC] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.60-4.57 (m, 1H), 3.75 (s, 3H), 2.65-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.96 (m, 1H), 1.45 (s, 9H) ppm.

Step 3) Synthesis of Compound 4-4

Lithium triethylborohydride (1.79 g, 16.9 mmol, 1 M in THF) was slowly added dropwise to a solution of compound 4-3 (3.74 g, 15.4 mmol) in toluene (50 mL) at -78 ° C for 70 min. Then, DIPEA (3.2 mL, 19.4 mmol), DMAP (0.19 g, 1.54 mmol) and TFAA (3 mL, 40.4 mmol) were sequentially added, and the mixture was reacted at room temperature for 2.0 hours. After completion of the reaction, saturated NH ₄ Cl solution (15mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (30mL × 3), combined organic phase was dried over anhydrous Na ₂ SO _4, purified by column chromatography After the reaction mixture was concentrated (Eluent: PE / EtOAc (v / v) = 10/1) gave 2.26 g of a yellow liquid, yield: 64.8%.

MS (ESI, pos.) m / z : 128.2 [M-BOC] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.65-6.52 (br, 1H), 4.96-4.91 (br, 1H), 4.68 -4.57 (m, 1H), 3.76 (s, 3H), 3.12-3.00 (m, 1H), 2.71-2.61 (m, 1H), 1.49-1.44 (br, 9H) ppm.

Step 4) Synthesis of Compound 4-5

Chloroiodomethane (1.40 g, 7.9 mmol) was slowly added dropwise to a solution of diethylzinc (0.49 g, 3.94 mmol) in toluene (6 mL) at 0 ° C. After reacting for 45 minutes, the compound 4-4 was further added dropwise. A solution of (0.3 g, 1.32 mmol) in toluene (4 mL) was applied dropwise. After completion of the reaction, saturated NH ₄ Cl solution (15mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (25mL × 3), combined organic phase was dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluting Detachment: PE/EtOAc (v/v) = 10/1) gave a yellow liquid, 0.19 g, yield: 59.7%.

MS (ESI, pos.) m / z : 142.2 [M-BOC] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.64-4.51 (m, 1H), 3.70 (s, 3H), 3.56-3.45 (m, 1H), 2.64-2.54 (m, 1H), 2.05-2.01 (m, 1H), 1.50, 1.41 (s, s, 9H), 0.75-0.65 (m, 3H) ppm.

Step 5) Synthesis of Compound 4-6

An aqueous solution (10 mL) of lithium hydroxide monohydrate (0.89 g, 21.2 mmol) was slowly added dropwise to a solution of compound 4-5 (1.02 g, 4.23 mmol) in THF (20 mL) at 0° C. Reaction for 12 hours. After the reaction was completed, THF was evaporated, EtOAc (EtOAc) (EtOAc (EtOAc) the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give 0.84 g of a white solid, yield: 87.5%.

MS (ESI, neg.) m / z : 226.2 [MH] ^- ; ¹ H NMR (400 MHz, CD ₃ OD): δ 4.53-4.46 (m, 1H), 3.48-3.42 (m, 1H), 2.70- 2.57 (m, 1H), 2.05-2.01 (m, 1H), 1.60-1.54 (m, 1H), 1.48, 1.41 (s, s, 9H), 0.89-0.80 (m, 1H), 0.73-0.66 (m) , 1H) ppm.

Step 6) Synthesis of Compound 4-7

DIPEA (1.95 mL, 11.8 mmol) was added to a solution of compound 4-6 (2.43 g, 10.7 mmol) in THF (25 mL) of compound HATU (4.88 g, 12.84 mmol) in THF (25 mL). Compound 3-16-0 (2.21 g, 11.9 mmol) was added portionwise, and after the addition, the mixture was reacted at room temperature for 4.0 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated. In 20 mL), the reaction was carried out at 40 ° C overnight. After the reaction was completed, glacial acetic acid was evaporated, the residue was taken from EtOAc (EtOAc)EtOAc. (v/v) = 1/2) The product obtained was 2.02 g, yield: 50%.

MS (ESI, pos.) m / z : 378.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (dd, 1H), 7.22, 7.20 (d,d,1H), 7.19 , 7.17 (d, d, 1H), 5.03-5.00 (m, 1H), 3.31-3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.12-2.07 (m, 1H), 1.53-1.48 ( m, 1H), 1.46 (s, 9H), 1.42-1.38 (m, 1H), 1.00-0.97 (m, 1 H) ppm.

Step 7) Synthesis of Compound 4-8

Compound 4-7 (1.03 g, 2.74 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj

MS (ESI, pos.) m / z : 278.2 [M+H] ⁺ .

Step 8) Synthesis of Compound 4-9

Compound 4-8 (0.66 g, 1.88 mmol), compound 1-18-2 (0.49 g, 2.82 mmol) and EDCI (0.54 g, 2.82 mmol) were suspended in DCM (10 mL). After (1.86 mL, 11.28 mmol), it was reacted at room temperature for 3.0 hours. After completion of the reaction, was added DCM (50mL) diluted with the reaction solution, washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc ( v/v) = 1/2) gave a solid of 0.69 g, yield: 85%.

MS (ESI, pos.) m / z : 435.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (dd, 1H), 7.22, 7.20 (d,d,1H), 7.19 , 7.17 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.13-4.08 (m, 1H), 3.63 (s, 3H), 3.42-3.36 ( m,1H), 2.62-2.55 (m, 1H), 2.21-2.09 (m, 2H), 1.53-1.45 (m, 1H), 0.97-0.89 (m, 7H), 0.50-0.46 (m, 1H) ppm .

Step 9) Synthesis of Compound 4-10

Compound 4-9 (3.08g, 7.1mmol), compound 1-6-2 (2.72g, 10.7mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.57 g, 0.7 mmol) and KOAc (2.09 g, 21.3 mmol) were placed in a reaction flask, and the mixture was poured under N ₂ and poured into DME (30 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (200 mL). The mixture was filtered and evaporated. (Eluent: PE / EtOAc (v / v) = 1/2).

MS (ESI, pos.) m / z : 483.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (dd, 1H), 7.65, 7.63 (d,d,1H), 7.45 , 7.42 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.13-4.08 (m, 1H), 3.63 (s, 3H), 3.42-3.36 ( m, 1H), 2.62-2.55 (m, 1H), 2.22-2.09 (m, 2H), 1.53-1.45 (m, 1H), 1.32, 1.29 (m, 12H), 0.97-0.89 (m, 7H), 0.50-0.46 (m, 1 H) ppm.

Step 10) Synthesis of Compound 4-11

Compound 4-10 (0.24 g, 0.5 mmol), compound 1-9 (0.29 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were placed in the reaction In a bottle, under N ₂ protection, DME (6 mL) and pure water (2 mL) were separately injected and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (40 mL), and then washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ A solution of PE/EtOAc (v/v) = 1 / 1)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62,7.60 (d, d, 1H), 7.53-7.49 (m, 2H), 7.41,7.38 (s, s, 1H), 7.32 (m, 1H), 7.10 , 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.14-5.10 (m, 1H), 4.13-4.08 (m, 1H), 3.79-3.74(m,2H),3.73-3.71 (m,1H),3.63(s,3H),3.45-3.36(m,2H),2.62-2.55(m,1H),2.22-2.11(m,2H) ), 2.03-1.90 (m, 4H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.53-1.45 (m, 1H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.95-0.91 (m, 1H), 0.90, 0.88 (m, m, 3H), 0.50 - 0.46 (m, 1H) ppm.

Step 11) Synthesis of Compound 4-12

Compound 4-11 (0.39 g, 0.5 mmol), compound 3-1 (0.21 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were placed in the reaction DME (5.0 mL) and pure water (1.0 mL) were separately injected into the bottle, and the reaction was carried out at 90 ° C for 6.0 hours under N ₂ protection. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.15 g of pale yellow solid.

MS (ESI, pos.) m / z : 467.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.62, 7.59 (d,d,1H), 7.53, 7.51 (d, d, 1H), 7.50, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.32 (m, 1H) , 7.26, 7.24 (s, s, 1H), 5.32, 5.30 (m, m, 2H), 5.29-5.25 (m, 1H), 5.14-5.10 (m, 1H), 4.41-4.36 (m, 1H), 4.13-4.08 (m, 1H), 3.85-3.73 (m, 5H), 3.68-3.65 (m, 1H), 3.63 (s, 6H), 3.42-3.36 (m, 1H), 2.62-2.55 (m, 1H) ), 2.30-1.89 (m, 11H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.53-1.45 (m, 1H), 1.30-1.16 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.94 - 0.91 (m, 1H), 0.90, 0.88 (m, m, 6H), 0.50 - 0.46 (m, 1H) ppm.

Example 5

synthetic route:

Step 1) Synthesis of Compound 5-1

1,3-cyclohexadiene (11.12g, 138.8mmol) was added dropwise to a solution of phenylhydrazine (10.0g, 92.5mmol) in DCM (90mL) at 10 ° C, reacted at room temperature for 1 hour, and reacted at room temperature 48 hour. After the reaction was completed, the solvent was evaporated, and then hexane (500 mL) was added, and the mixture was stirred and filtered, and the filtrate was dried over anhydrous sodium sulfate and evaporated to give a pale yellow solid (12.5 g, yield: 71.8%).

MS (ESI, pos.ion) m / z: 189.1 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 6.59 (s, 2H), 6.47 (s, 2H), 3.42 (s, 2H ), 3.20-3.18 (m, 2H), 1.52-1.39 (m, 4H) ppm.

Step 2) Synthesis of Compound 5-2

Compound 5-1 (5.0 g, 26.6 mmol) and sodium acetate (6.54 g, 79.7 mmol) were dissolved in methanol (100 mL) and reacted at 50 ° C for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was purified and purified (jjjjjjj

MS (ESI, pos.) m/z: 189.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.43-6.39 (m, 2H), 6.28 (s, 2H), 3.65 (s) , 2H), 3.45-3.41 (m, 2H), 2.48-2.44 (m, 2H), 2.09-2.01 (m, 2H) ppm.

Step 3) Synthesis of Compound 5-3

Compound 5-2 (4.0 g, 21.3 mmol) and palladium on carbon (0.4 g) were suspended in methanol (50 mL), and reacted at room temperature for 1.5 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and purified by recrystallization to afford white crystals (yield: 3.06 g).

MS (ESI, pos.) m/z: 191.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO): δ 7.18 (s, 2H), 6.21 (s, 2H), 3.47-3.44 (m, 2H), 1.61-1.54 (m, 4H), 1.42-1.38 (m, 4H) ppm.

Step 4) Synthesis of Compound 5-4

Pyridine (9.0 g, 114 mmol) was added dropwise to a solution of compound 5-3 (3.61 g, 19.0 mmol) in DCM (20 mL). Ment) was dropped into the reaction flask, and the reaction was completed at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc)EtOAc. Detachment: PE/DCM (v/v) = 10/1) gave 8.4 g of colorless oil, yield: 97.3%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.15 (s, 2H), 3.69 - 3.67 (m, 2H), 1.75-1.71 (m, 4H), 1.36-1.32 (m, 4H) ppm.

Step 5) Synthesis of Compound 5-5

Compound 5-4 (7.99 g, 17.6 mmol), Compound 1-7 (5.15 g, 18.0 mmol), tetratriphenylphosphine palladium (1.02 g, 0.88 mmol) and potassium carbonate (9.73 g, 70.4 mmol) were suspended in A mixed solvent (80 mL) of DME/H ₂ O (v/v = 3/1) was reacted at 90 ° C for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate, and evaporated and then purified by column chromatography (eluent: PE/DCM (v/v) = 8/1) gave a white solid, 4.08 g, yield: 50%.

MS (ESI, pos.ion) m / z: 465.5 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.14,7.12 (s, s, 1H), 7.07,7.05 (s, s, 1H), 7.04, 7.02 (s, s, 1H), 6.58, 6.56 (s, s, 1H), 5.77 (brs, 1H), 3.59-3.54 (m, 1H), 3.45-3.40 (m, 1H), 3.23-3.13 (m, 1H), 2.78-2.69 (m, 1H), 1.99-1.78 (m, 5H), 1.62-1.49 (m, 5H), 1.30-1.19 (m, 4H) ppm.

Step 6) Synthesis of Compound 5-6

Pyridine (1.22 mL, 15.2 mmol) was added dropwise to a solution of compound 5-5 (1.76 g, 3.8 mmol) in DCM (10 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (1.3 mL, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE/EtOAc (v/v) = 1/2) mp.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.14,7.12 (s, s, 1H), 7.10,7.08 (s, s, 1H), 7.06,7.04 (s, s, 1H), 7.00,6.98 (s, s, 1H), 3.74-3.71 (m, 1H), 3.41-3.38 (m, 1H), 3.23 - 3.13 (m, 1H), 2.78-2.69 (m, 1H), 2.03-1.78 (m, 5H), 1.62-1.49 (m, 5H), 1.30-1.19 (m, 4H) ppm.

Step 7) Synthesis of Compound 5-7

Compound 5-6 (1.19g, 2.0mmol), compound 1-6-2 (1.07g, 4.2mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (82 mg, 0.1 mmol) and KOAc (0.49 g, 5 mmol) were mixed in a reaction flask, and under a nitrogen atmosphere, DMF (10 mL) was added and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (100 mL). The mixture was filtered, and then filtered and washed with water (50 mL×3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE/EtOAc (v/v) = 1/3) afforded 0.44 g of pale yellow solid.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68,7.65 (s, s, 1H), 7.62,7.60 (s, s, 1H), 7.42,7.40 (s, s, 1H), 7.38,7.36 (s, s, 1H), 3.70-3.67 (m, 2H), 3.20-3.03 (m, 2H), 1.96-1.90 (m, 1H), 1.80-1.74 (m, 2H), 1.69-1.58 (m, 2H), 1.57-1.53 (m, 1H), 1.46-1.33 (m, 4H), 1.32, 1.29 (q, q, 24H), 1.23-1.17 (m, 1H), 1.14-1.01 (m, 3H) ppm.

Step 8) Synthesis of Compound 5-9

Compound 5-8 (6.86 g, 27.97 mmol) was dissolved in DCM (70 mL). EtOAc (23.7 g, 56 mmol) was added to the reaction system in portions at 0 ° C. 7.0 hours. After completion of the reaction, aqueous sodium thiosulfate solution (100 mL) quenched the reaction, diatomaceous earth filtration, the filtrate was extracted with DCM (100mL × 3), combined organic phases were dried over anhydrous Na ₂ SO _4, and concentrated after separation by column chromatography Purification (eluent: PE / EtOAc (v / v) = 6 / 1) yielded 5.78 g of pale yellow liquid, yield: 85%.

Step 9) Synthesis of Compound 5-10

Compound 5-9 (5.81 g, 23.9 mmol) was dissolved in DCM (70 mL), and Et ₂ NSF ₃ (4.85 mL, 35.9 mmol) was slowly dropped into the system at -78 ° C, and the reaction was completed at constant temperature 2.0. After the hour, the reaction was carried out at room temperature for 19 hours. After completion of the reaction, aqueous ammonium chloride (50mL) The reaction was quenched, the aqueous layer was extracted with DCM (100mL × 3), combined organic phases were dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent : PE / EtOAc (v / v) = 20/1) afforded a pale yellow liquid 5.0 g, yield: 79%.

MS (ESI, pos.) m / z : 266.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.60 (brs, 1H), 4.60 - 4.57, 4.94 - 4.72 (m, m, 1H), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J = 16 Hz) ppm.

Step 10) Synthesis of Compound 5-11

The compound 5-10 (5.0 g, 18.86 mmol) was dissolved in THF (40 mL), and then aqueous lithium hydroxide (1.5 g, 20 mL) was added to the system at 0 ° C, and reacted at room temperature for 2.0 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1M), THF was removed, and the aqueous layer was adjusted to pH 2 with dilute hydrochloric acid (1M), and extracted with EtOAc (80 mL×3). It was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give 4.54 g of a white solid, yield: 94%.

MS (ESI, pos.) m / z : 252.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.60 (brs, 1H), 4.60 - 4.57, 4.94 - 4.72 (m, m, 1H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J = 16 Hz) ppm.

Step 11) Synthesis of Compound 5-12

Compound 5-11 (2.37 g, 9.43 mmol) was dissolved in THF (30 mL), EtOAc (EtOAc) After completion of the reaction, methanol (4.0 mL) to quench the reaction, after of THF, the residue was dissolved in DCM (100mL) was removed, washed with water (40mL × 3) and saturated brine, dried over anhydrous Na ₂ SO _4, and concentrated to give Colorless oil 1.79 g, yield: 80%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 4.43-4.27 (m, 1H), 3.59-3.34 (m, 2H), 3.60-3.46 (m, 2H), 2.48-2.18 (m, 2H), 1.44 (d , 9H, J = 16 Hz) ppm.

Step 12) Synthesis of Compound 5-14

Compound 5-12 (1.8 g, 7.59 mmol) was dissolved in DCM (20 mL). EtOAc (EtOAc, EtOAc. 5.0 mL) was dropped into the system, and the reaction was carried out for 1.0 hour after constant temperature reaction for 1.0 hour. After completion of the reaction, the solid was removed by filtration. The filtrate was washed with saturated sodium sulphate (40 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was dissolved in ammonia methanol (20 mL, 7M) and reacted at 0 ° C for 0.5 hour. And reacted at room temperature for 1.0 hour. After cooling again to 0 ° C, an aqueous solution of glyoxal (2.0 mL, 40%) was added dropwise, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, the residue was dissolved in DCM (150 mL), washed with water and saturated saline solution (50mL × 3), dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated A solution of DCM/MeOH (v/v) = 60/1.

MS (ESI, pos.) m / z : 274.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 (s, 2H), 5.83-5.80 (m, 1H), 4.05-3.79 (m, 1H), 3.74 - 3.52 (m, 1H), 3.11-2.33 (m, 2H), 1.51 (s, 9H) ppm.

Step 13) Synthesis of Compound 5-15

Compound 5-14 (0.93 g, 3.4 mmol) was dissolved in DCM (30 mL). EtOAc (1.7 g, 7.5 mmol) was added to the system in portions at 0 ° C. After completion of the reaction, it was filtered, and the filtrate washed with saturated sodium sulfite solution (50mL × 3), dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give 1.07 g of a yellow solid, yield: 60%. Used directly in the next step.

MS (ESI, pos.) m / z : 526.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.13-5.08 (m, 1H), 3.91-3.87 (m, 1H), 3.58 -3.46 (m, 2H), 2.74 - 2.72 (m, 1 H), 1.51 (s, 9H) ppm.

Step 14) Synthesis of Compound 5-16

Compound 5-15 (1.03 g, 1.96 mmol) was dissolved in EtOH (10 mL), sodium sulfite (2.47 g, 19.6 mmol) and water (10 mL) were added and reacted at 90 ° C for 30 hours. After completion of the reaction, it was filtered, the filtrate was concentrated, the residue was dissolved in DCM (80mL), washed with water and saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc (v/v) = 6/1) 0.26 g of white solid was obtained, yield: 33%.

MS (ESI, pos.) m / z : 400.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.08 (s, 1H), 5.33-4.95 (m, 1H), 3.91-3.87 (m, 1H), 3.78-3.36 (m, 2H), 2.96-2.55 (m, 1H), 1.49 (s, 9H) ppm.

Step 15) Synthesis of Compound 5-17

At room temperature, hydrogen chloride in ethyl acetate solution (5mL, 4M) was added dropwise to compound 5-16 (0.80g, 2.0mmol) in EtOAc (4.0mL) solution, dropwise, to react overnight. After completion of the reaction, filtration gave a solid (0.33 g, yield: 90%). Used directly in the next step.

MS (ESI, pos.) m / z : 399.1 [M+H] ⁺ .

Step 16) Synthesis of Compound 5-18

Compound 5-17 (1.34 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) were suspended in DCM (10 mL) and stirred at 0 ° C for 5 min. DIPEA (2.38 mL, 14.4 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL), EtOAc (EtOAc) 1/2) gave 1.41 g of a pale yellow solid. Yield: 86%.

MS (ESI, pos.ion) m / z: 457.3 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.42 (s, 1H), 5.56,5.55 (d, d, 1H), 5.11 -5.06 (m, 1H), 4.32-4.28 (m, 1H), 4.21-4.19, 4.17-4.15, 4.13-4.11, 4.09-4.07 (m, m, m, m, 1H), 3.94-3.93, 3.91 3.89, 3.87-3.84, 3.82-3.81 (m, m, m, m, 1H), 3.66 (s, 3H), 2.93-2.75 (m, 1H), 2.54-2.34 (m, 1H), 2.28-2.16 ( m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H) ppm.

Step 17) Synthesis of Compound 5-19

Compound 5-18 (0.23 g, 0.5 mmol), compound 5-7 (0.28 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were placed in the reaction DME (5.0 mL) and pure water (1.0 mL) were separately injected into the bottle, and the reaction was carried out at 90 ° C for 6.0 hours under N ₂ protection. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.19 g of pale yellow solid.

MS (ESI, pos.ion) m / z: 479.5 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.99 (s, 1H), 7.60 (s, 1H), 7.39,7.36 ( s, s, 1H), 7.32, 7.30 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.81, 6.79 (s, s, 1H), 5.32, 5.29 (d, d, 2H) , 5.20-5.15 (m, 2H), 4.48-4.43 (m, 2H), 4.21-4.19, 4.17-4.15, 4.13-4.11, 4.09-4.07 (m, m, m, m, 2H), 3.94-3.93, 3.91-3.89, 3.87-3.84, 3.82-3.81 (m, m, m, m, 2H), 3.77-3.74 (m, 1H), 3.70-3.67 (m, 1H), 3.63 (s, 6H), 3.48- 3.38 (m, 2H), 2.92-2.74 (m, 2H), 2.52-2.31 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.97 (m, 1H), 1.95-1.89 (m, 1H) ), 1.87-1.83 (m, 1H), 1.71-1.50 (m, 5H), 1.38-1.16 (m, 6H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) Ppm.

Example 6

synthetic route:

Step 1) Synthesis of Compound 6-1

Compound 1-9 (0.58 g, 1.0 mmol), compound 3-17 (0.41 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were placed DME (5.0 mL) and pure water (1.0 mL) were respectively poured into a reaction flask, and the reaction was carried out at 90 ° C for 5.0 hours under N ₂ protection. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 100/1) afforded 0.32 g of pale yellow foam, yield: 45%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62-7.61,7.60-7.59 (m, m, 2H), 7.51,7.49 (s, s, 1H), 7.41,7.38 (s, s, 1H), 7.23, 7.21(d,d,1H), 7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.04-4.99(m,1H),3.82-3.71(m,4H),3.64 -3.57 (m, 1H), 3.45-3.42 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 1H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.53 (s, 9H), 1.30-1.17 (m, 4H) ppm.

Step 2) Synthesis of Compound 6-2

Compound 6-1 (0.72g, 1.0mmol), compound 1-6-2 (0.28g, 1.1mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (82 mg, 0.1 mmol) and KOAc (0.25 g, 2.5 mmol) were placed in a reaction flask and poured into DMF (5.0 mL) under N _{2 and} then reacted at 90 ° C for 5.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (30 mL). The mixture was filtered, and then filtered and washed with water (20 mL×3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE/EtOAc (v/v) = 1/2) afforded 0.35 g of pale yellow solid.

MS (ESI, pos.) m / z : 698.7 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 ( m, m, 3H), 7.55, 7.53 (s, s, 1H), 7.50-7.48 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 5.04-4.99 (m, 1H), 3.82 -3.73 (m, 4H), 3.69-3.66 (m, 1H), 3.64-3.57 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 1H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 5H), 1.84-1.74 (m, 2H), 1.61-1.55 (m, 2H), 1.53 (s, 9H), 1.32, 1.29 (q, q, 12H), 1.26- 1.17 (m, 3H), 1.07-1.01 (m, 1 H) ppm.

Step 3) Synthesis of Compound 6-3

Compound 6-2 (0.70 g, 1.0 mmol), compound 1-16 (0.37 g, 1.02 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In a reaction flask, EtOH (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 80/1) afforded 0.36 g of pale yellow solid.

MS (ESI, pos.) m / z : 808.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.51, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.23, 7.21. (d,d,1H), 5.05-4.99 (m, 2H), 3.82-3.73 (m, 5H), 3.64-3.57 (m, 2H), 3.31-3.24 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 2H), 2.29-2.15 (m, 2H), 2.10 - 1.89 (m, 7H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.53 ( s, 19H), 1.30-1.16 (m, 4H) ppm.

Step 4) Synthesis of Compound 6-4

Compound 6-3 (0.24 g, 0.3 mmol) was dissolved in EtOAc (3.0 mL). After the reaction was completed, the reaction mixture was evaporated,jjjjjjjj

MS (ESI, pos.) m / z : 607.8 [M+H] ⁺ .

Step 5) Synthesis of Compound 6-5

Compound 6-4 (0.15 g, 0.2 mmol), Compound 6-4-2 (88 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) DIPEA (0.26 mL, 1.6 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v) /v) = 60/1) gave a white solid, 109 mg, yield: 55%.

MS (ESI, pos. ion) m / z : 495.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 2H), 7.51, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.35-7.29 (m, 6H), 7.26, 7.24 ( s, s, 1H), 7.23, 7.21 (d, d, 1H), 7.19-7.15 (m, 4H), 5.91-5.89 (d, d, 2H), 5.35-5.34, 5.33-5.32 (m, m, 2H), 5.19-5.14 (m, 2H), 3.91-3.84 (m, 2H), 3.79-3.66 (m, 6H), 3.64 (s, 6H), 2.42-2.08 (m, 6H), 2.03-1.89 ( m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H) ppm.

Example 7

synthetic route:

Step 1) Synthesis of Compound 7-1

Compound 1-16 (0.55g, 1.5mmol), compound 1-6-2 (0.42g, 1.65mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.12 g, 0.15 mmol) and KOAc (0.37 g, 3.75 mmol) were placed in a reaction flask under N ₂ and then poured to DMF (3.0 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (20 mL), and the mixture was filtered, and then filtered and washed with water (15 mL × 3) and brine. (Eluent: PE / EtOAc (v / v) = 1 / 1).

MS (ESI, pos.) m / z : 364.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66 (s, 1H), 5.20-5.16 (m, 1H), 3.59-3.53 (m, 1H), 3.28-3.21 (m, 1H), 2.38-2.30 (m, 1H), 2.27-2.12 (m, 2H), 2.07-1.98 (m, 1H), 1.53 (s, 9H), 1.39 , 1.36 (q, q, 12H) ppm.

Step 2) Synthesis of Compound 7-2

The furan (15 mL) was slowly added to a solution of LDA (7.4 mL, 11 mmol) in THF (15 mL), and then 2,5-dimethoxybromobenzene (2.16 g, 10 mmol) in THF (5 mL) ) solution. The reaction was kept at -78 ° C for 30 min, quenched with water and allowed to warm to room temperature. It was extracted with diethyl ether (50×3), and dried over anhydrous sodium sulfate. The solvent was dried and purified by column chromatography (EtOAc:Hex=1:1) To white solid (2.1g, 86%)

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.06 (2H, s), 6.97 (2H, s), 6.54 (2H, s), 5.92 (2H, s), 3.78 (6H, s) ppm.

Step 3) Synthesis of Compound 7-3

Compound 7-2 (2.5 g) was dissolved in ethyl acetate (150 mL). Palladium carbon (0.6 g) was added and stirred under a hydrogen atmosphere overnight. After the reaction was completed, the catalyst was filtered off and the solvent was evaporated to give product 7-3 ( 2.38g, 92%)

^{1 H NMR (400MHz, CDCl3)} : δ 1.36-1.41 (m, 2H), 2.01-2.06 (m, 2H), 3.79 (s, 6H), 5.56-5.58 (m, 2H), 6.63 (s, 2H) Ppm.

Step 4) Synthesis of Compound 7-4

The compound 7-3 (2.06 g, 10 mmol) was dissolved in DCM (50 mL), and boron tribromide (7.7 mL, 80 mmol) was slowly added dropwise at -78 ° C, and the reaction was continued for 10 minutes at room temperature. 1 hour. After completion of the reaction, ice water (50mL) The reaction was quenched, the aqueous layer was extracted with DCM (50mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, purified by column chromatography and concentrated (Eluent: PE / EtOAc (v / v) = 10/1) gave an oily liquid 1.6 g, yield: 90%.

MS (ESI, pos.) m / z : 179.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.55 (s, 2H), 6.51 (br, 2H), 5.51-5.45 (m) , 2H), 1.78-1.65 (m, 2H), 1.00-0.87 (m, 2H) ppm.

Step 5) Synthesis of Compound 7-5

Pyridine (4.8 mL, 60 mmol) was slowly added dropwise to a solution of compound 7-3 (1.78 g, 10 mmol) in DCM (20 mL). After stirring for 10 min, trifluoromethanesulfonic acid anhydride (6.73 mL, 40 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, ice-water was added (25mL) The reaction was quenched and extracted with DCM (30mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo and purified by column chromatography (elution by Detachment: PE / EtOAc (v / v) = 40/1)

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36 (s, 2H), 5.53-5.47 (m, 2H), 1.69-1.56 (m, 2H), 0.91 - 0.78 (m, 2H) ppm.

Step 6) Synthesis of Compound 7-6

Compound 1-7 (0.29 g, 1.0 mmol), compound 7-5 (0.44 g, 1.0 mmol), potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) were reacted. In a bottle, under N ₂ protection, DME (4 mL) and water (1 mL) were separately injected and reacted at 90 ° C for 5 hours. After completion of the reaction, EtOAc (20mL) was diluted mixture was washed with saturated brine, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v ) = 8 / 1) 0.23 g of a colorless liquid was obtained, yield: 50%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.24,7.22 (s, s, 1H), 7.19,7.17 (s, s, 1H), 7.11,7.09 (s, s, 1H), 6.58,6.56 (s, s, 1H), 5.77 (brs, 1H), 5.70-5.63 (m, 1H), 5.42-5.36 (m, 1H), 3.58-3.55 (m, 1H), 3.51-3.48 (m, 1H), 2.02- 1.92 (m, 2H), 1.85-1.81 (m, 1H), 1.77-1.65 (m, 2H), 1.62-1.58 (m, 1H), 1.29-1.19 (m, 2H), 0.99-0.87 (m, 2H) )ppm.

Step 7) Synthesis of Compound 7-7

Compound 7-6 (0.23 g, 0.5 mmol), compound 7-1 (0.18 g, 0.5 mmol), potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) were placed In a reaction flask, under the protection of N ₂ , EtOH (4 mL) and water (1 mL) were separately poured and reacted at 90 ° C for 6 hours. After completion of the reaction, EtOAc (50mL) diluted with the reaction solution, washed with saturated brine, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v ) = 2 / 1) 0.16 g of a pale yellow solid was obtained, yield: 60%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.88 (s, 1H), 7.45,7.43 (s, s, 1H), 7.33,7.31 (s, s, 1H), 7.20,7.17 (s, s, 1H) , 6.58, 6.56 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.07-5.00 (m, 1H), 3.64-3.55 (m, 2H), 3.51- 3.48(m,1H),3.31-3.24(m,1H), 2.47-2.38(m,1H), 2.29-2.17(m,1H),2.10-1.92(m,4H),1.86-1.78(m,2H) ), 1.75-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.41 (s, 9H), 1.29-1.19 (m, 2H), 1.08-1.00 (m, 1H), 0.98-0.89 (m) , 1H) ppm.

Step 8) Synthesis of Compound 7-8

Pyridine (0.9 g, 11.4 mmol) was added dropwise to a solution of compound 7-7 (1.03 g, 1.9 mmol) in DCM (10 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (2.1 g, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE/EtOAc (v/v) = 6/1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.88 (s, 1H), 7.45,7.43 (s, s, 1H), 7.33,7.31 (s, s, 1H), 7.13,7.11 (s, s, 1H) , 7.08, 7.06 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.07-5.00 (m, 1H), 3.64-3.58 (m, 1H), 3.56- 3.53(m,1H), 3.49-3.46(m,1H),3.31-3.24(m,1H), 2.47-2.38(m,1H), 2.29-2.17(m,1H),2.10-1.92(m,4H) ), 1.86-1.78 (m, 2H), 1.75-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.41 (s, 9H), 1.33-1.27 (m, 1H), 1.25-1.19 (m , 1H), 1.08-1.00 (m, 1H), 0.98-0.89 (m, 1 H) ppm.

Step 9) Synthesis of Compound 7-10

Compound 7-9 (5.91 g, 29 mmol), NBS (5.76 g, 32 mmol) and p- TSA (1.0 g, 5.2 mmol) were mixed in a reaction flask and reacted at 100 ° C for 0.5 hour. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with DCM (100 mL) and water (50 mL), and the aqueous layer was extracted with DCM (50 mL×3). ₂ SO _{4 was} dried, concentrated and purified by column chromatography (eluent: PE/DCM (v/v) = 5/1) to give 5.72 g of a yellow powder. Yield: 70%.

MS (ESI, pos.) m / z : 285.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.55 (d, 1H, J = 4.0 Hz), 7.14 (d, 1H, J = 4.0 Hz), 4.29 (s, 2H) ppm.

Step 10) Synthesis of Compound 7-11

The compound 7-10 (5.58 g, 19.8 mmol) and the compound 1-11 (4.7 g, 21.8 mmol) were dissolved in DCM (100 mL), and the mixture was slowly dropped into DIPEA (3.62 mL, 21.9 mmol) at 0 ° C The reaction was carried out at room temperature for 3.0 hours. After completion of the reaction, water (50mL) The reaction was quenched and extracted with EtOAc (50mL × 3) to remove DCM, aqueous layer and the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, was isolated by column chromatography and concentrated Purification (eluent: PE/EtOAc (v/v) = 2/1) afforded 5.

MS (ESI, pos.) m / z : 418.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.49 (d, 1H, J = 4.0 Hz), 7.13 (t, 1H, J =4.0Hz), 5.23-5.02 (m, 2H), 4.48-4.37 (m, 1H), 3.60-3.38 (m, 2H), 2.29-2.26 (m, 2H), 2.11-1.92 (m, 2H), 1.44 (s, 9H) ppm.

Step 11) Synthesis of Compound 7-12

Compound 7-11 (7.92 g, 19 mmol) and NH ₄ OAc (22.2 g, 288 mmol) were suspended in xylene (100 mL) and reacted at 140 ° C for 5.0 hours. After completion of the reaction, was cooled to room temperature, water (100 mL) to quench the reaction, the aqueous layer was extracted with EtOAc (100mL × 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column Separation and purification (eluent: PE/EtOAc (v/v) = 4/1) afforded 6.

MS (ESI, pos.) m / z : 398.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 (br, 1H), 7.07 (s, 1H), 6.94 (s, 2H) ), 4.91-4.90 (m, 1H), 3.39 (s, 2H), 2.98 (s, 1H), 2.12 (s, 2H), 1.95 (s, 1H), 1.48 (s, 9H) ppm.

Step 12) Synthesis of Compound 7-13

Compound 7-12 (1.0 g, 2.5 mmol), compound 1-6-2 (0.96 g, 3.8 mmol), PdCl ₂ (dppf). CH ₂ Cl ₂ (0.11 g, 0.13 mmol) and KOAc (0.74 g, 7.5 mmol) were mixed in a reaction flask, and under a nitrogen atmosphere, DMF (12 mL) was added and reacted at 90 ° C for 4.0 hours. After the reaction was completed, the mixture was cooled to room temperature, and then the mixture was diluted with EtOAc (60 mL) and filtered. The filtrate was washed with water (30 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ and evaporated and then purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) 0.89 g, yield: 80%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.51 (br, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 4.94-4.93 (m, 1H), 3.39 ( s, 2H), 2.99 (s, 1H), 2.12-1.94 (m, 4H), 1.49 (s, 9H), 1.34 (s, 12H), 1.24 (m, 8H) ppm.

Step 13) Synthesis of Compound 7-14

Compound 7-13 (0.45 g, 1.0 mmol), compound 7-8 (0.67 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were placed In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 80/1) afforded 0.38 g of pale yellow solid.

MS (ESI, pos.) m / z : 842.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88 (s, 1H), 7.53, 7.51 (s, s, 1H), 7.50 , 7.48 (s, s, 1H), 7.47 (s, 1H), 7.40, 7.38 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.14, 7.13 (d, d, 1H), 7.01, 7.00 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.16-5.11 (m, 1H), 5.05-5.01 (m, 1H), 3.92-3.90 (m, 1H), 3.83-3.81 (m, 1H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H), 2.48-2.38 (m, 2H), 2.29-2.16 (m, 2H) , 2.12-1.95 (m, 6H), 1.90- 1.78 (m, 2H), 1.75-1.63 (m, 2H), 1.53 (s, 9H), 1.41 (s, 9H), 1.30-1.22 (m, 2H) , 1.08-1.00 (m, 1H), 0.98-0.89 (m, 1 H) ppm.

Step 14) Synthesis of Compound 7-15

Compound 7-14 (0.25 g, 0.3 mmol) was dissolved in EtOAc (3.0 mL). After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

MS (ESI, pos.) m / z : 641.3 [M+H] ⁺ .

Step 15) Synthesis of Compound 7-16

Compound 7-15 (0.16 g, 0.2 mmol), Compound 7-15-2 (90 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HOAT (41 mg, 0.3 mmol) DIPEA (0.26 mL, 1.6 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v) /v) = 60/1) gave a white solid, 93 mg, yield: 55%.

MS (ESI, pos.ion) m / z: 518.7 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.79 (s, 1H), 7.53,7.51 (s, s, 1H), 7.50, 7.48 (s, s, 1H), 7.41 (s, 1H), 7.40, 7.38 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.14, 7.13 (d, d, 1H) , 7.01, 7.00 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.24-5.19 (m, 3H), 5.13-5.08 (m, 1H), 4.47- 4.41 (m, 2H), 3.92-3.89 (m, 1H), 3.86-3.80 (m, 3H), 3.70-3.64 (m, 2H), 3.63 (s, 6H), 2.35-2.05 (m, 8H), 2.03-1.78(m,6H),1.75-1.62(m,4H),1.58-1.51(m,4H),1.40-1.31(m,8H),1.30-1.22(m,2H),1.18-1.00(m , 7H), 0.98-0.89 (m, 1 H) ppm.

Example 8

synthetic route:

Step 1) Synthesis of Compound 8-2

Compound 8-1 (1.54 g, 19 mmol), compound 8-1-2 (1.36 g, 10 mmol) was dissolved in freshly evaporated THF (25 mL). N. (1.6 M n-hexane solution, 6.7 mL), dropwise, and reacted at a constant temperature for 1.0 hour, and then slowly rose to room temperature (25 ° C) to react overnight. After completion of the reaction, the reaction solution was poured into water (50mL) and extracted with diethyl ether (50mL × 3), the organic phase was dried over anhydrous Na ₂ SO _4, concentrated in vacuo by silica gel column chromatography (eluent: PE / EtOAc ( v/v) = 5/1) gave 1.09 g of pale yellow solid, yield: 50.2%.

MS (ESI, pos.) m / z : 218.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.93-6.91 (t, 1H, J = 4.0 Hz), 6.83 (m, 2H) ), 4.71-4.69 (m, 2H), 3.71 (s, 6H), 2.11 (s, 3H) ppm.

Step 2) Synthesis of Compound 8-3

Pd/C (10%, 0.35 g) was added to a solution of compound 8-2 (1.74 g, 8.03 mmol) in anhydrous ethanol (40 mL), and reacted at room temperature (25 ° C) for 24 h under 10 atmospheres of H ₂ atmosphere. . After completion of the reaction, Pd/C was removed by filtration, and the title compound 8-3 was obtained as a white solid, 1.51 g, yield: 86%.

MS (ESI, pos.) m / z : 220.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.60-6.24 (s, 2H), 4.28-4.26 (m, 2H), 3.70 (s, 6H), 2.11 (s, 3H), 1.26-1.11 (m, 4H) ppm.

Step 3) Synthesis of Compound 8-4

Compound 8-3 (2.19 g, 10 mmol) was dissolved in DCM (50.0 mL) at -78 ° C, and boron tribromide (7.7 mL, 80 mmol) was slowly added dropwise to the solution, and the reaction was carried out for 10 minutes after constant temperature reaction. After the reaction was completed at room temperature for 1 hour, the reaction was completed, and the reaction mixture was diluted with ice water (50 mL), extracted with CH ₂ Cl ₂ (50 mL×3), and the organic phase was washed with saturated brine, anhydrous Na ₂ SO ₄ After drying, the residue was purified by chromatography (jjjjjlililili

MS (ESI, pos.) m / z : 192.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.42 (s, 2H), 5.77 (br, 2H), 4.24 - 4.22 (m) , 2H), 2.15 (s, 3H), 1.31-1.18 (m, 4H) ppm.

Step 4) Synthesis of Compound 8-5

Pyridine (4.8 mL, 60 mmol) was added to a solution of compound 8-4 (1.91 g, 10 mmol) in DCM (20.0 mL), and then, after reacting for 10 minutes, trifluoromethanesulfonic anhydride was slowly added dropwise to the solution. 6.73 mL, 40 mmol), and the reaction was completed at room temperature for 1 hour. After completion of the reaction, ice-water was added (25mL) The reaction was quenched, extracted with DCM (30mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent : PE / EtOAc (v / v) = 40/1) gave 4.32 g of white oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29 (s, 2H), 4.39 - 4.37 (m, 2H), 2.50 (s, 3H), 1.24-1.09 (m, 4H) ppm.

Step 5) Synthesis of Compound 8-6

Compound 8-5 (2.27 g, 5.0 mmol), compound 1-7 (1.43 g, 5.0 mmol), tetratriphenylphosphine palladium (0.29 g, 0.25 mmol) and potassium carbonate (1.73 g, 12.5 mmol) The mixed solvent (24 mL) of DME/H ₂ O (v/v = 3/1) was reacted at 90 ° C for 3 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate, and evaporated and then purified by column chromatography (eluent: PE/DCM (v/v) = 6/1) A colorless liquid 1.16 g was obtained, yield: 50%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.14,7.12 (s, s, 1H), 7.10,7.08 (s, s, 1H), 6.98,6.96 (s, s, 1H), 6.52,6.50 (s, s, 1H), 5.77 (brs, 1H), 4.40-4.37 (m, 1H), 4.04-4.01 (m, 1H), 3.58-3.55 (m, 1H), 3.52-3.50 (m, 1H), 2.25 ( s, 3H), 2.01-1.92 (m, 2H), 1.84-1.80 (m, 1H), 1.61-1.52 (m, 2H), 1.31-1.16 (m, 4H), 0.98-0.89 (m, 1H) ppm .

Step 6) Synthesis of Compound 8-7

Compound 8-6 (0.47 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), tetratriphenylphosphine palladium (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) A mixed solvent (8 mL) of DME/H ₂ O (v/v = 3/1) was reacted at 90 ° C for 3 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) 1/1) 0.27 g of a pale yellow solid was obtained, yield: 45%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.46,7.44 (s, s, 1H), 7.40 (s, 1H), 7.36,7.34 (s, s, 1H), 7.15,7.13 (s, s, 1H) , 6.52, 6.50 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24 - 4.18 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.52-3.50 (m, 1H), 2.40 (s, 3H), 2.30-2.15 (m, 3H), 2.13 - 2.03 (m, 1H), 2.01-1.92 (m, 3H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.57 (m , 1H), 1.31-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 7) Synthesis of Compound 8-8

Pyridine (1.22 mL, 15.2 mmol) was added dropwise to a solution of compound 8-7 (2.31 g, 3.8 mmol) in DCM (20 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (1.3 mL, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE/EtOAc (v/v) = 1/2).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.46,7.44 (s, s, 1H), 7.40 (s, 1H), 7.36,7.34 (s, s, 1H), 7.11,7.09 (s, s, 1H) , 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24 - 4.18 (m, 2H), 3.85-3.78(m,1H), 3.74-3.71(m,1H), 3.69-3.65(m,1H), 3.63(s,3H), 3.49-3.47(m,1H), 2.40(s,3H), 2.30-2.15(m,3H),2.13-1.92(m,4H),1.85-1.77(m,2H),1.75-1.67(m,1H),1.61-1.57(m,1H),1.32-1.15(m , 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 8) Synthesis of Compound 8-9

Compound 2-2 (0.58 g, 1.38 mmol), PdCl ₂ (PPh ₃ ) ₂ (98 mg, 0.14 mmol), tetra-n-butylammonium iodide (1.53 g, 4.14 mmol) and CuI (78 mg, 0.41 mmol) Triethylamine (2.0 mL) was slowly added to DMF (5 mL) under N.sub.2, and the mixture was stirred at room temperature for 10 min. After the reaction was completed, the celite was filtered, and the filtrate was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL×3). PE/EtOAc (v/v) = 3/1) gave product 0.3 g, yield: 55.8%.

MS (ESI, pos. ion) m/z: 39 </RTI> [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 5.32, 5.30 (d, d, 1H), 5.29 -5.24(m,1H),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H) , 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.32 (m, 9H) ppm.

Step 9) Synthesis of Compound 8-10

Compound 8-9 (0.34 g, 0.87 mmol) and K ₂ CO ₃ (0.60 g, 4.35 mmol) were dissolved in MeOH (2 mL) and THF (2 mL). After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Agent: PE / EtOAc (v / v) = 2 / 1) gave product 0.23 g, yield: 82.6%.

MS (ESI, pos.ion) m / z: 319.4 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.27 (s, 1H), 5.35-5.31 (m, 1.5H), 5.30- 5.29 (d, 0.5H, J = 4.0 Hz), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.66 (m, 1H), 3.63 (s, 3H), 3.36 (s) , 1H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 10) Synthesis of Compound 8-11

Compound 8-10 (0.12 g, 0.39 mmol), compound 8-8 (0.29 g, 0.39 mmol), PdCl ₂ (PPh ₃ ) ₂ (14.1 mg, 0.02 mmol), CuI (33 mg, 0.172 mmol), PPh ₃ (0.23 g, 0.86 mmol) was added to a reaction flask, and under a nitrogen atmosphere, DMF (10 mL) was added, and triethylamine (5.0 mL) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 10 minutes, and then reacted at 90 ° C for 10 hours. After the completion of the reaction, the celite was filtered, and water (20 mL) was added to the filtrate, and the mixture was combined with EtOAc (20 mL×3). Eluent: DCM / MeOH (v / v) = 60/1).

MS (ESI, pos.ion) m / z: 456.1 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.62 (s, 1H), 7.56,7.54 (s, s, 1H), 7.46 (s, 1H), 7.45, 7.43, 7.41 (s, d, s, 2H), 7.29, 7.26 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.51-5.47 (m, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41, 4.38, 4.36 (m, m, m, 1H), 4.34, 4.31, 4.30 (m, m, m, 1H), 4.24-4.18 (m, 2H), 4.11-4.08 (m, 1H), 3.89-3.78 (m, 2H), 3.73-3.67 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.58-3.55 (m, 1H), 2.37 (s, 3H), 2.32-1.90 (m, 12H), 1.82-1.68 (m, 3H), 1.59-1.55 (m, 1H), 1.34-1.17 ( m, 4H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 9

synthetic route:

Step 1) Synthesis of Compound 9-1

Compound 1-18 (0.18 g, 0.26 mmol), compound 9-1-0 (83.8 mg, 0.57 mmol), EDCI (0.11 g, 0.57 mmol) and HOAT (0.07 g, 0.52 mmol) was suspended in DCM (3 mL) DIPEA (0.5 mL, 2.6 mmol) was slowly added dropwise at 0 ° C, and the reaction was carried out for 3 hours at room temperature. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with aq. ) = 40/1) gave a pale yellow solid, 0.13 g, yield: 61.4%.

MS (ESI, pos.) m / z : 408.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 7.29, 7.26 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.51-5.47 (m, 1H), 5.44, 5.42 (m, m, 2H), 5.15-5.11 (m, 2H), 4.64-4.57 (m, 2H), 3.88-3.82 (m, 2H), 3.77-3.74 (m, 4H), 3.72-3.65 (m, 2H), 3.64 ( s,6H),2.34-2.06(m,6H),2.04-1.89(m,6H),1.87-1.83(m, 2H),1.64-1.60(m,2H), 1.36,1.34(d,d,6H ), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

Example 10

synthetic route:

Step 1) Synthesis of Compound 10-2

Compound 10-1 (1.12 g, 4.88 mmol) was dissolved in THF (10 mL), and borane (7.3 mL, 1M in THF) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 2.0 hours. After completion of the reaction, methanol (4.0 mL) to quench the reaction, removed of THF, the residue was dissolved in DCM (50mL), washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated by column Purification by chromatography (eluent: EtOAc/EtOAc (EtOAc/EtOAc)

MS (ESI, pos.) m / z : 216.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.02 (s, 1H), 3.99-3.87 (m, 1H), 3.75-3.68 (m, 1H), 3.66 (dd, 1H, J = 11.6 Hz, 2.0 Hz), 3.57 (dd, 1H, J = 11.6 Hz, 7.4 Hz), 2.76 (t, 1H, J = 10.5 Hz), 2.19- 2.06 (m, 2H), 1.46 (s, 9H), 1.01 (d, 3H, J = 6.2 Hz) ppm.

Step 2) Synthesis of Compound 10-4

Compound 10-2 (1.0 g, 4.64 mmol) was dissolved in EtOAc EtOAc (EtOAc) After the addition, the reaction was carried out for 1.0 hour at a constant temperature, and the reaction was carried out for 1.0 hour at room temperature After completion of the reaction, the solid was removed by filtration, filtrate was washed with saturated sodium sulfite solution (30mL × 3) washing, the organic phase was dried over anhydrous Na ₂ SO _4, and concentrated to give compound 10-3 as a colorless oil.

The compound 10-3 was dissolved in an ammonia methanol solution (10 mL, 7 M), and reacted at 0 ° C for 0.5 hour, the reaction was continued at room temperature for 1.0 hour, and the temperature was again lowered to 0 ° C, and then an aqueous solution of glyoxal (1.2 mL was slowly added dropwise. 40%), after completion, the reaction was carried out at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, the residue was dissolved in DCM (100mL), washed with water and saturated saline solution (30mL × 3), dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: DCM / MeOH (v / v) = &lt;RTI ID=0.0&gt;

MS (ESI, pos.ion) m / z: 252.3 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 6.97 (s, 2H), 4.90 (t, 1H, J = 8.0Hz), 3.76 (dd, 1H, J = 10 Hz, 7.2 Hz), 2.83 (t, 1H, J = 8.0 Hz), 2.64 - 2.33 (m, 2H), 2.32 - 2.12 (m, 1H), 1.47 (s, 9H) , 1.09 (d, 3H, J = 6.4 Hz) ppm.

Step 3) Synthesis of Compound 10-5

Compound 10-4 (0.51 g, 2.03 mmol) was dissolved in DCM (10 mL). EtOAc (1.0 g, 4.46 mmol) was added at 0 ° C. After completion of the reaction, the solid was removed by filtration and the filtrate was washed with saturated sodium sulfite solution (30mL × 3), dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give a yellow solid 0.92 g, yield: 90%. Used directly in the next step.

MS (ESI, pos.) m / z : 504.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.85 (t, 1H, J = 8.0 Hz), 3.75 (dd, 1H, J =10 Hz, 7.2 Hz), 2.84 (t, 1H, J = 10 Hz), 2.52-2.29 (m, 2H), 2.21 (d, 1H, J = 6.6 Hz), 1.48 (s, 9H), 1.08 (d, 3H, J = 6.4 Hz) ppm.

Step 4) Synthesis of Compound 10-6

Compound 10-5 (0.91 g, 1.8 mmol) was dissolved in ethanol (10 mL), sodium sulfite (2.0 g, 16 mmol) and water (10 mL) were added and reacted at 90 ° C for 30 hours. After completion of the reaction, the solid was removed by filtration, the filtrate was concentrated and the residue was added DCM (50mL) dissolved, washed with water (20mL × 2) and saturated brine, dried over anhydrous Na ₂ SO _4, after separation and purification by column chromatography and concentrated ( Eluent: PE / EtOAc (v / v) = 6 / 1).

MS (ESI, pos.ion) m / z: 378.2 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.04 (s, 1H), 4.85 (t, 1H, J = 8.4Hz), 3.75 (dd, 1H, J = 10.3 Hz, 7.3 Hz), 2.82 (t, 1H, J = 10.4 Hz), 2.58-2.36 (m, 2H), 2.29-2.11 (m, 1H), 1.08 (d, 3H) , J = 6.4 Hz) ppm.

Step 5) Synthesis of Compound 10-7

Compound 10-6 (0.63g, 1.66mmol), compound 1-6-2 (0.46g, 1.82mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (68 mg, 0.083 mmol) and KOAc (0.41 g, 4.14 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (5.0 mL) and reacted at 90 ° C for 2.0 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was diluted with ethyl acetate (40 mL), and the mixture was filtered, and the filtrate was filtered, washed with water (20 mL × 3) and brine, dried over Na ₂ SO ₄ Column chromatography and purification (eluent: PE /EtOAc (v / v) = 1/2)

MS (ESI, pos.) m / z : 378.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (s, 1H), 4.90-4.85 (m, 1H), 3.75-3.68 (m, 1H), 3.04-2.97 (m, 1H), 2.44-2.34 (m, 1H), 2.33-2.20 (m, 1H), 1.83-1.75 (m, 1H), 1.41 (s, 9H), 1.38 , 1.36 (m, m, 12H), 0.96-0.93 (m, 3H) ppm.

Step 6) Synthesis of Compound 10-8

Compound 10-7 (0.63 g, 1.66 mmol), compound 3-13 (0.75 g, 1.66 mmol), Pd(PPh ₃ ) ₄ (96 mg, 0.083 mmol) and potassium carbonate (0.57 g, 4.14 mmol) were placed in the reaction In a bottle, under N ₂ protection, DME (5 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (30 mL), washed with water (10mIL×3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: PE / EtOAc (v / v) = 1/2) mp.

MS (ESI, pos.) m / z : 552.7 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (s, 1H), 7.39, 7.37 (s, s, 1H), 7.36 , 7.34 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 6.75, 6.72 (s, s, 1H), 5.06-5.01 (m, 1H), 4.37-4.30 (m, 1H), 3.80-3.73 (m, 1H), 3.58-3.54 (m, 1H), 3.50-3.46 (m, 1H), 3.24-3.12 (m, 1H), 3.09-3.02 (m, 1H), 2.70-2.57 (m , 2H), 2.35-2.12 (m, 5H), 1.99-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.76-1.68 (m, 1H), 1.66-1.55 (m, 2H), 1.41 (s, 9H), 1.26-1.19 (m, 2H), 0.96-0.93 (m, 3H) ppm.

Step 7) Synthesis of Compound 10-9

Pyridine (0.97 mL, 12 mmol) was added dropwise to a solution of compound 10-8 (1.65 g, 3.0 mmol) in DCM (20 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (1.0 mL, 6.0) Ment) was dropped into the reaction flask, and the reaction was completed at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE/EtOAc (v/v) = 1/2).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.67 (s, 1H), 7.38,7.36 (t, t, 1H), 7.26,7.24 (s, s, 1H), 7.22,7.21 (s, s, 1H) , 7.20, 7.19 (s, s, 1H), 5.06-5.01 (m, 1H), 4.37-4.30 (m, 1H), 3.88-3.85 (m, 1H), 3.80-3.73 (m, 1H), 3.47- 3.44 (m, 1H), 3.24 - 3.12 (m, 1H), 3.09 - 3.02 (m, 1H), 2.70 - 2.57 (m, 2H), 2.35 - 2.13 (m, 5H), 2.03-1.92 (m, 2H) ), 1.82-1.78 (m, 1H), 1.76-1.68 (m, 1H), 1.66-1.55 (m, 2H), 1.41 (s, 9H), 1.30-1.19 (m, 2H), 0.96-0.93 (m , 3H) ppm.

Step 8) Synthesis of Compound 10-10

DIPEA (1.95 mL, 11.8 mmol) was added to a solution of compound 10-1 (2.45 g, 10.7 mmol) in THF (30 mL) of compound HATU (4.88 g, 12.84 mmol). Compound 3-16-0 (2.21 g, 11.9 mmol) was added portionwise, and after the addition, the mixture was reacted at room temperature for 4.0 hours. After the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated In 20 mL), the reaction was carried out at 40 ° C overnight. After the reaction was completed, glacial acetic acid was evaporated, the residue was purified eluting with EtOAc EtOAc EtOAc (v/v) = 1/2) The product was obtained 3.24 g, yield: 80%.

MS (ESI, pos.) m / z : 381.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.84 (d, 1H, J = 2.9 Hz), 7.44 (d, 1H, J =15.0 Hz), 7.33 (dd, 1H, J = 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J = 16.9 Hz), 4.27 (dd, 1H, J = 24.8 Hz, 17.3 Hz), 3.14 (dd) , 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J = 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J = 24.4 Hz, 17.2 Hz) , 1.41 (s, 9H), 0.95 (d, 3H, J = 12.7 Hz) ppm.

Step 9) Synthesis of Compound 10-11

Compound 10-10 (4.27g, 11.27mmol), compound 1-6-2 (4.29g, 16.9mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.65 g, 0.8 mmol) and KOAc (2.76 g, 28.17 mmol) were placed in a reaction flask, and under N ₂ , DME (30 mL) was added and reacted at 90 ° C for 3.0 hours. After the reaction was completed, DME was evaporated, EtOAc (50 mL) was evaporated, evaporated, evaporated, evaporated. PE/EtOAc (v/v) = 3/1) afforded 2.

MS (ESI, pos.) m / z : 428.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (dd, 1H), 7.65, 7.63 (d,d,1H), 7.27 , 7.25 (d, d, 1H), 5.07-5.02 (m, 1H), 3.85-3.78 (m, 1H), 3.14 - 3.07 (m, 1H), 2.51-2.42 (m, 1H), 2.30-2.16 ( m, 1H), 1.86-1.78 (m, 1H), 1.41 (s, 9H), 1.32, 1.29 (m, m, 12H), 0.96 - 0.93 (m, 3H) ppm.

Step 10) Synthesis of Compound 10-12

Compound 10-11 (0.25 g, 0.58 mmol), compound 10-9 (0.40 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (80 mg, 1.4 mmol) were placed in the reaction flask In the middle, under N ₂ protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (50 mL), and washed with water (30 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: DCM / MeOH (v / v) = 80/1).

MS (ESI, pos.) m / z : 418.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.66 (s, 1H), 7.62, 7.60 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.48 (m, 1H), 7.47, 7.45 (s, s, 1H), 7.41, 7.39 (t, t, 1H) , 7.22, 7.20 (s, s, 1H), 5.14-5.09 (m, 1H), 5.06-5.01 (m, 1H), 4.37-4.29 (m, 1H), 3.93-3.90 (m, 1H), 3.85- 3.73 (m, 3H), 3.23 - 3.02 (m, 3H), 2.70-2.57 (m, 2H), 2.51-2.42 (m, 1H), 2.35-2.12 (m, 6H), 2.00-1.90 (m, 2H) ), 1.86-1.78 (m, 2H), 1.76-1.68 (m, 1H), 1.66-1.56 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H), 1.27-1.17 (m, 2H) ), 0.96-0.93 (m, 6H) ppm.

Step 11) Synthesis of Compound 10-13

Compound 10-12 (0.25 g, 0.3 mmol) was dissolved in EtOAc (4.0 mL). After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj Used directly in the next step.

MS (ESI, pos.) m / z : 635.8 [M+H] ⁺ .

Step 12) Synthesis of Compound 10-14

Compound 10-13 (0.24 g, 0.31 mmol), Compound 1-18-2 (0.12 g, 0.68 mmol), EDCI (0.13 g, 0.68 mmol) and HOAT (85 mg, 0.62 mmol) was suspended in DCM (5.0 mL) DIPEA (0.51 mL, 3.1 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), and washed with brine and brine, and dried over anhydrous sodium sulfate, and then concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) ) = 50/1) gave 0.13 g of pale yellow solid, yield: 44%.

MS (ESI, pos.) m / z : 475.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.62, 7.59 (d, d , 1H), 7.58 (s, 1H), 7.52, 7.50 (d, d, 1H), 7.48 (m, 1H), 7.47, 7.45 (s, s, 1H), 7.41, 7.39 (t, t, 1H) , 7.22, 7.20 (s, s, 1H), 5.32-5.26 (m, 3H), 5.17-5.13 (m, 1H), 4.41-4.29 (m, 3H), 3.93-3.84 (m, 3H), 3.79- 3.76 (m, 1H), 3.63 (s, 6H), 3.61-3.54 (m, 2H), 3.23 - 3.13 (m, 1H), 2.70-2.58 (m, 2H), 2.57-2.47 (m, 1H), 2.38-2.09 (m, 8H), 2.00-1.90 (m, 2H), 1.84-1.75 (m, 2H), 1.73-1.56 (m, 3H), 1.27-1.17 (m, 2H), 0.97, 0.95 (m) , m, 6H), 0.93-0.89 (m, 12H) ppm.

Example 11

synthetic route:

Step 1) Synthesis of Compound 11-1

The compound 5-8 (11.0 g, 44.84 mmol) was dissolved in DCM (200 mL), and the mixture was slowly added dropwise to Et ₂ NSF ₃ (8.85 mL, 67.3 mmol) at -78 ° C, and the reaction was continued for 2.0 hours. The temperature was reacted for 19 hours. After the reaction was completed, the reaction was quenched with aqueous ammonium chloride (100 mL), and the aqueous layer was extracted with DCM (100 mL×3). The organic phase was combined, washed with saturated brine, dried over Na ₂ SO ₄ Purification (eluent: PE/EtOAc (v/v) = 20/1) afforded 7.75 g of pale yellow liquid, yield: 70%.

MS (ESI, pos.) m / z : 248.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.26, 5.13 (ds, ds, 1H), 4.55-4.41 (m, 1H) , 3.88-3.74 (m, 1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 2.52-2.44 (m, 1H), 2.40-2.32 (m, 1H), 1.42-1.47 (d, 9H, J = 20 Hz) ppm.

Step 2) Synthesis of Compound 11-2

The compound 11-1 (5.83 g, 23.58 mmol) was dissolved in THF (30 mL), and the aqueous solution of lithium hydroxide (1.98 g, 30 mL) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1M). After the THF was removed, the aqueous layer was adjusted to pH 2 with dilute hydrochloric acid (1M), and extracted with EtOAc (80 mL×3). It was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give 5.27 g of a white solid, yield: 96%.

MS (ESI, pos.) m / z : 234.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J = 16 Hz) ppm.

Step 3) Synthesis of Compound 11-3

The compound 11-2 (1.3 g, 5.57 mmol) was dissolved in THF (20 mL), and borane (8.3 mL, 1M in THF) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 2.0 hours. After completion of the reaction, methanol (4.0 mL) to quench the reaction, after of THF, the residue was dissolved in DCM (50mL) was removed, washed with water (20mL × 3) and saturated brine, dried over anhydrous Na ₂ SO _4, and concentrated to give Colorless oil 1.07 g, yield: 88%.

MS (ESI, pos.) m / z : 220.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.19-5.06 (m, 1H), 4.12-4.04 (m, 1H), 3.99 - 3.79 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.46 (m, 2H), 2.25-2.00 (m, 2H), 1.44 (s, 9H) ppm.

Step 4) Synthesis of Compound 11-5

Compound 11-3 (1.15 g, 5.24 mmol) was dissolved in DCM (20 mL) EtOAc (EtOAc:EtOAc: After the dropwise addition, the dropwise addition, and the constant temperature reaction for 1.0 hour, the reaction was carried out at room temperature for 1.0 hour. After the reaction was completed, the solid was removed by filtration, and the filtrate was washed with saturated sodium sulphate (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was dissolved in ammonia methanol solution (7 mL, 7M), and reacted at 0 ° C for 0.5 hour. After the reaction was continued at room temperature for 1.0 hour, the temperature was again lowered to 0 ° C, and an aqueous solution of glyoxal (1.1 mL, 40%) was slowly added dropwise thereto, and the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated, the residue was added DCM (50mL) was dissolved, washed with water (30mL × 3) and saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent : DCM / MeOH (v / v) = 100/1).

MS (ESI, pos.) m / z : 256.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.98 (s, 2H), 5.36-5.13 (m, 2H), 3.72-3.31 (m, 2H), 2.58-2.32 (m, 2H), 1.48 (s, 9H) ppm.

Step 5) Synthesis of Compound 11-6

Compound 11-5 (0.63 g, 2.47 mmol) was dissolved in DCM (8.0 mL), EtOAc (1. After completion of reaction, was added DCM (50mL) diluted with the reaction solution was filtered to remove solids, the filtrate was washed with saturated sodium sulfite solution (20mL × 3), dried combined organic phase was dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give a yellow solid 1.07 g of, producing Rate: 85.6%. Used directly in the next step.

MS (ESI, pos.) m / z : 508.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.34-5.08 (m, 2H), 3.72-3.28 (m, 2H), 2.58 -2.33 (m, 2H), 1.48 (s, 9H) ppm.

Step 6) Synthesis of Compound 11-7

Compound 11-6 (1.07 g, 2.12 mmol) was dissolved in ethanol (6.0 mL), sodium sulfite (2.14 g, 17 mmol) and water (6.0 mL) were added and reacted at 90 ° C for 30 hours. After completion of the reaction, the solid was removed by filtration, the filtrate was concentrated, the residue was added DCM (40mL) After dissolution, washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, after separation and purification by column chromatography and concentrated ( Eluent: PE / EtOAc (v / v) = 1 / 1).

MS (ESI, pos.) m / z : 382.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.04 (s, 1H), 5.35-5.09 (m, 2H), 3.98-3.63 (m, 1H), 3.58-3.29 (m, 1H), 2.55-2.34 (m, 2H), 1.48 (s, 9H) ppm.

Step 7) Synthesis of Compound 11-8

At room temperature, hydrogen chloride in ethyl acetate solution (5mL, 4M) was added dropwise EtOAc (4.0mL) Compound 11-7 (0.76g, 2.0mmol) was dropwise overnight. After completion of the reaction, filtration gave a solid (0.32 g, yield: 90%). Used directly in the next step.

MS (ESI, pos.) m / z : 282.1 [M+H] ⁺ .

Step 8) Synthesis of Compound 11-9

Compound 11-8 (1.27 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) were suspended in DCM (10 mL) and stirred at 0 ° C for 5 min. DIPEA (2.38 mL, 14.4 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL), EtOAc (EtOAc) 1/2) gave 1.35 g of a pale yellow solid, yield: 85.6%.

MS (ESI, pos.) m/z: 439.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.41 (s, 1H), 5.32, 5.30 (d,d,1H), 5.19 -5.18, 5.17-5.16, 5.15-5.14, 5.06-5.05, 5.04-5.03, 5.02-5.01 (m, m, m, m, m, m, 1H), 4.93-4.88 (m, 1H), 4.45-4.41 (m, 1H), 4.3-4.01 (m, 1H), 3.75-3.64 (m, 1H), 3.63 (s, 3H), 3.02-2.85 (m, 1H), 2.38-2.24 (m, 1H), 2.23 - 2.12 (m, 1 H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 9) Synthesis of Compound 11-10

Compound 11-9 (0.48 g, 1.1 mmol), compound 1-10 (0.27 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were placed in the reaction DME (5.0 mL) and pure water (1.0 mL) were separately injected into the bottle, and the reaction was carried out at 90 ° C for 6.0 hours under N ₂ protection. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Isolation and purification (eluent: DCM / MeOH (v/v) = 50/1)

MS (ESI, pos.ion) m / z: 454.5 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 8.00 (s, 2H), 7.39,7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.32, 5.30 (d, d, 2H), 5.19, 5.11 (m, m, 2H), 5.07-5.02 (m, 2H), 4.45-4.41 (m, 2H) , 4.3-4.01 (m, 2H), 3.77-3.72 (m, 4H), 3.71-3.69, 3.68-3.67, 3.66-3.65 (m, m, m, 2H), 3.63 (s, 6H), 2.98-2.81 (m, 2H), 2.30-2.12 (m, 4H), 2.03-1.97 (m, 2H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H) , 1.30 - 1.24 (m, 2H), 1.22-1.16 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 12

synthetic route:

Step 1) Synthesis of Compound 12-2

12-1 (24.4 g, 92.5 mmol) was added dropwise to a solution of phenylhydrazine (10.0 g, 92.5 mmol) in xylene (250 mL) at room temperature, and reacted at a constant temperature for 1 hour, and then reacted at 100 ° C for 8 hours. After the reaction was completed, the solvent was evaporated, and then hexane (500 mL) was added, and the mixture was stirred and filtered, and the filtrate was dried over anhydrous sodium sulfate and evaporated to give a pale yellow solid (24.7 g, yield: 71.8%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.59 (d, J = 7.6 Hz, 2H), 3.66 (s, 3H), 3.57 (d, 5H) ppm.

Step 2) Synthesis of Compound 12-3

Compound 12-2 (9.89 g, 26.6 mmol) and pyridine (6.30 g, 79.7 mmol) were dissolved in methanol (100 mL) and reacted at 50 ° C for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was purified and purified (jjjjjjjj

MS (ESI, pos.ion) m / z: 372.9 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 6.43-6.39 (d, J = 7.3Hz, 2H), 5.67 (s, 2H ), 3.64 (s, 6H), 3.52 (s, 3H) ppm.

Step 3) Synthesis of Compound 12-4

Compound 12-3 (9.00g, 24.2mmol) and _{K 2 CO 3 (10.01g, 72.6mmol} ) was dissolved in DCM (100mL) was added dropwise CH at _{0 ℃ 3 I (7.56g, 53.2mmol} ). After the dropwise addition, the mixture was reacted for 5 h at room temperature. After the reaction was completed, the solid was removed by filtration, and then concentrated and purified by column chromatography (eluent: DCM) to afford 8.8 g of white solid.

MS (ESI, pos.) m/z: 401.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.43-6.39 (d, J = 7.8 Hz, 2H), 3.82 (s, 6H) ), 3.50 (s, 3H), 3.66 (s, 3H) ppm.

Step 4) Synthesis of Compound 12-5

Compound 12-4 (8.52 g, 21.3 mmol) and a catalytic amount of palladium on carbon (0.8 g) were suspended in methanol (80 mL) and allowed to react at room temperature for 1.5 hours under a normal pressure hydrogen system. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and purified by recrystallization to yield white crystals (yield: 7.76 g).

MS (ESI, pos. ion) m/z: 40: </RTI> [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.43-6.39 (d, J = 7.4 Hz, 2H), 3.82 (s, 6H) ), 3.73 (s, 3H), 3.53 (s, 3H), 1.77 (m, 2H), 2.50 (m, 2H) ppm.

Step 5) Synthesis of Compound 12-6

The metal Na (1.83 g, 80.5 mmol) was added to a solution of Naphthalene (12.7 g, 96.6 mmol) in DME (50 mL) at 0 ° C, stirred for 30 min, and then added dropwise 12-5 (5.36 g, 16.1 mmol) of DME ( 100 mL) solution, after completion, the reaction was stirred at this temperature. After 2 h, the reaction was completed. The reaction was quenched by adding 10 mL of ethanol. The mixture was extracted with 100 mL of water, EA (100 mL×3), dried over anhydrous sodium sulfate and concentrated. Hexan: EA = 6:1) gave 3.87 g of a white solid. Yield: 91%.

MS (ESI, pos.) m/z: 265.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.43-6.39 (d, J = 7.5 Hz, 2H), 3.90 (s, 6H) ), 3.54 (dd, J = 1.8, 1.8 Hz, 2H), 3.29 (s, 3H), 3.12 (s, 3H), 2.24 (m, 2H), 1.43 (m, 2H) ppm.

Step 6) Synthesis of Compound 12-7

Compound 12-6 (3.87 g, 14.7 mmol) was added to 30 mL of dioxane solution, and a 20% sulfuric acid solution (100 mL) was slowly added at 0 ° C. After the addition was completed, the reaction was carried out at 50 ° C for 11 hours. Cooled to room temperature, 200mL of EtOAc, the organic adding 30mL saturated NaCl solution, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography, eluent Hexane / EtOAc = 5/1, to give 2.72g of white solid, The yield was 85%.

MS (ESI, pos.) m/z: 219.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.43-6.39 (d, 2H), 3.90 (s, 6H), 3.54 , J = 1.8 Hz, 2H), 2.24 (m, 2H), 1.43 (m, 2H) ppm.

Step 7) Synthesis of Compound 12-8

At -78 ° C, boron tribromide (9.0 mL, 22.5 mmol, 2.5 M / L DCM solution) was slowly added dropwise to a solution of compound 12-7 (1.48 g, 6.8 mmol) in DCM (20.0 mL) The reaction was carried out at room temperature for 1.0 hour. After the reaction was completed, the reaction mixture was poured into ice water (50.0 mL), and the aqueous layer was extracted with DCM (50mL×3), and the organic phase was combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ Separation (eluent: PE / EtOAc (v / v) = 10/1) afforded 1.

MS (ESI, pos.) m / z : 191.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.59 (s, 2H), 5.49 (br, 2H), 3.64-3.58 (m) , 2H), 2.50-2.41 (m, 2H), 2.15-2.05 (m, 2H) ppm.

Step 8) Synthesis of Compound 12-9

Pyridine (9.00 g, 114 mmol) was added dropwise to a solution of compound 12-8 (3.61 g, 19.0 mmol) in DCM (50.0 mL), and stirred for 10 min. After the completion of the reaction, the reaction mixture was stirred at room temperature for 1.0 hr. After concentration, it was separated by column chromatography (eluent: EtOAc/EtOAc (EtOAc/EtOAc).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36 (s, 2H), 3.61-3.55 (m, 2H), 2.56-2.47 (m, 2H), 2.20-2.12 (m, 2H) ppm.

Step 9) Synthesis of Compound 12-10

Compound 12-9 (0.45 g, 1.0 mmol), compound 1-7 (0.29 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In a reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected under N ₂ and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Detachment: PE / EtOAc (v / v) = 8 / 1) gave a pale yellow liquid 0.23 g, yield: 50%.

MS (ESI, pos.) m / z : 465.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.08, 7.06 (s, s, 1H), 7.04, 7.02 (s, s, 1H), 7.01, 6.99 (s, s, 1H), 6.53, 6.51 (s, s, 1H), 5.77 (brs, 1H), 3.89-3.86 (m, 1H), 3.65-3.62 (m, 1H), 3.58-3.55(m,1H), 3.51-3.48(m,1H), 2.58-2.51(m,1H), 2.48-2.40(m,1H), 2.23-2.15(m,1H),2.13-2.05(m , 2H), 1.98-1.90 (m, 2H), 1.71-1.67 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, 1H) ppm.

Step 10) Synthesis of Compound 12-11

Compound 12-10 (0.23 g, 0.5 mmol), compound 7-1 (0.18 g, 0.5 mmol), potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) were placed In a reaction flask, under the protection of N ₂ , EtOH (4 mL) and water (1 mL) were separately poured and reacted at 90 ° C for 6 hours. After completion of the reaction, EtOAc (50mL) diluted with the reaction solution, washed with saturated brine, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v ) = 2 / 1) 0.15 g of a pale yellow solid was obtained, yield: 54.3%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.89 (s, 1H), 7.32,7.30 (s, s, 1H), 7.11,7.09 (s, s, 1H), 6.97,6.95 (s, s, 1H) , 6.53, 6.51 (s, s, 1H), 5.05-5.01 (m, 1H), 3.95-3.91 (m, 2H), 3.64-3.55 (m, 2H), 3.51-3.48 (m, 1H), 3.31 3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.47-2.38 (m, 2H), 2.28-1.90 (m, 8H), 1.71-1.67 (m, 1H), 1.41 (s, 9H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, 1H) ppm.

Step 11) Synthesis of Compound 12-12

Pyridine (0.9 g, 11.4 mmol) was added dropwise to a solution of compound 12-11 (1.05 g, 1.9 mmol) in DCM (10 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (2.1 g, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE / EtOAc (v / v) = 3 / 1) mp.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.89 (s, 1H), 7.61,7.59 (s, s, 1H), 7.34,7.31 (s, s, 1H), 7.07,7.04 (s, s, 1H) , 6.97, 6.95 (s, s, 1H), 5.05-5.01 (m, 1H), 3.95-3.91 (m, 2H), 3.74-3.71 (m, 1H), 3.64-3.58 (m, 1H), 3.49- 3.46 (m, 1H), 3.31-3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.47-2.38 (m, 2H), 2.28-1.90 (m, 8H), 1.71-1.67 (m, 1H) ), 1.41 (s, 9H), 1.40-1.36 (m, 1H), 1.25-1.19 (m, 1 H) ppm.

Step 12) Synthesis of Compound 12-13

Compound 12-12 (0.68 g, 1.0 mmol), compound 3-17 (0.41 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 80/1) gave 0.45 g of pale yellow solid.

MS (ESI, pos.) m / z : 822.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.89 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.53, 7.50 (s, s, 1H), 7.43, 7.41 (s, s, 1H), 7.36, 7.34 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 6.97, 6.95 (s, s, 1H), 5.05-4.99 (m, 2H), 3.95-3.91 (m, 2H), 3.82-3.76 (m, 3H), 3.64-3.57 (m, 2H), 3.31-3.24 (m, 1H), 2.62-2.49 (m, 2H), 2.47-2.36 (m, 3H), 2.28-1.92 (m, 10H), 1.73-1.69 (m, 1H), 1.41 (s, 18H), 1.35-1.29 ( m, 1H), 1.27-1.21 (m, 1 H) ppm.

Step 13) Synthesis of Compound 12-14

Compound 12-13 (0.25 g, 0.3 mmol) was dissolved in EtOAc (3.0 mL). After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

MS (ESI, pos.) m / z : 621.8 [M+H] ⁺ .

Step 14) Synthesis of Compound 12-14-2

L-valine (1.17 g, 10 mmol) was dissolved in 13 ml of NaOH (1M) aqueous solution, and then reduced to 0 ° C, and phenyl chloroformate (1.72 g, 11.0 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was incubated at 0 ° C. After 5 h, the mixture was washed with EtOAc (20 mL EtOAc). Drying and spin drying gave 1.8 g of a white solid. Yield: 75.9%.

MS (ESI, pos.) m / z : 238.1 [M+H] ⁺ .

Step 15) Synthesis of Compound 12-15

Compound 12-14 (0.15 g, 0.2 mmol), Compound 12-14-2 (100 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) DIPEA (0.26 mL, 1.6 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v) /v) = 60/1) gave a white solid, 0.15 g, yield: 70.8%.

MS (ESI, pos.) m / z : 530.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.83 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 2H), 7.53, 7.50 (s, s, 1H), 7.43, 7.41 (s, s, 1H), 7.36-7.30 (m, 5H), 7.24-7.23, 7.22-7.21, 7.20-7.19 (m, m ,m,3H),7.13-7.12,7.11-7.10(m,m,4H),6.97,6.95(s,s,1H),5.49, 5.46(d,d,2H),5.29-5.20(m,2H ), 4.48-4.42 (m, 2H), 3.95-3.91 (m, 2H), 3.85-3.76 (m, 4H), 3.69-3.60 (m, 2H), 2.56-1.87 (m, 17H), 1.73-1.69 (m, 1H), 1.35-1.29 (m, 1H), 1.27-1.21 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 13

synthetic route:

Step 1) Synthesis of Compound 13-1

Compound 10-1 (3.0 g, 13.1 mmol) and compound 2-3-0 (3.63 g, 13.1 mmol) were dissolved in DCM (40 mL). After completion, the reaction was carried out at room temperature for 2.0 hours. After completion of the reaction, water (50mL) The reaction was quenched, the aqueous layer was extracted with DCM (50mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give crude product 3.27 g, yield Rate: 62.9%. Used directly in the next step.

MS (ESI, pos.) m / z : 399.3 [M+H] ⁺ .

Step 2) Synthesis of Compound 13-2

Compound 13-1 (3.27 g, 8.2 mmol) and ammonium acetate (5.1 g, 66 mmol) were suspended in toluene (30 mL) and reacted at 110 ° C for 5.0 hours. After completion of the reaction, was cooled to room temperature, water (50mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (80mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column Purification by chromatography (eluent: PE /EtOAc (v/v) = 4/1)

MS (ESI, pos.) m / z : 407.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.45 (m, 4H), 7.20 (s, 1H), 4.93 (t, 1H) , J = 8.2 Hz), 3.88-3.66 (m, 1H), 2.90 (t, 1H, J = 8.0 Hz), 2.50-2.47 (m, 2H), 2.27-2.25 (m, 1H), 1.48 (s, 7H), 1.26 (s, 2H), 1.12 (d, 3H, J = 6.2 Hz) ppm.

Step 3) Synthesis of Compound 13-3

Compound 13-2 (2.8g, 6.9mmol), compound 1-6-2 (1.93g, 7.6mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.28 g, 0.34 mmol) and KOAc (1.7 g, 17.25 mmol) were placed in a reaction flask under N ₂ and then poured into DME (30 mL) and reacted at 90 ° C for 2.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (200 mL). The mixture was filtered over Celite, and the filtrate was washed with water (20 mL×3) and brine, dried over Na ₂ SO ₄ Chromatographic separation and purification (eluent: EtOAc/EtOAc (v/v) = 1/2)

MS (ESI, pos.) m / z : 454.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35 (m, 4H), 7.10 (s, 1H), 4.93 (t, 1H) , J = 8.2 Hz), 3.88-3.66 (m, 1H), 2.90 (t, 1H, J = 8.0 Hz), 2.50-2.47 (m, 2H), 2.27-2.25 (m, 1H), 1.48 (s, 9H), 1.26 (s, 12H), 1.02 (d, 3H, J = 6.2 Hz) ppm.

Step 4) Synthesis of Compound 13-4

Compound 13-3 (0.26 g, 0.58 mmol), compound 1-9 (0.34 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (0.08 g, 1.4 mmol) were placed in the reaction In a bottle, under N ₂ protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (40 mL), and then washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: PE / EtOAc (v / v) = 1 / 1) gave a pale yellow solid (0.3 g, yield: 68%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62-7.61,7.60-7.59 (m, m, 3H), 7.56-7.55,7.53-7.52 (m, m, 2H), 7.42,7.40 (s, s, 1H ), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 4.88-4.84 (m, 1H), 3.92-3.90 (m, 1H), 3.80-3.71 (m, 3H), 3.45-3.42 (m, 1H), 3.09-3.02 (m, 1H), 2.33-2.18 (m, 2H), 2.03-1.90 (m, 4H), 1.84- 1.78 (m, 2H), 1.74-1.66 (m, 1H), 1.61-1.55 (m, 2H), 1.41 (s, 9H), 1.30-1.17 (m, 4H), 0.96-0.93 (m, 3H) ppm .

Step 5) Synthesis of Compound 13-5

Compound 13-4 (0.44 g, 0.58 mmol), compound 10-7 (0.22 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (80 mg, 1.4 mmol) were placed in a reaction flask In the middle, under N ₂ protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (50 mL), and washed with water (30 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: DCM / MeOH (v / v) = 80/1)

MS (ESI, pos.) m / z : 431.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H) ), 7.26, 7.24 (s, s, 1H), 4.97-4.92 (m, 1H), 4.88-4.84 (m, 1H), 3.92-3.90 (m, 1H), 3.80-3.71 (m, 5H), 3.09 -3.02 (m, 2H), 2.35-2.18 (m, 4H), 2.03-1.89 (m, 4H), 1.87-1.80 (m, 2H), 1.76-1.66 (m, 2H), 1.64-1.57 (m, 2H), 1.41 (s, 18H), 1.30-1.16 (m, 4H), 0.96-0.93 (m, 6H) ppm.

Step 6) Synthesis of Compound 13-6

Compound 13-5 (0.26 g, 0.3 mmol) was dissolved in EtOAc (4.0 mL). After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjjj Used directly in the next step.

MS (ESI, pos.) m / z : 661.4 [M+H] ⁺ .

Step 7) Synthesis of Compound 13-7

Compound 13-6 (0.20 g, 0.31 mmol), Compound 1-18-2 (0.12 g, 0.68 mmol), EDCI (0.13 g, 0.68 mmol) and HOAT (85 mg, 0.62 mmol) was suspended in DCM (20 mL) DIPEA (0.51 mL, 3.1 mmol) was slowly added dropwise at 0 ° C, and the reaction was carried out at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), and washed with brine and brine, and dried over anhydrous sodium sulfate, and then concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) ) = 50/1) gave a pale yellow solid, 125 mg, yield: 41%.

MS (ESI, pos. ion) m / z : 488.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H) ), 7.26, 7.24 (s, s, 1H), 5.32, 5.29 (d, d, 2H), 5.15-5.10 (m, 1H), 5.07-5.02 (m, 1H), 4.42-4.37 (m, 2H) , 3.92-3.85 (m, 3H), 3.77-3.71 (m, 3H), 3.63 (s, 6H), 3.61-3.55 (m, 2H), 2.38-2.09 (m, 6H), 2.03-1.89 (m, 4H), 1.87-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.30-1.16 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.93-0.89 (m, 12H) ppm .

Example 14

synthetic route:

Step 1) Synthesis of Compound 14-2

PPh ₃ MeBr (5.05 g, 14.2 mmol) was suspended in THF (50 mL), and a solution of potassium tert-butoxide (14.9 mL, 14.9 mmol, 1.0 M) in THF was slowly added dropwise at -20 ° C. After reacting at 5 ° C for 30 minutes, the compound 14-1 (1.72 g, 7.07 mmol) was added, and after the addition was completed, the reaction was carried out at room temperature for 1.0 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. (Eluent: PE / EtOAc (v / v) = 5 / 1).

MS (ESI, pos.) m / z : 242.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 5.01 (d, 2H, J = 10.8 Hz), 4.36 (t, 1H) , J = 11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q, 1H, J = 14.6 Hz), 2.57-2.50 (m, 1H), 1.38 (s, 9H) ppm.

Step 2) Synthesis of Compound 14-3

Chloroiodomethane (6.6 g, 37.24 mmol) was slowly added dropwise to a solution of diethylzinc (2.3 g, 18.6 mmol) in toluene (30 mL) at 0 ° C, and the reaction was continued for 45 minutes at constant temperature. A solution of compound 14-2 (1.5 g, 6.22 mmol) in toluene (15 mL) was evaporated and evaporated. After completion of the reaction, saturated NH ₄ Cl solution (20mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (25mL × 3), combined organic phases were dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE / EtOAc (v / v) = 10/1) gave a colorless liquid, 0.58 g, yield: 36.5%.

MS (ESI, pos. ion) m / z : 156.2 [M-BOC] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.33-4.47 (m, 1H), 3.71 (s, 3H), 3.29-3.37 (m, 2H), 2.17-2.25 (m, 1H), 1.75-1.86 (m, 1H), 1.44, 1.40 (s, s, 9H), 0.50-0.62 (m, 4H) ppm.

Step 3) Synthesis of Compound 14-4

Compound 14-3 (0.69 g, 2.7 mmol) was dissolved in EtOAc (EtOAc)EtOAc. After the reaction was completed, the reaction mixture was concentrated to give 0.5 g, m.

MS (ESI, pos.ion) m / z: 156.2 [M + H] +; 1 H NMR (400MHz, CD 3 OD): δ 4.66-4.62 (m, 1H), 4.45-4.44 (m, 1H), 3.86 (s, 3H), 3.61-3.60 (m, 1H), 2.39-2.34 (m, 1H), 2.19-2.14 (m, 1H), 1.49-1.46 (m, 1H), 1.19-1.16 (m, 1H) ), 0.88-0.87 (m, 1H), 0.81 - 0.79 (m, 1 H) ppm.

Step 4) Synthesis of Compound 14-5

Compound 14-4 (0.53 g, 2.77 mmol), Compound 1-18-2 (0.73 g, 4.16 mmol) and EDCI (1.06 g, 5.55 mmol) were suspended in DCM (10 mL). After DIPEA (2.4 mL, 14.52 mmol), it was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: PE/EtOAc (v) /v) = 1/1) 0.60 g of a colorless liquid was obtained, yield: 70%.

MS (ESI, pos.) m / z : 313.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.44-5.42 (br, 1H), 4.71-4.68 (m, 1H), 4.29 -4.20 (m, 1H), 3.73 (s, 3H), 3.72-3.69 (m, 1H), 3.67 (s, 3H), 3.59-3.54 (m, 1H), 2.20-2.15 (m, 1H), 2.06 -2.01 (m, 1H), 1.95-1.90 (m, 1H), 1.05-0.93 (m, 6H), 0.66-0.61 (m, 4H) ppm.

Step 5) Synthesis of Compound 14-6

An aqueous solution (5 mL) of lithium hydroxide (0.134 g, 3.2 mmol) was slowly added dropwise to a solution of compound 14-5 (0.2 g, 0.64 mmol) in THF (5.0 mL) at 0 ° C, hour. After the reaction was completed, THF was evaporated, water (30 mL), EtOAc (EtOAc (EtOAc) (EtOAc) ×3), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ and evaporated.

MS (ESI, pos.) m / z : 299.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.06 (br, 1H), 5.76 (br, 1H), 4.73-4.69 (m) , 1H), 4.23-4.18 (m, 1H), 3.79 (d, 1H, J = 9.7 Hz), 3.66 (s, 3H), 3.49 (d, 1H, J = 9.7 Hz), 2.26-2.18 (m, 1H), 2.07-1.93 (m, 2H), 1.00-0.94 (m, 6H), 0.68-0.64 (m, 4H) ppm.

Step 6) Synthesis of Compound 14-7

Compound 2-3-0 (0.31 g, 1.11 mmol) and compound 14-6 (0.3 g, 1.0 mmol) were dissolved in MeCN (10 mL), and DIPEA (0.21 mL, 1.27 mmol). After the dropwise addition, the reaction was carried out at room temperature for 2.0 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAc (30 mL) was evaporated. Purification (eluent: PE / EtOAc (v/v) = 1 / 1) afforded 0.365 g of pale yellow solid.

MS (ESI, pos.) m / z : 495.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H), 5.32 , 5.29 (br, br, 1H), 5.31 (s, 2H), 4.72-4.70 (m, 1H), 4.35-4.30 (m, 1H), 3.67 (s, 3H), 3.61-3.59 (m, 1H) , 3.55-3.49 (m, 1H), 2.20-2.07 (m, 2H), 1.83-1.76 (m, 1H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H) ppm.

Step 7) Synthesis of Compound 14-8

Compound 14-7 (0.33 g, 0.67 mmol) and NH ₄ OAc (1.04 g, 13.43 mmol) were suspended in xylene (10 mL) and reacted at 120 ° C for 5.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (20mL × 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column Separation and purification (eluent: PE/EtOAc (v/v) = 1/2) afforded 0.19 g of a yellow solid.

MS (ESI, pos.) m / z : 475.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 7.45-7.41 (m, 2H), 7.29-7.26 (m, 2H), 5.46, 5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.41-4.37 (m, 1H), 3.71-3.67 (m, 1H), 3.67 (s, 3H) , 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23 - 2.11 (m, 1H), 2.05-1.97 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.52 - 0.39 (m, 4H) ppm.

Step 8) Synthesis of Compound 14-9

Compound 14-8 (0.19g, 0.4mmol), compound 1-6-2 (0.15g, 0.6mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (33 mg, 0.04 mmol) and KOAc (0.12 g, 1.19 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (5.0 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL). The mixture was filtered and evaporated. (Eluent: PE / EtOAc (v / v) = 1/2).

MS (ESI, pos.) m / z : 523.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64-7.57 (m, 4H), 7.21 (s, 1H), 5.46, 5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.42-4.37 (m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H) , 2.39-2.32 (m, 1H), 2.23 - 2.11 (m, 1H), 2.05-1.97 (m, 1H), 1.35 (m, 6H), 1.32 (m, 6H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H) ppm.

Step 9) Synthesis of Compound 14-10

Compound 1-9 (0.30 g, 0.52 mmol), compound 14-9 (0.27 g, 0.52 mmol), Pd(PPh ₃ ) ₄ (60.3 mg, 0.052 mmol) and potassium carbonate (0.22 g, 1.57 mmol) were placed In a reaction flask, under N ₂ protection, DME (6.0 mL) and water (1.5 mL) were separately injected and reacted at 90 ° C for 3.0 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (30 mL). Washed with water (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , evaporated, evaporated, 0.22 g, yield: 50.8%.

MS (ESI, pos. ion) m / z : 415.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.57 (s , 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H) ), 7.07, 7.05 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H), 4.42-4.41, 4.40-4.39, 4.38-4.37 (m, m, m , 1H), 3.92-3.90 (m, 1H), 3.74-3.66 (m, 3H), 3.63 (s, 3H), 3.50-3.42 (m, 2H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H) ppm.

Step 10) Synthesis of Compound 14-11

Compound 14-10 (0.42g, 0.5mmol), compound 1-6-2 (0.17g, 0.6mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (41 mg, 0.05 mmol) and KOAc (0.17 g, 1.25 mmol) were mixed in a reaction flask, and under a nitrogen atmosphere, DMF (5.0 mL) was added and reacted at 90 ° C for 4.0 hours. After the reaction was completed, the mixture was cooled to room temperature, and then the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ and evaporated and then purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) Solid 0.21 g, yield: 52%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.66,7.64 (s, s, 1H), 7.62-7.61,7.60-7.59 (m, m, 3H), 7.58,7.57 (s, s, 1H), 7.56 ( s, 1H), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H) , 4.42-4.41, 4.40-4.39, 4.38-4.37 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.76-3.66 (m, 4H), 3.63 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23 - 2.11 (m, 1H), 2.05-1.90 (m, 5H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H) , 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ), 0.55-0.43 (m, 4H) ppm.

Step 11) Synthesis of Compound 14-12

The compound 14-6 (1.39 g, 4.66 mmol) was dissolved in THF (20 mL), and the borane (10 mL, 1M in THF) was slowly added dropwise to the reaction flask under a nitrogen atmosphere at 0 ° C. 3.0 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Rate: 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.32, 5.29 (d,d,1H), 4.98 (brs,1H), 4.39-4.34 (m,1H),4.33-4.27 (m,1H),3.73-3.72 , 3.70-3.69, 3.68-3.67, 3.66-3.65 (m, m, m, m, 2H), 3.63 (s, 3H), 3.25-3.18 (m, 1H), 3.10-3.03 (m, 1H), 2.15 -2.03 (m, 1H), 1.90-1.82 (m, 1H), 1.47-1.38 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.50- 0.37 (m, 4H) ppm.

Step 12) Synthesis of Compound 14-13

Compound 14-12 (0.99 g, 3.48 mmol) was dissolved in DCM (15 mL). EtOAc (2.07 g, 4.88 mmol) oxidant was added portionwise to the reaction flask at 0 ° C. Reaction for 2.0 hours. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), filtered, and the filtrate was evaporated. v/v) = 1/2) 0.49 g of colorless oil was obtained, yield: 50%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.61-9.60 (m, 1H), 5.32,5.30 (d, d, 1H), 4.40-4.38 (m, 1H), 4.33,4.31,4.29 (m, m, m,1H), 3.63(s,3H), 3.62-3.57 (m,1H),3.34-3.27(m,1H),2.43-2.37(m,1H),2.24-2.12(m,1H), 1.80- 1.73 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H) ppm.

Step 13) Synthesis of Compound 14-14

Compound 14-13 (0.5 g, 1.76 mmol) and aqueous ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1.0 mL) was slowly dropped into the reaction flask at 0 °C. In the middle, the reaction was completed at room temperature overnight. After the reaction was completed, the reaction mixture was evaporated and evaporated, mjjjjjj

MS (ESI, pos.) m / z : 321.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.97 (s, 2H), 5.56, 5.55 (d, d, 1H), 5.20 -5.16 (m, 1H), 4.33, 4.31, 4.29 (m, m, m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.52-3.46 (m, 1H), 2.46- 2.38 (m, 1H), 2.28-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.55-0.42 (m, 4H) ppm.

Step 14) Synthesis of Compound 14-15

Compound 14-14 (2.69 g, 8.4 mmol) was dissolved in DCM (30 mL), and N-iodosuccinimide (3.8 g, 16.8 mmol) was added portionwise to the reaction flask at constant temperature. hour. After the completion of the reaction, the reaction mixture was washed with EtOAc EtOAc. Rate: 60%.

MS (ESI, pos.) m / z : 573.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.56, 5.55 (d, d, 1H), 5.22-5.18 (m, 1H) , 4.45, 4.43, 4.42 (m, m, m, 1H), 3.80-3.73 (m, 1H), 3.66 (s, 3H), 3.51-3.45 (m, 1H), 2.51-2.43 (m, 1H), 2.28-2.11 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.56 - 0.43 (m, 4H) ppm.

Step 15) Synthesis of Compound 14-16

Compound 14-15 (1.87 g, 3.27 mmol) was suspended in a mixed solvent (50 mL) of ethanol and water (v/v = 3/7), and sodium sulfate (3.7 g, 29 mmol) was added to the mixture and refluxed for 17 hours. After the completion of the reaction, the ethanol was removed, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated. Agent: PE / EtOAc (v / v) = 1/2).

MS (ESI, pos.) m / z : 447.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34 (s, 1H), 5.56, 5.55 (d, d, 1H), 4.89 -4.85 (m, 1H), 4.43, 4.41, 4.39 (m, m, m, 1H), 3.77-3.71 (m, 1H), 3.66 (s, 3H), 3.54-3.48 (m, 1H), 2.48- 2.40 (m, 1H), 2.28-2.16 (m, 1H), 2.14-2.06 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.55-0.42 (m, 4H) ppm.

Step 16) Synthesis of Compound 14-17

Compound 14-16 (0.32 g, 0.72 mmol), compound 14-11 (0.58 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were suspended in DME (4.0 mL) and water (1.0 mL) were reacted at 90 ° C for 4.0 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL), washed with water (20 mL × 3) and brine, dried over anhydrous sodium sulfate /v) = 50/1) The product was obtained in 0.43 g, yield: 60%.

MS (ESI, pos.) m/z: 500.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 2H), 7.57 (s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (m, 3H), 6.13, 6.11 (s, s, 1H), 5.91, 5.89 (s, s, 1H), 5.49-5.43 (m, 2H), 5.21. -5.17(s,s,1H),5.32,5.29(d,d,2H),5.02-4.98(m,1H),4.93-4.89(m,1H),4.41,4.39,4.37(m,m,m , 2H), 3.92-3.90 (m, 1H), 3.77-3.66 (m, 5H), 3.63 (s, 6H), 3.50-3.44 (m, 2H), 2.40-2.32 (m, 2H), 2.23-2.11 (m, 2H), 2.06-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 0.97-0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.55-0.42 (m, 8H) ppm.

Example 15

synthetic route:

Step 1) Synthesis of Compound 15-1

Compound 4-6 (3.91 g, 17.22 mmol) and compound 2-3-0 (5.47 g, 19.81 mmol) were dissolved in DCM (60 mL). After the dropwise addition, the reaction was carried out at room temperature for 3.0 hours. After completion of the reaction, water (50mL) The reaction was quenched, the aqueous layer was extracted with DCM (100mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, after separation and purification by column chromatography and concentrated ( Eluent: PE / EtOAc (v / v) = 5 / 1) afforded 4.5 g of white solid.

MS (ESI, pos.) m / z : 425.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.53 -5.09 (m, 2H), 4.78-4.67 (m, 1H), 3.59-3.46 (m, 1H), 2.69-2.62 (m, 1H), 2.43-2.40 (m, 1H), 1.42 (s, 9H) , 1.00-0.96 (m, 1H), 0.76-0.69 (m, 2H) ppm.

Step 2) Synthesis of Compound 15-2

Compound 15-1 (4.5 g, 10.64 mmol) and ammonium acetate (16.4 g, 212.73 mmol) were suspended in xylene (50 mL) and reacted at 120 ° C for 5.0 hours. After completion of the reaction, was cooled to room temperature, water (50mL) The reaction was quenched, the aqueous layer was extracted with EtOAc (100mL × 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column Separation and purification (eluent: PE / EtOAc (v / v) = 8 / 1) gave product 2.14 g, yield: 50%.

MS (ESI, pos.) m / z : 404.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.52 (br, 2H), 7.49-7.46 (d, 2H, J = 12 Hz), 7.21 (s, 1H), 5.27-5.24 (d, 1H, J = 10.0 Hz), 3.31-3.27 (m, 1H), 1.71-1.67 (m, 2H), 1.52 (s, 9H), 0.89 -0.86 (m, 1H), 0.64-0.69 (m, 2H) ppm.

Step 3) Synthesis of Compound 15-3

Compound 15-2 (2.1g, 5.2mmol), compound 1-6-2 (1.59g, 6.25mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.43 g, 0.52 mmol) and KOAc (1.54 g, 15.63 mmol) were placed in a reaction flask under N ₂ and then poured in DMF (20 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (100 mL). The mixture was filtered over Celite, and the filtrate was washed with water (60 mL×3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE / EtOAc (v / v) = 2 / 1) afforded product 2.27 g, yield: 97%.

MS (ESI, pos.) m / z : 452.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81-7.79 (d, 2H, J = 8.04 Hz), 7.60 (br, 2H) ), 7.26 (s, 1H), 5.28-5.26 (d, 1H, J = 8.0 Hz), 3.53 (br, 1H), 3.30-3.27 (br, 1H), 1.67-1.66 (m, 2H), 1.52 ( s, 9H), 1.34 (s, 12H), 0.89-0.86 (m, 1H), 0.69-0.64 (m, 2H) ppm.

Step 4) Synthesis of Compound 15-4

An ethyl acetate solution (5.0 mL, 4 M) of hydrogen chloride was added dropwise to a solution of compound 15-3 (0.9 g, 2 mmol) in EtOAc (10 mL). After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj Used directly in the next step.

MS (ESI, pos.) m / z : 425.2 [M+H] ⁺ .

Step 5) Synthesis of Compound 15-5

Compound 15-4 (0.37 g, 0.75 mmol), Compound 1-18-2 (0.13 g, 0.75 mmol) and EDCI (0.3 g, 1.58 mmol) were suspended in DCM (5.0 mL) DIPEA (1.0 mL, 6.01 mmol) was added dropwise, and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL), EtOAc (EtOAc) 1/2) gave 324 mg of a pale yellow solid. Yield: 85%.

MS (ESI, pos.) m/z: 509.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (brs, 1H), 7.68-7.67 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.10 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.55-4.51 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.55 (m, 1H), 3.47-3.40 (m, 1H), 2.27-1.99 (m, 4H), 1.94-1.82 (m, 1H), 0.97, 0.95 ( m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 6) Synthesis of Compound 15-6

Compound 15-5 (0.54 g, 1.07 mmol), compound 1-9 (0.62 g, 1.07 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.11 mmol) and potassium carbonate (0.37 g, 2.67 mmol) In a reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected under N ₂ and reacted at 90 ° C for 5.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (50 mL), and then washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Eluent: DCM / MeOH (v / v) = 100/1)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.63 (s, 1H), 7.62-7.61,7.60-7.59 (m, m, 2H), 7.56-7.55,7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 4.89-4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.74-3.71 (m, 2H), 3.63 (s, 3H) ), 3.45-3.38 (m, 2H), 2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.03-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.43-1.36 (m, 1H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H), 0.91, 0.89 (m, m, 3H), 0.50-0.46 (m, 1 H) ppm.

Step 7) Synthesis of Compound 15-7

Compound 15-6 (0.33g, 0.4mmol), compound 1-6-2 (0.15g, 0.6mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (33 mg, 0.04 mmol) and KOAc (0.12 g, 1.19 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (5.0 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (30 mL), and the mixture was filtered, and then filtered and washed with water (10 mL×3) and brine. (Eluent: PE / EtOAc (v / v) = 1/2) afforded 0.25 g of beige solid, yield: 80.1%.

MS (ESI, pos.) m / z : 781.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 ( m, m, 4H), 7.58, 7.56 (s, s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 4.89-4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.76-3.71 (m, 2H), 3.69-3.66 (m, 1H), 3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.46-2.39 (m, 1H), 2.21-2.09 (m, 1H), 2.00 -1.90 (m, 4H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.43-1.36 (m, 1H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 ( m, 2H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H), 0.90, 0.89 (m, m, 3H), 0.50-0.46 (m) , 1H) ppm.

Step 8) Synthesis of Compound 15-8

Compound 4-6 (1.06 g, 4.66 mmol) was dissolved in THF (10 mL), and borane (10 mL, 1M in THF) was slowly added dropwise to the reaction flask under nitrogen at 0 ° C. 3.0 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Rate: 65%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 4.37 (brs, 1H), 3.94-3.78 (m, 3H), 2.93-2.86 (m, 1H), 2.11-2.03 (m, 1H), 1.83-1.77 (m , 1H), 1.46 (s, 9H), 1.41-1.33 (m, 1H), 1.09-1.03 (m, 1H), 0.65-0.62 (m, 1H) ppm.

Step 9) Synthesis of Compound 15-9

Compound 15-8 (0.74 g, 3.48 mmol) was dissolved in DCM (10 mL). EtOAc (2.07 g, 4.88 mmol) oxidant was added portionwise to the reaction flask at 0 ° C. Reaction for 2.0 hours. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), filtered, and the filtrate was evaporated. v/v) = 3 / 2) gave a colorless oil, 0.5 g, yield: 68%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.75-9.72 (m, 1H), 4.19-4.14 (m, 1H), 3.24-3.18 (m, 1H), 2.41-2.34 (m, 1H), 1.82-1.80 , 1.78-1.86 (m, m, 1H), 1.45 (s, 9H), 1.41-1.34 (m, 1H), 1.26-1.21 (m, 1H), 0.83-0.80 (m, 1H) ppm.

Step 10) Synthesis of Compound 15-10

Compound 15-9 (0.37 g, 1.76 mmol) and aqueous ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1 mL) was slowly dropped into the reaction flask at 0 °C. After completion, the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was evaporated and evaporated, mjjjjjj

MS (ESI, pos.) m / z : 250.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.04 (s, 2H), 4.92-4.88 (m, 1H), 3.31-3.25 (m, 1H), 2.48-2.41 (m, 1H), 2.00-1.98, 1.96-1.94 (m, m, 1H), 1.45-1.43 (m, 1H), 1.42 (s, 9H), 1.41-1.39 ( m, 1H), 1.02-0.95 (m, 1 H) ppm.

Step 11) Synthesis of Compound 15-11

The compound 15-10 (0.5 g, 2.0 mmol) was dissolved in DCM (60 mL), and N-iodobutanediamine (0.9 g, 4.0 mmol) was added portionwise to the reaction flask at a constant temperature. hour. After the completion of the reaction, the reaction mixture was washed with brine, dried over anhydrous sodium sulfate. Rate: 65%.

MS (ESI, pos.) m / z : 502.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.93-4.89 (m, 1H), 3.49-3.42 (m, 1H), 2.57 -2.46(m,1H), 2.12-2.10,2.09-2.07(m,m,1H),1.45-1.43(m,1H),1.42(s,9H),1.41-1.39(m,1H),1.02- 0.95 (m, 1 H) ppm.

Step 12) Synthesis of Compound 15-12

Compound 15-11 (0.75 g, 1.5 mmol) was suspended in a mixed solvent of ethanol and water (v/v = 3/7) (12.5 mL), and sodium sulfite (1.7 g, 13.5 mmol) was added to the mixture to reflux. hour. After the completion of the reaction, the ethanol was removed, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Agent: PE / EtOAc (v / v) = 3 / 2) gave 0.45 g of white solid.

MS (ESI, pos.) m / z : 376.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.41 (s, 1H), 4.71-4.68 (m, 1H), 3.34-3.28 (m, 1H), 2.50-2.43 (m, 1H), 2.05-2.03, 2.01-1.99 (m, m, 1H), 1.45-1.43 (m, 1H), 1.42 (s, 9H), 1.41-1.39 ( m, 1H), 1.02-0.94 (m, 1 H) ppm.

Step 13) Synthesis of Compound 15-13

A solution of hydrogen chloride in ethyl acetate (5 mL, 4M) was then evaporated . After completion of the reaction, filtration gave a solid (0.65 g, yield: 93.4%). Used directly in the next step.

MS (ESI, pos.) m / z : 276.1 [M+H] ⁺ .

Step 14) Synthesis of Compound 15-14

Compound 15-13 (0.63 g, 1.8 mmol), Compound 1-18-2 (0.35 g, 1.98 mmol) and EDCI (0.38 g, 1.98 mmol) were suspended in DCM (20 mL) and stirred at 0 ° C for 5 min. DIPEA (2.38 mL, 14.4 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2.0 hours. After the completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc (EtOAc) 1/2) gave 0.65 g of a pale yellow solid, yield: 83.5%.

MS (ESI, pos.) m/z: 433.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38 (s, 1H), 5.32, 5.30 (d, d, 1H), 4.89 - 4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.63 (s, 3H), 3.51-3.45 (m, 1H), 2.55-2.48 (m, 1H), 2.22 2.11 (m, 1H), 2.09-2.06, 2.05-2.03 (m, m, 1H), 1.49-1.41 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H) , 0.90, 0.89 (m, m, 3H), 0.50-0.46 (m, 1 H) ppm.

Step 15) Synthesis of Compound 15-15

Compound 15-14 (0.31 g, 0.72 mmol), compound 15-7 (0.57 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were suspended in DME (4.0 mL) and water (1.0 mL) were reacted at 90 ° C for 4.0 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL), washed with water (20 mL × 3) and brine, dried over anhydrous sodium sulfate /v) = 50/1) gave the product 0.42 g, yield: 60%.

MS (ESI, pos. ion) m/z: 486.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.84 (s, 1H), 7.62 (s, 1H), 7.61 to 7.59 ( m, 2H), 7.56-7.52 (m, 2H), 7.51-7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 5.32, 5.30 (d, d, 2H), 4.92-4.85 (m, 2H), 4.08, 4.06, 4.04 (m, m, m, 2H), 3.92-3.90 (m, 1H) ), 3.77-3.71 (m, 3H), 3.63 (s, 6H), 3.45-3.38 (m, 2H), 2.46-2.38 (m, 2H), 2.22-2.09 (m, 2H), 2.03-1.89 (m ,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.43-1.36(m,2H),1.30-1.16(m,4H),0.97,0.95(m,m,6H) , 0.94 - 0.92 (m, 2H), 0.91, 0.89 (m, m, 6H), 0.50 - 0.46 (m, 2H) ppm.

Example 16

synthetic route:

Step 1) Synthesis of Compound 16-1

Compound 15-3 (0.45 g, 1.0 mmol), compound 1-9 (0.58 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In a reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected under N ₂ and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Detachment: PE / EtOAc (v / v) = 8 / 1) gave a pale yellow liquid, 0.55 g, yield: 72.6%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62-7.61,7.60-7.59 (m, m, 2H), 7.56-7.55,7.53-7.52 (m, m, 2H), 7.47 (s, 1H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 4.75-4.72 (m, 1H) , 3.92-3.90 (m, 1H), 3.74-3.71 (m, 2H), 3.45-3.42 (m, 1H), 3.29-3.23 (m, 1H), 2.42-2.35 (m, 1H), 2.03-1.90 ( m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.43 (s, 9H), 1.41-1.34 (m, 2H), 1.30-1.17 (m, 4H), 1.02- 0.95 (m, 1 H) ppm.

Step 2) Synthesis of Compound 16-2

Compound 16-1 (0.39 g, 0.52 mmol), Compound 1-6-2 (0.15 g, 0.57 mmol), Pd (dppf) Cl ₂ . CH ₂ Cl ₂ (60 mg, 0.073 mmol) and KOAc (0.13 g, 1.3 mmol) were placed in a reaction flask under N ₂ and then poured in DMF (4.0 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (40 mL). The mixture was filtered, and then filtered and washed with water (10 mL×3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE / EtOAc (v / v) = 1/2) afforded product 0.3 g, yield: 78.4%.

MS (ESI, pos.) m / z : 736.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 ( m, m, 3H), 7.58, 7.56 (s, s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.47 (s, 1H), 7.31, 7.29 (s, s, 1H) , 4.75-4.72 (m, 1H), 3.92-3.90 (m, 1H), 3.76-3.71 (m, 2H), 3.69-3.66 (m, 1H), 3.29-3.23 (m, 1H), 2.42-2.35 ( m, 1H), 2.00-1.90 (m, 4H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.43 (s, 9H), 1.42-1.36 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.26-1.17 (m, 3H), 1.07-1.01 (m, 1H), 1.00-0.95 (m, 1 H) ppm.

Step 3) Synthesis of Compound 16-3

Compound 16-2 (0.74 g, 1.0 mmol), compound 15-12 (0.38 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 80/1) gave 0.45 g of pale yellow solid.

MS (ESI, pos.) m / z : 429.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.95 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m , 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.47 (s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 4.82-4.79 (m, 1H), 4.75-4.72 (m, 1H), 3.92-3.90 (m, 1H), 3.77-3.71 (m, 3H), 3.29-3.23 (m, 2H), 2.42 - 2.34 (m, 2H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H) , 1.43 (s, 18H), 1.40-1.34 (m, 4H), 1.30-1.16 (m, 4H), 1.02-0.95 (m, 2H) ppm.

Step 4) Synthesis of Compound 16-4

Compound 16-3 (0.26 g, 0.3 mmol) was dissolved in EtOAc (3.0 mL). After the reaction was completed, the reaction mixture was evaporated,jjjjjjjjj

MS (ESI, pos.) m / z : 657.8 [M+H] ⁺ .

Step 5) Synthesis of Compound 16-5

Compound 16-4 (0.16 g, 0.2 mmol), Compound 3-18-2 (79.4 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HOAT (41 mg, 0.3 mmol) in DCM (3.0 mL) DIPEA (0.26 mL, 1.6 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v) /v) = 60/1) gave a white solid, 0.1 g, yield: 50%.

MS (ESI, pos.ion) m / z: 500.6 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.84 (s, 1H), 7.62 (s, 1H), 7.61-7.60, 7.59-7.58 (m, m, 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.51, 6.49 (s, s, 2H), 4.89-4.82 (m, 2H), 4.12, 4.10, 4.08 (m, m, m, 2H), 3.92-3.90 (m, 1H), 3.77-3.71 (m, 3H), 3.65 (s, 6H), 3.37-3.31 (m, 2H), 2.44-2.35 (m, 2H), 2.24 2.13 (m, 2H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.47-1.31 (m, 4H), 1.30-1.16 (m, 4H) ), 1.12 - 0.99 (m, 2H), 0.95, 0.94, 0.93, 0.91, 0.89 (m, m, m, m, m, 2H), 0.88-0.87, 0.86-0.85, 0.84, 0.82 (m, m, d, d, 12H), 0.51, 0.49, 0.48, 0.47 (m, m, m, m, 2H) ppm.

Example 17

synthetic route:

Step 1) Synthesis of Compound 17-2

Anhydrous sodium sulfate (3.48 g, 24.5 mmol) was added to a solution of ( R )-1-phenylethylamine (1.3 mL, 10.1 mmol) in toluene (15 mL), and then ethyl glyoxylate (1 mL, 10.1) After mmol), the reaction was carried out at room temperature for 1.0 hour. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to give 1.9 g of a yellow liquid, yield: 91.8%. It was used directly in the next reaction without further purification.

Step 2) Synthesis of Compound 17-3

TFA (0.75 mL, 10.1 mmol) was added to a solution of compound 17-2 (2.0 g, 9.7 mmol) in DMF (15 mL). After stirring for 10 min, then freshly distilled 1,3-cyclopentadiene was added. 1.29 g, 19.5 mmol) and two drops of water were added and allowed to react at room temperature for 12 hours. After the reaction was completed, DMF was removed, the residue was added to a NaHCO ₃ solution (10%, 20 mL), the pH of the solution was adjusted to 8 with Na ₂ CO ₃ , and extracted with petroleum ether (25 mL×3), and the organic phase was combined and saturated. washed with brine, dried over anhydrous Na ₂ SO _4, purified by column chromatography separation was concentrated (eluent: PE / EtOAc (v / v ) = 10/1) to give 2.38 g of a pale yellow liquid, yield: 90.0%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.35-7.17 (m, 5H), 6.42 (br, 1H), 6.28-6.26 (br, 1H), 4.34-4.30 (m, 2H), 3.82-3.78 (m , 2H), 3.04-3.02 (m, 1H), 2.90 (br, 1H), 2.20 (br, 1H), 2.13 (m, 1H), 1.41 (d, 3H, J = 6.6 Hz), 0.95 (t, 3H, J = 7.2 Hz) ppm.

Step 3) Synthesis of Compound 17-4

The Pd / C (0.2g) was added to compound 17-3 (2.0g, 7.37mmol) in ethanol (60 mL) solution at 20 atm H ₂ atmosphere at room temperature for 24 hours. After completion of the reaction, Pd/C was removed by filtration, and the filtrate was concentrated to give a yellow liquid (1.2 g, yield: 96.2%).

MS (ESI, pos.) m / z : 170.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.21-4.15 (m, 2H), 3.55 (br, 1H), 3.33 (br) , 1H), 2.63 (br, 1H), 2.32 (br, 1H), 1.64-1.60 (m, 2H), 1.53-1.47 (m, 2H), 1.42-1.36 (m, 2H), 1.28 (t, 3H) , J = 7.1 Hz) ppm.

Step 4) Synthesis of Compound 17-5

Compound 17-4 (1.69g, 10mmol) was dissolved in MeOH (20mL), the at 0 deg.] C, were added dropwise Et ₃ N (1.67mL, 12mmol), and _{BOC 2 O (2.41mL, 10.5mmol)} , dropwise, The reaction was carried out at room temperature overnight. After completion of the reaction, the methanol, the residue was dissolved in DCM (50mL) was removed, washed with water (20mL × 3) and saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give a colorless oil 2.37 g, yield: 88%.

Step 5) Synthesis of Compound 17-6

An aqueous solution (10 mL) of lithium hydroxide monohydrate (0.48 g, 11.35 mmol) was slowly added dropwise to a solution of compound 17-5 (0.61 g, 2.27 mmol) in THF (25 mL) at 0° C. Reaction for 12 hours. After the reaction was completed, THF was evaporated, EtOAc (EtOAc) (EtOAc) (EtOAc) The organic phase was combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ and evaporated.

MS (ESI, pos.) m / z : 242.3 [M+H] ⁺ .

Step 6) Synthesis of Compound 17-7

Compound 17-6 (1.34 g, 5.57 mmol) was dissolved in THF (20 mL), and borane (8.3 mL, 1M in THF) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 2.0 hours. After completion of the reaction, methanol (4.0 mL) to quench the reaction, removed of THF, the residue was dissolved in DCM (50mL), washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated to give a colorless Oil 1.01 g, yield: 80%.

MS (ESI, pos.) m / z : 228.3 [M+H] ⁺ .

Step 7) Synthesis of Compound 17-9

Compound 17-7 (1.19 g, 5.24 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc: EtOAc. After the completion of the reaction, the reaction was carried out for 1.0 hour at room temperature. After completion of the reaction, the mixture was filtered, and the filtrate was washed with saturated aqueous sodium sulfate (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated. After the above mixture was reacted at 0 ° C for 0.5 hour, it was reacted at room temperature for 1.0 hour. After the above system was again cooled to 0 ° C, an aqueous solution of glyoxal (1.1 mL, 40%) was slowly added dropwise, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, the residue was added DCM (60mL) was dissolved, washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) gave a pale yellow solid.

MS (ESI, pos.) m / z : 264.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99 (s, 2H), 4.88-4.85 (m, 1H), 4.49-4.44 (m, 1H), 2.57-2.53 (m, 1H), 2.04-1.96 (m, 1H), 1.89-1.84 (m, 1H), 1.74-1.62 (m, 2H), 1.59-1.46 (m, 2H) , 1.44 (s, 9H) ppm.

Step 8) Synthesis of Compound 17-10

Compound 17-9 (0.65 g, 2.47 mmol) was dissolved in DCM (8.0 mL). EtOAc (1. After the reaction was completed, the reaction mixture was diluted with DCM (30 mL), filtered, and the filtrate was washed with saturated sodium sulfite (20 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated to give a white solid 1.27 g, yield 100% The next step is to react.

MS (ESI, pos.) m / z : 516.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.33-5.30 (m, 1H), 4.39 - 4.35 (m, 1H), 2.76 -2.72 (m, 1H), 2.04-1.92 (m, 2H), 1.83-1.71 (m, 2H), 1.61-1.51 (m, 2H), 1.44 (s, 9H) ppm.

Step 9) Synthesis of Compound 17-11

Compound 17-10 (1.12 g, 2.12 mmol) was dissolved in ethanol (6.0 mL) and water (6.0 mL). After completion of the reaction was filtered, the filtrate was concentrated, the residue was added DCM (80mL) was dissolved, washed with water and saturated saline solution (20mL × 3), dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE / EtOAc (v / v) = 1 / 1) gave a white solid.

MS (ESI, pos.) m / z : 390.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36 (s, 1H), 4.81-4.78 (m, 1H), 4.47-4.43 (m, 1H), 2.65-2.61 (m, 1H), 2.04-1.96 (m, 1H), 1.93-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.59-1.48 (m, 2H) , 1.44 (s, 9H) ppm.

Step 10) Synthesis of Compound 17-12

Pyridine (0.9 g, 11.4 mmol) was added dropwise to a solution of compound 3-13 (0.86 g, 1.9 mmol) in DCM (10 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (2.1 g, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE / EtOAc (v / v) = 5 / 1) gave a pale yellow liquid, 0.94 g, yield: 85%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26,7.24 (s, s, 1H), 7.17,7.15 (s, s, 1H), 7.08,7.06 (s, s, 1H), 7.03,7.01 (t, t,1H), 4.03, 4.01, 3.99, 3.97 (m, m, m, m, 1H), 3.88-3.85 (m, 1H), 3.47-3.44 (m, 1H), 3.08-2.97 (m, 1H) , 2.81, 2.78, 2.76, 2.74 (m, m, m, m, 1H), 2.56-2.46 (m, 1H), 2.43, 2.41, 2.39, 2.37 (m, m, m, m, 1H), 2.18- 2.04 (m, 2H), 2.03-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.61-1.52 (m, 2H), 1.30-1.19 (m, 2H) ppm.

Step 11) Synthesis of Compound 17-13

Compound 17-2 (0.92g, 1.58mmol), compound 1-6-2 (0.92g, 3.63mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (60 mg, 0.073 mmol) and KOAc (0.47 g, 4.7 mmol) were placed in a reaction flask under N ₂ and then poured into DMF (10.0 mL) and reacted at 90 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (60 mL). The mixture was filtered, and then filtered and washed with water (10 mL×3) and brine, dried over Na ₂ SO ₄ The product was separated and purified (eluent: PE) to give the product (yield: 0.63 g).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26,7.24 (s, s, 1H), 7.17,7.15 (s, s, 1H), 7.08,7.06 (s, s, 1H), 7.03,7.01 (t, t,1H), 4.01 (m, 4H), 3.88-3.85 (m, 1H), 3.47-3.44 (m, 1H), 3.08-2.97 (m, 1H), 2.78, (m, 4H), 2.56-2.46 (m, 1H), 2.41 (m, 4H), 2.18-2.04 (m, 2H), 2.03-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.61-1.52 (m, 2H), 1.30 - 1.19 (m, 26 H) ppm.

Step 12) Synthesis of Compound 17-14

Compound 17-13 (0.58 g, 1.0 mmol), compound 17-11 (0.39 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 80/1) afforded 0.4 g of pale yellow solid.

MS (ESI, pos.) m / z : 810.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.75 (s, 1H), 7.60 (s, 1H), 7.51, 7.49 (s , s, 1H), 7.41, 7.39 (t, t, 1H), 7.24, 7.22 (s, s, 1H), 7.18, 7.16 (s, s, 1H), 4.85-4.81 (m, 1H), 4.79- 4.76 (m, 1H), 4.50-4.46 (m, 2H), 4.37-4.30 (m, 1H), 3.78-3.74 (m, 1H), 3.24-3.12 (m, 1H), 2.70-2.57 (m, 2H) ), 2.54-2.50 (m, 2H), 2.25-2.12 (m, 3H), 2.04-1.96 (m, 3H), 1.95-1.89 (m, 1H), 1.88-1.83 (m, 3H), 1.73-1.45 (m, 11H), 1.44 (s, 18H), 1.30-1.24 (m, 1H), 1.22-1.16 (m, 1H) ppm.

Step 13) Synthesis of Compound 17-15

Compound 17-14 (0.24 g, 0.3 mmol) was dissolved in EtOAc (3.0 mL). After the reaction was completed, the mixture was evaporated. mjjjjjjjj

MS (ESI, pos.) m / z : 609.8 [M+H] ⁺ .

Step 14) Synthesis of Compound 17-16

Compound 17-15 (0.15 g, 0.2 mmol), Compound 1-18-2 (100 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HOAT (41 mg, 0.3 mmol) DIPEA (0.26 mL, 1.6 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL), washed with brine and brine, dried over anhydrous Na ₂ SO ₄ and concentrated and purified by column chromatography (eluent: DCM/MeOH (v) /v) = 60/1) gave 0.12 g of a white solid. Yield: 65%.

MS (ESI, pos.) m / z : 462.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.89 (s, 1H), 7.61 (s, 1H), 7.44, 7.42 ( s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.28, 7.26 (s, s, 1H), 7.25, 7.23 (t, t, 1H), 5.32, 5.30 (d, d, 2H) , 4.98-4.94 (m, 2H), 4.80-4.75 (m, 2H), 4.45, 4.43-4.42, 4.41 (m, m, m, 2H), 4.27-4.20 (m, 1H), 3.87-3.84 (m , 1H), 3.79-3.76 (m, 1H), 3.63 (s, 6H), 3.29, 3.26, 3.24, 3.22 (m, m, m, m, 1H), 3.21-3.12 (m, 1H), 2.83, 2.81, 2.79, 2.77 (m, m, m, m, 1H), 2.59-2.45 (m, 3H), 2.23-1.94 (m, 8H), 1.92-1.88 (m, 1H), 1.83-1.78 (m, 2H), 1.69-1.55 (m, 8H), 1.47-1.36 (m, 2H), 1.30-1.24 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) )ppm.

Example 18

synthetic route:

Step 1) Synthesis of Compound 18-1

Compound 3-18 (0.73 g, 1.88 mmol), Compound 1-18-2 (0.4 g, 2.25 mmol) and EDCI (0.43 g, 2.25 mmol) were dissolved in DCM (5.0 mL) After DIPEA (1.24 mL, 7.52 mmol), it was reacted at room temperature for 3.0 hours. After completion of the reaction, water (10mL) The reaction was quenched, the aqueous layer was extracted with DCM (15mL × 3), washed with saturated brine and dried organic phase was dried over anhydrous Na ₂ SO _4, separated and purified by column chromatography (eluted was concentrated Agent: PE / EtOAc (v / v) = 1/2) gave a solid 0.75 g, yield: 85%.

MS (ESI, pos.) m / z : 471.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87-7.80 (m, 1H), 7.71-7.66 (m, 2H), 5.47 -5.42 (m, 2H), 4.34-4.30 (m, 1H), 3.86-3.84 (m, 1H), 3.70 (s, 3H), 3.64-3.62 (m, 1H), 3.04-2.98 (m, 1H) , 2.25-2.21 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.35 (s, 12H), 0.88-0.84 (m, 6H) ppm.

Step 2) Synthesis of Compound 18-2

Compound 18-1 (0.27 g, 0.58 mmol), compound 3-13 (0.26 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (0.08 g, 1.4 mmol) were placed in the reaction In a bottle, under N ₂ protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (40 mL), and then washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: PE / EtOAc (v / v) = 1 / 1) gave 0.25 g of pale yellow solid, yield: 68%.

MS (ESI, pos.) m / z : 645.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.61, 7.60 (m, d, 2H), 7.49 (t, 2H) , 7.24, 7.22 (m, m, 1H), 7.08, 7.06 (s, s, 1H), 6.64, 6.62 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.24-5.20 (m , 1H), 4.39, 4.37, 4.35 (m, m, m, 1H), 4.12-4.05 (m, 1H), 3.84-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.56 (m, 1H), 2.54, 2.52, 2.50, 2.48 (m, m , m, m, 1H), 2.38-2.28 (m, 1H), 2.24-1.88 (m, 9H), 1.87-1.83 (m, 1H), 1.64-1.52 (m, 2H), 1.31-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 3) Synthesis of Compound 18-3

Pyridine (0.9 g, 11.4 mmol) was added dropwise to a solution of compound 18-2 (1.22 g, 1.9 mmol) in DCM (10 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (2.1 g, 7.6 mmol) was dropped into the reaction flask, and the mixture was dropped and allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE / EtOAc (v / v) = 5 / 1) gave 1.25 g of pale yellow liquid, yield: 85%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62-7.61,7.60 (m, d, 2H), 7.49 (t, 2H), 7.24,7.22,7.20 (m, m, s, 2H), 7.04,7.02 ( s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.24-5.20 (m, 1H), 4.40, 4.38, 4.36 (m, m, m, 1H), 4.12-4.05 (m, 1H) , 3.84-3.76 (m, 2H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.56-3.53 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.39-2.28 (m, 1H), 2.24-1.88 (m, 9H), 1.87-1.83 (m, 1H), 1.64-1.52 (m, 2H), 1.35-1.29 (m, 1H), 1.25- 1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 4) Synthesis of Compound 18-4

Compound 18-3 (0.60g, 0.77mmol), compound 1-6-2 (0.22g, 0.85mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (30 mg, 0.036 mmol) and KOAc (0.13 g, 1.3 mmol) were placed in a reaction flask under N ₂ and then poured to DMF (8.0 mL) and reacted at 90 ° C for 3.0 hours. After completion of the reaction, was cooled to room temperature, EtOAc (70mL) was diluted with the reaction solution, diatomaceous earth. The filtrate was washed with water (10mL × 3) and saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column Separation and purification (eluent: PE / EtOAc (v / v) = 1/2) afforded product (yield: 82.

MS (ESI, pos.) m / z : 754.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57 (m2H), 7.39 (m, 2H), 7.22 (m, 2H), 7.04,7.02(s,s,1H), 5.32,5.29(d,d,1H), 5.24-5.20(m,1H), 4.38(m,1H),4.12-4.05(m,1H),3.84-3.76 (m, 2H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.56-3.53 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.39 -2.28(m,1H),2.24-1.88(m,9H),1.87-1.83(m,1H),1.64-1.52(m,2H),1.35-1.29(m,1H),1.25-1.19(m, 13H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 5) Synthesis of Compound 18-5

Compound 18-4 (0.44 g, 0.58 mmol), compound 2-2 (0.24 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (80 mg, 1.4 mmol) were placed in a reaction flask In the middle, under N ₂ protection, EtOH (4.0 mL) and purified water (1.0 mL) were separately poured and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (50 mL), and washed with water (30 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Agent: DCM / MeOH (v / v) = 50/1).

MS (ESI, pos. ion) m / z : 461.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60 (m, d, 2H) ), 7.58, 7.56 (s, s, 1H), 7.50, 7.48 (t, t, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.23, 7.22 ( m, m, 1H), 5.32, 5.30 (d, d, 2H), 5.28-5.20 (m, 2H), 4.41-4.35 (m, 2H), 4.12-4.05 (m, 1H), 3.87-3.76 (m , 4H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.37-1.88 (m, 16H), 1.69-1.65 (m, 1H), 1.62-1.52 (m, 1H), 1.30-1.21 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 19

synthetic route:

Step 1) Synthesis of Compound 19-1

Compound 1-10 (0.54 g, 1.0 mmol), compound 2-2 (0.42 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were placed In a reaction flask, under the protection of N ₂ , EtOH (5.0 mL) and pure water (1.0 mL) were separately poured and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Detachment: PE / EtOAc (v / v) = 1/2) gave a pale yellow liquid, 0.5 g, yield: 71%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.81 (s, 1H), 7.66,7.64 (s, s, 1H), 7.61,7.59 (s, s, 1H), 7.51,7.49 (s, s, 1H) , 7.26, 7.24 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41-4.37 (m, 1H), 3.85-3.78 (m, 1H), 3.77-3.73(m,3H), 3.69-3.65(m,2H),3.63(s,3H),2.30-1.89(m,8H),1.87-1.83(m,1H),1.80-1.74(m,2H ), 1.64-1.60 (m, 1H), 1.57-1.53 (m, 1H), 1.32, 1.29 (q, q, 12H), 1.28-1.24 (m, 1H), 1.23-1.16 (m, 2H), 1.07 -1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 2) Synthesis of Compound 19-3

Compound 19-2 (2.0 g, 15.3 mmol) was dissolved in MeOH (20 mL), and then dichloro-n-hydrazide (3.4 mL, 46.9 mmol) was slowly added dropwise at 0 ° C, and the reaction was carried out at 80 ° C for 3.5 hours. After completion of the reaction, the reaction mixture was concentrated to give a white solid (yield: 2.76 g, yield: 99.5%).

¹ H NMR (400 Hz, CDCl ₃ ): δ 3.68 (s, 3H), 3.58 (t, 1H), 3.56 (s, 1H), 3.32 (m, 1H), 3.02 (m, 1H), 2.77 (m, 1H), 2.52 (s, 1H), 2.21 (m, 1 H), 1.96 (m, 1 H) ppm.

Step 3) Synthesis of Compound 19-4

Compound 19-3 (3.1g, 17.1mmol) added in one portion to a vigorously stirred solution of benzyl chloroformate (3.7mL, 26.3mmol) and potassium carbonate (10.6g, 76.7mmol) in _{THF / H 2 O (20mL /} 10mL In the mixture, after the addition, the reaction was carried out at room temperature overnight. After the completion of the reaction, the pH of the reaction mixture was adjusted to 3 with dilute aqueous hydrochloric acid (1M), and then extracted with EtOAc (50 mL×3). Separation and purification (eluent: PE/EtOAc (v/v) = 4/1) afforded:

¹ H NMR (400 Hz, CDCl ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 ( m, 1H) ppm.

Step 4) Synthesis of Compound 19-5

Compound 19-4 (1.0 g, 3.6 mmol) was dissolved in DCM (20 mL). &lt;RTI ID=0.0&gt;&gt; After the reaction was completed, the reaction mixture was purified and purified (jjjjjjjj

¹ H NMR (400 Hz, CDCl ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1 H) ppm.

Step 5) Synthesis of Compound 19-6

Compound 19-5 (1.0 g, 3.6 mmol) was dissolved in toluene (20 mL). EtOAc (EtOAc (EtOAc) After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL). v/v) = 6/1) 0.54 g of a colorless liquid was obtained, yield: 46.7%.

¹ H NMR (400 Hz, CDCl ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 ( m, 1H) ppm.

Step 6) Synthesis of Compound 19-7

Compound 19-6 (0.58 g, 1.8 mmol) was dissolved in MeOH (10 mL). After the reaction was completed, it was filtered, and the filtrate was concentrated to give the product (0.33 g, yield: 98.9%). Used directly in the next step.

¹ H NMR (400 Hz, CDCl ₃ ): δ 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1 H) ppm.

Step 7) Synthesis of Compound 19-8

Compound 19-6 (3.48 g, 18.6 mmol), compound 1-18-2 (3.26 g, 18.6 mmol) and EDCI (7.1 g, 37 mmol) were suspended in DCM (50 mL). (12.3 mL, 74.4 mmol), dropwise, and allowed to react at room temperature overnight. After the completion of the reaction, the reaction mixture was washed with brine, dried over anhydrous sodium sulfate g, yield: 39.1%.

¹ H NMR (400 Hz, CDCl ₃ ): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H) , 3.50 (s, 3H), 3.45 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H) ppm.

Step 8) Synthesis of Compound 19-9

Compound 19-8 (0.9 g, 2.6 mmol) was dissolved in THF (5.0 mL). EtOAc (EtOAc) After the completion of the reaction, the pH of the reaction mixture was adjusted to 2 with dilute hydrochloric acid (1M), EtOAc (EtOAc (EtOAc) g, yield: 99%, used directly in the next reaction.

¹ H NMR (400 Hz, CDCl ₃ ): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H) , 3.50 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H) ppm.

Step 9) Synthesis of Compound 19-10

Compound 19-9 (1.54 g, 4.66 mmol) was dissolved in THF (10 mL), and borane (10 mL, 1M in THF) was slowly added dropwise to the reaction flask under nitrogen at 0 ° C. 3.0 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Rate: 65%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 5.32,5.30 (d, d, 1H), 4.36,4.34,4.32,4.30,4.28 (m, m, m, m, m, 3H), 3.99-3.97 (m , 4H), 3.73-3.72, 3.71-3.69, 3.67-3.66 (m, m, m, 2H), 3.63 (s, 3H), 3.61-3.59, 3.57-3.55 (m, m, 1H), 3.40-3.38 , 3.36-3.34 (m, m, 1H), 25.42-2.36 (m, 1H), 2.17-2.04 (m, 1H), 1.94-1.88 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 10) Synthesis of Compound 19-11

Compound 19-10 (1.1 g, 3.48 mmol) was dissolved in DCM (10 mL). EtOAc (2.07 g, 4.88 mmol) oxidant was added portionwise to the reaction flask at 0 ° C. Reaction for 2.0 hours. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), filtered, and the filtrate was evaporated. v/v) = 3 / 2) gave 0.71 g of colorless oil, yield: 65%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.49-9.48 (m, 1H), 5.32,5.29 (d, d, 1H), 4.79-4.75 (m, 1H), 4.34,4.32,4.30 (m, m, m,1H), 3.98-3.97 (m, 4H), 3.76-3.75, 3.73-3.71 (m, m, 1H), 3.63 (s, 3H), 3.40-3.38, 3.36-3.34 (m, m, 1H) , 2.64-2.62, 2.61-2.59 (m, m, 1H), 2.22-2.10 (m, 1H), 2.00-1.93 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m) , m, 3H) ppm.

Step 11) Synthesis of Compound 19-12

Compound 19-11 (0.55 g, 1.76 mmol) and aqueous ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1 mL) was slowly dropped into the reaction flask at 0 °C. After completion, the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was evaporated and evaporated, mjjjjjj

MS (ESI, pos.) m / z : 353.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99 (s, 2H), 5.60-5.56 (m, 1H), 5.32, 5.29 (d,d,1H), 4.43,4.41, 4.39 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.94-3.93 (m, 1H), 3.71-3.70, 3.67-3.66 (m , m, 1H), 3.63 (s, 3H), 2.77-2.71 (m, 1H), 2.36-2.30 (m, 1H), 2.24-2.11 (m, 1H), 0.97, 0.95 (m, m, 3H) , 0.90, 0.89 (m, m, 3H) ppm.

Step 12) Synthesis of Compound 19-13

Compound 19-12 (0.70 g, 2.0 mmol) was dissolved in DCM (60 mL), and N-iodobutanediamine (0.9 g, 4.0 mmol) was added portionwise to the reaction flask at constant temperature. hour. After the completion of the reaction, the reaction mixture was washed with EtOAc EtOAc. Rate: 65%.

MS (ESI, pos.) m / z : 605.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.32, 5.29 (d,d,1H), 5.29-5.26 (m,1H) , 4.40, 4.38, 4.36 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.93-3.92 (m, 1H), 3.70-3.69, 3.67-3.65 (m, m, 1H), 3.63 (s, 3H), 2.75-2.69 (m, 1H), 2.36-2.30 (m, 1H), 2.24-2.11 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 13) Synthesis of Compound 19-14

Compound 19-13 (0.91 g, 1.5 mmol) was suspended in a mixed solvent of ethanol and water (v/v = 3/7) (12.5 mL), and sodium sulfite (1.7 g, 13.5 mmol) was added to the mixture to reflux. hour. After the completion of the reaction, the ethanol was removed, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Agent: PE / EtOAc (v / v) = 3 / 2).

MS (ESI, pos.) m / z : 479.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34 (s, 1H), 5.32, 5.29 (d,d,1H), 5.25 -5.21 (m, 1H), 4.42, 4.40, 4.38 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.93-3.92 (m, 1H), 3.70-3.69, 3.67-3.65 (m , m, 1H), 3.63 (s, 3H), 2.76-2.74, 2.73-2.70 (m, m, 1H), 2.38, 2.36-2.34, 2.32 (m, m, m, 1H), 2.24-2.11 (m , 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 14) Synthesis of Compound 19-15

Compound 19-14 (0.35 g, 0.72 mmol), compound 19-1 (0.51 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were suspended in DME (4.0 mL) and water (1.0 mL) were reacted at 90 ° C for 4.0 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL), washed with water (20 mL × 3) and brine, dried over anhydrous sodium sulfate /v) = 50/1) The product was obtained in the form of 0.35 g, yield: 52.3%.

MS (ESI, pos.ion) m / z: 465.6 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.90 (s, 1H), 7.81 (s, 1H), 7.39,7.37 ( s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.61-5.60, 5.59-5.58, 5.57 (m, m, m, 1H), 5.32, 5.30 (d, d, 2H), 5.29- 5.25 (m, 1H), 4.42-4.37 (m, 2H), 3.98-3.96, 3.94-3.92 (m, m, 5H), 3.85-3.78 (m, 1H), 3.77-3.73 (m, 4H), 3.71 -3.69, 3.68-3.64 (m, m, 2H), 3.63 (s, 6H), 2.83-2.81, 2.80-2.77 (m, m, 1H), 2.46-2.39 (m, 1H), 2.30-1.89 (m , 10H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H), 0.97, 0.95 (m, m, 6H) , 0.91, 0.89 (m, m, 6H) ppm.

Example 20

synthetic route:

Step 1) Synthesis of Compound 20-1

At room temperature, hydrogen chloride in ethyl acetate solution (5.0mL, 4M) was added dropwise compound 20-1 (1.72g, 4.13mmol) in EtOAc (10mL) solution, dropwise for 8.0 hours. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj Used directly in the next step.

MS (ESI, pos.) m / z : 317.5 [M+H] ⁺ .

Step 2) Synthesis of Compound 20-3

Compound 20-2 (1.4 g, 3.6 mmol), compound 1-18-2 (0.69 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) were suspended in DCM (10 mL) DIPEA (2.38 mL, 14.4 mmol) was added and the mixture was reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL), EtOAc (EtOAc) 1/2) gave a pale yellow solid 1.45 g, yield: 85%.

MS (ESI, pos.) m/z: 474.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (brs, 1H), 7.68-7.67 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.10 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.55-4.51 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.55 (m, 1H), 3.47-3.40 (m, 1H), 2.27-1.99 (m, 4H), 1.94-1.82 (m, 1H), 0.97, 0.95 ( m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 3) Synthesis of Compound 20-4

Compound 20-3 (0.76 g, 1.61 mmol), Compound 1-6-2 (0.45 g, 1.77 mmol), Pd (dppf) Cl ₂ . CH ₂ Cl ₂ (66 mg, 0.081 mmol) and KOAc (0.4 g, 4.03 mmol) were placed in a reaction flask under N ₂ and then poured to DMF (4.0 mL) and reacted at 120 ° C for 4.0 hours. After completion of the reaction, the mixture was cooled to room temperature, and then the mixture was diluted with ethyl acetate (40 mL) and filtered. The filtrate was washed with water (30 mL × 3) and brine, dried over anhydrous sodium sulfate. g, yield: 55%.

MS (ESI, pos.) m / z : 474.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (m, 1H), 7.94 - 7.93 (m, 1H), 7.65 - 7.64 , 7.63-7.62 (m, m, 1H), 7.41-7.34 (m, 2H), 5.32, 5.30 (d, d, 1H), 4.71-4.66 (m, 1H), 4.31-4.26 (m, 1H), 3.63(s,3H), 3.62-3.55(m,1H), 3.48-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),1.32,1.29(q,q , 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 4) Synthesis of Compound 20-5

Compound 20-4 (99 mg, 0.21 mmol), compound 19-1 (0.15 g, 0.21 mmol), tetratriphenylphosphine palladium (25 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) were suspended in DME/H ₂ O (v/v = 3/1) mixed solvent (4.0 mL) was reacted at 90 ° C for 5.0 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjj = 40/1) gave a pale yellow solid, 87 mg, yield: 44%.

MS (ESI, pos.) m / z : 463.1 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.90 (m, 1H), 8.00-7.99 (m, 1H), 7.81 ( s, 1H), 7.52-7.51, 7.50-7.49 (m, m, 1H), 7.44, 7.42 (m, m, 1H), 7.41, 7.40 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.22, 7.20, 7.18 (m, m, m, 1H), 5.56, 5.55 (d, d, 1H) , 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.62-4.57 (m, 1H), 4.41, 4.39, 4.37 (m, m, m, 1H), 4.32, 4.30, 4.29 (m, m, m, 1H), 4.07-4.04 (m, 1H), 3.85-3.78 (m, 1H), 3.77-3.73 (m, 3H), 3.66 (s, 3H), 3.65-3.64 (m, 1H), 3.63 (s, 3H), 2.92-2.80 (m, 2H), 2.30-2.15 (m, 5H), 2.13-1.80 (m, 11H), 1.64-1.57 (m, 2H), 1.30-1.16 ( m, 4H), 1.02, 1.01 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.94, 0.92 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 21

synthetic route:

Step 1) Synthesis of Compound 21-1

The freshly distilled 1,3-cyclopentadiene (9.20 g, 138.8 mmol) was added dropwise to a solution of phenylhydrazine (10 g, 92.5 mmol) in DCM (100 mL) at -10 ° C, and reacted at room temperature for 1 hour at room temperature. 0.5 hours. After completion of the reaction, the solvent was removed, n-hexane (500 mL) was added, and the mixture was stirred and filtered, and the filtrate was concentrated to give a pale yellow solid (10.5 g, yield: 65.2%). It was used in the next reaction without further purification.

MS (ESI, pos.) m / z : 175.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.57 (s, 2H), 6.68 (s, 2H), 3.55 (s, 2H) ), 3.22-3.21 (m, 2H), 1.56-1.42 (m, 2H) ppm.

Step 2) Synthesis of Compound 21-2

Compound 21-1 (5.50 g, 31.6 mmol) and sodium acetate (7.77 g, 94.7 mmol) were dissolved in methanol (100 mL), and then reacted at 50 ° C for 3 hours. After the completion of the reaction, the reaction mixture was concentrated, and then purified by column chromatography (eluent: DCM) to yield 5.10 g of white solid.

MS (ESI, pos.) m / z : 175.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.80-6.79 (m, 2H), 6.35 (s, 2H), 3.55 (s) , 2H), 4.10-4.09 (m, 2H), 2.25-2.18 (m, 2H) ppm.

Step 3) Synthesis of Compound 21-3

Pyridine (9.0 g, 114 mmol) was added dropwise to a solution of the compound 21-2 (3.31 g, 19.0 mmol) in DCM (100 mL), and the mixture was stirred for 10 min, and then trifluoromethanesulfonic acid anhydride (21.0 g) was slowly added dropwise. , 76.0 mmol), dropwise, and reacted at room temperature for 1.0 hour. After the reaction was completed, the reaction was quenched with water (50.0 mL), EtOAc (EtOAc)EtOAc. Agent: PE/DCM (v/v) = 20/1) gave 7.9 g of colorless oil, yield: 95.0%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34 (s, 2H), 6.64-6.61 (m, 2H), 4.12-4.08 (m, 2H), 1.89-1.85 (m, 1H), 1.82-1.78 (m) , 1H)ppm.

Step 4) Synthesis of Compound 21-4

Compound 21-3 (0.44 g, 1.0 mmol), compound 1-7 (0.29 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In a reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected under N ₂ and reacted at 90 ° C for 4.0 hours. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ Detachment: PE / EtOAc (v / v) = 8 / 1) gave 0.25 g of pale yellow liquid, yield: 55.7%.

MS (ESI, pos.) m / z : 449.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.15, 7.13 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.06, 7.04 (s, s, 1H), 6.95-6.91 (m, 1H), 6.63-6.60 (m, 1H), 6.57, 6.55 (s, s, 1H), 5.77 (brs, 1H), 4.40-4.36 (m, 1H), 3.93-3.90 (m, 1H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.31-2.27 (m, 1H), 2.23-2.20 (m ,1H),2.07-2.01(m,1H),1.98-1.92(m,1H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.34-1.28(m,1H),1.25 - 1.19 (m, 1 H) ppm.

Step 5) Synthesis of Compound 21-5

Compound 21-4 (0.22 g, 0.5 mmol), compound 2-7 (0.25 g, 0.5 mmol), potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) were placed In a reaction flask, DME (4 mL) and water (1 mL) were respectively poured under N ₂ and reacted at 90 ° C for 6 hours. After completion of the reaction, EtOAc (50mL) diluted with the reaction solution, washed with saturated brine, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v ) = 1 / 1) 0.2 g of a pale yellow solid was obtained, yield: 59.8%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.63-7.62,7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56,7.55-7.54 (m, m, 2H), 7.41, 7.38 (s, s, 1H), 7.28, 7.25 (s, s, 1H), 7.17, 7.15 (s, s, 1H), 6.96-6.95 (m, 2H), 6.57, 6.55 (s, s, 1H) , 5.32, 5.30 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.33-2.15 (m, 5H), 2.13 -1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.34-1.28 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 6) Synthesis of Compound 21-6

Pyridine (0.3 mL, 4.0 mmol) was added dropwise to a solution of compound 21-5 (0.67 g, 1.0 mmol) in DCM (5.0 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (0.34 mL) , 2.0 mmol) was dropped into the reaction flask, and the mixture was dropped, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc)EtOAc. Detachment: PE / EtOAc (v / v) = 2 / 1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.63-7.62,7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56,7.55-7.54 (m, m, 2H), 7.38, 7.35 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.09, 7.07 (s, s, 1H), 7.03, 7.01 (s, s, 1H), 6.96-6.95 (m, 2H) , 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.51-3.48 (m, 1H), 2.33-2.15 (m, 5H), 2.13 -1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 7) Synthesis of Compound 21-7

Compound 21-6 (0.8 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.45 g of pale yellow solid.

MS (ESI, pos.) m / z : 473.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.63-7.62, 7.61-7.60 (m, m , 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.46, 7.44 (d, d, 2H), 7.28, 7.25 (d, d, 2H), 6.96- 6.95 (m, 2H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.44 - 4.41, 4.39, 4.37 (m, m, m, 3H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 3H), 3.78-3.73 (m, 1H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 2.33-2.15 ( m,8H),2.13-2.03 (m,2H),2.02-1.91 (m,5H),1.72-1.68 (m,1H),1.30-1.24 (m,2H),0.97,0.95 (m,m,6H) ), 0.90, 0.89 (m, m, 6H) ppm.

Example 22

synthetic route:

Step 1) Synthesis of Compound 22-2

Compound 22-1 (11.12g, 138.8mmol) was added dropwise to a solution of phenylhydrazine (10.0g, 92.5mmol) in DCM (50.0mL) at 10 ° C, and the reaction was carried out for 1.0 hour at room temperature and 0.5 hour at room temperature. . After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj

MS (ESI, pos.) m / z : 189.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.71 (d, 2H), 6.20-6.19 (m, 2H), 3.08-3.05 (m, 2H), 2.46-2.44 (m, 2H), 2.30-2.23 (m, 1H), 0.96-0.93 (m, 3H) ppm.

Step 2) Synthesis of Compound 22-3

Compound 22-2 (5.94 g, 31.6 mmol) and sodium acetate (7.77 g, 94.7 mmol) were dissolved in methanol (100 mL), and reacted at 50 ° C for 3.0 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated to give a white solid (yield: 5.5 g).

MS (ESI, pos.) m / z : 189.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.65-6.64 (m, 2H), 6.47 (s, 2H), 5.41 (br) , 2H), 3.76-3.72 (m, 2H), 2.64-2.57 (m, 1H), 1.15-1.12 (m, 3H) ppm.

Step 3) Synthesis of Compound 22-4

The compound 22-3 (5.07 g, 27.0 mmol) and Pd/C (500 mg) were suspended in methanol (50.0 mL), and reacted at room temperature for 1.5 hours under a hydrogen atmosphere at normal pressure. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and purified by recrystallization to yield white solid (yield:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 6.40 (s, 2H), 5.77 (br, 2H), 3.10-3.08 (m, 2H), 2.42-2.34 (m, 1H), 2.08-2.04 (m, 2H ), 1.34-1.30 (m, 2H), 0.90-0.87 (m, 3H) ppm.

Step 4) Synthesis of Compound 22-5

Pyridine (9.0 g, 114 mmol) was added dropwise to a solution of the compound 22-4 (3.61 g, 19.0 mmol) in DCM (90.0 mL), and then, after stirring for 10 min, trifluoromethanesulfonic acid anhydride (21.0 g) , 76.0 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc) /v) = 20/1) gave 8.45 g of colorless oil, yield: 98.0%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.27 (s, 2H), 3.22-3.19 (m, 2H), 2.17-2.10 (m, 1H), 2.03-1.99 (m, 2H), 1.29-1.25 (m , 2H), 1.03-1.01 (m, 3H) ppm. Step 5) Synthesis of Compound 22-6

Compound 22-5 (0.45 g, 1.0 mmol), compound 1-7 (0.29 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: PE / EtOAc (v / v) = 8 / 1) afforded 0.35 g of colorless liquid.

MS (ESI, pos.) m / z : 465.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.11, 7.09 (s, s, 1H), 7.06, 7.05 (s, s, 1H), 7.04, 7.03 (s, s, 1H), 6.57, 6.55 (s, s, 1H), 5.77 (brs, 1H), 3.58-3.54 (m, 1H), 3.53-3.47 (m, 2H), 3.16-3.12(m,1H),2.44-2.37(m,1H),2.06-1.92(m,4H),1.82-1.78(m,1H),1.59-1.55(m,1H),1.31-1.19(m , 4H), 0.86, 0.84 (t, t, 3H) ppm.

Step 6) Synthesis of Compound 22-7

Pyridine (1.29 mL, 16 mmol) was added dropwise to a solution of compound 22-6 (1.86 g, 4.0 mmol) in DCM (5.0 mL), and then, after stirring for 10 min, trifluoromethanesulfonic anhydride (1.35 mL, 8.0 mmol) was dropped into the reaction flask, and the mixture was dropped, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Detachment: PE/EtOAc (v/v) = 2/1) afforded 1.95 g of colorless liquid, yield: 81.7%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.12,7.10 (s, s, 1H), 7.07-7.02 (m, 3H), 3.88-3.85 (m, 1H), 3.51-3.47 (m, 2H), 3.16 -3.12(m,1H),2.44-2.37(m,1H),2.06-1.92(m,4H),1.82-1.78(m,1H),1.59-1.55(m,1H),1.31-1.19(m, 4H), 0.86, 0.84 (t, t, 3H) ppm.

Step 7) Synthesis of Compound 22-8

Compound 22-7 (0.6 g, 1.0 mmol), compound 3-1 (0.88 g, 2.1 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were placed In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.35 g of pale yellow solid.

MS (ESI, pos.ion) m / z: 444.6 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.81 (s, 1H), 7.80 (s, 1H), 7.36,7.35 ( s, s, 1H), 7.34, 7.32 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.24, 7.23 (s, s, 1H), 5.32, 5.30 (d, d, 2H) , 5.29-5.25 (m, 2H), 4.41, 4.39, 4.37 (m, m, m, 2H), 3.85-3.78 (m, 3H), 3.77-3.74 (m, 1H), 3.69-3.64 (m, 2H) ), 3.63(s,6H), 3.52-3.49(m,1H), 3.17-3.13(m,1H), 2.40-2.33(m,1H),2.30-1.89(m,14H),1.87-1.83(m , 1H), 1.64-1.60 (m, 1H), 1.35-1.24 (m, 3H), 1.22-1.16 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.87 (t, 3H) ppm.

Example 23

synthetic route:

Step 1) Synthesis of Compound 23-1

Pyridine (0.32 mL, 4.0 mmol) was added dropwise to a solution of compound 12-4 (0.46 g, 1.0 mmol) in DCM (5OmL), and, after stirring for 10 min, trifluoromethanesulfonic anhydride (0.34 mL) , 2.0 mmol) was dropped into the reaction flask, and the mixture was dropped, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc). Detachment: PE / EtOAc (v / v) = 8 / 1) gave a colorless liquid 0.52 g, yield: 87.2%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.65,7.62 (s, s, 1H), 7.07,7.05 (s, s, 1H), 7.04,7.02 (s, s, 1H), 7.00,6.98 (s, s, 1H), 3.89-3.86 (m, 1H), 3.74-3.71 (m, 1H), 3.65-3.62 (m, 1H), 3.49-3.46 (m, 1H), 2.58-2.51 (m, 1H), 2.48-2.40 (m, 1H), 2.23-2.17 (m, 1H), 2.16-2.05 (m, 2H), 1.98-1.90 (m, 2H), 1.71-1.67 (m, 1H), 1.42-1.36 (m , 1H), 1.25-1.19 (m, 1H) ppm.

Step 2) Synthesis of Compound 23-2

Compound 23-1 (0.6 g, 1.0 mmol), compound 3-1 (0.88 g, 2.1 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were placed In the reaction flask, DME (5.0 mL) and pure water (1.0 mL) were separately injected, and the mixture was treated under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, water (20mL) diluted with the reaction solution, the aqueous layer was extracted with EtOAc (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo purified by column chromatography Separation and purification (eluent: DCM / MeOH (v/v) = 50/1) afforded 0.45 g of pale yellow solid.

MS (ESI, pos.ion) m / z: 443.5 [M + 2H] 2+; 1 H NMR (400MHz, CDCl 3): δ 7.83 (s, 1H), 7.81 (s, 1H), 7.37,7.36 ( s, s, 1H), 7.35, 7.34 (s, s, 1H), 7.28, 7.26 (s, s, 1H), 6.97, 6.95 (s, s, 1H), 6.07, 6.05 (d, d, 1H) , 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 2H), 4.41, 4.39, 4.37 (m, m, m, 1H), 4.33, 4.31, 4.30 (m, m, m, 1H) , 3.95-3.91 (m, 2H), 3.85-3.74 (m, 4H), 3.69-3.65 (m, 2H), 3.64 (s, 3H), 3.63 (s, 3H), 2.56-2.49 (m, 1H) , 2.47-2.40 (m, 1H), 2.30 - 1.92 (m, 15H), 1.76-1.72 (m, 1H), 1.34-1.24 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 24

synthetic route:

Step 1) Synthesis of Compound 24-2

Compound 24-1 (2.1 g, 9.17 mmol) was dissolved in THF (20 mL). After the reaction was completed, the THF was evaporated, EtOAc EtOAc (EtOAc m. , Yield: 72%.

MS (ESI, pos.) m / z : 217 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, 1H, J = 8.0 Hz), 6.96 (d, 1H, J = 1.6 Hz), 6.64 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.

Step 2) Synthesis of Compound 24-3

The compound 24-2 (1.51 g, 7.00 mmol) was dissolved in anhydrous THF (5 mL). CDI (0.83 g, 5.12 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 2.0 hours, then cooled to 0 ° C. Ammonia water (20 mL) was added, and the reaction was completed at room temperature overnight. After completion of the reaction, removed of THF, the residue was extracted with ethyl acetate (100 mL) was dissolved, washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo to give a pale yellow solid 1.2g, yield: 80%.

MS (ESI, pos.ion) m / z: 217 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.

Step 3) Synthesis of Compound 24-4

Compound 24-3 (1.5 g, 7.00 mmol), Compound 24-3-2 (2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in EtOAc (15 mL) Under a nitrogen atmosphere, DIPEA (5.8 mL, 35 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 8.0 hours. After completion of the reaction, the solvent was removed, the residue was added EtOAc (100mL) was dissolved, washed with water and saturated brine, dried over anhydrous Na ₂ SO _4, was purified by column chromatography concentrated in vacuo (eluent: PE / EtOAc (v / v) = 1/3) a colorless transparent oil 0.66 g, yield: 20%.

MS (ESI, pos.) m / z : 470.33 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d, 1H) , J = 8.0 Hz), 7.05 (d, 1H, J = 8.0 Hz), 5.57 (d, 1H, J = 8.0 Hz), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 1H), 3.89 -3.86 (m, 2H), 3.68 (s, 3H), 2.24 - 2.15 (m, 2H), 2.09 - 2.00 (m, 2H), 1.09 (d, 3H, J = 6.0 Hz), 0.97 (d, 3H) , J = 6.0 Hz) ppm.

Step 4) Synthesis of Compound 24-5

The compound 24-4 (0.6 g, 1.28 mmol) was dissolved in THF (10 mL), and the aqueous solution of lithium hydroxide (0.27 g, 6 mL) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature for 5.0 hours. After completion of the reaction, removed of THF, the residue was added EtOAc (50mL), washed with water and saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. Purification by column chromatography (eluent: PE / EtOAc (v / v ) = 1/3) 0.55 g of a white solid was obtained, yield: 96%.

MS (ESI, pos.ion) m / z: 452.33 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 11.31 (s, 1H), 8.07 (d, 1H, J = 8.0Hz), 7.79 (d, 1H, J = 2.0 Hz), 7.53 (dd, 1H, J = 8.0 Hz, 2.0 Hz), 5.78 (d, 1H, J = 8.0 Hz), 5.10 (dd, 1H, J = 8.0 Hz, 2.0 Hz), 4.33 (t, 1H, J = 8.0 Hz), 4.14 - 4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.66 (s, 3H), 2.53-2.51 (m, 1H), 2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.04-1.79 (m, 2H), 0.93 (d, 1H, J = 2.0 Hz) ppm.

Step 5) Synthesis of Compound 24-6

Compound 24-5 (0.2g, 0.44mmol), Pd (dppf) Cl 2. CH ₂ Cl ₂ (0.04 g, 0.049 mmol), anhydrous potassium acetate (0.11 g, 1.12 mmol) and compound 1-6-2 (0.13 g, 0.51 mmol) were mixed in a reaction flask and poured into DMF (5 mL) under nitrogen atmosphere. The reaction was carried out at 80 ° C for 3.0 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (20 mL), and the mixture was filtered and filtered, and then filtered, washed with water (20 mL × 3) and brine, dried over Na ₂ SO ₄ Separation and purification (eluent: PE / EtOAc (v/v) = 2 / 1) afforded pale yellow solid.

MS (ESI, pos.ion) m / z: 499.26 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 11.08 (s, 1H), 8.22 (d, 1H, J = 8.0Hz), 8.11(s,1H), 7.83(d,1H, J =8.0Hz), 5.71(d,1H, J =8.0Hz), 5.17(d,1H, J =6.0Hz), 4.35(t,1H, J = 8.0 Hz), 4.15-4.10 (m, 1H), 3.88-3.86 (m, 1H), 3.67 (s, 3H), 2.71-2.67 (m, 1H), 2.34-2.32 (m, 1H), 2.09- 1.99 (m, 2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H) ppm.

Step 6) Synthesis of Compound 24-7

Compound 24-6 (0.12 g, 0.23 mmol), compound 19-1 (0.11 g, 0.16 mmol), Pd(PPh ₃ ) ₄ (30 mg, 0.03 mmol) and potassium carbonate (60 mg, 0.44 mmol) were mixed in a reaction flask. Under a nitrogen atmosphere, DME (3 mL) and water (1 mL) were separately injected and reacted at 90 ° C for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ and purified by column chromatography (eluent: MeOH/DCM (v/v) = 1/25) gave 98.7 mg of pale yellow solid, yield: 65%.

MS (ESI, pos.) m / z : 475.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.97-7.96 (m, 1H), 7.81 (s, 1H), 7.56 ( d, 2H), 7.47, 7.45-7.44, 7.42 (d, m, d, 2H), 7.39, 7.37 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 5.56, 5.55 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.21-5.15 (m, 1H), 4.41, 4.39, 4.37 (m, m, m, 1H), 4.29 , 4.27, 4.26 (m, m, m, 1H), 4.03-4.01 (m, 1H), 3.85-3.78 (m, 1H), 3.77-3.73 (m, 3H), 3.68-3.67 (m, 1H), 3.66 (s, 3H), 3.63 (s, 3H), 3.51-3.43, 3.42-3.34 (m, m, 2H), 2.50-2.42 (m, 1H), 2.37-1.80 (m, 15H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 25

synthetic route:

Step 1) Synthesis of Compound 25-2

25-1 (1.9 g, 10 mmol) was dissolved in DCM (20 mL). EtOAc (EtOAc m . After the reaction was completed, it was diluted with 20 mL of EtOAc. EtOAc. , yield: 77%

MS (ESI, pos.) m / z : 208.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (d, 1H), 7.11 (d, 1H), 3.43 (s, 3H) ), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H) ppm.

Step 2) Synthesis of Compound 25-3

25-2 (1.6 g, 6.67 mmol) was dissolved in a solution of sodium methoxide (0.54 g, 10 mmol) in methanol 20 mL, and the mixture was heated and refluxed in an oil bath. After 10 h, the reaction was completed, and the solvent was concentrated under reduced pressure. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate

MS (ESI, pos.) m / z : 176.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (d, 1H), 7.11 (d, 1H), 3.8 (s, 3H) ), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H) ppm.

Step 3) Synthesis of Compound 25-4

25-3 (1.3g, 6.31mmol) was dissolved in DCM (20mL), NBS (1.35g, 7.6mmol) was added in portions at room temperature, and the reaction was stirred at room temperature. After 5h, the reaction was completed and 50mL was added. Diluted with DCM, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, dried, and purified by column chromatography (eluent: EA: PE = 1:15) to give white solids: 1.4 g, yield: 87.8%

MS (ESI, pos.) m / z : 255.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88 (d, 1H), 3.8 (s, 3H), 3.56-3.53 (m) , 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H) ppm.

Step 4) Synthesis of Compound 25-5

Compound 1-7 (0.33 g, 1.14 mmol), compound 25-4 (0.32 g, 1.25 mmol), potassium carbonate (0.39 g, 2.84 mmol) and Pd(PPh ₃ ) ₄ (65.7 mg, 0.057 mmol) DME (8.0 mL) and water (2.0 mL) were separately injected into a reaction flask under N ₂ and reacted at 90 ° C for 12 hours. After completion of the reaction, was cooled to room temperature, EtOAc (50mL) After the reaction mixture was diluted, washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 8/1) 0.27 g of a white solid was obtained, yield: 65%.

MS (ESI, pos.) m / z : 334.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (s, 1H), 7.11, 7.09 (s, s, 1H), 6.63 , 6.61 (s, s, 1H), 5.77 (brs, 1H), 3.95 (s, 3H), 3.66-3.58 (m, 2H), 3.43-3.40 (m, 1H), 3.33 - 3.28 (m, 1H) , 2.08-2.02 (m, 1H), 1.98-1.91 (m, 3H), 1.81-1.77 (m, 1H), 1.69-1.65 (m, 1H), 1.58-1.54 (m, 1H), 1.50-1.46 ( m, 1H), 1.25-1.18 (m, 3H), 1.14-1.08 (m, 1 H) ppm.

Step 5) Synthesis of Compound 25-6

Pyridine (0.26 mL, 3.2 mmol) and compound 25-5 (0.27 g, 0.8 mmol) were dissolved in DCM (10 mL) at 0 ° C, stirred for 10 min, then trifluoromethanesulfonic acid anhydride (0.27 mL, 1.6 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, ice-water was added (25mL) The reaction was quenched, the aqueous layer was extracted with DCM (25mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, purified by column chromatography and concentrated (eluent: PE) gave 0.34 g of a colorless oily product, yield: 90.5%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.37 (s, 1H), 7.30,7.28 (s, s, 1H), 7.18,7.16 (s, s, 1H), 3.98-3.96 (m, 1H), 3.95 (s, 3H), 3.61-3.58 (m, 1H), 3.43-3.40 (m, 1H), 3.28-3.25 (m, 1H), 2.08-1.91 (m, 4H), 1.81-1.77 (m, 1H) , 1.69-1.65 (m, 1H), 1.58-1.54 (m, 1H), 1.50-1.46 (m, 1H), 1.29-1.18 (m, 3H), 1.14-1.08 (m, 1H) ppm.

Step 6) Synthesis of Compound 25-7

Compound 25-6 (0.47 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) DME (4.0 mL) and water (1.0 mL) were separately poured into a reaction flask under N ₂ and reacted at 90 ° C for 6.0 hours. After completion of the reaction, was cooled to room temperature, EtOAc (30mL) diluted with the reaction solution, washed with saturated brine, dried over anhydrous Na ₂ SO _4, concentrated in vacuo. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 2/1) 0.5 g of a white solid was obtained, yield: 82%.

MS (ESI, pos.ion) m / z: 610.8 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 8.40 (s, 1H), 7.81 (s, 1H), 7.38,7.36 (s , s, 1H), 7.30, 7.28 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m , m, m, 1H), 3.95 (s, 3H), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 2H), 3.63 (s, 3H), 3.61-3.58 (m, 1H), 3.43 -3.40 (m, 1H), 2.30-2.15 (m, 3H), 2.13-1.88 (m, 6H), 1.86-1.82 (m, 1H), 1.69-1.65 (m, 1H), 1.63-1.59 (m, 1H), 1.50-1.46 (m, 1H), 1.30-1.15 (m, 3H), 1.14-1.08 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) )ppm.

Step 7) Synthesis of Compound 25-8

Compound 25-7 (1.69g, 2.77mmol) was dissolved in DCM (20mL). After -78 deg.] C, was slowly added dropwise BBr ₃ (0.36mL, 3.88mmol), dropwise, at room temperature for 1.0 hr. After the reaction was completed, the reaction mixture was poured into ice water (20 mL), the aqueous layer was extracted with DCM (20 mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ : PE / EtOAc (v / v) = 1 / 1).

MS (ESI, pos.ion) m / z: 596.7 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 8.04 (s, 1H), 7.81 (s, 1H), 7.38,7.36 (s , s, 1H), 7.29, 7.26 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m , m, m, 1H), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 2H), 3.63 (s, 3H), 3.62-3.60 (m, 1H), 3.53-3.51 (m, 1H) , 2.30-2.15(m,3H),2.13-1.88(m,6H),1.86-1.82(m,1H),1.67-1.59(m,2H), 1.48-1.44(m,1H),1.30-1.24( m, 2H), 1.21-1.09 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 8) Synthesis of Compound 25-9

Pyridine (0.25 g, 3.2 mmol) and compound 25-8 (0.48 g, 0.8 mmol) were dissolved in DCM (5.0 mL) at 0 ° C, stirred for 10 min, then trifluoromethanesulfonic anhydride (0.45 g) , 1.6 mmol), dropwise, and reacted at room temperature for 1.0 hour. After completion of the reaction, ice-water was added (10 mL) quenched the reaction, the aqueous layer was extracted with DCM (25mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO _4, purified by column chromatography and concentrated (Eluent: PE / EtOAc (v / v) = 2 / 1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.36 (s, 1H), 7.81 (s, 1H), 7.38,7.36 (s, s, 1H), 7.30,7.28 (s, s, 1H), 5.32,5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m, m, m, 1H), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 3H), 3.63 (s, 3H), 3.51-3.48 (m, 1H), 2.30-2.15 (m, 3H), 2.13-1.88 (m, 6H), 1.86-1.82 (m, 1H), 1.66 -1.59 (m, 2H), 1.47-1.44 (m, 1H), 1.34-1.24 (m, 2H), 1.21-1.09 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 ( m, m, 3H) ppm.

Step 9) Synthesis of Compound 25-11

A mixture of Na ₂ SO ₃ (7.16 g, 56.8 mmol) in ethanol (100 mL) and water (125 mL) was slowly added dropwise to a solution of compound 25-10 (5.0 g, 22.7 mmol) in EtOH (60 mL). The reaction was carried out at 70 ° C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, adjusted to pH 2 with hydrochloric acid (2M), and then concentrated, then brine (100 mL) was added, and the mixture was refluxed until all the residue was dissolved. Water (10 mL) was added, and then the reaction mixture was cooled. At 0 ° C, a solid precipitated. After the solid was completely precipitated, it was filtered to give the product 5.70 g, yield: 89%.

MS (ESI, pos.ion) m / z: 282.5 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 8.75 (br, 1H), 8.31 (m, 1H), 8.07 (m, 2H )ppm.

Step 10) Synthesis of Compound 25-12

The hydrazine chloride (5.0 mL) was added dropwise to a solution of the compound 25-11 (3.0 g, 10.6 mmol) and DMF (1 drop) in toluene (50 mL). After the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. After completion of the reaction, the pH was adjusted to 4 with hydrochloric acid (6M), and the organic layer was separated, dried and concentrated. PE (15 mL) was added to the remaining slurry, and a solid precipitated, which was filtered to give compound 25-12 .

MS (ESI, pos.) m / z : 281.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18, 8.17 (d, d, 1H), 8.03, 8.00 (d, d, 1H), 7.84, 7.81 (d, d, 1H), 5.47 (br, 2H) ppm.

Step 11) Synthesis of Compound 25-13

Compound 25-12 (2.12 g, 7.5 mmol) was dissolved in HI (25.0 mL, 57% aqueous). After the reaction was completed, it was cooled, and the reaction mixture was obtained as a purple-yellow, and then diluted with EtOAc (50 mL), and washed with sodium thiosulfate solution, saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. chromatography (mobile _{phase: CH 3 CN / H 2 O} = 22 / 78-52 / 48 ( containing 0.01% NH ₃ .H ₂ O buffer)) to afford the product 1.86g.

MS (ESI, pos.) m / z : 251.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.60 (m, 1H), 7.18-7.15 (m, 2H), 4.85 (brs, 4H) ppm.

Step 12) Synthesis of Compound 25-14

Triethylamine (4.05 mL, 29.6 mmol) was slowly added dropwise to a solution of compound 25-13 (1.86 g, 7.4 mmol) in acetone (20 mL). Compound 25-10-2 (1.28 g, 4.8 mmol) was added at 0 ° C, and the reaction was carried out at a constant temperature for 5.0 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL), and the pH was adjusted to 4 with hydrochloric acid (2M). The solid was transferred to a reaction flask, and a solution of potassium carbonate (1.5 g, 10.87 mmol) in water (10 mL). After completion of the reaction, the pH was adjusted to 4 with hydrochloric acid (2M), and a solid was precipitated. After filtration, a solid crude product was obtained and washed with water. After separation by high performance liquid chromatography (mobile phase: CH ₃ CN/H ₂ O = 35/65-65/35 (containing 0.75% CF ₃ COOH buffer)), 1.00 g of the product was obtained, yield: 45%.

MS (ESI, pos.) m / z : 464.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m, 1H) , 7.43, 7.41 (d, d, 1H), 7.28-7.22 (m, 5H), 6.30 (brs, 1H), 5.14-5.13 (m, 2H), 4.86-4.80 (m, 1H), 3.68-3.62 ( m, 1H), 3.50-3.43 (m, 1H), 2.22-1.98 (m, 4H) ppm.

Step 13) Synthesis of Compound 25-15

A catalytic amount of Pd / C (0.35g) was added to the compound 25-14 (3.73g, 8.03mmol) in EtOAc (40mL) solution, at 10 atm H ₂ atmosphere, the reaction 40 ℃ 5.0 hours. After completion of the reaction, Pd/C was removed by filtration, and the title compound 25-15 (2.27 g, yield: 86%) was obtained.

MS (ESI, pos.) m / z : 330.5 [M+H] ⁺ .

Step 14) Synthesis of Compound 25-16

Compound 25-15 (3.29 g, 10.0 mmol), Compound 1-18-2 (1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) were dissolved in DCM (30 mL) DIPEA (6.6 mL, 39.9 mmol) was added and the mixture was reacted at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was diluted with DCM (50 mL), washed with water (30 mL×3), brine and brine, dried over anhydrous sodium sulfate / EtOAc (v/v) = 2 / 1) gave product 2.43 g, yield: 50%.

MS (ESI, pos.) m / z : 487.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m, 1H) , 7.43, 7.41 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H), 5.08-5.04 (m, 1H), 4.31-4.26 (m, 1H), 3.63 ( s, 3H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.38-2.31 (m, 1H), 2.10- 1.97 (m, 2H), 1.91-1.71 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H) ppm.

Step 15) Synthesis of Compound 25-17

Compound 25-16 (0.44 g, 0.91 mmol), compound 1-6-2 (0.46 g, 1.82 mmol), Pd (dppf) Cl ₂ . CH ₂ Cl ₂ (71.0 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) were dissolved in DMF (5 mL), and the mixture was reacted at 90 ° C for 3.0 hr under nitrogen atmosphere, and the mixture was diluted with EtOAc (50 mL). . The filtrate was washed with water (20 mL × 3) and brine, dried over anhydrous sodium sulfate, evaporated, evaporated, evaporated. Rate: 88%.

MS (ESI, pos.) m / z : 535.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02 (t, 1H), 7.80, 7.78 (d, d, 1H), 7.46 , 7.44 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H), 5.08-5.04 (m, 1H), 4.31-4.96 (m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.38-2.31 (m, 1H), 2.10- 1.97 (m, 2H), 1.91-1.71 (m, 2H), 1.32, 1.29 (m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H) ppm.

Step 16) Synthesis of Compound 25-18

Compound 25-17 (0.33 g, 0.61 mmol), compound 25-6 (0.44 g, 0.61 mmol), Pd(PPh ₃ ) ₄ (35.3 mg, 0.03 mmol) and potassium carbonate (0.25 g, 1.83 mmol) DME (5 mL) and water (1 mL) were reacted at 90 ° C for 4.0 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the mixture was diluted with EtOAc (50 mL). The product was obtained in an amount of 0.39 g, yield: 65%.

MS (ESI, pos.) m / z : 494.1 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (s, 1H), 8.26 (m, 1H), 8.15, 8.13 ( d,d,1H), 7.81(s,1H),7.55,7.53(s,s,1H),7.39,7.37(d,d,1H),7.34,7.32(s,s,1H),5.56,5.55 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.08-5.02 (m, 1H), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m , m, m, 1H), 4.27, 4.25, 4.23 (m, m, m, 1H), 3.85-3.78 (m, 4H), 3.66 (s, 3H), 3.65-3.64 (m, 1H), 3.63 ( s, 3H), 3.52-3.49 (m, 1H), 3.47-3.39 (m, 1H), 3.38-3.30 (m, 1H), 2.30-2.15 (m, 3H), 2.13-1.81 (m, 13H), 1.68-1.62 (m, 2H), 1.31-1.20 (m, 3H), 1.13-1.07 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93 , 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 26

synthetic route:

Example 26 was prepared according to the synthetic method of Example 1.

Compound ^{26-2: 1 H NMR (400MHz,} CDCl 3): δ 3.99-3.87 (br, 1H), 3.68-3.51 (m, 2H), 3.48-3.39 (m, 1H), 3.34-3.25 (m, 1H ), 2.05-1.92 (m, 2H), 1.88-1.71 (m, 2H), 1.45 (s, 9H) ppm.

Compound 26-3: ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.46 (d, 1H, J = 2.8 Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 2.01-1.93 ( m, 2H), 1.91-1.84 (m, 2H), 1.43 (s, 9H) ppm.

Compound 26-4: MS (ESI, pos.) m / z : 238.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.96 (s, 1H), 4.94 (dd, 1H, J = 7.68 Hz, 2.40 Hz), 3.38 (t, 2H, J = 6.24 Hz), 2.17-2.03 (m, 2H), 1.99-1.91 (m, 2H), 1.48 (s, 9H) ppm.

Compound 26-5: MS (ESI, pos.) m / z : 490.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.89 (dd, 1H, J = 7.64 Hz, 2.52 Hz) , 3.36 (t, 2H), 2.14 - 2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H) ppm.

Compound 26-6: MS (ESI, pos.) m / z : 364.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.04 (d, 1H, J = 1.84 Hz), 4.89 ( Dd, 1H, J = 7.72 Hz, 2.56 Hz), 3.36 (t, 2H), 2.18-2.03 (m, 2H), 1.97-1.82 (m, 2H), 1.47 (s, 9H) ppm.

Compound 26-7: MS (ESI, pos.) m / z : 379.4 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.05-5.00 (m, 2H), 3.77-3.73 (m, 4H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H) ), 2.47-2.38 (m, 2H), 2.28-2.17 (m, 2H), 2.10 - 1.97 (m, 6H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.41 (s, 18H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

Compound 26-8: MS (ESI, pos.ion) m / z: 557 [M + H] +.

Compound 26-9: MS (ESI, pos.) m / z : 436.5 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.56, 5.55 (d, d, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 2H), 4.41-4.37 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.73 (m, 4H), 3.66 (s, 6H), 3.65-3.61 (m, 2H), 2.30 -2.16(m,6H),2.13-1.89(m,8H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.30-1.24(m,2H),1.22-1.16(m, 2H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 27

synthetic route:

Example 27 was prepared according to the synthetic method of Example 2.

Compound 27-1: MS (ESI, pos.) m / z : 264.1 [M+H] ⁺ .

Compound 27-2: MS (ESI, pos.) m/z: 421.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35 (s, 1H), 5.32, 5.29 (brs, brs , 1H), 5.20-5.15 (m, 1H), 4.41-4.37 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 2.28-2.17 (m, 3H), 2.11 - 1.96 (m, 2H), 0.97 - 0.95 (m, 3H), 0.91 - 0.89 (m, 3H) ppm.

Compound 27-3: MS (ESI, pos.) m / z : 412.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78-7.75 (m, 2H), 7.65-7.63 (m) , 2H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12 -2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H) ppm.

Compound 27-4: MS (ESI, pos.) m / z : 392.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78-7.75 (m, 2H), 7.65-7.63 (m) , 2H), 7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31 -2.21 (m, 2H), 2.12 - 2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H) ppm.

Compound 27-5: MS (ESI, pos.) m / z : 292.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76-7.73 (m, 2H), 7.66-7.63 (m) , 2H), 7.21-7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m, 1H), 3.49-3.39 (m, 1H), 2.31 -2.21 (m, 2H), 2.12 - 2.01 (m, 1 H), 1.98 - 1.85 (m, 1 H) ppm.

Compound 27-6: MS (ESI, pos.) m/z: 450.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65-7.60 (m, 2H), 7.47-7.43 (m) , 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88 -0.86 (d, 6H) ppm.

Compound 27-7: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H) ), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.5-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H) ), 2.34 - 2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.32-1.45 (m, 12H), 1.04-1.02 (m, 1H), 0.88 - 0.86 (d, 6H) ppm.

Compound 27-8: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 ( s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.29 (d, d, 1H) , 5.23-5.19 (m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 2H), 3.69-3.64 ( m,1H), 3.63(s,3H), 3.45-3.42(m,1H), 2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.78(m,2H),1.61- 1.55 (m, 2H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 27-9: MS (ESI, pos.) m / z : 781.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61 , 7.60-7.59 (m, m, 4H), 7.58, 7.56 (s, s, 1H), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32 , 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.75-3.71 ( m, 2H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 2.30-2.15 (m, 3H), 2.13-1.90 (m, 6H), 1.84-1.74 (m, 3H), 1.61- 1.53 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 27-10: MS (ESI, pos.) m / z : 474.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60- 7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 ( s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.23 -5.19 (m, 1H), 4.41-4.36 (m, 1H), 4.34-4.30 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.71 (m, 3H), 3.69-3.66 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.30-2.16 (m, 6H), 2.13-1.89 (m, 8H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m , 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 28

synthetic route:

Example 28 was prepared according to the synthetic procedure analogous to Example 3.

Compound 28-1: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (s, 1H), 5.55-5.51 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.41-4.37 (m, 1H) ), 3.78-3.72 (m, 1H), 3.63 (s, 3H), 3.61-3.54 (m, 1H), 2.25-1.87 (m, 5H), 1.39, 1.36 (q, q, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 28-2: MS (ESI, pos.) m / z : 595.7 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (s, 1H), 7.39, 7.37 (s, s , 1H), 7.38, 7.36 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 6.75, 6.72 (s, s, 1H), 5.32-5.28 (m, 2H), 4.41-4.30 ( m, 2H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 3.58-3.54 (m, 1H), 3.50-3.46 (m, 1H), 3.24- 3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.30 - 1.92 (m, 10H), 1.82-1.78 (m, 1H), 1.66-1.55 (m, 2H), 1.26-1.19 (m, 2H) ), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 28-3: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (s, 1H), 7.38, 7.35 (t, t, 1H), 7.26, 7.24 (s, s, 1H), 7.22, 7.21. , s, 1H), 7.20, 7.19 (s, s, 1H), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.88-3.78 (m, 2H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.47-3.44 (m, 1H), 3.24 - 3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.30 - 1.92 (m, 10H), 1.82-1.78 ( m, 1H), 1.66-1.55 (m, 2H), 1.30-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 28-4: MS (ESI, pos.) m / z : 367.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.68 (s, 1H), 7.42-7.40 (m, 1H) ), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H) ppm.

Compound 28-5: MS (ESI, pos.) m / z : 414.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (s, 1H), 7.45-7.43 (m, 1H) ), 7.32-7.30 (m, 1H), 5.12-5.10 (m, 1H), 3.45-3.43 (m, 2H), 2.95-2.94 (m, 1H), 2.25-2.22 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H) ppm.

Compound 28-6: MS (ESI, pos.ion) m / z: 314.2 [M + H] +.

Compound 28-7: MS (ESI, pos.ion) m / z: 485.4 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ 10.62 (brs, 1H), 8.22 (m, 1H), 7.73-7.65 (m, 2H), 5.72 (d, 1H, J = 8.0 Hz), 5.43 (d, 1H, J = 8.0 Hz), 4.35-4.31 (m, 1H), 3.95-3.88 (m, 1H) , 3.78-3.75 (m, 1H), 3.69-3.67 (m, 4H), 3.08-3.04 (m, 1H), 2.43-2.37 (m, 1H), 2.25-2.15 (m, 2H), 1.91 (s, 1H), 1.74-1.72 (m, 1H), 1.52-1.50 (m, 1H), 1.35 (s, 12H), 1.24 (t, 2H, J = 8.0 Hz), 1.12-1.10 (m, 1H), 0.93 -0.88 (m, 1 H) ppm.

Compound 28-8: MS (ESI, pos.) m / z : 468.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.62 7.61, 7.60-7.59 (m, m, 2H), 7.59 (s, 1H), 7.48, 7.46 (s, s, 1H), 7.41, 7.40 (t, t, 1H), 7.23, 7.21 (d, d, 1H), 7.20, 7.19 (s, s, 1H), 5.39, 5.36 (d, d, 1H), 5.32-5.28 (m, 2H), 5.13-5.09 (m, 1H), 4.46-4.30 (m, 3H) ), 3.93-3.90 (m, 1H), 3.85-3.76 (m, 3H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.24 - 3.12 (m, 1H), 2.70-2.57 (m , 2H), 2.42 - 2.34 (m, 1H), 2.30 - 1.86 (m, 14H), 1.84-1.80 (m, 1H), 1.66-1.49 (m, 3H), 1.27-1.10 (m, 3H), 0.98 -0.95 (m, 6H), 0.92 - 0.89 (m, 6H) ppm.

Example 29

synthetic route:

Example 29 was prepared according to the synthetic method of Example 8.

Compound 29-1: ¹ H NMR (400MHz, CDCl ₃ ): δ 7.46, 7.44 (s, s, 1H), 7.40 (s, 1H), 7.36, 7.34 (s, s, 1H), 7.15, 7.13 (s , s, 1H), 6.52, 6.50 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24 - 4.18 ( m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.52-3.50 (m, 1H), 2.40 ( s, 3H), 2.30-2.15 (m, 3H), 2.13-2.03 (m, 1H), 2.01-1.92 (m, 3H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.57 (m, 1H), 1.31-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound ^{29-2: 1 H NMR (400MHz,} CDCl 3): δ 7.46,7.44 (s, s, 1H), 7.40 (s, 1H), 7.36,7.34 (s, s, 1H), 7.11,7.09 (s , s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24 - 4.18 ( m, 2H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 3.49-3.47 (m, 1H), 2.40 ( s, 3H), 2.30-2.15 (m, 3H), 2.13 - 1.92 (m, 4H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.57 (m, 1H), 1.32-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 29-3: MS (ESI, pos.) m/z: 39 </RTI> [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 5.32, 5.30 (d, d) , 1H), 5.29-5.24 (m, 1H), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.65 (m, 1H), 3.63 (s, 3H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.32 (m, 9H) ppm.

Compound 29-4: MS (ESI, pos.) m/z: 319.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 5.35-5.31 (m, 1.5 H), 5.30-5.29 (d, 0.5H, J = 4.0 Hz), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.66 (m, 1H), 3.63 (s, 3H) ), 3.36 (s, 1H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 29-5: MS (ESI, pos.) m/z: 456.1 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62 (s, 1H), 7.56, 7.54 (s, s, 1H), 7.46 (s, 1H), 7.45, 7.43, 7.41 (s, d, s, 2H), 7.29, 7.26 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.51 -5.47 (m, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41, 4.38, 4.36 (m, m, m, 1H), 4.34, 4.31, 4.30 (m) ,m,m,1H),4.24-4.18(m,2H),4.11-4.08(m,1H),3.89-3.78(m,2H),3.73-3.67.(m,2H),3.66(s,3H ), 3.65 (s, 3H), 3.58-3.55 (m, 1H), 2.37 (s, 3H), 2.32-1.90 (m, 12H), 1.82-1.68 (m, 3H), 1.59-1.55 (m, 1H) ), 1.34-1.17 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 30

synthetic route:

Example 30 was prepared according to the synthetic procedure analogous to Example 21.

Compound ^{30-1: 1 H NMR (400MHz,} CDCl 3): δ 7.63-7.62,7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-756,7.55-7.54 (m, m, 2H), 7.41, 7.38 (s, s, 1H), 728, 7.25 (s, s, 1H), 7.17, 7.15 (s, s, 1H), 6.96-6.95 (m, 2H), 6.57, 6.55 (s , s, 1H), 5.32, 5.30 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H) ), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.33-2.15 (m ,5H),2.13-1.92 (m,4H),1.90-1.86 (m,1H),1.67-1.63 (m,1H),1.34-1.28 (m,1H),1.25-1.19 (m,1H),0.97 , 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound ^{30-2: 1 H NMR (400MHz,} CDCl 3): δ 7.63-7.62,7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56,7.55-7.54 (m, m, 2H), 7.38, 7.35 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.09, 7.07 (s, s, 1H), 7.03, 7.01 (s, s, 1H), 6.96-6.95 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H) ), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.51-3.48 (m, 1H), 2.33-2.15 (m ,5H),2.13-1.92 (m,4H),1.90-1.86 (m,1H),1.67-1.63 (m,1H), 1.38-1.32 (m,1H),1.25-1.19 (m,1H),0.97 , 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 30-3: MS (ESI, pos.) m / z : 473.6 [M+2H] ²⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.63-7.62, 7.61 7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.46, 7.44 (d, d, 2H), 7.28, 7.25 (d, d, 2H), 6.96-6.95 (m, 2H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.37 (m , m, m, 3H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 3H), 3.78-3.73 (m, 1H), 3.69-3.64 (m, 2H), 3.63 (s, 6H) , 2.33-2.15 (m, 8H), 2.13 - 2.03 (m, 2H), 2.02-1.91 (m, 5H), 1.72-1.68 (m, 1H), 1.30-1.24 (m, 2H), 0.97, 0.95 ( m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Biological activity

To verify the effect of the compounds described herein on HCV, the inventors used the HCV Replicon System as an evaluation model. The HCV replicon was first reported in Science. 1999 Jul 2; 285 (5424) , 110-3. The HCV replication system has become one of the most important tools for studying HCV RNA replication, pathogenicity and viral persistence, for example, the replicon has been used to successfully demonstrate the minimum 5'-NCR region required for HCV RNA replication, and HCV The replication subsystem has been successfully used as an evaluation model for antiviral drugs. The inventors of the present invention are in accordance with the methods described in Science. 1999 Jul 2; 285 (5424) , 110-3, and J. Virol. 2003 Mar; 77(5) , 3007-19 (hereby incorporated by reference) authenticating.

Briefly, the inventors tested the compounds described herein using human hepatoma cell line Huh-7, which stably transfects the HCV genotype GT1a, GT1b or GT2a replicons, respectively, and were resistant to Y93H, L31F, P32L, and I302V, respectively. Mutants and wild-type HCV 1b were tested for the compounds described herein. The HCV replication system used herein comprises the G418 resistance gene NEO and the luciferase reporter gene, and the level of replication of HCV in the host cell can be characterized by the expression level of the NEO gene or the expression level of the luciferase gene. Furthermore, the effects of the compounds described herein on HCV viral replication can be assessed. In this context, the expression level of the NEO gene is detected by an instant quantitative polymerase chain reaction (qPCR) assay, and the expression level of the luciferase gene is detected by chemiluminescence.

Introduction to the operation process: 1. Determination of compound EC based on luciferase activity ₅₀ :

Huh-7 cells transfected with the HCV replication system were seeded in 96-well plates containing 8000 cells per well. The compounds described herein were each subjected to a 5-fold gradient dilution to give 10 concentration gradients. The compounds described herein were added to wells containing Huh-7 cells transfected with the HCV replication system and incubated for 72 hours in a carbon dioxide incubator. 40 μl of luciferase luminescent substrate Bright-Glo (Promega) was added to the wells, and after 5 minutes, it was detected by a chemiluminescence detection system Topcount microplate flash luminescence counter, and determined by GraphPad Prism software, respectively. EC ₅₀ (concentration for 50% of maximal effect) of each compound. Herein, two batches of experiments were performed for each compound, and wells in which no compound was added were set as a negative control.

2. qPCR detection of antibiotic G418 resistance gene NEO gene determination compound EC ₅₀ :

Huh-7 cells transfected with the HCV replication system were seeded in 96-well plates containing 8000 cells per well. The compounds described herein were each subjected to a 5-fold gradient dilution to give 10 concentration gradients. The compounds described herein were added to wells containing Huh-7 cells transfected with the HCV replication system and incubated for 72 hours in a carbon dioxide incubator. The expression level of the NEO gene was determined by qPCR reaction, and the EC ₅₀ (concentration for 50% of maximal effect) of each compound was determined using GraphPad Prism software, respectively. Herein, two batches of experiments were performed for each compound, and wells in which no compound was added were set as a negative control.

3. Results

_50, the compounds described herein can be determined can be effectively suppressed based on the previously determined EC HCV genotype 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a. Among them, the EC ₅₀ range for HCV genotype 1b is 1 pm to 99 nM. Table 2 provides representative compounds of the present invention is directed to the content of ₅₀ values (nM) EC HCV 1a and HCV 1b genotype, EC ₅₀ values are based on the luciferase activity determined.

Based on the experimental results of Y93H, L31F, P32L, I302V resistant mutants and wild-type HCV 1b, the results of molecular modeling and computer-aided design analogy demonstrate that the compounds of the present invention play a role in inhibiting the mechanism of HCV NS5A protein. Superior anti-HCV effect.

It is obvious to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, and may be embodied in other specific forms without departing from the essential characteristics. The present embodiments are to be considered in all respects as illustrative and not restrictive All changes within the scope are included in this article.

The compounds of the present invention may inhibit HCV by a mechanism other than or in addition to NS5A inhibition. In one embodiment, a compound of the invention inhibits HCV replicon, and in another embodiment, a compound of the invention inhibits NS5A. The compounds of the present invention inhibit multiple genotypes of HCV.

In the description of the present specification, reference is made to the terms "one embodiment", "some embodiments", The description of the "examples", "specific examples" or "some examples" and the like are intended to be included in the particular features, structures, materials or features described in connection with the embodiments or examples. In the present specification, the schematic representation of the above terms does not necessarily mean the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.

Although the embodiments of the present invention have been shown and described, it is understood that the foregoing embodiments are illustrative and not restrictive Variations, modifications, substitutions and variations of the above-described embodiments are possible within the scope of the invention, and the scope of the invention is defined by the scope of the claims and the equivalents thereof.

Claims (64)

a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, or a compound of the formula (I). A pharmaceutically acceptable salt or prodrug: Wherein each of A and A' is independently a bond, an alkylene group, an alkenylene group, a cycloalkylene group, a heterocycloalkylene group, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, - (CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ ) -C(=O)-O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Wherein each X ¹ , X ^{1 '} or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; Is a carbocyclic or heterocyclic group; W ₂ is a fused bicyclic group or a fused heterobicyclic group; each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b - Each a and b are independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0, 1, 2 or 3; each p is independent Ground is 0, 1, 2 or 3; each r is independently 0, 1 or 2; each f and f' is independently 0, 1, 2, 3 or 4; e is 0, 1, 2, 3 or 4 Each X and X' is independently N or CR ⁷ ; each Y and Y' is independently H, oxime, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl An optical, alpha-amino acid group or an optical isomer of an a-amino acid group, or each Y and Y' is independently the structural unit: -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )- (CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² Or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ^12; each U is independently -C (= O) -, - C (= S) -, - S (= O) - or -S (= O) ₂ -; each t is independently 2, 3 or 4; each k is independently 0, 1 or 2; each R ^1, R ^2, R ³ and R ⁴ are independently H, deuterium, alkyl, heteroalkyl, aralkyl group , cycloalkyl, heterocyclyl, heteroaryl or aryl; or R ¹ , R ² and X-CH arbitrarily form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; or R ³ , R ⁴ and X'-CH optionally form a 3-8 membered heterocyclic ring or 3-8 members. a carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; each R ^{5 is} independently H, hydrazine, hydroxy, alkyl, Heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=O)-, alkyl-C(=O)-, carbamidine , alkyl-OS(=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl; each R ^5a and R ^5a' independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O )NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ¹³ , -N(R ¹³ ) C(=O)-R ¹³ , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC( =O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, Alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, hetero Arylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl Sulfhydryl, alkyl decyloxy, alkoxy fluorenyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy a heterocyclylamino or aryloxy group; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)- , R ¹³ R ¹³ aNS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ ^{-, R 13 S (= O} ) 2 -, aliphatic, halogenated aliphatic, aliphatic hydroxyl, aliphatic amino group, an aliphatic alkoxy Alkylamino aliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclic aliphatic,cycloalkylaliphatic,aryloxyaliphatic,heterocyclicoxyaliphatic,cycloalkane Alkoxy aliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; each R ^{6a is} independently H, hydrazine, Hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O )-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl , R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy, R ¹³ R ^13a NC(=O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, nitro, Aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy Heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylalkyl, alkyloxy, alkoxy Alkyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylamino or aryloxy Each of R ⁷ and R ^{7a is} independently H, hydrazine, F, Cl, Br, I, aliphatic, heteroalkyl, halogenated aliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylamino Aliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclylaliphatic,cycloalkylaliphatic,aryloxyaliphatic,heterocyclyloxyaliphatic,cycloalkyloxy a base aliphatic, an arylamino aliphatic, a heterocyclic amino aliphatic, a cycloalkylamino aliphatic, an aryl, a heteroaryl, a heterocyclic or a carbocyclic group; each of R ⁸ and R ^{8a is} independently H, 氘, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl - OC(=O)-, alkyl-C(=O)-, carbachol Alkyl group -OS (= O) _r -, alkyl -S (= O) _r O-, alkyl -S (= O) _r - sulfo or amino acyl; each of R ^9, R ^9a, R ¹⁰ and R ¹¹ independently H, anthracene, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclyl An alkyl or cycloalkylalkyl group; each R ^{12 is} independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N( R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; R ¹¹ , R ¹² and the atom to which it is attached may form a 4-7 membered ring; and each of R ¹³ and R ^{13a is} independently H, oxime, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl a heteroaryl or aralkyl group; when R ¹³ and R ^13a are bonded to the same nitrogen atom, R ¹³ , R ^13a and a nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a thick Double ring Wherein each of the following groups: alkylene, alkenylene, cycloalkylene, ^{heterocycloalkylene, - (CR 8 R 8a)} n -O- (CR 8 R 8a) p -, - (CR 8 R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O )-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O) -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(= S)-(CR ⁸ R ^8a ) _p -, -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t - N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² , -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-( CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² , NR ⁶ , CR ⁷ R ^7a , CR ⁷ , -(CH ₂ ) _a - , -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b -, -(CH ₂ ) _a -O-(CH ₂ ) _b -, R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ¹³ OS(=O) ₂ -, alkyl-OC(=O)-, alkyl-C(=O)-, alkyl-OS(=O) _r -, alkyl-S (= O) _r O-, alkyl-S(=O) _r -, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ aR ¹³ N-alkyl, R ¹³ S(=O)-alkyl, R ¹³ R ^13a NC(=O)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=O)-alkoxy , R ¹³ R ^13a NC(=O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a-amino acid group, C _5-12 fused bicyclic, C _5-12 fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclo, alkoxy, aliphatic, halogenated aliphatic, hydroxyaliphatic, amino fat Groups, alkoxy aliphatics, alkylamino aliphatics, alkylthio aliphatics, aryl aliphatics, heteroaryl aliphatics, heterocyclic aliphatics, cycloalkyl aliphatics, Oxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic,cycloalkylaminoaliphatic,haloalkyl,alkenyl,alkynyl,aryl Amino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, hetero A cycloalkoxy group, a heterocyclylamino group, a heterocyclylalkylamino group or an aryloxy group may be optionally selected from one or more selected from the group consisting of hydrazine, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkane. Oxyl, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy substituted alkane Oxyl, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy substituted Substituted by a substituent of an alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ - or carboxyalkoxy group. The compound of claim 1, wherein Is a C _3-8 carbocyclic group or a C _2-10 heterocyclic group; and W ₂ is a C _5-12 fused bicyclic group or a C _5-12 fused heterocyclic group. The compound of claim 1, wherein The structural unit is the following substructure: The structural unit is the following substructure: Wherein each X ^{3 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ⁴ and X ^{5 is} independently O, S, NR ⁶ , C(=O) Or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each Q ^{3 is} independently N or CR ⁷ ; e is 0, 1, 2, 3 or 4; each i is independently 0, 1, 2, 3 or 4; each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, Cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(= O) NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorene , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyl acyl group, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl group, -CF _3, -OCF _3, mercapto, nitro, C _1-6 alkyl Group, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ is independently hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkane , C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy Alkyl C _1-6 alkyl, C _{2-10heterocyclyloxy} C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 Alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2 a -10} heterocyclic group or a C _3-10 carbocyclic group; each of R ⁷ and R ^{7a is} independently H, fluorene, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _{6 -10} aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 Alkyl, C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _{a 1-9heteroaryl} group, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heterocycloalkane a C _3-10 cycloalkyl group, a C _2-10 heterocyclic group, a C _6-10 aryl group, a C _1-9 heteroaryl group or a C _6-10 aryl C _1-6 alkyl group; when R ¹³ and R ^{13a is} attached to the same nitrogen atom, and R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring. The compound of claim 1, wherein The structural unit is the following substructure: Independently the following substructures: Wherein each of Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CH; each f is independently 0, ¹ , ² , 3 or 4; each R ^5a and R ^{5a' is} independently H,氘, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C( =O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl Mercapto, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl, C _1-6 alkyl sulfonyl, C _1-6 alkoxy sulfonyl, C _1-6 alkyl Sulfosyl, C _1-6 alkylsulfonyloxy, C _1-6 alkylsulfinyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl a group, -CF ₃ , -OCF ₃ , fluorenyl, nitro or C _1-6 alkylamino; each R ^{6 is} independently hydrogen, deuterium, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O) -, R ¹³ C(=O)-, R ¹³ R ¹³ aNS(=O)-, R ¹³ OS(=O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkane group, C _1-6 alkoxy C _1-6 alkyl group C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _{1- a 6} alkyl group, a C _2-10 heterocyclic group C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 Alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _{1 -6} alkyl; or a 3-8 membered ring when R ¹³ and R ^13a attached to the same nitrogen atom, R ^13, R ^13a, and the nitrogen atom optionally form a substituted or unsubstituted, fused bicyclic or spiro bicyclic. The compound of claim 1, wherein each of A and A' is independently a bond, a C _1-6 alkylene group, a C _2-6 alkenylene group, a C _3-8 cycloalkylene group, C _2-10 heterocycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-N (R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=O) _r -N( R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O)-O-(CR ⁸ R ^8a ) _p -, or each A and A 'Independently the following groups: Wherein each X ¹ , X ^{1 '} or X ^{2 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; t is 0, 1, 2, 3 or 4; each Y ¹ and Y ^{2 is} independently N or CR ⁷ ; Z is -(CH ₂ ) _a -, -CH=CH-, -N=CH-, -(CH ₂ ) _a -N(R ⁵ )-(CH ₂ ) _b - or -(CH ₂ ) _a -O-(CH ₂ ) _b -; each a and b are independently 0, 1, 2 or 3; each c is independently 1 or 2; each d is independently 1 or 2; each n is independently 0 , 1, 2 or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkane , C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl- OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently Hydrogen, hydrazine, R ¹³ R ^13a NC(=O)-, R ¹³ OC(=O)-, R ¹³ C(=O)-, R ¹³ R ^13a NS(=O)-, R ¹³ OS(=O )-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 Alkyl, C _{1-9heteroaryl} C _1-6 alkyl, C _{2-10heterocyclyl} C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryl Oxy C _1-6 alkyl, C _2-10 heterocyclooxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _{1- 6} alkyl, C _2-10 heterocyclylamino C _1-6 alkyl, C _3-10 cycloalkylamino C _1-6 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _{2-10heterocyclyl} or C _3-10 carbocyclyl; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, R ^13a R ¹³ NC _1-6 alkyl, R ¹³ S(=O)-C _1-6 alkyl, R ¹³ R ^13a NC(= O)-C _1-6 alkyl, R ^13a R ¹³ NC _1-6 alkoxy, R ¹³ S(=O)-C _1-6 alkoxy, R ¹³ R ^13a NC(=O)-C _{1 -6} alkoxy, C _6-10 aryl, C _1-9 heteroaryl, C _1-6 alkoxy, C _1-6 alkyl Group, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl group, a mercapto group, a nitro group , C _6-10 aryl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino or C _6-10 aryloxy; each R ⁷ and R ^{7a are} independently H, 氘, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1- 6} alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl , C _2-10 heterocyclyl C _1-6 alkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _6-10 aryloxy C _1-6 alkyl, C _2-10 heterocyclic Oxy C _1-6 alkyl, C _3-10 cycloalkyloxy C _1-6 alkyl, C _6-10 arylamino C _1-6 alkyl, C _2-10 heterocyclylamino C _1-6 An alkyl group, a C _3-10 cycloalkylamino C _1-6 alkyl group, a C _6-10 aryl group, a C _1-9 heteroaryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; R ¹³ and R ^{13a are} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1-9heteroaryl} or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and a nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; and each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F , Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 Aryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O) -,carbamoyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - sulfo or amino acyl; The compound of claim 1, wherein each of A and A ^{' is} independently a bond, -CH ₂ -, -(CH ₂ ) ₂ -, -CH=CH-, -CH=CH-CH ₂ -, -N(R ⁵ )-, -C(=O)-, -C(=S)-, -C(=O)-O-, -C(=O)N(R ⁵ )-,- OC(=O)N(R ⁵ )-, -OC(=O)O-, -N(R ⁵ )C(=O)N(R ⁵ )-, -(R ⁵ )NS(=O) ₂ -, -S(=O) ₂ -, -OS(=O) ₂ -, -(R ⁵ )NS(=O)-, -S(=O)-, -OS(=O)-, or each A and A ^{' are} independently the following groups: Wherein X ¹ is O or S; Y ¹ is N or CH; t is 0, 1, 2 or 3; each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 hetero Alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS (=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ^{6 is} independently hydrogen, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _{2 a -10} heterocyclic group or a C _3-8 carbocyclic group; each R ^{6a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R ^13a R ¹³ N-, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, fluorenyl or nitro And each of R ¹³ and R ^{13a is} independently H, 氘, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 alkyl; when R ¹³ and R ^{13a are} attached to the same nitrogen atom, R ¹³ , R ^13a and the nitrogen atom A substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring may be optionally formed. The compound of claim 1, wherein each of R ¹ , R ² , R ³ and R ^{4 is} independently H, C _1-8 alkyl, C _1-8 heteroalkyl, C _6-10 Aryl C _1-6 alkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _1-9 heteroaryl or C _6-10 aryl, or R ¹ , R ² and X-CH Optionally forming a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclo ring or a C _5-12 spiro bicyclo ring; R ³ , R ⁴ and X′-CH optionally form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, a C _5-12 fused bicyclic ring, a C _5-12 fused heterobicyclic ring, a C _5-12 spiro bicyclic ring or a C _{5 -12} spiro double ring. The compound of claim 7, wherein R ¹ , R ² and X-CH, or R ³ , R ⁴ and X′-CH may optionally form a 3-8 membered heterocyclic ring, C _5-12 fused. Bicyclic, C _5-12 fused heterobicyclic, C _5-12 spiro bicyclic or C _5-12 spiro bicyclic. The compound of claim 7, wherein the heterocyclic or fused ring or spiro ring system formed by R ¹ , R ² and YX-CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _{6 -10} aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4. The compound of claim 7, wherein the heterocyclic or fused ring or spiro ring system formed by R ³ , R ⁴ and Y′-X′-CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino, C _1-3 alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy , C _{1-9heteroaryl} C _1-3 alkyl or C _2-10 heterocyclyl; each R ^{6 is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} -hydroxyalkyl, C _1-3 aminoalkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, C _1-3 alkylthio C _{1- a 3-} alkyl group, a C _6-10 aryl C _1-3 alkyl group, a C _1-9 heteroaryl group, a C _6-10 aryl group, a C _2-10 heterocyclic group or a C _3-8 carbocyclic group; n ₁ and n _{2 are} independently ₁ , ₂ , 3 or 4. The compound of claim 1, which has the structure shown in formula (II): among them, The structural unit is the following substructure: Independently for the following substructure: Each Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; each Q ^{3 is} independently N and CH; each X ^{3 is} independently O, S , NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; each X ^{1 is} independently O, S, NR ⁶ or CR ⁷ R ^7a ; e is 0, 1, 2, 3 or 4; Independently 0, 1, 2, 3 or 4; each f and f' is independently 0, 1, 2, 3 or 4; each X ⁴ and X ^{5 is} independently O, S, NR ⁶ , C (= O) or CR ⁷ R ^7a ; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each A and A' is independently a bond, C _1-6 alkylene, C _2-6 alkenylene, C _3-8 cycloalkylene, C _2-10 heterocycloalkyl, -(CR ⁸ R ^8a ) _n -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - , -(CR ⁸ R ^8a ) _n -C(=O)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O )-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-O-( ^C R ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a _n - N(R ⁵ )-S(=O) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=O) _r -O-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=O)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=O ) -O-(CR ⁸ R ^8a ) _p -, or each A and A' are independently the following groups: Each R ^{5 is} independently H, hydrazine, hydroxy, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl- C(=O)-, carbamethyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl- S(=O) _r - or aminosulfonyl; each R ^5a , R ^{5a '} and R ^{6a are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyanide Base, R ^13a R ¹³ N-, -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O )NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S (=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a )-, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl , C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy, C _1-6 alkane Isosulfonyloxy, C _1-6 alkoxy, C _1-6 alkyl, C _6-10 aryl, -CF ₃ , -OCF ₃ , fluorenyl, nitro, C _1-6 alkylamino, C _3-10 cycloalkyl or C _6-10 aryl group; each R ⁶ Site hydrogen, ^{deuterium, R 13 R 13a NC (=} O) -, R 13 OC (= O) -, R 13 C (= O) -, R 13 R 13a NS (= O) -, R 13 OS ( =O)-, R ¹³ S(=O)-, R ¹³ R ^13a NS(=O) ₂ -, R ¹³ OS(=O) ₂ -, R ¹³ S(=O) ₂ -, C _1-6 Aliphatic, C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _1-9 heteroaryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, a C _2-10 heterocyclic group or a C _3-10 carbocyclic group; each of R ⁷ and R ^{7a is} independently H, 氘, F, Cl, Br, I, C _1-6 aliphatic, C _2-6 heterocycloalkane , C _1-6 alkoxy C _1-6 aliphatic, C _1-6 alkylamino C _1-6 aliphatic, C _6-10 aryl C _1-6 aliphatic, C _2-10 heterocyclic C _1-6 aliphatic, C _3-10 cycloalkyl C _1-6 aliphatic, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclic or C _3-10 carbocyclyl Each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, cyano, nitro, F, Cl, Br, I, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 ring Alkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkyl-OC (= O)-, C _1-6 alkyl-C(=O)-, carbamethyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or aminosulfonyl; each R ¹³ and R ^{13a are} independently H, 氘, C _1-6 alkyl, C _2-6 heteroalkane a C _3-10 cycloalkyl group, a C _2-10 heterocyclic group, a C _6-10 aryl group, a C _1-9 heteroaryl group or a C _6-10 aryl C _1-6 alkyl group; when R ¹³ and R ^{13a is} attached to the same nitrogen atom, and R ¹³ , R ^13a and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, spirobicyclic or fused bicyclic ring; each n is independently 0, 1, 2 or 3; each p is independently 0, 1, 2 or 3; each r is independently 0, 1 or 2; t is 0, 1, 2, 3 or 4; and each Y ₄ and Y ₄ 'is independently one Key, O, S, -(CH ₂ ) _n -, -CH=CH-, -S(=O) _r -, -CH ₂ O-, -CH ₂ S-, -CF ₂ -, -CHR ^5a - , -CR ^5a R ^6a , -CH ₂ S(=O) _r or -CH ₂ N(R ⁶ )-. The compound of claim 11, which has the structure shown in formula (III): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently NR ⁶ , O, S, C(=O) or (CR ⁷ R ^7a ) _i ; each X ³ and X ^{5 is} independently O, S , NR ⁶ , C (=O) or (CR ⁷ R ^7a ) _e ; and each of i and e are independently 0, 1, 2, 3 or 4. The compound of claim 11, which has the structure shown in formula (IV): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or ( CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; and each i and e are independently 0, 1, 2, 3 or 4. The compound of claim 11, which has the structure shown in formula (V): Wherein each of Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; each X ³ and X ^{5 is} independently O, S, NR ⁶ , C (=O) Or (CR ⁷ R ^7a ) _e ; and each i and e are independently 0, 1, 2, 3 or 4. The compound of claim 11, which has the structure shown in formula (VI): Wherein Q ⁴ is O, S, C(=O), NR ⁶ or (CH ₂ ) _i ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ Is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; and each i and e are independently 0, 1, 2, 3 or 4. The compound of claim 1, wherein each Y and Y' is independently an α-amino acid group. The compound according to claim 16, wherein the α-amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, guanidine Acid, alanine, aspartame, aspartic acid, glutamic acid, glutamine, valine, serine, tyrosine, arginine, histidine, cysteine, glycine, Creatine, N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine a group formed by tyrosine or hydroxyproline. The compound of claim 17, wherein the α-amino acid in the α-amino acid group is in the D configuration. The compound of claim 17, wherein the α-amino acid in the α-amino acid group is in the L configuration. The compound according to any one of claims 1 to 15, wherein each of Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² or -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 20, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U -(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 21, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound according to claim 21, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 21, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _{t k} -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 24, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t - U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 24, wherein each Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 25, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t - C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 24, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t - R ¹² . The compound of claim 28, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t - C(=O)-R ¹³ . The compound of claim 29, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-R ¹³ . The compound of claim 28, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _t - C(=O)-OR ¹³ . The compound of claim 31, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-C(=O)-OR ¹³ . The compound of claim 20, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 33, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 20, wherein each Y and Y' is independently -[U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U -(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 35, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 36, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _t - C(=O)-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 35, wherein each Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 38, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -O-(CR ⁹ R ^9a ) _t -R ¹² . The compound of claim 20, wherein each Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-R ¹² , wherein R ¹¹ , R ¹² and the atoms attached thereto can form a 4-7 membered ring. The compound of claim 20, wherein each of R ⁹ , R ^9a , R ¹⁰ and R ^{11 is} independently H, hydrazine, C _1-6 alkyl, C _2-6 heteroalkyl, C _{3 -10} cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 haloalkyl, C _{a 1-6} hydroxyalkyl group, a C _1-9 heteroaryl C _1-6 alkyl group, a C _2-10 heterocyclic C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; R ^{12 is} independently R ^13a R ¹³ N-, -C(=O)R ¹³ , -C(=S)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , -OC(=O)NR ¹³ R ^13a , -OC(=O)OR ¹³ , -N(R ¹³ )C(=O)NR ¹³ R ^13a , -N(R ¹³ )C(=O)OR ^13a , -N(R ¹³ )C(=O)-R ^13a , R ¹³ R ^13a NS(=O) ₂ -, R ¹³ S(=O) ₂ -, R ¹³ S(=O) ₂ N(R ^13a -, R ¹³ OS(=O) ₂ -, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl , C _{1-9heteroaryl} or C _6-10 aryl C _1-6 alkyl; or R ¹¹ , R ¹² and the atom attached thereto may form a 4-7 membered ring; each R ¹³ and R ^13a independently Is H, 氘, C _1-6 alkyl, C _2-6 heteroalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl or C _6-10 aryl C _1-6 Group; R ¹³ and R ^13a when attached to the same nitrogen atom, R ^13, R ^13a, and the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, fused bicyclic or spiro bicyclic; each t is independently 0, 1, 2, 3 or 4; and each k is independently 0, 1 or 2. The compound of claim 41, wherein each of R ⁹ , R ^9a , R ¹⁰ and R ^{11 is} independently H, hydrazine, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or Phenyl; each R ^{12 is} independently -C(=O)R ¹³ , -C(=O)-OR ¹³ , -C(=O)NR ¹³ R ^13a , methyl, ethyl, propyl, phenyl , cyclohexyl, morpholinyl or acridinyl; or R ¹¹ , R ¹² and the atom to which it is attached may form a 4-7 membered ring; and each of R ¹³ and R ^{13a is} independently H, hydrazine, methyl, or Base, propyl, phenyl, cyclohexyl, morpholinyl or acridinyl. The compound of claim 11, which has the structure shown in formula (VII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl , C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 An alkyl group, a C _2-10 heterocyclic C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, C _6-10 Aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl C _1-6 alkyl It may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano. The compound of claim 11, which has the structure shown in formula (VIII): Wherein each of R ¹⁴ and R ^{14a is} independently H, hydrazine, C _1-3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, three Fluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl; wherein said C _1-3 hydroxy Alkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, pyridazine The group, cyclopentyl, cyclopropyl, cyclohexyl or C _1-9 heteroaryl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano. The compound according to claim 1, which has a structure represented by the formula (IX): Wherein each of Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; i is 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independent The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{2 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group. The compound according to claim 1, which has a structure represented by the formula (X): Wherein each of Q ¹ and Q ^{2 is} independently a bond, NR ⁶ , O, S, C(=O) or (CH ₂ ) _i ; i is 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independent The ground is H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl , C _2-10 heterocyclic group, C _3-8 cycloalkyl group, C _6-10 aryl C _1-6 alkyl group, C _1-9 heteroaryl C _1-6 alkyl group, C _2-10 heterocyclic ring a C _1-6 alkyl group or a C _3-8 cycloalkyl C _1-6 alkyl group; and each n _{1 is} independently 1, 2, 3 or 4; wherein said C _1-6 alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _2-10 heterocyclyl, C _3-8 naphthenic , C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl or C _3-8 cycloalkyl The C _1-6 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, a hydroxyl group, and a cyano group. The compound of claim 1, which has the structure shown in formula (XI): Wherein each R ^5a and R ^{5a' is} independently H, oxime, oxo (=O), benzyl, C _1-4 alkyl, F, Cl, Br or I; each R ¹⁴ and R ^{14a are} independently H, 氘, C _1-4 alkyl, C _6-10 aryl, C _2-10 heterocyclyl or C _3-8 cycloalkyl; each R ¹⁶ and R ^{16a are} independently hydroxy, C _1-4 alkane a oxy group, a C _6-10 aryloxy group, a C _2-10 heterocyclic group or a C _3-8 cycloalkyl group; wherein the benzyl group, the C _1-4 alkyl group, the C _6-10 aryl group, C _2-10 heterocyclyl, C _1-4 alkyloxy, C _3-8 cycloalkyl, C _6-10 aryloxy may be optionally selected from one or more selected from the group consisting of ruthenium, F, Cl, Substituted by a substituent of Br, a hydroxyl group or a cyano group; The structural unit is of the following substructure: Independently the following groups: Each A and A' is independently the following group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures: The compound of claim 47, wherein each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I And each R ¹⁴ and R ^{14a are} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each R ¹⁶ and R ^{16a are} independently Hydroxyl, methoxy, ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano. The compound according to claim 1, which has a structure represented by the formula (XII): Wherein each of Q ¹ , Q ² , Q ⁴ and Q ^{5 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; each f and f′ is independently 0, 1, 2, 3 or 4 Each X ³ and X ^{5 is} independently O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; e is 0, 1, 2, 3 or 4; each R ^5a and R ^5a' Independently H, hydrazine, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' is} independently N or CR ⁷ ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, Phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each of R ¹⁶ and R ^{16a is} independently hydroxy, methoxy, ethoxy, phenoxy, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl group may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently a group : A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures: The compound according to claim 1, which has a structure represented by formula (XIII): Wherein each of Q ¹ , Q ² and Q ^{4 is} independently O, S, C(=O), NR ⁶ or CH ₂ ; X ³ is O, S, NR ⁶ , C(=O) or (CR ⁷ R ^7a ) _e ; X ⁴ is O, S, NR ⁶ , C(=O) or CR ⁷ R ^7a ; each R ⁶ , R ⁷ and R ^{7a are} independently hydrogen, deuterium, methyl, ethyl, isopropyl , phenyl or cyclohexyl; each R ^5a and R ^{5a' is} independently H, hydrazine, methyl, oxo (=O), benzyl, ethyl, F, Cl, Br or I; each Y ¹ , Y ² , Y ^{1 '} and Y ^{2 ' are} independently N or CR ⁷ ; each f and f' is independently 0, 1, 2, 3 or 4; each i and e are independently 0, 1, 2, 3 or 4; each R ¹⁴ and R ^{14a are} independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl; each R ¹⁶ and R ^16a independently Is a hydroxyl group, a methoxy group, an ethoxy group, a phenoxy group, Or a tert-butoxy group; wherein the methyl group, ethyl group, phenyl group, benzyl group, cyclohexyl group, 1-methylpropyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, phenoxy group The base, tert-butoxy or tert-butyl may be optionally substituted by one or more substituents selected from the group consisting of ruthenium, F, Cl, Br, hydroxy, cyano; and each of A and A' is independently group: A heterocyclic or fused ring or spiro ring system in which R ¹ , R ² and N-CH are independently formed is selected from the following substructures: A heterocyclic or fused ring or spiro ring system in which R ³ , R ⁴ and N-CH are independently formed is selected from the following substructures: The compound of claim 1, which comprises the structure of one of the following: Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate or pharmaceutically acceptable salt thereof. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 51. The pharmaceutical composition according to claim 52, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. The pharmaceutical composition of claim 52, which further comprises other anti-HCV drugs. The pharmaceutical composition according to claim 54, wherein the anti-HCV drug is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes a type 1 helper T cell response. , interfering RNA, anti-sense RNA, Imiqimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavi infliximab (Bavituximab), Civacir ^TM, boceprevir (boceprevir), telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS- 9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), Vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032), sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R -7128), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916 , lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, or a combination thereof. The pharmaceutical composition according to claim 55, wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha- 2a, complex alpha interferon, interferon gamma or a combination thereof. The pharmaceutical composition according to any one of claims 52 to 56, which further comprises at least one HCV inhibitor. The pharmaceutical composition according to claim 57, wherein the HCV inhibitor is for inhibiting at least one of an HCV replication process and inhibiting HCV viral protein function. The pharmaceutical composition of claim 58 wherein the HCV replication process is selected from the complete viral cycle of HCV entry, husking, translation, replication, assembly or release of HCV. The pharmaceutical composition according to claim 58, wherein the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and an internal ribosome entry point required for HCV virus replication ( IRES) and inosine monophosphate dehydrogenase (IMPDH). A pharmaceutical composition according to any one of claims 1 to 51, or a pharmaceutical composition according to any one of claims 52 to 60, for use in the preparation of a medicament, The medicament is for inhibiting at least one of an HCV replication process and inhibiting HCV viral protein function. The use of the HCV replication process is selected from the complete viral cycle of HCV entry, husking, translation, replication, assembly or release of HCV, as described in claim 61. The use of the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) required for HCV viral replication, as described in claim 62. And inosine monophosphate dehydrogenase (IMPDH). A pharmaceutical composition according to any one of claims 1 to 51, or a pharmaceutical composition according to any one of claims 52 to 60, for use in the preparation of a medicament, The medicament is for preventing, treating, treating or ameliorating a HCV infection or a hepatitis C disease in a patient.