TW201632514A - Compounds as hepatitis C virus inhibitors and pharmaceutical uses thereof - Google Patents

Abstract

The invention provides compounds as hepatitis C virus inhibitors and pharmaceutical uses thereof. Specifically, the invention provides compounds of Formula (I) or a stereoisomer, a tautomer, an enantiomer, 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 hepatitis C disorders. Furthermore, the invention provides pharmaceutical compositions containing the compound disclosed herein and the methods of using of the compound or pharmaceutical compositions thereof in the treatment of HCV infection or HCV disorders.

Description

Compounds as hepatitis C inhibitors and their use in medicine

The present invention pertains to the field of medicine, and in particular to compounds for the treatment of hepatitis C virus (HCV) infection, compositions of said compounds, and uses and methods of use thereof.

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.

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 poly Proteins are 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-NS5B sites are trans. The NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease and possibly assisting membrane localization of NS3 and other viral replicase components. The 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.

The invention relates to a method of combating HCV infection. The compound or the pharmaceutical composition provided by the invention has a good inhibitory effect on HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a, and the compound or pharmaceutical composition provided by the invention is resistant to HCVGT1b L31V, GT1b Y93H. It also has a good inhibitory effect. Therefore, the present invention provides a full-genic HCV inhibitory drug having anti-drug resistance and has good bioavailability.

In one aspect, the invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an enantiomer, a nitrogen of a compound of formula (I) or a compound of formula (I). An oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, Wherein, A is _{^{- (CR 7 R 7a) m}} -, - CR 7 = CR 7a -, - (CH 2) n O -, - N = CR 7 -, - NR 7 -CR 7 R 7a -, - CR ⁷ R ^7a -NR ⁷ -, -O(CH ₂ ) _n -, -CR ⁷ =N-, -S(CH ₂ ) _n -, -(CH ₂ ) _n S- or -NR ^9a -; X and X ¹ each independently N or CR ^7b ; Y and Y ¹ are each independently H, oxime, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, -C(=O -(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ or α -amino acid group; wherein the α -amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, styrene Amino acid, threonine, tryptophan, valine, alanine, aspartame, aspartic acid, glutamic acid, glutamine, valine, serine, tyrosine, arginine Acid, histidine, cysteine, glycine, sarcosine, N , N -dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, high a group formed by phenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline; R ¹ , R ² , R ³ and R ⁴ are each independently H, oxime, alkyl , arylalkyl, cycloalkyl, heterocyclic, a heteroaryl or aryl group; or R ¹ , R ² and X-CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, a fused bicyclic ring, a fused heterobicyclic ring, a spiro bicyclo or a spiro bicyclo ring; Or R ³ , R ⁴ and X ¹ -CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, a fused bicyclic ring, a fused heterobicyclic ring, a spiro bicyclo or a spiro bicyclo ring; each R ⁵ and R ⁶ Independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl , nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, alkoxy, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy , heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylalkyl, alkyloxy, Alkoxyindenyl, heterocyclylalkylamino or aryloxy; each R ⁷ , R ^7a , R ^7b , R ⁸ , R ^8a and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, Amino, F, Cl, Br, I, cyano, haloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, hetero Cyclo, cycloalkyl, decyl, nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl Amino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, Heterocyclylamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbamethyl, alkyl-OS(=O) _r- , alkyl-S(=O) _r O-, alkyl -OS (= O) _r O-, alkyl -S (= O) _r -, heterocyclyl alkylamino or aryloxy group; each R ⁹ and R ¹⁰ are independently H, deuterium, alkyl Base, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, alkyl-OC(=O)-, alkyl-C(=O)-, carbamoyl, alkyl- OS(=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl; each f, n and t are independently 0, 1, 2 , 3 or 4; m is 1, 2, 3 or 4; and each r is independently 0, 1 or 2; each of the following groups: alkyl, alkoxy, cycloalkyl, heterocyclic, aromatic , heteroaryl, arylalkyl, -C(=O)-(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ , α-amino acid group, 3- 8-membered heterocyclic ring, 3-8 membered carbocyclic ring, fused bicyclic ring, fused heterobicyclic ring, spirobicyclo, spirobicyclo, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, heteroarylalkyl, ring Alkylalkyl, heterocyclylalkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, aryloxy, heteroaryloxy, arylalkoxy, heteroaryl Alkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbachiryl, alkyl- OS(=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl is independently optionally 1, 2, 3 or 4 selected from Hydroxy, hydrazine, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, fluorenyl, nitro, aryloxy, arylamino, heteroaryloxy, heteroarylalkyl, oxo (=O), carboxyl, hydroxy substituted alkoxy a hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy substituted alkane base-S (= Substituted by a substituent of O)-, a hydroxy-substituted alkyl-S(=O) ₂ - or a carboxy-substituted alkoxy group.

In some embodiments, each of R ¹ , R ² , R ^{3 ,} and R ^{4 is} independently H, C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _3-10 cycloalkyl, a C _2-10 heterocyclic group, a C _1-9 heteroaryl group or a C _6-10 aryl group; or R ¹ , R ² and X-CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, C _5-12 fused bicyclic, C _5-12 fused heterobicyclic, C _5-12 spiro bicyclo or C _5-12 spiro bicyclo; or R ³ , R ⁴ and X ¹ -CH arbitrarily form 3-8 a heterocyclic ring, 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; wherein the 3-8 member Heterocycle, 3-8 membered carbocyclic ring, C _5-12 fused bicyclic ring, C _5-12 fused heterobicyclic ring, C _5-12 spiro bicyclic ring or C _5-12 spiro bicyclo ring are optionally independently 1, 2 3 or 4 selected from H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylthio, C _6-10 Base amino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl substituted C _2-10 heterocyclyl group, or the group Generations.

In some embodiments, wherein R ^1, R ² and the heterocyclic ring formed YX-CH, a fused ring system, or spiro ring system selected from the following sub-formulas: The heterocyclic ring, fused ring or spiro ring system formed by R ³ , R ⁴ and Y ¹ -X ¹ -CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylthio, C _{6- 10} arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 ring An alkyl group or a C _2-10 heterocyclic group; each R ^{9b 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 a -6} 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 cycloalkyl group; and each of n ₁ and n _{2 is} independently 1, 2 3 or 4.

In other embodiments, each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 haloalkoxy C _1-3 alkyl, 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 _1-9 heteroaryl C _1-3 alkyl, C _{a 3-8} cycloalkyl group or a C _2-10 heterocyclic group; and each R ^{9b is} independently hydrogen, hydrazine, 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 _1-3 alkyl, C _{6- 10} Aryl C _1-3 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _2-10 heterocyclyl or C _3-8 cycloalkyl.

In other embodiments, each R ¹⁵ is independently H, deuterium, oxo (= O), F, Cl , Br, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, tris Fluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or pyridazinyl; and each R ^{9b is} independently hydrogen, deuterium, methyl, ethyl Base, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxymethyl, ethoxymethyl, phenylmethyl, phenyl, cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.

In some embodiments, each of R ⁷ , R ^7a , R ^{7b ,} and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 , C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl , C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 Aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-6 alkoxy, C _{1- 9} heteroaryl C _1-6 alkoxy, C _2-10 heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclic group, 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-OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclyl C _{1 -6} alkylamino or C _6-10 aryloxy; and each r is independently 0, 1 or 2.

In some embodiments, Y and Y ¹ are each independently H, hydrazine, C _1-6 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 or -C (= O) - (CR 8 R 8a) t -N (R 9) -R 10; each R ⁸ and R ^8a are independently H, anthracene, hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclic C _{1 -6} alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _{1-9heteroaryloxy} , C _6-10 aryl C _1-6 alkoxy, C _{1-9heteroaryl} C _1-6 alkoxy, C _2-10 heterocyclyloxy, C _{2 -10} heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclic group, C _1-6 alkyl -OC (= O) -, C 1-6 alkyl -C (= O) -, Carbamidyl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-OS(=O) _r O -, C _1-6 alkyl group -S (= O) _r - C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryl group; R ⁹ and R ¹⁰ are each independently H, deuterium, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclic group, C _6-10 aryl group, C _1-9 heteroaryl group, C _6-10 aryl C _1-6 alkyl group, 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; t is 0, 1, 2, 3 or 4; and each r is independently 0, 1 or 2.

In other embodiments, R ⁹ and R ¹⁰ are each independently H, hydrazine, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl-OC ( =O)-, ethyl-OC(=O)-, propyl-OC(=O)-, isopropyl-OC(=O)-, tert-butyl-OC(=O)-, methyl- C(=O)-, ethyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, isobutyl-C(=O)-, Carbamidyl, methylcarbamyl, ethylcarbamethyl, methyl-OS(=O) ₂ -, cyclopropyl-OS(=O) ₂ -, methyl-S(=O) ₂ O -, cyclopropyl-S(=O) ₂ O- or aminosulfonyl.

In some embodiments, the compound of the invention has the structure of formula (II), (IIa), (IIb) or (III), or the formula (II), (IIa), (IIb) or (III) Structural stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs: Wherein A is -O-, -S-, -NH-, -CH ₂ -S-, -CH ₂ -O-, -CH ₂ -NH-, -O-CH ₂ -, -NH-CH ₂ - , -S-CH ₂ - or -CH ₂ -CH ₂ -; wherein each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _{1 -3} alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 haloalkoxy C _1-3 alkyl, 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- 9} heteroaryl C _1-3 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclyl; and each of n ₁ and n ₂ are independently 2, 3 or 4.

In other embodiments, each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _{1 -6} alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _{1-9heteroaryl} C _1-6 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkoxy , C _2-10 heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, 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-OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryl Oxygen.

In other embodiments, wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, Trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or pyridazinyl.

In some embodiments, each R ⁵ and R ^{6 are} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _{1- 6} haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, fluorenyl, nitro, C _6-10 aryl, C _1-9 Heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _6-10 arylamino, C _{1- C9} heteroaryl group, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl-C _1-6 alkylamino, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _2-10 heterocyclyloxy, C _2-10 Heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _1-6 alkoxy fluorenyl, C _2-10 Heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy.

In other embodiments, each of R ⁵ and R ^{6 is} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxymethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, cyclopropyl, cyclobutyl, ring A pentyl group, a cyclohexyl group, a phenyl group, a phenyloxy group, a phenylamino group, a decyl group or a nitro group.

In some embodiments, each R ⁸ and R ^{8a are} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, isopropoxy, methoxymethyl, 1 -methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, phenyl, pyranyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, vinyl, allyl, ethynyl, morpholinyl, fluorenyl, nitro, benzyl or anilino groups.

In another aspect, the invention provides a pharmaceutical composition, the pharmaceutical composition package Contains any of the above compounds.

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

In other embodiments, further comprising other anti-HCV drugs, wherein the other anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, promote production of type 1 Helper T cell response compounds, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviximab, hepatitis C immunoglobulins, Civacir ^TM, boceprevir, telaprevir, erlotinib, daclatasvir, US Secretary of telaprevir, A horse Wei, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, Grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir, EDP239, ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, cilostry, sovaprevir, ACH-1095 , VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI- 938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, radipavir, odalasvir, ritonavir, furaprevir, setrobuvir, alistorivir, BIT-225, AV-4025, ACH-3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD -6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, arapa Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB- 5300, miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX- 700, AL-335, JNJ-47910382, AL-704, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12 or a combination thereof; 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 other embodiments, wherein the additional anti-HCV agent is for inhibiting HCV replication and/or inhibiting HCV viral protein; the HCV replication process Includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, as well as for HCV viral replication. Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).

In another aspect, the invention provides the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for inhibiting the HCV replication process and/or inhibiting the function of an HCV viral protein; the HCV replication process comprising HCV entry, HCV Shelling, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome entry point required for HCV viral replication. (IRES) and inosine monophosphate dehydrogenase (IMPDH).

In another aspect, the invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment, treatment or alleviation of HCV infection or hepatitis C disease.

Another aspect of the invention relates to a process for the preparation, isolation and purification of compounds comprised by formula (I), (II), (IIa), (IIb) and (III).

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.

[Definitions and general terms]

Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formula or formula. 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 that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. Conversely, various features of the invention have been described in a single embodiment for the sake of brevity, but also It may be provided alone or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. 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" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. The description is fully incorporated herein by reference.

The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to one or more than one (i. For example, "a component" refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. The test object, for example, also refers to a primate (such as a human, a male or a female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the test article is a primate. In other embodiments, the test article is a human.

The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

The use of "in some embodiments" or "in other embodiments" before the definition of the technical features in the present invention means that the technical features defined herein may be derived from "in some embodiments" or "in other embodiments". The technical features are arbitrarily combined into a complete technical solution.

"Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chirality" is a molecule that has the property of not overlapping with its mirror image; and "achiral" refers to A mirror whose molecules can overlap.

"Enantiomer" refers to two isomers of a compound that are not superimposable but are mirror images of each other.

"Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

The stereochemical definitions and rules used in the present invention generally follow 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", John Wiley & Sons, Inc., New York, 1994 .

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the first codes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The first codes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds with a first code of (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as ( R )-, ( S )- or ( R , S )-configuration presence. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.

The racemate of any resulting end product or intermediate can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separate. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981 ); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert) E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012 ); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962 ); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972 ); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007 ).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamines. Structure. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1 H )-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

Annular tautomerism is a kind of proton transfer tautomerism in which protons can occupy two or more positions in a heterocyclic ring. These two isomers coexist in a balanced system and are relatively high. The rates change from each other. For example: 1 H - and 3 H -imidazole; 1 H , 2 H - and 4 H -1,2,4-triazole; 1 H - and 2 H -isoindole. The structural fragment of the present invention, the following structural fragments Aa and Ab, or Ba and Bb, are intra-cyclic tautomers; since the two isomers coexist, the present invention only mentions one isomer for simplicity of description. The structure, that is, any one of the structures of the intra-cyclic tautomers is referred to anywhere, and it means that the other structure is also mentioned at the same time. For example, although only the compound containing the Aa structural fragment is given in the present invention, the compounds are mutually The compound containing the structural fragment Ab of the isomer is also substantially simultaneously provided; for example, although only the compound containing the Ba structural fragment appears in the present invention, the tautomer of the compound containing the structural fragment Bb is substantially simultaneously given. .

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention. A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, 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 can be 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. When a substituent is described as a "independently selected" group, each substituent is selected independently of each other, and thus each substituent may be the same or different from each other.

In addition, it should be noted that, unless otherwise explicitly indicated, the descriptions used in the present invention are "individually" and "individually independent" 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.

In each part of the specification, the substituents of the compounds of the invention are disclosed in terms of the type or scope of the group. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent attached Alkylene group or arylene group group.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.

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-methyl-3-pentyl (-CH (CH 2 CH 3)} CH (CH 3) 2) 2,3-dimethyl-2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH ₃ ) ₃ ), n-heptyl, n-octyl, and so on.

The term "haloalkyl" or "haloalkoxy" denotes an alkyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy Base.

The term "hydroxyalkyl" or "hydroxy substituted alkyl" means that the alkyl group is 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, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

The term "aminoalkyl" or "amino-substituted alkyl" means that the alkyl group is substituted by one or more amino groups, wherein the alkyl group has the meaning as described herein.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group Contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.

The term "alkoxyalkyl" denotes an alkoxy group attached to the remainder of the molecule through an alkyl group, wherein the alkoxy group and the alkyl group have the meanings as described herein. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, methoxyethyl, 2-methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy Ethyl ethyl, 1-propoxymethyl, 2-propoxyethyl, 1-butoxymethyl, 2-methyl-1-propoxyethyl, 2-butoxymethyl, etc. Wait.

The term "alkylalkyl" or "alkoxy" refers to an alkyl or alkoxy group attached to the remainder of the molecule through a thiol group, wherein alkyl, alkoxy and fluorenyl have the meanings as described herein. In some embodiments, such embodiments may be alkyl-OC(=O)-, alkyl-OS(=O) _r- , alkyl-C(=O)-, alkyl-S(=O ) _r -.

The term "alkyloxy" or "alkoxy" refers to an alkyl or alkoxy group attached to the rest of the molecule through a decyloxy group, wherein the alkoxy group, the alkyl group and the decyloxy group have the present invention The meaning of the description. In some embodiments, such embodiments may be an alkyl O- -C (= O), alkyl -OC (= O) O-, alkyl -S (= O) _r O-, alkyl -OS (=O) _r O-.

The term "mercapto" refers to a monovalent radical remaining after removal of a hydroxyl group by an organic or inorganic oxyacid having the formula R-M(=O)-. Usually the M atoms in the sulfhydryl group are carbon and sulfur. The term "decyloxy" means that the group of a thiol group attached to the remainder of the molecule through an oxygen atom is of the formula R-M(=O)O-.

The term "haloalkoxyalkyl" denotes a radical of the haloalkoxy group attached to the remainder of the molecule through an alkyl group, wherein haloalkoxy and alkyl have the meanings as described herein.

The term "alkylamino" or "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 an alkylamino group having one or two _C1-6 alkyl groups attached to the nitrogen atom. In other embodiments, the alkylamino group is an alkylamino group having one or two C _1-3 alkyl groups attached to a nitrogen atom. 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 "alkylaminoalkyl" denotes an alkylamino group attached to the rest of the molecule through an alkyl group. A group wherein an alkylamino group and an alkyl group have the meanings as described herein.

The term "alkylthio" denotes a group wherein an alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein alkyl has the meaning as described herein.

The term "alkylthioalkyl" denotes a radical of the alkylthio group attached to the remainder of the molecule through an alkyl group, wherein alkylthio and alkyl have the meanings as described herein.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp ² double bond, wherein the alkenyl group The group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 - 4 carbon atoms. Examples of alkenyl groups 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 containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), and the like. .

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atom.

The term "cycloalkylalkyl" denotes a group wherein a cycloalkyl group is attached to the remainder of the molecule through an alkyl group, wherein cycloalkyl and alkyl have the meanings as described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from Nitrogen, sulfur and oxygen atoms, but at least one of the rings is not aromatic. Unless otherwise stated, a heterocyclic group can be a carbon or a nitrogen group, and a -CH ₂ - group can be optionally substituted with -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, morpholinyl, thiomorpholinyl, pyridazinyl, dioxoalkyl, dithiaalkyl, thia Oxanyl, oxazinyl, homoacridinyl, oxetanyl, thiaheptanyl, oxazepine Base, diaza Base , porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxan, 2-oxa-5-azabicyclo[2.2.1]hept-5 -base. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-acridone Base, 3,5-dioxoacridinyl and pyrimidinone. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, cyclobutylidene, 1,1-dioxothiomorpholinyl. The heterocyclyl group can be optionally substituted with one or more substituents described herein.

In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3-8 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen and sulfur. And oxygen atoms. Unless otherwise stated, a heterocyclic group consisting of 3-8 atoms may be a carbon or a nitrogen group, and a -CH ₂ - group may be optionally substituted by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of the heterocyclic group consisting of 4 to 7 atoms include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline. , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, morpholinyl, thiomorpholinyl, pyridazinyl, dioxoalkyl, dithiaalkyl, Thiothecyl, oxazinyl, homoacridinyl, oxetanyl, thiaheptanyl, oxazepine Base, diaza Base base. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-acridine Keto group, 3,5-dioxoacridinyl and pyrimidinone. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, cyclobutylidene, 1,1-dioxothiomorpholinyl. The heterocyclic group consisting of 3-8 atoms may be optionally substituted by one or more substituents described herein.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 4 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Replaced. Unless otherwise stated, a heterocyclic group consisting of 4 atoms may be a carbon group or a nitrogen group, and a -CH ₂ - group may be optionally substituted by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of the heterocyclic group consisting of 4 atoms include, but are not limited to, azetidinyl, oxetanyl, thiacyclobutyl. The heterocyclic group consisting of 4 atoms may be optionally substituted by one or more substituents described herein.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 5 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. . Unless otherwise stated, a heterocyclic group consisting of 5 atoms may be a carbon group or a nitrogen group, and a -CH ₂ - group may be optionally substituted with -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of the 5-atomic heterocyclic group include, but are not limited to, pyrrolidinyl group, 2-pyrroline group, 3-pyrroline group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, Tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, cyclobutyl fluorenyl. The heterocyclic group consisting of 5 atoms may be optionally substituted by one or more substituents described herein.

In another embodiment, the heterocyclic group is a 6 atom heterocyclic group, and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. . Unless otherwise stated, a heterocyclic group consisting of 6 atoms may be a carbon group or a nitrogen group, and a -CH ₂ - group may be optionally substituted by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, morpholinyl, thiomorpholinyl, pyridazine Base, dioxoalkyl, dithiaalkyl, thiamethane. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-acridinone, 3,5-dioxoacridinyl and pyrimidinone. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a 1,1-dioxothiomorpholinyl group. The 6 atomic heterocyclyl group may be optionally substituted with one or more substituents described herein.

In still another embodiment, the heterocyclic group is a heterocyclic group of 7 to 12 atoms, and refers to a saturated or partially unsaturated spirobicyclic or fused bicyclic ring containing 7 to 12 ring atoms, wherein at least one ring atom Selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclic group consisting of 7 to 12 atoms may be a carbon or a nitrogen group, and a -CH ₂ - group may be optionally substituted by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of the heterocyclic group consisting of 7 to 12 atoms include, but are not limited to, porphyrin group, 1,2,3,4-tetrahydroisoquinolyl group, 1,3-benzodioxanyl group, 2- Oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclic group consisting of 7-12 atoms may be optionally substituted by one or more substituents described herein.

The term "heterocyclyloxy" or "heterocyclylamino" denotes a radical to which the heterocyclyl is attached to the rest of the molecule through an oxygen or nitrogen atom, wherein the heterocyclyl has the meanings indicated herein.

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 "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "aryloxy" denotes a group in which an aryl group is attached to the remainder of the molecule through an oxygen atom, wherein the aryl group has the meanings described herein.

The term "arylamino" "arylamino" means that the amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some of these embodiments, the aromatic ring on the arylamino group can be further substituted.

The term "arylalkyl" embraces an aryl-substituted alkyl group wherein the alkyl group is attached to the remainder of the molecule; the term "arylalkoxy" includes an aryl-substituted alkoxy group wherein the oxygen atom is attached to the remainder of the molecule The term "arylalkylamino" includes an aryl-substituted alkylamino group wherein the nitrogen atom is attached to the remainder of the molecule. Wherein aryl, alkyl, alkoxy and alkylamino have the meanings as described herein.

The term "heteroaryl" denotes a monocyclic, bicyclic and tricyclic ring system containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring of 5-7 atoms and one or more attachment points are attached to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furanyl, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 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 (such as 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-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazine group; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (such as 2-indenyl), fluorenyl, quinolyl (eg 2-quinolyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 3-isoquine) Lolinyl or 4-isoquinolinyl), imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyrimidinyl, imidazole And [1,2- b ]pyridazinyl, [1,2,4]triazolo[4,3- b ]pyridazinyl,[1,2,4]triazolo[1,5- a ] Pyrimidinyl, [1,2,4]triazolo[1,5- a ]pyridinyl, and the like.

The term "heteroaryloxy" denotes a group of a heteroaryl group attached to the remainder of the molecule through an oxygen atom, wherein the heteroaryl group has the meanings described herein.

The term "heteroarylamino" "heteroarylamino" means that the amino group is substituted by one or two heteroaryl groups.

The term "heteroarylalkyl" includes heteroaryl substituted alkyl wherein alkyl is attached to the remainder of the molecule; the term "heteroarylalkoxy" includes heteroaryl substituted alkoxy wherein the oxygen atom The remainder of the molecule is attached; the term "heteroarylalkylamino" includes a heteroaryl substituted alkylamino group wherein the nitrogen atom is attached to the remainder of the molecule. Wherein heteroaryl, alkyl, alkoxy and alkylamino have the meanings as described herein.

The terms "carbocyclyl" and "carbocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 carbon atoms, but at least one of which is not Aromatic. Unless otherwise indicated, -CH ₂ on the carbocyclic - groups may be optionally substituted with -C (= O) - instead. In some embodiments the carbocyclic group contains 3-8 carbon atoms. In some embodiments, the carbocyclic group contains 5 carbon atoms. In some embodiments, the carbocyclic group contains 6 carbon atoms.

The terms "fused bicyclic" and "fused bicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated, bicyclic ring system which refers to a non-aromatic bicyclic ring. system. Such a system may comprise an independent or conjugated unsaturated system, but the core structure does not comprise an aromatic ring or an aromatic heterocyclic ring (but an aromatic group may serve as a substituent thereon). In some embodiments, the fused bicyclic ring contains 5-12 carbon atoms.

The term "spirocyclo", "spirobicyclo", as used interchangeably herein, refers to a monovalent or multivalent saturated or partially unsaturated ring system wherein one ring originates from a particular ring carbon atom on the other ring. In some embodiments, the spirobicyclic ring contains 5-12 carbon atoms.

For example, as described below, a saturated paracyclic ring system (rings B and B') is referred to as a "fused bicyclic ring", while ring A and ring B share a carbon atom in two saturated ring systems, It is called "spiral ring" or "spiral double ring".

When a ring atom in a "fused bicyclic ring" or "spirobicyclic ring" contains at least one hetero atom, a "fused bicyclic group" or a "spirobicyclic group" is referred to as a "fused heterobicyclic ring" or a "spirobicyclic ring". Each of these rings may be a carbocyclic group or a heterocyclic group. In some embodiments, the fused heterobicyclic or spiro heterobicycle contains 5-12 carbon atoms.

The term "oxo" means substituted by =0.

The term "hydroxy" means -OH.

The term "amino" means -NH ₂ .

The term "cyano" means -CN.

The term "mercapto" means -SH.

The term "nitro" means -NO ₂ .

The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "heteroatom" refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro- 2H -pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N -substituted pyrrolidinyl) NR).

The term "consisting of n atoms", where n is an integer, typically describes the number of ring atoms in the molecule in which the number of ring atoms is n. For example, an acridinyl group is a heterocycloalkyl group composed of 6 atoms, and 1,2,3,4-tetrahydronaphthalene is a carbocyclic group composed of 10 atoms.

The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

As described in the present invention, a ring system in which a substituent is bonded to a central ring (as shown by formulas (b1), (b2), (b3)) represents a substituent (R ⁵ ) _n , R ⁶ (R ¹⁵ ) _n1 may be substituted at any substitutable position on the ring.

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, Boc), benzyloxycarbonyl (CBZ, 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. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylnonane) Ethyl, 2-(trimethyldecyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(di) Phenylphosphino)ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005 .

The term "prodrug" as used herein, denotes a compound which is converted in vivo to a compound of formula (I), (II), (IIa), (IIb) and (III). 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 of a phenyl ester, an aliphatic (C _1-24 ) ester, a decyloxymethyl ester, 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.

"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 "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 and are described in the literature: SMBerge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977 , 66: 1-19. 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 by other methods such as ion exchange methods described in 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 a suitable base 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, and aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

The term "treating" any disease or condition as used in the present invention, in some embodiments thereof, refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms). In other embodiments, "treating" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetates, aspartates, benzoates, besylate, bromide/hydrobromide, bicarbonate/carbonic acid Salt, hydrogen sulfate/sulfate, camphor sulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconic acid Salt, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, C Diacid salt, mandelic acid salt, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitic acid Salt, phorate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturate, propionate, stearate, succinate, sulfosalicyrate, tartrate, toluene Salt and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, almonds Acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, pyridazine, and tromethamine. .

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K, or by The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington 's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa , (1985); and "Handbook pharmaceutically acceptable salts: properties, selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and A list of additional suitable salts can be found in Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Further, the compounds disclosed in the present invention, including their salts, may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the invention is intended to include both solvated and unsolvated forms.

Any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, those in which a radioisotope such as ³ H, ¹⁴ C and ¹⁸ F is present, or in which a non-radioactive isotope is present, such as ² H and ¹³ C. Such isotopically enriched compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution determination, or can be used in patients with radiation therapy. ¹⁸ F enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compound of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.

In addition, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index. It should be understood that the indole in the present invention is regarded as a substituent of the compounds of the formulae (I), (II), (IIa), (IIb) and (III). Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as hydrazine, the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor of at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation). The present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D ₂ O, acetone - d _6, DMSO- d ₆ solvate of those.

In another aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (I), (II), (IIa), (IIb) and (III).

In another aspect, the invention relates to a process for the preparation, isolation and purification of compounds comprised by formula (I), (II), (IIa), (IIb) and (III).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.

"Union" means a fixed combination in a single dosage unit form or for combined administration A kit of parts wherein the compounds and combination partners disclosed herein can be administered separately at the same time or can be administered separately at intervals of time, particularly to allow the partners to exhibit cooperation, such as synergy. The terms "co-administered" or "co-administered" and the like as used herein are intended to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and is intended to include wherein the substance does not have to be administered by the same route of administration or simultaneously. Treatment plan. The term "pharmaceutical combination product" as used herein denotes a product obtained by mixing or combining more than one active ingredient, and includes both a fixed combination of active ingredients and a non-fixed combination. The term "fixed combination" means that the active ingredient, such as a compound of the present invention and a combination partner, is administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, such as a compound of the present invention and a combination partner, are administered to a patient as a separate entity simultaneously, together or without specific time constraints, wherein the administration provides a therapeutically effective amount of both compounds in the patient. . The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

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

Description of the compounds of the invention

The invention relates to a method of combating HCV infection. The compounds or pharmaceutical compositions of the invention have a good inhibitory effect on HCV infection.

In one aspect, the invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an enantiomer, a nitrogen of a compound of formula (I) or a compound of formula (I). An oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, Wherein, A is _{^{- (CR 7 R 7a) m}} -, - CR 7 = CR 7a -, - (CH 2) n O -, - N = CR 7 -, - NR 7 -CR 7 R 7a -, - CR ⁷ R ^7a -NR ⁷ -, -O(CH ₂ ) _n -, -CR ⁷ =N-, -S(CH ₂ ) _n -, -(CH ₂ ) _n S- or -NR ^9a -; X and X ¹ each independently N or CR ^7b ; Y and Y ¹ are each independently H, oxime, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, -C(=O -(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ or α -amino acid group; wherein the α -amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, styrene Amino acid, threonine, tryptophan, valine, alanine, aspartame, aspartic acid, glutamic acid, glutamine, valine, serine, tyrosine, arginine acid, histidine, cysteine, glycine, sarcosine, N, N - dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, a group formed by phenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline; R ¹ , R ² , R ³ and R ⁴ are each independently H, oxime, alkyl , arylalkyl, cycloalkyl, heterocyclic, a heteroaryl or aryl group; or R ¹ , R ² and X-CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, a fused bicyclic ring, a fused heterobicyclic ring, a spiro bicyclo or a spiro bicyclo ring; Or R ³ , R ⁴ and X ¹ -CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, a fused bicyclic ring, a fused heterobicyclic ring, a spiro bicyclo or a spiro bicyclo ring; each R ⁵ and R ⁶ Independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl , nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, alkoxy, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy , heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylalkyl, alkyloxy, Alkoxyindenyl, heterocyclylalkylamino or aryloxy; each R ⁷ , R ^7a , R ^7b , R ⁸ , R ^8a and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, Amino, F, Cl, Br, I, cyano, haloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, hetero Cyclo, cycloalkyl, decyl, nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl Amino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, Heterocyclylamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbamethyl, alkyl-OS(=O) _r- , alkyl-S(=O) _r O-, alkyl -OS (= O) _r O-, alkyl -S (= O) _r -, heterocyclyl alkylamino or aryloxy group; each R ⁹ and R ¹⁰ are independently H, deuterium, alkyl Base, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, alkyl-OC(=O)-, alkyl-C(=O)-, carbamoyl, alkyl- OS(=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl; each f, n and t are independently 0, 1, 2 , 3 or 4; m is 1, 2, 3 or 4; and each r is independently 0, 1 or 2; each of the following groups: alkyl, alkoxy, cycloalkyl, heterocyclyl, aromatic , heteroaryl, arylalkyl, -C(=O)-(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ , α-amino acid group, 3 -8 membered heterocyclic ring, 3-8 membered carbocyclic ring, fused bicyclic ring, fused heterobicyclic ring, spirobicyclo, spirobicyclo, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, heteroarylalkyl, Cycloalkylalkyl, heterocyclylalkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, aryloxy, heteroaryloxy, arylalkoxy, heteroaryl Alkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbamethyl, alkyl -OS(=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl is independently selected by 1, 2, 3 or 4 From hydroxy, hydrazine, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, fluorenyl, nitro, aryloxy, arylamino, heteroaryloxy, heteroarylalkyl, oxo (=O), carboxy, hydroxy substituted alkane Oxyl, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy substituted alkyl-S ( Substituted by a substituent of a hydroxy-substituted alkyl-S(=O) ₂ - or carboxy-substituted alkoxy group.

In some embodiments, A is -O-, -S-, -NH-, -CH ₂ -S-, -CH ₂ -O-, -CH ₂ -NH-, -O-CH ₂ -, -NH -CH ₂ -, -S-CH ₂ - or -CH ₂ -CH ₂ -.

In some embodiments, each R ⁵ and R ^{6 are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _{1 -6} haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl, C _{1- 9} heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _6-10 arylamino group, C _{1 -9heteroarylamino} , C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _1-9 heteroaryl a C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkoxy group, a C _1-9 heteroaryl C _1-6 alkoxy group, a C _2-10 heterocyclic oxy group, a C _{2− 10} heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclic group, C _1-6 alkyl acyl, acyl C _1-6 alkyl group, C _1-6 alkoxy acyl, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy.

In some embodiments, each R ⁵ and R ^{6 are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-3 alkyl, C _{1 -3} haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _2-8 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl, C _{1- 9} heteroaryl, C _6-10 aryl-C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkoxy, C _6-10 arylamino group, C _{1 -9heteroarylamino} , C _6-10 aryl C _1-3 alkylamino, C _1-9 heteroaryl C _1-3 alkylamino, C _1-9 heteroaryloxy, C _1-9 heteroaryl Group C _1-3 alkyl, C _6-10 aryl C _1-3 alkoxy, C _1-9 heteroaryl C _1-3 alkoxy, C _2-8 heterocyclooxy, C _{2- 8} heterocyclyl a C _1-3 alkoxy group, C _2-8 heterocyclyl group, C _1-3 acyl group, C _1-3 alkyl acyl group, C _1-3 alkoxy, acyl, C _2-8 heterocyclyl C _1-3 alkylamino or C _6-10 aryloxy.

In some embodiments, each R ⁵ and R ^{6 are} independently H, hydrazine, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxymethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, cyclopropyl, cyclobutyl, ring A pentyl group, a cyclohexyl group, a phenyl group, a phenyloxy group, a phenylamino group, a decyl group or a nitro group.

In some embodiments, each R ¹ , R ² , R ^{3 ,} and R ^{4 are} independently H, C _1-6 alkyl, 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 form a 3-8 membered heterocyclic ring, 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 ¹ —CH optionally form 3-8 a heterocyclic ring, 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; wherein the 3-8 a heterocyclic ring, 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, optionally independently 1, 2 , 3 or 4 selected from the group consisting of H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylthio, C _6-10 Arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 naphthenic C _2-10 substituent group or heterocyclic group Replaced.

In some embodiments, the heterocyclic, fused ring or spiro ring system formed by R ¹ , R ² and YX-CH is selected from the following substructures:

In some embodiments, wherein the heterocyclic, fused ring or spiro ring system formed by R ³ , R ⁴ and Y ¹ -X ¹ -CH is selected from the group consisting of:

In some embodiments, each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylthio , C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclic group.

In some embodiments, each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 haloalkoxy C _1-3 alkyl, 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 _1-9 heteroaryl C _1-3 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclic group.

In some embodiments, each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, tri Fluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or pyridazinyl.

In some embodiments, each R ^{9b is} independently hydrogen, deuterium, 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 _2-10 heterocyclic or C _3-8 cycloalkyl.

In some embodiments, each R ^{9b 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 _1-3 alkyl, C _6-10 aryl C _1-3 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _2-10 heterocyclic or C _3-8 cycloalkyl.

In some embodiments, each R ^{9b is} independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxymethyl, ethoxy Methyl, phenylmethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, each of R ⁷ , R ^7a , R ^{7b ,} and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _{1- 6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 Aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkane , C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _{6- 10} aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-6 alkoxy, C _{1 -9heteroaryl} C _1-6 alkoxy, C _2-10 heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, C _{1- 6-} alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachiryl, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkane -S(=O) _r O-, C _1-6 alkyl-OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclyl C _{a 1-6} alkylamino group or a C _6-10 aryloxy group; and each r is independently 0, 1, or 2.

In some embodiments, each of R ⁷ , R ^7a , R ^{7b ,} and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _{1- 3-} alkyl, C _1-3 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _2-8 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl-C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-9 heteroaryl, a C _1-3 alkoxy , C _3-8 cycloalkyl C _1-3 alkyl, C _2-8 heterocyclic C _1-3 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _{6- 10} aryl C _1-3 alkylamino, C _1-9 heteroaryl C _1-3 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-3 alkoxy, C _{1 -9heteroaryl} C _1-3 alkoxy, C _2-8 heterocyclyloxy, C _2-8 heterocyclyl C _1-3 alkoxy, C _2-8 heterocyclylamino, C _{1- 3-} alkyl-OC(=O)-, C _1-3 alkyl-C(=O)-, carbamethyl, C _1-3 alkyl-OS(=O) _r -, C _1-3 alkane --S(=O) _r O-, C _1-3 alkyl-OS(=O) _r O-, C _1-3 alkyl-S(=O) _r -, C _2-8 heterocyclic C _1-3 alkylamino or C _6-10 aryloxy; and each r is independently 0, 1 or 2.

In some embodiments, each of R ⁷ , R ^7a , R ^{7b ,} and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, methyl, Ethyl, vinyl, ethynyl, cyclopropyl or phenyl; and each r is independently 1 or 2.

In some embodiments, wherein Y and Y ¹ are each independently H, 氘, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1-9heteroaryl} , C _6-10 aryl C _1-6 alkyl or -C(=O)-(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ .

In some embodiments, each R ⁸ and R ^{8a are} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl C _{1 -6} alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _{2- 10} heterocyclyl C _1-6 alkyl, C _6-10 aryl group, C _1-9 heteroaryl group, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl aryl C _{1 -6} alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _2-10 heterocycle Alkoxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, C _1-6 alkyl fluorenyl, C _1-6 alkyl decyloxy, C _{1- 6} alkoxyfluorenyl, C _1-6 alkylsulfonyl, C _1-6 alkoxysulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyloxy , C _1-6 alkylsulfinyloxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, carbachol, C _{1- 6-} alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-OS(=O) _r O-, C _1-6 alkyl -S(=O _r -, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy.

In some embodiments, each R ⁸ and R ^{8a are} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, C _1-4 alkyl, C _1-4 decyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _2-8 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 aryl C _{1 -3} alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-9 heteroaryl C _1-3 alkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _{2- 8} heterocyclyl C _1-3 alkyl, C _6-10 aryl group, C _1-9 heteroaryl group, C _6-10 aryl-amino group a C _1-3 alkoxy, C _1-9 heteroaryl aryl C _{1 -3} alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-3 alkoxy, C _1-9 heteroaryl C _1-3 alkoxy, C _2-8 heterocyclic Alkoxy, C _2-8 heterocyclyl C _1-3 alkoxy, C _2-8 heterocyclylamino, C _1-3 alkyl fluorenyl, C _1-3 alkyl decyloxy, C _{1- 3} alkoxyfluorenyl, C _1-3 alkylsulfonyl, C _1-3 alkoxysulfonyl, C _1-3 alkylsulfinyl, C _1-3 alkylsulfonyloxy , C _1-3 alkylsulfinyloxy, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, carbachol, C _{1- 4-} alkyl-OS(=O) _r -, C _1-4 alkyl-S(=O) _r O-, C _1-4 alkyl-OS(=O) _r O-, C _1-4 alkyl -S(=O) _r - , C _2-8 heterocyclyl C _1-3 alkylamino or C _6-10 aryloxy.

In some embodiments, each R ⁸ and R ^{8a are} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, n-butyl, isobutyl Base, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, isopropoxy, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, phenyl, pyranyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, vinyl, allyl, ethynyl, morpholinyl, fluorenyl, nitro, benzyl or anilino.

In some embodiments, R ⁹ and R ¹⁰ are each independently H, hydrazine, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _{1-9heteroaryl} , C _6-10 aryl C _1-6 alkyl, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, amino Mercapto, C _1-6 alkyl-OS(=O) _r -, C _1-6 alkyl-S(=O) _r O-, C _1-6 alkyl-S(=O) _r - or amino Sulfonyl.

In some embodiments, R ⁹ and R ¹⁰ are each independently H, hydrazine, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl-OC ( =O)-, ethyl-OC(=O)-, propyl-OC(=O)-, isopropyl-OC(=O)-, tert-butyl-OC(=O)-, methyl- C(=O)-, ethyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, isobutyl-C(=O)-, Carbamidyl, methylcarbamyl, ethylcarbamethyl, methyl-OS(=O) ₂ -, cyclopropyl-OS(=O) ₂ -, methyl-S(=O) ₂ O -, cyclopropyl-S(=O) ₂ O- or aminosulfonyl.

In some embodiments, t is 0, 1, 2, 3 or 4.

In some embodiments, each r is independently 0, 1, or 2.

In some embodiments, each of n ₁ and n _{2 is} independently ₁ , ₂ , 3, or 4.

In some embodiments, the compound of the invention has the structure of formula (II), (IIa), (IIb) or (III), or formula (II), (IIa), (IIb) or (III) Structural stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

In some embodiments, the compounds of the invention have the structure shown below: Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

A compound of the present invention (herein, a compound of the formula "I), (II), (IIa), (IIb) or (III) or a formula (I), (II), (IIa), Stereoisomers, geometric isomers, tautomers, enantiomers, oxynitrides, hydrates, solvates, metabolites, and pharmaceutically acceptable compounds of (IIb) or (III) Salts or prodrugs") can be used in the manufacture of pharmaceutical products for the treatment of acute and chronic HCV infections, 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. 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), (II), (IIa), (IIb) or (III), and may also Further comprising 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 of a different group suitable for chemical or toxicological and pharmaceutical formulation. The score is matched to the mammal used for treatment. 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 intermediates for the preparation or purification of compounds of formula (I), (II), (IIa), (IIb) or (III), or formula (I), (II), The salt of the isolated enantiomer of the compound of (IIa), (IIb) or (III), but not necessarily a pharmaceutically acceptable salt.

If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, 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 base or an organic base 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 to treat hepatitis C virus (HCV) infection or hepatitis C disease.

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, Bavi infliximab, hepatitis C immunoglobulin, Civacir ^TM, boceprevir, telaprevir, erlotinib, he MasterCard Wei, simivir, anapivir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir, EDP239, ravidasvir, velpatasvir, samatasvir , elbasvir, MK-8325, GSK-2336805, PPI-461, cilostry, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938 , PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir Deleobuvir, tegobuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, radipavir, odalasvir, ritonavir, furaprevir, setrobuvir, alistorivir, BIT-225, AV-4025, ACH -3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD-6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab , WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, alisporivir, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB-5300, miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, MK- 8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12, or a combination thereof; In some embodiments, the interferon is interferon alpha- 2b, pegylated interferon alpha , interferon alpha- 2a, pegylated interferon α -2a, composite α - interferon, interferon γ A combination thereof. The pharmaceutical composition further comprises at least one HCV inhibitor for inhibiting HCV replication and/or inhibiting HCV viral protein; the HCV replication process comprising HCV entry, HCV uncoating, HCV translation , HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, as well as internal ribosome entry points (IRES) and muscles required for HCV viral replication. Glycoside monophosphate dehydrogenase (IMPDH).

When useful in therapy, a therapeutically effective amount of a compound of the invention, especially a compound of formula (I), (II), (IIa), (IIb) or (III), and a pharmaceutically acceptable salt thereof, can be used as unprocessed Administration of the chemical can also be provided as an active ingredient of the pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, especially formula (I), A compound of (II), (IIa), (IIb) or (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 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), (II), (IIa), (IIb) or (III), 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 another aspect of the present invention, there is also provided a process for the preparation of a pharmaceutical formulation comprising the compound of the invention, especially a compound of formula (I), (II), (IIa), (IIb) or (III) Or a pharmaceutically acceptable salt thereof is admixed with one or more pharmaceutically acceptable carriers, diluents or excipients. 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 presented in unit dosage form, each unit dosage containing a predetermined amount of active ingredient. The dose 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/kg. Between monotherapy/day, often monotherapy is 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 concentration of the compound to be administered optimally is generally effective in providing an antiviral effect 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 dose of the compound and the additional drug is usually in a monotherapy regimen, which is about 10-150 of the normal dose. %, more preferably about 10-80% of the normal 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. Oral administration or injection administration is preferred.

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. It is also possible to add a disintegrating or solubilizing agent (for example, agar, calcium carbonate or sodium carbonate) which will improve the availability of the drug when the capsule is taken.

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 to pass the powder mixture through a tablet press. It is to break down the poorly formed mass and make it 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 transparent or opaque protective covering material consisting of a shellac seal, a sugar coating or a polymeric material coating 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), (II), (IIa), (IIb) or (III), and pharmaceutically acceptable salts thereof, may also be administered in liposome delivery systems, such as small unilamellar liposomes Large monolayer liposomes and multilamellar liposomes. Liposomes can be composed of a variety of phospholipids, such as cholesterol, octadecylamine or phospholipid choline.

The compounds of the present invention, especially the compounds of formula (I), (II), (IIa), (IIb) or (III), and pharmaceutically acceptable salts thereof, can also be used as individual carriers by using monoclonal antibodies (compounds and Coupling) delivery. 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 can be formulated into ointments, creams, suspensions, and washes. Agents, powders, solutions, pastes, gels, sprays, aerosols, oil preparations 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 inhibiting the HCV replication process and/or inhibiting the function of an HCV viral protein; the HCV replication process comprising HCV entry, HCV Shelling, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome entry point required for HCV viral replication. (IRES) and inosine monophosphate dehydrogenase (IMPDH). Any of the compounds or pharmaceutical compositions of the invention may be used to treat hepatitis C virus (HCV) infection or hepatitis C disease.

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 Interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate catalase inhibitor, amantadine, rimantadine, Bavi infliximab, hepatitis C immunoglobulin, Civacir ^TM, boceprevir, telaprevir, erlotinib, daclatasvir, Division Meipip, anapivir, vaniprevir, faldaprevir, paritaprevir, danpo puvir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir, EDP239, ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, cilostry, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136 , IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916 , lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, radipavir, odalasvir, ritonavir, Furaprevir, setrobuvir, alistorivir, BIT-225, AV-4025, ACH-3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD-6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, alisporivir, MK-3682, MK-8408, GS-9857, CD -AdNS3,pibrentasvir,RG-101, glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB-5300, mimirirsen, chronvac-C, MK-1075, ACH-0143422 , WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP -560, TD-6450, EDP-239, SB-9200, IT X-5061, ID-12 or a combination thereof. The interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or combination.

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 combined with this hair The compounds are administered simultaneously or at different times. In the latter case, the administration can be carried out staggered, for example, 6h, 12h, 1st, 2d, 3d, 1st, 2nd, 3rd, 1st, or 2nd.

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 invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I), (II), (IIa), (IIb) or (III). Shown. 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. The general reagents were purchased 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., and Qingdao Ocean Chemical Plant.

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 , DMSO- d ₆ , CD ₃ OD or acetone- d ₆ 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 performed by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) For evaluation, where UV detection was 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 maintained at 40 °C.

The following abbreviations are used throughout the invention:

resolve resolution Synthesis method 1

Compound s-10 can be produced by the synthesis method 1, wherein R ¹⁵ and R ^{8a are} as defined in the present invention. Compound s-1 is reacted with trifluoromethanesulfonic anhydride under the action of a base to obtain compound s-2 , and compound s-2 is brominated to obtain compound s-3 , and compound s-3 is reacted with compound s-4 under the action of a base. Compound s-5 , compound s-5 and ammonium acetate are closed to obtain compound s-6 , compound s-6 is oxidized to obtain compound s-7 , and compound s-7 is deprotected to obtain compound s-8 , compound s-8 and compound s -9 is obtained by a condensation reaction to give the compound s-10 .

Synthesis method 2

Compound s-23 can be prepared by the synthesis method 2, wherein R ¹⁵ and R ^{8 are} as defined in the present invention. Compound s-11 is obtained by the action of a reducing agent to obtain compound s-12 , compound s-12 is acetylated to obtain compound s-13 , compound s-13 is demethylated to give compound s-14 , and compound s-14 is used in alkali. The reaction with trifluoromethanesulfonic anhydride gives compound s-15 , and the compound s-15 is brominated to obtain compound s-16 . Compound s-16 and compound s-17 are esterified under the action of a base to obtain compound s-18 , compound s The compound s-19 is obtained by reacting -18 with ammonium acetate, and the compound s-19 is reacted under the catalysis of palladium to obtain the compound s-20 . The compound s-20 is deprotected and then reacted with the compound s-22 to obtain the compound s-23 .

Synthesis Method 3:

Compound s-27 can be prepared by the synthesis method 3, wherein R ¹⁵ and R ⁸ are each independently as defined in the present invention. Compound s-8 and compound s-20 are coupled under the catalysis of palladium to give compound s-24 . After compound s-24 is deprotected, it is condensed with compound s-26 to give compound s-27 .

Synthesis Method 4:

Compound s-28 can be prepared by Synthetic Method 4, wherein R ¹⁵ , R ⁸ , R ^8a are each independently as defined in the present invention. Compound s-20 and compound s-23 are coupled under the catalysis of palladium to give compound s-28 .

Example Example 1

synthetic route:

Synthesis step Step 1) Synthesis of Compound 1-2A

Trifluoromethanesulfonic anhydride (10.44 g, 37.0 mmol) was added dropwise to a solution of compound 1-1A (5.0 g, 30.83 mmol) and pyridine (3.0 g, 37.0 mmol) in dichloromethane (60 mL) at 0 °. After the addition, the reaction was carried out for 8 h at room temperature. After the reaction was completed, 30 mL of water was added, and the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness eluted with EtOAc (EtOAc: EtOAc (V:V) = 10:1) The product was obtained in 8.5 g, yield 94.4%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 8.02 (d, J = 8.7Hz, 1H), 7.54 (d, J = 2.2Hz, 1H), 7.44 (dd, J = 8.7,2.4Hz, 1H) , 3.02 (t, J = 6.0 Hz, 2H), 2.66-2.61 (m, 2H), 2.10-2.03 (m, 2H) ppm.

Step 2) Synthesis of Compound 1-3A

Compound 1-2A (3.0 g, 10.2 mmol), copper bromide (4.5 g, 20.4 mmol) was added to a solvent of EtOH (30 mL) at 60 ° C for 2 h. After completion of the reaction, the mixture was filtered over celite, and the filtrate was dried. The residue was dissolved in EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjj g, yield 95%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (d, J = 8.7 Hz, 1H), 7.31 - 7.22 (m, 2H), 4.75 (t, J = 4.1 Hz, 1H), 3.47-3.33 (m, 1H), 2.99 (dt, J = 17.4, 4.2 Hz, 1H), 2.65-2.45 (m, 2H) ppm.

Step 3) Synthesis of Compound 1-4A

Compound 1-3A (2.5 g, 6.7 mmol), DIPEA (1.3 g, 10.0 mmol), acetonitrile (20 mL) was placed in a flask and heated to 50 ° C, then compound 1-7 (1.6 g, 7.4 mmol) was slowly added dropwise. A solution of acetonitrile (10 mL) was added and the mixture was evaporated and evaporated. = 4:1), the product was obtained in 3.0 g, yield 88%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.22 (d, J = 8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t, 1H), 3.47 (t, 2H) , 3.17 (t, 2H), 2.99 (t, 4H), 2.65 (m, 2H), 1.25 (t, 9H) ppm; MS-ESI, m/z : 508.10 [M+H] ⁺ .

Step 4) Synthesis of Compound 1-5A

Compound 1-4A (2.7g, 5.3mmol), ammonium acetate (2.5g, 31.8mmol) were added to toluene (30mL) in a reaction solvent 12h 115 ℃, was added water (10mL) After completion of the reaction, and then EtOAc (30mL × 2) Extraction, the organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to silica gel.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.12 (s, 1H), 7.32 (m, 2H), 5.18 (t, 1H), 3.85 (t, 2H), 3.27 (t, 2H), 2.99 (t, 2H), 2.45 (m, 4H), 1.28 (t, 9H) ppm; MS-ESI, m/z : 488.8 [M+H] ⁺ .

Step 5) Synthesis of Compound 1-6A

Manganese dioxide (3.2 g, 37 mmol) was added in portions to a solution of compound 1-5A (1.8 g, 3.7 mmol) in dichloromethane (40 mL), and the mixture was stirred at room temperature for 4 days, and the reaction was completed with diatomaceous earth. Filtration, the filtrate was washed with water, dried and purified by silica gel column chromatography (PE:EtOAc (V:V) = 3:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.92 (s, 1H), 7.52 (m, 2H), 7.32 (m, 2H), 5.18 (t, 1H), 3.37 (t, 2H), 2.59 (t, 2H), 2.35 (m, 2H ), 1.26 (t, 9H) ppm; MS-ESI, m / z: 485.9 [m + H] +.

Step 6) Synthesis of Compound 1-2

Compound 1-1 (15.0 g, 92.49 mmol), triethyl decane (70.0 g, 601 mmol), TFA (300 mL) was added to a two-necked flask to reflux reaction. The reaction was monitored by TLC, and the reaction was complete after 6 h. The mixture was poured into ice water and extracted with EtOAc (100 mL×2). The organic phase was neutralized with sodium hydrogen carbonate solution, washed with water, dried, and evaporated to dryness. %.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.20 (t, J = 7.8Hz, 1H), 6.93 (d, J = 7.4Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 3.90 (s , 3H), 2.97 (d, J = 15.4, 7.5 Hz, 4H), 2.20-2.11 (m, 2H) ppm.

Step 7) Synthesis of Compound 1-3

Ethyl chloroform (6.4 g, 82 mmol) was slowly added dropwise to a solution of compound 1-2 (10 g, 67.5 mmol) of aluminum trichloride (11.7 g, 87.8 mmol) in DCM (80 mL). After the addition was completed, the reaction was continued for 4 h at room temperature. After the reaction was completed, the mixture was poured into ice water, extracted with DCM (60 mL×2), dried, dried and evaporated to dryness and purified by silica gel column chromatography (PE: DCM) = 5:1), the product was obtained in 8.9 g, yield 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.20 (t, J = 7.8Hz, 1H), 6.93 (d, J = 7.4Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 3.90 (s , 3H), 2.97 (t, J = 15.4, 7.5 Hz, 4H), 2.20-2.11 (m, 2H) ppm.

Step 8) Synthesis of Compound 1-4

Boron tribromide (8.7 g, 35 mmol) was slowly added dropwise to a solution of the compound 1-3 (5.5 g, 29 mmol) in DCM (50 mL) at 0 ° C, and the reaction was continued after the completion of the reaction. The mixture was poured into EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjj %.

^{1 H NMR (400MHz, DMSO- d} 6): δ 7.66 (d, J = 8.4Hz, 1H), 6.69 (d, J = 8.4Hz, 1H), 3.13 (t, J = 7.5Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.01-1.94 (m, 2H) ppm.

Step 9) Synthesis of Compound 1-5

Trifluoromethanesulfonic anhydride (1.3 g, 4.7 mmol) was added dropwise to a mixture of compound 1-4 (0.75 g, 4.3 mmol) and pyridine (0.5 g, 6.0 mmol) in dichloromethane (20 mL) at 0 °. After the addition, the mixture was reacted at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, the mixture was washed with water, and then the organic phase was dried, and dried, and then purified by gel column chromatography (PE) to give the product 1.2 g, yield 91%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.76 (d, J = 8.6Hz, 1H), 7.19 (d, J = 8.6Hz, 1H), 3.35 (t, J = 7.5Hz, 2H), 3.05 (t , J = 7.6 Hz, 2H), 2.61 (s, 3H), 2.23 - 2.11 (m, 2H) ppm.

Step 10) Synthesis of Compound 1-6

Compound 1-5 (1.2 g, 3.9 mmol) and copper bromide (1.7 g, 7.6 mmol) were added to a solvent of EtOH (20 mL) at 60 ° C for 2 h. After completion of the reaction, the mixture was filtered over Celite, and the filtrate was dried. Diluted with DCM (20 mL × 2), EtOAc (EtOAc) 80.5%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J = 7.6Hz , 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.29-2.14 (m, 2H) ppm.

Step 11) Synthesis of Compound 1-8

Triethylamine (0.6 g, 6 mmol) was added dropwise to a mixture of compound 1-6 (1.4 g, 3.6 mmol) and compound 1-7 (1.0 g, 4.6 mmol) in dichloromethane (20 mL) at 0 °C After the addition, the reaction was carried out at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture was washed with water, and the organic phase was dried, dried, and purified by column chromatography (PE: EtOAc (V:V) = 6:1) The yield was 79%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 5.13 (s, 1H), 4.43 (s, 2H), 3.36 (t, 2H), 3.16 (t, 2H), 3.07 (t, 4H), 2.29 (m, 4H), 1.36 (t, 9H) ppm; MS-ESI, m/z : 522.8 [M+H] ⁺ .

Step 12) Synthesis of Compound 1-9

Compound 1-8 (1.1 g, 2.1 mmol), ammonium acetate (0.81 g, 10.5 mmol) was added to a solvent of toluene (20 mL) at 115 ° C for 12 h. After completion of the reaction, water (10 mL) was added and then EtOAc (30 mL) 2) Extraction, the organic phase was washed with water, dried over anhydrous sodium sulfate, and then evaporated to silica gel, EtOAc (V: EtOAc (V:V) = 4:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.88 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 5.33 (s, 1H), 4.83 (s, 1H), 3.36 (t, 4H), 3.16 (t, 2H), 2.86 (t, 4H), 2.29 (m, 2H), 1.35 (t, 9H) ppm; MS-ESI, m/z : 502.8 [M+H] ⁺ .

Step 13) Synthesis of Compound 1-11

Compound 1-9 (0.4 g, 0.8 mmol), pinacol borate 1-10 (0.24 g, 0.95 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (0.07 g, 0.086 mmol) and AcOK (0.23 g, 2.0 mmol) were suspended in 20 mL of DMF and heated to 100 ° C under nitrogen for 4 h. The reaction solution was cooled to room temperature, and then added with EtOAc (30 mL, EtOAc) (EtOAc) 1), the product was obtained in an amount of 0.3 g, and the yield was 78%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 5.33 (s, 1H), 4.83 (s, 1H), 3.36 (t, 4H), 3.16 (t, 2H), 2.86 (t, 4H), 2.29 (m, 2H), 1.35 (t, 9H), 1.25 (t, 12H) ppm; MS-ESI, m/z : 480.4 [M+H] ⁺ .

Step 14) Synthesis of Compound 1-12

Compound 1-11 (0.8 g, 1.7 mmol), compound 1-6A (0.73 g, 1.5 mmol), Pd(PPh ₃ ) ₄ (0.20 g, 0.17 mmol) and K ₂ CO ₃ (0.69 mg, 5.0 mmol) It was suspended in EtOH/H ₂ O (30 mL, V: V = 3:1) and heated to 90 ° C for 3 h under nitrogen atmosphere. After the reaction was completed, most of the solution was spun, and then extracted with DCM (20 mL×2). The organic phase was combined, dried, dried, and purified by column chromatography (PE:EtOAc (V:V) = 2:1) Gray solid 0.5 g, yield 40%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (s, 1H), 7.52 (d, 2H), 7.32 (m, 2H), 7.22 (m, 2H), 5.33 (s, 1H), 4.93 (s, 2H), 3.26 (m, 4H), 3.10 (m, 4H), 2.76 (m, 4H), 2.19 (m, 6H), 1.25 (m, 9H), 1.29 (m, 9H) ppm; MS-ESI, m/z : 689.22 [M+H] ⁺ .

Step 15) Synthesis of Compound 1-13

At 0 ℃ the HCl / EtOAc (4N, 4mL) was added dropwise to compound 1-12 (0.5g, 0.7mmol) in methylene chloride solvent (15mL) dropwise at room temperature after the reaction was stirred 6h. After completion of the reaction, the reaction mixture was dried and purified with ethyl acetate.

MS-ESI, m/z : 489.3 [M+H] ⁺ .

Step 16) Synthesis of Compound 1

Compound 1-13 (0.40 g, 0.82 mmol), compound 1-14 (0.316 g, 1.8 mmol), EDCI (0.377 g, 1.97 mmol) and ethyl 2-indanoacetate (0.07 g, 0.49 mmol) In 10 mL of dichloromethane, DIPEA (0.530 g, 4.1 mmol) was added dropwise to the reaction mixture at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the completion of the reaction, the mixture was stirred for 1 hr (2 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. ) = 1:1), a gray solid of 0.35 g was obtained, yield 53%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.36 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 4H), 2.56 (m, 2H), 2.36 (m, 4H), 2.09 (m, 6H) ), 1.05 (m, 12H) ppm; MS-ESI, m/z : 802.7 [M+H] ⁺ .

Example 2

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 2-4A

Compound 1-3A (2.5 g, 6.7 mmol), DIPEA (1.3 g, 10.0 mmol), acetonitrile (20 mL) was placed in a bottle and heated to 50 ° C, then 5-methyl-Boc-valine 2 was slowly added dropwise. -7 (1.38g, 6.04mmol) in acetonitrile (10mL). After the reaction was completed, the reaction was completed. After the reaction was completed, the reaction mixture was evaporated. EtOAc was evaporated. (PE: EtOAc (V:V) = 4:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.22 (d, J = 8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t, 1H), 3.47 (t, 2H) , 3.17(t,1H), 2.99(t,4H), 2.65(m,2H), 1.35(t,3H),1.25(t,9H)ppm;MS-ESI, m/z :522.1M+H] ⁺ .

Step 2) Synthesis of Compound 2-5A

Compound 2-4A (1.5 g, 2.9 mmol), ammonium acetate (1.6 g, 21 mmol) was added to toluene (30 mL) in EtOAc (EtOAc) (EtOAc) The organic layer was washed with water, dried over anhydrous sodium sulfate sulfatessssssssssssssssssssss

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.12 (s, 1H), 7.32 (m, 2H), 5.18 (t, 1H), 3.85 (t, 2H), 3.27 (t, 1H), 2.99 (t, 2H), 2.45 (m, 4H), 1.35 (t, 3H), 1.28 (t, 9H) ppm; MS-ESI, m/z : 502.8 [M+H] ⁺ .

Step 3) Synthesis of Compound 2-6A

Manganese dioxide (1.7 g, 20 mmol) was added portionwise to a solution of compound 2-5A (1.0 g, 2.0 mmol) in dichloromethane (40 mL), and the mixture was stirred at room temperature for 4 days. After the reaction was completed, it was filtered over Celite. The filtrate was washed with water, dried, dried with EtOAc EtOAc EtOAcjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.92 (s, 1H), 7.52 (m, 2H), 7.32 (m, 2H), 5.18 (t, 1H), 3.37 (t, 1H), 2.59 (t, 2H), 2.35 (m, 2H), 1.35 (t, 3H), 1.26 (t, 9H) ppm; MS-ESI, m/z : 500.8 [M+H] ⁺ .

Step 4) Synthesis of Compound 2-8

Triethylamine (0.9 g, 8.9 mmol) was added dropwise to compound 1-6 (2.3 g, 5.95 mmol), compound 2-7 (1.23 g, 5.36 mmol) in dichloromethane (20 mL) at 0 °C In the solution, the mixture was reacted at room temperature, and the reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added, washed with saturated sodium chloride, and the organic phase was dried, dried under reduced pressure, and purified by gel column chromatography (PE: EtOAc (V:V) = 6: 1), 1.6 g of product was obtained in a yield of 50.3%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 5.13 (s, 1H), 4.43 (s, 2H), 3.36 (t, 2H), 3.16 (t, 2H), 3.07 (t, 3H), 2.29 (m, 4H), 1.45 (t, 3H), 1.36 (t, 9H) ppm, MS-ESI, m/z : 535.8 [M+H] ⁺ .

Step 5) Synthesis of Compound 2-9

The compound 2-8 (1.6 g, 3.0 mmol), ammonium acetate (1.4 g, 18 mmol) was added to a solvent of toluene (20 mL), and the mixture was stirred at 115 ° C for 12 h. After the reaction, water was added, and then extracted with EtOAc (30 mL×2). The organic layer was washed with water, dried over anhydrous sodium sulfate sulfatessssssssssssssssssssss

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.88 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 5.33 (s, 1H), 4.83 (s, 1H), 3.36 (t, 4H), 3.16 (t, 1H), 2.86 (t, 4H), 2.29 (m, 2H), 1.39 (t, 3H), 1.35 (t, 9H) ppm; MS-ESI, m/z : 516.2 [M+H] ⁺ .

Step 6) Synthesis of Compound 2-11

Compound 2-9 (1.0 g, 1.94 mmol), pinacol borate 1-10 (0.6 g, 2.1 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (0.17 g, 0.19 mmol) and AcOK (0.57 g, 5.82 mmol) were suspended in 20 mL of DMF and heated to 100 ° C under nitrogen for 4 h. The reaction solution was cooled to room temperature, and then added with 10 mL of water and then EtOAc (EtOAc) (EtOAc) 1), the product was obtained in an amount of 0.9 g, yield 90%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 5.33 (s, 1H), 4.83 (s, 1H), 3.36 (t, 4H), 3.16 (t, 1H), 2.86 (t, 4H), 2.29 (m, 2H), 1.35 (t, 12H), 1.25 (t, 12H) ppm; MS-ESI, m/z : 494.4 [M+H] ⁺ .

Step 7) Synthesis of Compound 2-12

Compound 2-11 (1.0 g, 2.0 mmol), compound 2-6A (0.9 g, 1.8 mmol), Pd(PPh ₃ ) ₄ (0.23 g, 0.2 mmol) and K ₂ CO ₃ (0.84 mg, 6.1 mmol) It was suspended in 30 mL of EtOH/H ₂ O (V: V = 3:1) and heated to 90 ° C for 3 h under nitrogen atmosphere. After the reaction was completed, most of the solution was evaporated under reduced pressure and purified (EtOAc) (EtOAc) (EtOAc) , a gray solid of 1.0 g was obtained, yield 69%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (s, 1H), 7.52 (d, 2H), 7.32 (m, 2H), 7.22 (m, 2H), 5.33 (s, 1H), 4.93 (s, 2H), 3.26 (m, 4H), 3.10 (m, 2H), 2.76 (m, 4H), 2.19 (m, 6H), 1.35 (t, 6H), 1.29 (m, 9H), 1.25 (m, 9H) ) ppm; MS-ESI, m/z : 717.8 [M+H] ⁺ .

Step 8) Synthesis of Compound 2-13

At 0 ℃ the HCl / EtOAc (4N, 5mL) was added dropwise to compound 2-12 (1.1g, 1.5mmol) in methylene chloride solvent (15mL) dropwise at room temperature after the reaction was stirred 6h. After completion of the reaction, the reaction mixture was dried and evaporated to ethylamine.

MS-ESI, m/z : 517.9 [M+H] ⁺ .

Step 9) Synthesis of Compound 2

Compound 2-13 (0.60 g, 0.905 mmol), compound 1-14 (0.349 g, 1.99 mmol), EDCI (0.417 g, 2.17 mmol) and ethyl 2-indanoacetate (0.077 g, 0.543 mmol) DIPEA (0.585 g, 4.525 mmol) was added dropwise to the reaction mixture in 10 mL of dichloromethane at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the completion of the reaction, the mixture was stirred for 1 hr (2 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. ) = 1:1), 0.6 g of a gray solid was obtained, and the yield was 79.7%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.36 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 2H), 2.36 (m, 4H), 2.09 (m, 6H), 1.35 (m, 6H) ), 1.05 (m, 12 H) ppm; MS-ESI, m/z : 832.4 [M+H] ⁺ .

Example 3

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 3-7

At 0 ℃ the HCl / EtOAc (4N, 6mL) was added dropwise compound 1-6A (1.8g, 3.7mmol) in methylene chloride solvent (15mL) dropwise with stirring at room temperature after the reaction. After completion of the reaction, the reaction mixture was dried and evaporated to ethylamine.

MS-ESI, m/z : 385.8 [M+H] ⁺ .

Step 2) Synthesis of Compound 3-9

Compound 3-7 (1.5 g, 3.27 mmol), compound 1-14 (0.687 g, 3.92 mmol), EDCI (0.752 g, 3.92 mmol) and ethyl 2-indanoacetate (0.186 g, 1.31 mmol) DIPEA (1.27 g, 9.82 mmol) was added dropwise to the reaction solution in 10 mL of dichloromethane at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the completion of the reaction, the mixture was stirred for 1 hr. EtOAc (V:V). ) = 1:1), a gray solid of 1.4 g was obtained with a yield of 79%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.92 (s, 1H), 7.52 (m, 2H), 7.32 (m, 2H), 5.18 (t, 1H), 4.18 (t, 1H), 3.37 (t, 3H), 3.07 (t, 1H), 2.85 (m, 2H), 2.59 (m, 2H), 2.45 (m, 2H), 1.01 (m, 6H) ppm; MS-ESI, m/z : 543.2 [M +H] ⁺ .

Step 3) Synthesis of Compound 3-12

Compound 1-11 (0.7 g, 1.5 mmol), compound 3-9 (0.873 g, 1.6 mmol), Pd(PPh ₃ ) ₄ (0.17 g, 0.15 mmol) and K ₂ CO ₃ (0.61 mg, 4.4 mmol) It was suspended in 30 mL of EtOH/H ₂ O (V: V = 3:1) and heated to 90 ° C for 3 h under nitrogen atmosphere. After the reaction was completed, most of the solution was evaporated under reduced pressure and purified (EtOAc) (EtOAc) (EtOAc) , a gray solid of 0.8 g was obtained, and the yield was 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.36 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 4H), 2.56 (m, 3H), 2.36 (m, 4H), 2.09 (m, 6H) , 1.05 (m, 9H) ppm; MS-ESI, m/z : 747.5 [M+H] ⁺ .

Step 4) Synthesis of Compound 3-13

To the compound 3-12 (0.7 g, 0.9 mmol) in dichloromethane (15 mL), EtOAc (EtOAc) After completion of the reaction, the reaction mixture was dried and evaporated to ethylamine.

MS-ESI, m/z : 647.4 [M+H] ⁺ .

Step 5) Synthesis of Compound 3

Suspension of compound 3-13 (0.60 g, 0.835 mmol), compound 3-14 (0.21 g, 1.0 mmol), EDCI (0.192 g, 1.0 mmol) and ethyl 2-indanoacetate (0.048 g, 0.334 mmol) DIPEA (0.324 g, 2.505 mmol) was added dropwise to the reaction solution in 10 mL of dichloromethane at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the reaction was completed, aqueous ammonia (2 mL) was added and the mixture was stirred for 1 hr, and the organic phase was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. :V) = 1:1), 0.45 g of a gray solid was obtained, yield 64%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 4H), 7.36 (m, 4H), 7.21 (m, 3H), 5.43 (s, 2H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 4H), 2.36 (m, 4H), 2.09 (m, 6H), 1.05 (m, 6H) ) ppm; MS-ESI, m/z : 837.7 [M+H] ⁺ .

Example 4

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 4-7

To the compound 2-6A (0.8 g, 2 mmol) in dichloromethane (15 mL), EtOAc (EtOAc) After completion of the reaction, the reaction mixture was dried and evaporated to ethylamine.

MS-ESI, m/z : 400.2 [M+H] ⁺ .

Step 2) Synthesis of Compound 4-9

Compound 4-7 (0.9 g, 2.3 mmol), compound 1-14 (0.47 g, 2.7 mmol), EDCI (0.52 g, 2.7 mmol) and ethyl 2-indanoacetate (0.13 g, 0.91 mmol) DIPEA (0.87 g, 6.7 mmol) was added dropwise to the reaction mixture in dichloromethane (10 mL) at 0 ° C. After the completion of the reaction, the mixture was stirred for 1 hr (2 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. ) = 1:1), a gray solid of 0.8 g was obtained, and the yield was 60%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.92 (s, 1H), 7.52 (m, 2H), 7.32 (m, 2H), 5.18 (t, 1H), 4.18 (t, 1H), 3.37 (t, 3H), 2.85 (m, 2H), 2.59 (m, 2H), 2.45 (m, 2H), 1.25 (m, 3H), 1.01 (m, 6H) ppm; MS-ESI, m/z : 557.3 [M +H] ⁺ .

Step 3) Synthesis of Compound 4-12

Compound 1-11 (0.731 g, 1.5 mmol), compound 4-9 (0.853 g, 1.5 mmol), Pd(PPh ₃ ) ₄ (0.17 g, 0.15 mmol) and K ₂ CO ₃ (0.61 mg, 4.4 mmol) It was suspended in EtOH/H ₂ O (30 mL, V:V=3:1) and heated to 90 ° C for 3 h under nitrogen atmosphere. After the reaction was completed, most of the solution was evaporated under reduced pressure, and the mixture was evaporated, evaporated, evaporated, evaporated. 1) A gray solid of 0.7 g was obtained with a yield of 60%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.36 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 4H), 2.56 (m, 2H), 2.36 (m, 4H), 2.09 (m, 6H) ), 1.35 (m, 3H), 1.05 (m, 9H) ppm; MS-ESI, m/z : 792.3 [M+H] ⁺ .

Step 4) Synthesis of Compound 4-13

To the compound 4-12 (0.8 g, 1.0 mmol) in dichloromethane (15 mL), EtOAc (EtOAc) After completion of the reaction, the reaction mixture was dried and purified by ethylamine.

MS-ESI, m/z : 661.5 [M+H] ⁺ .

Step 5) Synthesis of Compound 4

Compound 4-13 (0.60 g, 0.92 mmol), compound 3-14 (0.23 g, 1.1 mmol), EDCI (0.21 g, 1.1 mmol) and ethyl 2-indanoacetate (0.06 g, 0.37 mmol) DIPEA (0.360 g, 2.8 mmol) was added dropwise to the reaction mixture in 10 mL of dichloromethane at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the completion of the reaction, the mixture was stirred for 1 hr (2 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. ) = 1:1), a gray solid of 0.40 g was obtained, and the yield was 50%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 4H), 7.36 (m, 4H), 7.21 (m, 3H), 5.43 (s, 2H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.10 (m, 4H), 2.66 (m, 4H), 2.36 (m, 3H), 2.09 (m, 6H), 1.59 (m, 3H) ), 1.05 (m, 6H) ppm; MS-ESI, m/z : 852.5 [M+H] ⁺ .

Example 5

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 5-3

Triethylamine (0.98 g, 9.68 mmol) was added dropwise to compound 1-6 (2.5 g, 5.81 mmol) and compound 5-2 (1.5 g, 5.81 mmol) in dichloromethane (20 mL) at 0 °C. After the addition, the reaction was carried out at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture was washed with water (10 mL), washed with saturated sodium chloride, and then dried and evaporated to dryness. :V) = 6:1), the product was obtained in 2.0 g, yield 55%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.67 (d, J = 8.6Hz, 1H), 7.20 (d, J = 8.4Hz, 1H), 5.28 (ddd, J = 60.3,53.6,16.3Hz, 2H) , 4.43 (dt, J = 15.2, 8.0 Hz, 1H), 3.82-3.66 (m, 1H), 3.46-3.34 (m, 5H), 3.32 (t, J = 7.5 Hz, 2H), 3.23 (dd, J =10.7, 7.7 Hz, 1H), 3.05 (t, J = 7.4 Hz, 2H), 2.61-2.46 (m, 2H), 2.25-2.12 (m, 2H), 1.77 (s, 1H), 1.45 (d, J =10.3 Hz, 9H) ppm; MS-ESI, m/z : 566.2 [M+H] ⁺ .

Step 2) Synthesis of Compound 5-4

Compound 5-3 (2.1 g, 3.71 mmol), ammonium acetate (1.72 g, 22.3 mmol) was added to a solvent of toluene (20 mL) at 115 ° C for 12 h. After completion of the reaction, water was added and then extracted with EtOAc (30 mL×2) The organic layer was washed with water, dried over anhydrous sodium sulfate

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.16 (s, 1H), 7.10 (d, J = 8.6Hz, 1H), 5.00 (t, J = 7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J = 4.9 Hz, 1H), 3.41-3.32 (m, 4H), 3.11 (dt, J = 15.1, 6.8 Hz, 5H), 2.78 (d, J = 47.9 Hz, 1H), 2.63-2.39 ( m, 2H), 2.25-2.15 (m, 2H), 1.51 (s, 9H) ppm; MS-ESI, m/z : 546.3 [M+H] ⁺ .

Step 3) Synthesis of Compound 5-6

Compound 5-4 (1.55 g, 2.84 mmol), pinacol borate 1-10 (0.866 g, 3.41 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (0.232 g, 0.284 mmol) and AcOK (0.835 g, 8.52 mmol) were suspended in 20 mL of DMF and heated to 100 ° C under nitrogen for 4 h. The reaction solution was cooled to room temperature, and then added with 10 mL of water, and the mixture was applied to EtOAc (EtOAc). :1), the product was obtained in 1.3 g, yield 87%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.16 (s, 1H), 7.10 (d, J = 8.6Hz, 1H), 5.00 (t, J = 7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J = 4.9 Hz, 1H), 3.41-3.32 (m, 4H), 3.11 (m, 5H), 2.78 (d, 1H), 2.63-2.39 (m, 2H), 2.25-2.15 (m, 2H) , 1.51 (s, 9H), 1.25 (m, 12H) ppm; MS-ESI, m/z : 524.3 [M+H] ⁺ .

Step 4) Synthesis of Compound 5-7

Compound 5-6 (0.500 g, 0.955 mmol), compound 4-9 (0.53 g, 0.955 mmol), Pd(PPh ₃ ) ₄ (0.110 g, 0.095 mmol) and K ₂ CO ₃ (0.391 mg, 2.87 mmol) It was suspended in 30 mL of EtOH/H ₂ O (V: V = 3:1) and heated to 90 ° C for 3 h under nitrogen atmosphere. After the reaction was completed, the mixture was evaporated to dryness crystals crystals crystals crystals 2), 0.5 g of a gray solid was obtained, and the yield was 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.36 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 3.11 (m, 5H), 3.00 (m, 4H), 2.66 (m, 4H), 2.56 (m, 2H), 2.36 (m, 3H) ), 2.09 (m, 6H), 1.35 (m, 3H), 1.05 (m, 9H) ppm; MS-ESI, m/z : 804.8 [M+H] ⁺ .

Step 5) Synthesis of Compound 5-8

HCl/EtOAc (4N, 4 mL) was added dropwise to a solution of compound 5-7 (0.6 g, 0.7 mmol) in dichloromethane (15 mL). After completion of the reaction, the reaction mixture was dried and evaporated to ethylamine.

MS-ESI, m/z : 705.4 [M+H] ⁺ .

Step 6) Synthesis of Compound 5

Compound 5-8 (0.55 g, 0.72 mmol), compound 3-14 (0.178 g, 0.852 mmol), EDCI (0.163 g, 0.852 mmol) and ethyl 2-indanoacetate (0.04 g, 0.284 mmol) DIPEA (0.275 g, 2.13 mmol) was added dropwise to the reaction mixture in 10 mL of dichloromethane at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature for 2 h. After the completion of the reaction, the mixture was stirred for 1 hr (2 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. ) = 1:3), a gray solid of 0.35 g was obtained, and the yield was 55%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.52 (d, 4H), 7.36 (m, 4H), 7.31 (m, 3H), 5.43 (s, 2H), 5.10 (s, 2H), 3.56 (m, 4H), 3.21 (m, 5H), 3.09 (m, 4H), 3.01 (m, 4H), 2.66 (m, 4H), 2.26 (m, 2H), 2.09 (m, 6H) ), 1.59 (m, 3H), 1.05 (m, 6H) ppm; MS-ESI, m/z : 896.0 [M+H] ⁺ .

Example 6

synthetic route:

Synthesis step Step 1) Synthesis of Compound 7-2A

6-Bromo 2-naphthylamine hydrochloride 7-1A (2.00 g, 7.73 mmol, 1.00 eq) was added to DMF (15 mL), then DMAP (0.02 g, 0.16 mmol, 0.02 eq), Et ₃ N (3.70) </RTI></RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; After the reaction was completed, the reaction mixture was poured into 30 mL of water, and a white solid was precipitated. After stirring for 0.5 hr, the mixture was directly filtered, and the filter cake was washed three times with water and dried to give the product 1.78 g of white solid.

^{1 H NMR (400MHz, DMSO- d} 6): δ 10.20 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 8.9Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.56 (dd, J = 8.7, 1.5 Hz, 1H), 2.11 (s, 3H) ppm.

Step 2) Synthesis of Compound 7-3A

Compound 7-2A (5.0 g, 18.93 mmol, 1.00 eq), KNO ₃ (2.30 g, 22.71 mmol, 1.20 eq) was dissolved in AcOH (35 mL) solvent, and H ₂ SO _{4 was} added dropwise at 20 ° C ( 5.14 mL, 94.65 mmol, 5.00 eq), after completion of the addition, the reaction was carried out at 30 ° C for 7 h. After the completion of the reaction, the mixture was poured into water (50 mL), and a brown solid was precipitated, which was directly filtered. The filter cake was washed with water (20 mL × 3) and dried to give 5.34 g of a brown solid.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.98 (s, 1H), 8.49 (d, J = 9.2Hz, 1H), 8.03 (s, 1H), 7.92 (t, J = 8.0Hz, 2H), 7.72 (dd, J = 9.2, 1.4 Hz, 1H), 2.31 (s, 3H) ppm.

Step 3) Synthesis of Compound 7-4A

Compound 7-3A (3.78 g, 12.23 mmol, 1.00 eq) was added to THF (20 mL) and dissolved in a flask, and then 6N HCl (10.5 mL, 61.10 mmol, 5.00 eq) was added and heated to 80 ° C for 7 h. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was poured into 50 mL of ice water, and a yellow solid was precipitated, filtered, and the filter cake was washed with water (15 mL × 3) and dried to give a product of 3.00 g of a brown solid, yield 91.90%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.60 (d, J = 9.3Hz, 1H), 7.84 (s, 1H), 7.68 (t, J = 8.6Hz, 2H), 6.94 (d, J = 9.0Hz , 1H), 6.46 (s, 2H) ppm; MS-ESI, m/z : 267.1 [M+H] ⁺ .

Step 4) Synthesis of Compound 7-5A

Compound 7-4A (4.00 g, 14.97 mmol, 1.00 eq) was dissolved in 1,4-dioxane (30 mL), and Na ₂ S ₂ O ₄ (8.68 g, 44.93 mmol, 3.00) was added dropwise under ice bath. Eq), an aqueous solution of Na ₂ CO ₃ (1.58 g, 14.97 mmol, 1.00 eq) (30 mL). After the reaction was completed, it was poured directly into water (30 mL), and the mixture was filtered, filtered, and filtered, washed with water (15mL×3), and dried to give a product of product:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.89 (d, J = 1.4Hz, 1H), 7.60 (d, J = 9.0Hz, 1H), 7.49 (dd, J = 9.0,1.7Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 3.70 (d, J = 18.9 Hz, 4H) ppm; MS-ESI, m/z : 237.2 [M+H] ⁺ .

Step 5) Synthesis of Compound 7-6A

( S ) -N -tert-Butoxycarbonylpyrrolidine-2-carboxylic acid (9.06 g, 42.17 mmol, 1.00 eq), ethyl chloroformate (4.58 g, 42.17 g, 1.00 eq) Et ₃ N (8.8 mL, 63.26 mmol, 1.50 eq) was slowly added dropwise at -10 ° C. After the addition was completed, the mixture was kept for 10 min, filtered, and the filter cake was washed with DCM (10 mL×2) and the filtrate was used. The compound 7-5A (10 g, 42.17 mmol, 1.00 eq) was dissolved in DCM (80 mL), and the mixture was cooled to -5 ° C, and the filtrate was added dropwise, and the mixture was allowed to react at room temperature for 2 h. After the reaction was completed, water (100 mL) was directly added, and the mixture was separated, and then, the aqueous phase was extracted with DCM (50mL×2), and the organic phase was combined, dried, and dried to give a crude product of 18.00 g of brownish black solid, yield 95.18%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.90 (s, 1H), 7.65 (d, J = 9.0Hz, 1H), 7.47 (d, J = 8.1Hz, 1H), 7.40 (d, J = 8.6Hz , 1H), 7.16 (d, J = 8.6 Hz, 1H), 4.61-4.34 (m, 3H), 4.00 (d, J = 5.1 Hz, 1H), 2.43 (s, 2H), 2.13 (dd, J = 12.8, 7.1 Hz, 2H), 1.90-1.63 (m, 2H), 1.54 (s, 9H) ppm; MS-ESI, m/z : 434.2 [M+H] ⁺ .

Step 6) Synthesis of Compound 7-7A

Compound 7-6A (18.00 g, 43.27 mmol, 1.00 eq) was added to acetic acid (80 mL) and heated directly to 50 ° C for 5 h. After the reaction was completed, a portion of acetic acid was removed, and then EtOAc (100 mL), water (50 mL) was added and the mixture was stirred, and the residue was evaporated to pH = 8 and then the mixture was separated, and the aqueous phase was extracted with EtOAc (20 mL×2). The organic phase was washed with water (50 mL), and then evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.92 (s, 1H), 7.52 (m, 2H), 7.32 (m, 2H), 5.18 (t, 1H), 3.37-3.21 (t, 2H), 2.59- 2.30 (t, 2H), 2.35-2.11 (m, 2H), 1.26 (t, 9H) ppm; MS-ESI, m/z : 416.2 [M+H] ⁺ .

Step 7) Synthesis of Compound 7-1

Compound 5-6 (600 mg, 1.15 mmol, 1.0 eq), Compound 7-7A (477 mg, 1.15 mmol, 1.0 eq), potassium carbonate (316 mg, 2.29 mmol, 2.0 eq), tetratriphenylphosphine palladium (29 mg, 0.034 mmol, 0.03 eq) was added to 10 mL of ethanol and 3 mL of water and reacted at 90 ° C for 18 h. The reaction mixture was poured into 50 mL of water and extracted with dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate. A white solid product of 0.68 g was obtained in a yield of 80.9%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.61-10.64 (m, 2H), 8.67 (s, 1H), 7.79 (dd, J = 98.4,31.8Hz, 5H), 7.39 (d, J = 7.2Hz, 1H), 7.21 (s, 1H), 5.26 (d, J = 4.3 Hz, 1H), 5.06 (t, J = 7.3 Hz, 1H), 3.93-3.78 (m, 1H), 3.62-3.47 (m, 2H) ), 3.43 - 3.29 (m, 4H), 3.27 - 3.04 (m, 5H), 2.90 - 2.70 (m, 1H), 2.51 (ddd, J = 19.3, 13.9, 6.6 Hz, 2H), 2.29 (d, J = 4.2 Hz, 2H), 2.17-2.03 (m, 4H), 1.54 (d, J = 11.0 Hz, 18H) ppm; MS-ESI, m/z : 733.20 [M+H] ⁺ .

Step 8) Synthesis of Compound 7-2

Compound 7-1 (0.68 g, 0.93 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 63.1%.

^{1 H NMR (600MHz, DMSO- d} 6): δ 8.48 (d, J = 8.3Hz, 1H), 8.04 (s, 1H), 7.78 (d, J = 50.0Hz, 1H), 7.73-7.51 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 4.46 (t, J = 7.0 Hz, 1H), 4.20 (t, J = 7.7 Hz, 1H), 3.32 (d, J = 7.2 Hz, 4H), 3.25 (s, 3H), 3.08 (dt, J = 24.6, 6.9 Hz, 4H), 3.01-2.91 (m, 2H), 2.74 (dd, J = 10.1, 5.5 Hz, 1H) ), 2.40 (dd, J = 13.6, 7.1 Hz, 1H), 2.29-2.15 (m, 2H), 2.05 (dd, J = 13.7, 6.8 Hz, 2H), 1.82 (td, J = 13.5, 6.3 Hz, 2H), 1.69-1.52 (m, 1 H) ppm; MS-ESI, m/z : 533.3 [M+H] ⁺ .

Step 9) Synthesis of Compound 7

Compound 7-2 (250 mg, 0.469 mmol, 1.0 eq), Compound 7-3 (209 mg, 1.03 mmol, 2.2 eq), ethyl 2- cyanoacetate (61 mg, 0.43 mmol, 0.8 eq) and DIPEA (35 mg) , 0.27 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 5:10:1), 300 mg of a white solid product was obtained in a yield of 72.7%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.35-10.31 (m, 2H), 8.65 (s, 1H), 7.91 (d, J = 45.9Hz, 2H), 7.69 (d, J = 23.4Hz, 2H) , 7.48 (s, 1H), 7.36 (d, J = 6.2 Hz, 1H), 7.15 (d, J = 19.1 Hz, 1H), 5.93-5.71 (m, 2H), 5.70-5.54 (m, 1H), 5.38 (t, J = 7.7 Hz, 1H), 4.83-4.31 (m, 2H), 4.14 - 3.98 (m, 1H), 3.88 (d, J = 20.9 Hz, 2H), 3.73 (d, J = 5.9 Hz) , 6H), 3.66-3.54 (m, 2H), 3.45 (d, J = 8.8 Hz, 1H), 3.39 (t, J = 22.3 Hz, 6H), 3.24 - 2.88 (m, 7H), 2.79 (dd, J =10.1, 9.2 Hz, 1H), 2.72-2.58 (m, 1H), 2.51 (dd, J = 12.3, 7.7 Hz, 1H), 2.36 (dd, J = 23.8, 11.5 Hz, 1H), 2.22-2.11 (m, 2H), 1.99 (s, 2H), 1.17 (dd, J = 18.8, 5.7 Hz, 4H), 0.89 (dd, J = 6.9, 4.0 Hz, 2H) ppm; MS-ESI, m/z : 879.3 [M+H] ⁺ .

Example 7

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 10-1

Compound 2-12 (1.25 g, 1.74 mmol, 1.0 eq) was added to DCM (15 mL). The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 89%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.43 (s, 1H), 8.00 (s, 1H), 7.71 (d, J = 12.3Hz, 4H), 7.40 (d, J = 7.9Hz, 1H), 7.21 (s, 1H), 4.71 (dd, J = 8.5, 5.9 Hz, 1H), 4.58-4.43 (m, 1H), 3.43 (ddd, J = 30.0, 14.4, 6.3 Hz, 2H), 3.25-3.00 (m , 4H), 2.42 (dd, J = 12.8, 8.4 Hz, 1H), 2.30 (dt, J = 20.9, 8.3 Hz, 1H), 2.24 - 2.08 (m, 4H), 1.99 (dd, J = 12.6, 5.9 Hz, 2H), 1.52-1.37 (m, 2H), 1.34-1.25 (m, 6H) ppm; MS-ESI, m/z : 517.3 [M+H] ⁺ .

Step 2) Synthesis of Compound 10

Compound 10-1 (280 mg, 0.54 mmol, 1.0 eq), Compound 10-2 (294 mg, 1.36 mmol, 2.5 eq), ethyl 2- cyanoacetate (61 mg, 0.43 mmol, 0.8 eq) and DIPEA (35 mg) , 0.27 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 368 mg of a pale yellow solid product was obtained in a yield of 74.2%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.21-10.33 (m, 2H), 8.80-8.46 (m, 1H), 8.07-7.85 (m, 2H), 7.82-7.62 (m, 2H), 7.51 (dd , J = 42.1, 33.3 Hz, 1H), 7.33 (s, 1H), 7.26-7.04 (m, 1H), 5.49 (dt, J = 14.2, 7.7 Hz, 2H), 5.28-5.16 (m, 1H), 4.75-4.62 (m, 1H), 4.41-4.29 (m, 2H), 4.03 (dd, J = 16.4, 9.9 Hz, 2H), 3.90-3.68 (m, 6H), 3.54-2.94 (m, 10H), 2.42 (ddd, J = 33.7, 17.1, 9.5 Hz, 2H), 2.20-2.08 (m, 3H), 1.90 (ddd, J = 52.2, 26.1, 7.8 Hz, 10H), 1.68-1.49 (m, 3H), 1.40-1.27 (m, 6H), 1.17 (d, J = 5.8 Hz, 2H) ppm; MS-ESI, m/z : 915.5 [M+H] ⁺ .

Example 8

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 11-2

Compound 4-7 (1.27 g, 2.7 mmol), compound 7-3 (0.62 g, 3 mmol), EDCI (0.62 g, 3.3 mmol) and ethyl 2-indanoacetate (0.15 g, 1.1 mmol) DIPEA (1.1 g, 8.2 mmol) was added dropwise to the reaction mixture in dichloromethane (20 mL) at 0 ° C. The solvent was evaporated, the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj = 3: 1) gave 0.93 g of a brown solid, yield 60%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 13.71-10.69 (m, 1H), 8.57-8.34 (m, 1H), 7.94 (dd, J = 70.9,22.8Hz, 2H), 7.59 (dd, J = 24.5 , 15.0 Hz, 1H), 7.43 (s, 1H), 5.96 (dd, J = 87.7, 33.4 Hz, 1H), 5.46 (dd, J = 38.5, 30.6 Hz, 1H), 4.73-4.23 (m, 2H) , 3.70 (s, 3H), 3.36 (s, 3H), 2.55-2.12 (m, 2H), 2.04 (s, 3H), 1.44-1.35 (m, 3H), 1.13 (d, J = 5.9 Hz, 3H MS (ESI, pos. ion) m/z : 572.2 [M+H] ⁺ .

Step 2) Synthesis of Compound 11-3

Compound 5-6 (0.65 g, 1.2 mmol), compound 11-2 (0.69 g, 1.2 mmol), Pd(PPh ₃ ) ₄ (0.2 g, 0.12 mmol) and K ₂ CO ₃ (0.6 g, 3.6 mmol) It was suspended in a mixed solvent of EtOH (20 mL) and water (4 mL), and heated to 90 ° C under a nitrogen atmosphere. The mixture was extracted with EtOAc (EtOAc) (EtOAc) Purification with V:V) = 1:3) gave 0.45 g of a brown solid.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 13.55-10.67 (m, 1H), 8.05-7.82 (m, 2H), 7.75-7.59 (m, 3H), 7.41-7.29 (m, 1H), 7.18 (d , J = 8.5 Hz, 1H), 6.21-5.87 (m, 1H), 5.67-5.36 (m, 1H), 5.05 (t, J = 7.3 Hz, 1H), 4.46 (ddd, J = 76.6, 33.7, 27.1 Hz, 2H), 3.92-3.80 (m, 3H), 3.75-3.66 (m, 2H), 3.54 (s, 1H), 3.37 (s, 6H), 3.30 (s, 2H), 3.20-3.04 (m, 6H), 2.64-2.42 (m, 3H), 2.30 - 1.95 (m, 6H), 1.51 (s, 9H), 1.26 (m, 6H) ppm; MS (ESI, pos.ion) m/z : 820.4 [ M+H] ⁺ .

Step 3) Synthesis of Compound 11-4

The compound 11-3 (0.45 g, 0.54 mmol) was dissolved in DCM (10 mL), and the ethyl acetate solution (4M/L, 3 mL) was slowly added dropwise at 0 ° C. After the addition was completed, the reaction was carried out for 3 h at room temperature. . The solvent was spun off and the residue was taken with ethyl acetate and filtered. The filter cake was dissolved in water (10 mL), and the pH was adjusted to 8-9 with potassium carbonate, and filtered to give the product 0.35 g.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 13.55-10.67 (m, 1H), 8.05-7.82 (m, 2H), 7.75-7.59 (m, 3H), 7.41-7.29 (m, 1H), 7.18 (d , J = 8.5Hz, 1H), 6.21-5.87 (m, 1H), 5.67-5.36 (m, 1H), 5.05 (t, J = 7.3Hz, 1H), 4.46 (ddd, J = 76.6,33.7,27.1 Hz, 2H), 3.92-3.80 (m, 3H), 3.75-3.66 (m, 2H), 3.54 (s, 1H), 3.37 (s, 6H), 3.30 (s, 1H), 3.20-3.04 (m, 6H), 2.64-2.42 (m, 3H), 2.30 - 1.95 (m, 7H), 1.26 (m, 6H) ppm; MS (ESI, pos.ion) m/z : 720.2 [M+H] ⁺ .

Step 4) Synthesis of Compound 11

Compound 11-4 (0.35 g, 0.49 mmol), compound 11-5 (0.1 g, 0.53 mmol), EDCI (0.11 g, 0.58 mmol) and ethyl 2-indanoacetate (0.028 g, 0.19 mmol) DIPEA (0.19 g, 1.5 mmol) was added dropwise to the reaction mixture in dichloromethane (20 mL) at 0 ° C. The solvent was evaporated, the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjj 2:1), 0.3 g of a white solid was obtained with a yield of 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.59 (s, 1H), 7.98 (d, J = 13.6Hz, 1H), 7.68 (dd, J = 20.5,8.0Hz, 3H), 7.35 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 5.98-5.68 (m, 1H), 5.56 (dd, J = 20.1, 6.7 Hz, 2H), 5.36-5.24 (m, 2H), 4.70-4.28 (m, 3H), 4.19-3.82 (m, 3H), 3.79-3.56 (m, 6H), 3.40 (s, 6H), 3.29 (d, J = 11.8 Hz, 2H), 3.14 - 3.04 ( m, 6H), 2.34-1.97 (m, 5H), 1.83-1.40 (m, 4H), 1.39-1.22 (m, 7H), 1.13 (d, J = 6.0 Hz, 2H), 0.91 - 0.71 (m, 6H) ppm; MS (ESI, pos.ion) m/z : 891.5 [M+H] ⁺ .

Example 9

synthetic route:

Synthesis steps:

Compound 10-0 (280 mg, 0.54 mmol, 1.0 eq), Compound 11-5 (256 mg, 1.36 mmol, 2.5 eq), ethyl 2- cyanoacetate (61 mg, 0.43 mmol, 0.8 eq) and DIPEA (35 mg) , 0.27 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. The product was obtained as a pale yellow solid, 150 mg, yield 32.2%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.96-10.36 (m, 2H), 8.83-8.50 (m, 1H), 7.94 (dd, J = 39.4,12.5Hz, 2H), 7.83-7.62 (m, 2H ), 7.46 (dd, J = 92.2, 12.5 Hz, 2H), 7.21 (d, J = 17.5 Hz, 1H), 5.60-5.40 (m, 2H), 5.26 (dd, J = 20.5, 11.7 Hz, 1H) , 4.82-4.63 (m, 1H), 4.39-4.23 (m, 2H), 3.72 (d, J = 6.9 Hz, 6H), 3.25-3.01 (m, 4H), 2.57-2.25 (m, 2H), 2.14 (dd, J = 20.5, 14.8 Hz, 3H), 2.05-1.95 (m, 1H), 1.94-1.77 (m, 3H), 1.66 (dd, J = 7.2, 4.4 Hz, 3H), 1.30 (d, J) = 5.2 Hz, 6H), 1.20 (t, J = 13.7 Hz, 4H), 1.05 (dd, J = 15.6, 6.7 Hz, 2H), 0.99-0.94 (m, 2H), 0.89 (dd, J = 13.8, 6.3 Hz, 6H), 0.77 (dd, J = 12.2, 6.6 Hz, 2H) ppm; MS-ESI, m/z : 859.5 [M+H] ⁺ .

Example 10

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 15-2

Compound 15-1 (0.664 g, 2.73 mmol, 1.05 eq) and compound 1-6 (1.0 g, 2.6 mmol, 1.0 eq) were added to acetonitrile (10 mL), and triethylamine (0.39 g) was added dropwise at 0 °C. , 3.9 mmol, 1.5 eq), and reacted at room temperature for 2 h. The solvent was evaporated, EtOAc (EtOAc)EtOAc.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (d, J = 8.5Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 5.54-5.35 (m, 1H), 5.20 (dd, J = 25.2, 13.6 Hz, 1H), 4.62 (dt, J = 21.6, 8.3 Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 1H), 3.06 (t, J = 7.5 Hz, 2H) ), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J = 14.2, 7.3 Hz, 2H), 1.48 (m, 13H), 0.9 (t, J = 5.6 Hz, 3H) ppm.

Step 2) Synthesis of Compound 15-3

Compound 15-2 (1.42 g, 2.6 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.31 g of a pale yellow solid was obtained, yield 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (d, J = 188.0Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz , 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61-3.22 (m, 1H) , 3.12 (dt, J = 15.0, 7.1 Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (m, 12H), 0.9 (t, J = 5.6 Hz, 3H) ) ppm; MS-ESI, m/z : 530.2 [M+H] ⁺ .

Step 3) Synthesis of Compound 15-4

Compound 15-3 (1.26 g, 2.37 mmol, 1.0 eq), EtOAc (0.63 g, 2.49 mmol, 1.05 eq), potassium acetate (0.70 g, 7.1 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water (60 mL), EtOAc (EtOAc m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (d, J = 186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48-3.40 (m, 1H), 3.38-2.88 (m, 4H), 2.80-2.59 (m , 1H), 2.19-2.07 (m, 2H), 1.52-1.34 (m, 12H), 1.36 (s, 12H), 0.9 (t, J = 5.6 Hz, 3H) ppm; MS-ESI, m/z : 508.3 [M+H] ⁺ .

Step 4) Synthesis of Compound 15-6

Compound 15-4 (558 mg, 1.10 mmol, 1.0 eq), Compound 2-6A (473 g, 1.10 mmol, 1.0 eq), potassium carbonate (0.30 g, 2.21 mmol, 2.0 eq), tetratriphenylphosphine palladium (38 mg) , 0.033 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1), 0.70 g of a white solid product was obtained, yield 87%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.30-3.11 (m, 4H), 2.44 -2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00-1.86 (m, 2H), 1.55-1.34 (m, 21H), 1.32-1.18 (m, 3H), 0.9 (t, J = 5.6 Hz, 3H) ppm; MS-ESI, m/z : 731.3 [M+H] ⁺ .

Step 5) Synthesis of Compound 15-7

Compound 15-6 (0.70 g, 0.95 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 85%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.15 (m, 1H), 3.15-2.85 (m, 6H), 2.28 (ddd, J = 39.8, 14.5, 9.4 Hz, 3H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 5H), 1.32-1.18 (m, 3H), 0.9 (t, J = 5.6 Hz) , 3H) ppm; MS-ESI, m/z : 531.4 [M+H] ⁺ .

Step 6) Synthesis of Compound 15

Compound 15-6 (265 mg, 0.5 mmol, 1.0 eq), Compound 1-14 (193 mg, 1.1 mmol, 2.2 eq), ethyl 2- cyanoacetate (57 mg, 0.4 mmol, 0.8 eq) and DIPEA (32 mg) , 0.25 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 232 mg of a white solid product was obtained in a yield of 55%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 3H), 2.72 (dd, J = 26.7, 14.6) Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 3H), 1.32-1.18 (m, 4H) 0.89 (m, 15H) ppm ;MS-ESI, m/z : 845.4 [M+H] ⁺ .

Example 11

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 16-2

Compound 16-1 (0.81 g, 2.73 mmol, 1.05 eq) and compound 1-6 (1.0 g, 2.6 mmol, 1.0 eq) were added to acetonitrile (10 mL) and triethylamine (0.39 g) was added dropwise at 0 °C. , 3.9 mmol, 1.5 eq), and reacted at room temperature for 2 h. The solvent was evaporated, and water (20 mL) was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (d, J = 8.5Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 6.50 (t, 1H), 5.54-5.35 (m, 1H) , 5.20 (dd, J = 25.2, 13.6 Hz, 1H), 4.62 (dt, J = 21.6, 8.3 Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 4H), 3.06 (t , J = 7.5 Hz, 2H), 2.83 - 2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J = 14.2, 7.3 Hz, 2H), 1.48 (m, 10H) ppm.

Step 2) Synthesis of Compound 16-3

Compound 16-2 (1.56 g, 2.6 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.38 g of a pale yellow solid was obtained, yield 91%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (d, J = 188.0Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz , 1H), 6.50 (t, 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61 -3.22 (m, 4H), 3.12 (dt, J = 15.0,7.1Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (s, 9H) ppm; MS- ESI, m/z : 582.2 [M+H] ⁺ .

Step 3) Synthesis of Compound 16-4

Compound 16-3 (1.38 g, 2.37 mmol, 1.0 eq), bispinol borate (0.63 g, 2.49 mmol, 1.05 eq), potassium acetate (0.70 g, 7.1 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water (60 mL), EtOAc (EtOAc m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (d, J = 186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 6.5 (t, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48 (dd, J = 35.4, 12.0 Hz, 1H), 3.38- 2.88 (m, 7H), 2.80-2.59 (m, 1H), 2.19-2.07 (m, 2H), 1.52 (s, 9H), 1.36 (s, 12H) ppm; MS-ESI, m/z : 560.3 [ M+H] ⁺ .

Step 4) Synthesis of Compound 16-5

Compound 16-4 (615 mg, 1.10 mmol, 1.0 eq), Compound 2-6A (473 g, 1.10 mmol, 1.0 eq), potassium carbonate (0.30 g, 2.21 mmol, 2.0 eq), tetratriphenylphosphine palladium (38 mg) , 0.033 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.82 g was obtained in a yield of 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 6.50 (t, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.30-3.11 (m,7H),2.44-2.21(m,2H), 2.20-2.08(m,2H),2.00-1.86(m,2H),1.55(d, J =6.7Hz,18H),1.32-1.18(m , 3H) ppm; MS-ESI, m/z : 783.3 [M+H] ⁺ .

Step 5) Synthesis of Compound 16-6

Compound 16-5 (0.82 g, 1.05 mmol, 1.0 eq) was added to DCM (10 mL). The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 89%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 6.50 (t, 1H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.15 (m, 4H), 3.15-2.85 (m, 6H), 2.28 (ddd, J = 39.8, 14.5, 9.4 Hz, 3H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 2H), 1.32-1.18 (m, 3H) ppm; MS-ESI, m/z : 583.4 [M+H] ⁺ .

Step 6) Synthesis of Compound 16

Compound 16-6 (291 mg, 0.5 mmol, 1.0 eq), Compound 1-14 (193 mg, 1.1 mmol, 2.2 eq), ethyl 2- cyanoacetate (57 mg, 0.4 mmol, 0.8 eq) In 15 mL), EDCI (211 mg, 1.1 mmol, 2.2 eq) was further added and allowed to react at room temperature for 3 h. The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. :1), 256 mg of a white solid product was obtained in a yield of 57%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 3H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 3H), 3.06 (s, 4H), 2.72 (dd, J = 26.7, 14.6) Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 1H), 1.32-1.18 (m, 3H) 0.89 (dd, J = 16.3) , 5.8 Hz, 12H) ppm; MS-ESI, m/z : 897.4 [M+H] ⁺ .

Example 12

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 22-2

Compound 22-1 (0.63 g, 2.7 mmol, 1.05 eq) and compound 1-6 (1.0 g, 2.6 mmol, 1.0 eq) were added to acetonitrile (10 mL) and triethylamine (0.39 g) was added dropwise at 0 °C. , 3.9 mmol, 1.5 eq), and reacted at room temperature for 2 h. The solvent was evaporated, and water (20 mL) was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (d, J = 8.5Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 5.54-5.35 (m, 1H), 5.20 (dd, J = 25.2, 13.6 Hz, 1H), 4.62 (dt, J = 21.6, 8.3 Hz, 1H), 4.06-3.52 (m, 3H), 3.31 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 7.5) Hz, 2H), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J = 14.2, 7.3 Hz, 2H), 1.48 (d, J = 10.1 Hz, 10H) ppm.

Step 2) Synthesis of Compound 22-3

Compound 22-2 (1.40 g, 2.59 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.23 g of a pale yellow solid was obtained, yield 91.2%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (d, J = 188.0Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz , 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61-3.22 (m, 2H) , 3.12 (dt, J = 15.0, 7.1 Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (s, 9H) ppm; MS-ESI, m/z : 520.2 [M+H] ⁺ .

Step 3) Synthesis of Compound 22-4

Compound 22-3 (1.23 g, 2.37 mmol, 1.0 eq), bis-n--------------- ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water and filtered to give a white solid crystals.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (d, J = 186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48 (dd, J = 35.4, 12.0 Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m, 1H), 2.19-2.07 (m, 2H), 1.52 (s, 9H), 1.36 (s, 12H) ppm; MS-ESI, m/z : 498.4 [M+H] ⁺ .

Step 4) Synthesis of Compound 22-5

Compound 22-4 (550 mg, 1.10 mmol, 1.0 eq), Compound 7-7A (460 g, 1.10 mmol, 1.0 eq), potassium carbonate (0.30 g, 2.21 mmol, 2.0 eq), tetratriphenylphosphine palladium (38 mg) , 0.033 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.765 g was obtained in a yield of 97.8%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.14 (dd, J = 20.9, 13.7 Hz) , 5H), 2.81-2.62 (m, 1H), 2.44-2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J = 6.7 Hz, 18H ) ppm; MS-ESI, m/z : 707.4 [M+H] ⁺ .

Step 5) Synthesis of Compound 22-6

Compound 22-5 (0.76 g, 1.1 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 92%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.21 (m, 2H), 3.15-2.85 (m, 7H), 2.28 (ddd, J = 39.8, 14.5, 9.4 Hz, 3H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 2H) ppm; MS-ESI, m/z : 507.4 [M+H] ⁺ .

Step 6) Synthesis of Compound 22

Compound 22-6 (280 mg, 0.552 mmol, 1.0 eq), Compound 1-14 (213 mg, 1.22 mmol, 2.2 eq), ethyl 2- cyanoacetate (62 mg, 0.44 mmol, 0.8 eq) and DIPEA (35 mg) , 0.27 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 5:10:1), 270 mg of a white solid product was obtained in a yield of 59.50%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J = 26.7, 14.6) Hz, 1H), 2.59-2.07 (m, 5H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J = 16.3, 5.8 Hz, 12H) ppm; MS-ESI, m/z : 821.2 [M+H] ⁺ .

Example 13

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 31-1

Compound 1-11 (0.8 g, 1.7 mmol, 1 eq), compound 1-5A (0.73 g, 1.5 mmol, 0.9 eq), Pd (PPh ₃ ) ₄ (0.20 g, 0.17 mmol, 0.1 eq) and K ₂ CO ₃ (0.69 mg, 5.0 mmol, 3 eq) was suspended in EtOH/H ₂ O (30 mL, V:V=3:1) and heated to 90 ° C for 3 h under nitrogen. After the reaction was completed, most of the solution was spun out, and then extracted with DCM (20 mL×2). The organic phase was combined, dried, dried, and purified by silica gel column chromatography (PE: EA (V:V) = 2:1). Gray solid 0.5 g, yield 40%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (s, 1H), 7.52 (d, 2H), 7.22 (m, 2H), 5.33 (s, 1H), 4.93 (s, 2H), 3.26 (m, 4H), 3.20 (m, 2H), 3.10 (m, 4H), 2.76-2.62 (m, 4H), 2.19-1.95 (m, 6H), 1.25 (m, 9H), 1.29 (m, 9H) ppm; MS-ESI, m/z : 691.5 [M+H] ⁺ .

Step 2) Synthesis of Compound 31-2

At 0 ℃ the HCl / EtOAc (4N, 4mL) was added dropwise to 31-1 (0.5g, 0.7mmol, 1eq) in dichloromethane solvate (15mL) dropwise at room temperature after the reaction was stirred 6h. After completion of the reaction, the reaction mixture was dried and purified with ethyl acetate.

MS-ESI, m/z : 491.6 [M+H] ⁺ .

Step 3) Synthesis of Compound 31

Compound 31-2 (0.40 g, 0.82 mmol, 1 eq), compound 1-14 (0.316 g, 1.8 mmol, 2.2 eq), EDCI (0.377 g, 1.97 mmol, 2.4 eq) and ethyl 2- cyanoacetate (0.07 g, 0.49 mmol, 0.6 eq) was suspended in dichloromethane (10 mL). DIPEA (0.530 g, 4.1 mmol, 5 eq) was added dropwise to the reaction mixture at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature. 2h. After the reaction was completed, the mixture was stirred with EtOAc (V: V). 1:1), a gray solid of 0.35 g was obtained with a yield of 53%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.62 (d, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56-3.42 ( m, 4H) 3.31 (m, 2H), 3.16-2.83 (m, 4H), 2.72-2.63 (m, 4H), 2.56-2.41 (m, 4H), 2.38 (m, 2H), 2.36-2.21 (m , 4H), 2.09-1.82 (m, 6H), 1.05 (m, 12H) ppm; MS-ESI, m/z : 806.3 [M+H] ⁺ .

Example 14

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 32-2

Compound 1-6 (1.45g, 2.65mmol, 1.0eq) and (3 S) -2- (t-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid 32-1 (0.82 g, 0.34 mmol, 1.1 eq) was added to acetonitrile (10 mL), and triethylamine (0.39 g, 3.9 mmol, 1.5 eq) was added dropwise at 0 ° C. The solvent was evaporated, and water (20 mL) was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.74-7.61 (m, 1H), 7.20 (d, J = 8.5Hz, 1H), 5.28 (ddd, J = 62.1,49.1,16.3Hz, 2H), 4.32 ( d, J = 51.5 Hz, 1H), 3.95 (d, J = 29.9 Hz, 1H), 3.32 (t, J = 6.0 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.97-2.82 ( m,1H), 2.27-2.11 (m, 2H), 2.06-1.94 (m, 1H), 1.85-1.76 (m, 1H), 1.69-1.62 (m, 2H), 1.56 (dd, J = 11.3, 6.9 Hz, 1H), 1.46 (d, J = 18.4 Hz, 9H), 1.36-1.30 (m, 1 H) ppm.

Step 2) Synthesis of Compound 32-3

Compound 32-2 (1.45 g, 2.65 mmol, 1.0 eq) and ammonium acetate (1.22 g, 15.9 mmol, 6.0 eq) were added to toluene (10 mL) and reacted at 115 ° C for 15 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.1 g of a pale yellow solid was obtained, yield 79%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.73 (d, J = 211.3Hz, 1H), 7.84 (d, J = 8.5Hz, 1H), 7.12 (t, J = 13.6Hz, 2H), 4.43 (d , J = 8.5 Hz, 1H), 4.16 (s, 1H), 3.41 (d, J = 18.3 Hz, 1H), 3.11 (dt, J = 23.2, 7.3 Hz, 4H), 2.19 (dt, J = 15.0, 7.6 Hz, 2H), 2.00 (d, J = 10.0 Hz, 1H), 1.87 (td, J = 11.1, 5.1 Hz, 1H), 1.77-1.67 (m, 4H), 1.53 (s, 9H) ppm; MS -ESI, m/z : 528.10 [M+H] ⁺ .

Step 3) Synthesis of Compound 32-4

Compound 32-3 (1.03 g, 1.95 mmol, 1.0 eq), EtOAc (0.52 g, 2.05 mmol, 1.05 eq), potassium acetate (0.57 g, 5.86 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (57 mg, 0.078 mmol, 0.04 eq) was added to DMF (10 mL). The reaction mixture was poured into water, and then filtered to afford white crystals (yield: EtOAc (V:V) = 5:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.67 (d, J = 221.7Hz, 1H), 7.79 (s, 0.5H), 7.66 (d, J = 7.7Hz, 1H), 7.25 (s, 0.5H) , 7.19 (s, 1H), 4.45 (s, 1H), 4.17 (s, 1H), 3.42 (d, J = 20.6 Hz, 1H), 3.19 (t, J = 7.5 Hz, 2H), 3.10-3.02 ( m, 2H), 2.11 (dd, J = 14.6, 7.3 Hz, 2H), 2.02 (d, J = 9.9 Hz, 1H), 1.93-1.84 (m, 1H), 1.74 (dd, J = 15.4, 10.4 Hz) , 4H), 1.53 (s, 9H), 1.36 (s, 12H) ppm; MS-ESI, m/z : 506.25 [M+H] ⁺ .

Step 4) Synthesis of Compound 32-5

Compound 32-4 (0.6 g, 1.2 mmol, 1 eq), compound 7-7A (0.49 g, 1.2 mmol, 1 eq), Pd (PPh ₃ ) ₄ (0.14 g, 0.12 mmol, 0.1 eq) and K ₂ CO ₃ (0.49 mg, 3.6 mmol, 3 eq) was suspended in EtOH / H ₂ O (30 mL, 3:1) and then warmed to 90 ° C for 3 h. After the reaction was completed, most of the solution was spun, and then extracted with DCM (20 mL×2), and the organic phase was combined, dried, dried, and purified by silica gel column chromatography (PE: EtOAc (V:V) = 2:1) Gray solid 0.6 g, yield 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.98 (s, 1H), 7.72 (d, 2H), 7.32 (m, 2H), 7.22 (m, 2H), 5.53 (s, 1H), 4.63 (s, 2H), 3.26 (m, 4H), 3.10-2.85 (m, 4H), 2.76-2.51 (m, 4H), 2.23-2.09 (m, 6H), 1.82-1.69 (m, 2H), 1.25 (m, 9H), 1.29 (m, 9H) ppm.

Step 5) Synthesis of Compound 32-6

To a solution of compound 32-5 (0.5 g, 0.7 mmol, 1 eq) in dichloromethane (15 mL), EtOAc. After completion of the reaction, the reaction mixture was dried and purified with ethyl acetate.

Step 6) Synthesis of Compound 32

Compound 32-6 (0.67 g, 1.02 mmol, 1 eq), compound 1-14 (0.429 g, 2.45 mmol, 2.4 eq), EDCI (0.472 g, 2.45 mmol, 2.4 eq) and ethyl 2- cyanoacetate (0.116 g, 0.817 mmol, 0.8 eq) was suspended in dichloromethane (10 mL). DIPEA (0.792 g, 6.13 mmol, 6 eq) was added dropwise to the reaction mixture at 0 ° C. After the dropwise addition, the mixture was stirred at room temperature. 2h. After the completion of the reaction, the mixture was stirred for 1 hr. EtOAc (V:V). ) = 1:1), a gray solid of 0.4 g was obtained with a yield of 51%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (s, 1H), 7.72 (d, 2H), 7.46 (m, 2H), 7.21 (m, 2H), 5.43 (s, 1H), 5.10 (s, 2H), 3.56-3.45 (m, 4H) 3.16-3.01 (m, 4H), 3.10-2.87 (m, 4H), 2.66-2.51 (m, 4H), 2.56-2.39 (m, 2H), 2.36 (m) , 4H), 2.09-1.93 (m, 6H), 1.81-1.72 (m, 2H) 1.23-1.05 (m, 12H) ppm.

Example 15

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 33-2

Add lithium (0.56 g, 80 mmol, 4 eq) to tetrahydrofuran (20 mL), add TMSCl (7.67 mL, 60 mmol, 3 eq) at 0 ° C, then add compound 33-1 (2.08 g, 20 mmol, 1 eq) dropwise. After completion, the reaction was carried out for 6 days at room temperature. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. 4.9 g of a yellow oil was obtained in a yield of 98%.

GC/MS: [M ⁺ ] = 250.2.

Step 2) Synthesis of Compound 33-3

Compound 33-2 (4.9 g, 19.6 mmol, 1 eq) was dissolved in tetrahydrofuran (50 mL). EtOAc (EtOAc, EtOAc. The reaction was carried out at 40 ° C for 1 h, then quenched with water (100 mL). The combined organic layers were washed with water (50 mL), EtOAc EtOAc (EtOAc)

GC/MS: [M ⁺ ] = 248.1.

Step 3) Synthesis of Compound 33-4

Compound 33-3 (4.96g, 20mmol, 1eq) was dissolved in methanol (50mL) was added dropwise bromine at 0 ℃ (3.1mL, 60mmol, 3eq ) in methanol (10 mL) was added dropwise at room temperature after the reaction overnight. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue obtained was purified by column chromatography (PE) to afford 2.5 g of product.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17 (s, 2H), 3.09 (s, 4H) ppm.

Step 4) Synthesis of Compound 33-5

Compound 33-4 (2.5 g, 9.54 mmol, 1 eq), tributyl(1-ethoxyethene)tin (2.93 mL, 8.60 mmol, 0.9 eq) and dichloroditriphenylphosphine palladium (0.35 g, 0.48 mmol, 0.05 eq) was dissolved in dioxane (25 mL), protected with nitrogen, and reacted at 100 ° C for 1 h. The celite was filtered, and the filtrate was combined with dichloromethane (20 mL). . The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.62 (d, J = 8.4,1H), 7.40 (d, J = 8.4, 1H), 3.41 (t, J = 7.6Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H), 2.49 (s, 3H) ppm.

Step 5) Synthesis of Compound 33-6

Compound 33-5 (1.2 g, 5.33 mmol, 1 eq), copper bromide (2.38 g, 10.7 mmol, 2 eq) was added to a solvent of EtOH (20 mL) at 60 ° C for 2 h. After completion of the reaction, the mixture was filtered over Celite. The mixture was dried with EtOAc EtOAc (EtOAc) (EtOAc) The red oil was 1.38 g, and the yield was 85%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J = 7.6Hz , 2H), 3.07 (t, J = 7.6 Hz, 2H) ppm.

Step 6) Synthesis of Compound 33-8

Triethylamine (0.6 g, 6 mmol, 1.5 eq) was added dropwise to compound 33-6 (1.1 g, 3.6 mmol, 1 eq), compound 1-7 (1.0 g, 4.6 mmol, 1.3 eq) at 0 °C. In a mixture of dichloromethane (20 mL), the mixture was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture was washed with water (10 mL), washed with saturated sodium chloride, dried, dried, and purified by gel column chromatography (PE) : EtOAc (V:V) = 6:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 5.13 (m, 1H), 4.43 (s, 2H), 3.36 (m, 2H), 3.16 (m, 2H), 3.07 (m, 4H), 2.29 (m, 2H), 1.36 (t, 9H) ppm; MS-ESI, m/z : 438.1 [M+H] ⁺ .

Step 7) Synthesis of Compound 33-9

Compound 33-8 (1.13 g, 2.6 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was evaporated to dryness, EtOAc (V:V) 5:1), 1.01 g of a pale yellow solid was obtained, yield 93%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (s, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz, 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J =15.0, 7.1 Hz, 4H), 2.85-2.59 (m, 2H), 1.52 (s, 9H) ppm; MS-ESI, m/z : 418.2 [M+H] ⁺ .

Step 8) Synthesis of Compound 33-11

Compound 33-9 (1.0 g, 2.4 mmol, 1.0 eq), bispinol, botanic acid (0.63 g, 2.5 mmol, 1.05 eq), potassium acetate (0.71 g, 7.2 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water, and then filtered to afford white crystals (yield: EtOAc (V:V) = 5:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48 (dd, J = 35.4, 12.0 Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m , 2H), 1.52 (s, 9H), 1.36 (s, 12H) ppm; MS-ESI, m/z : 466.4 [M+H] ⁺ .

Step 9) Synthesis of Compound 33-13

Compound 33-11 (512mg, 1.1mmol, 1.0eq) , the compounds 7-7A (460mg, 1.1mmol, 1.0eq) , potassium carbonate (0.30g, 2.2mmol, 2.0eq), tetrakis triphenylphosphine palladium (38 mg , 0.033 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.727 g was obtained in a yield of 98%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.14 (dd, J = 20.9, 13.7 Hz) , 5H), 2.81-2.62 (m, 2H), 2.44 - 2.21 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J = 6.7 Hz, 18H) ppm; MS-ESI, m/ z : 675.4 [M+H] ⁺ .

Step 10) Synthesis of Compound 33-14

Compound 33-13 (0.72 g, 1.07 mmol, 1.0 eq) was added to DCM (10 mL). EtOAc (EtOAc) The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 93%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.21 (m, 2H), 3.15-2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 2H) ppm; MS-ESI, m/z : 475.4 [M+H] ⁺ .

Step 11) Synthesis of Compound 33

Compound 33-14 (238 mg, 0.5 mmol, 1.0 eq), Compound 1-14 (193 mg, 1.1 mmol, 2.2 eq), ethyl 2- cyanoacetate (57 mg, 0.4 mmol, 0.8 eq) and DIPEA (32 mg) , 0.25 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 241 mg of a white solid product was obtained in a yield of 61%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J = 26.7, 14.6) Hz, 2H), 2.59-2.07 (m, 3H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J = 16.3, 5.8 Hz, 12H) ppm; MS-ESI, m/z : 789.3 [M+H] ⁺ .

Example 16

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 34-1

Compound 1-1 (8.1 g, 50 mmol, 1 eq), n-butylamine (4.38 g, 60 mmol, 1.2 eq) and TFA (1.14 g, 10 mmol, 0.2 eq) were added to toluene (100 mL) and refluxed at 120 ° C overnight. The solvent was evaporated, EtOAc EtOAc m. The residue obtained was dissolved in acetonitrile (100 mL). EtOAc (EtOAc) After further cooling to room temperature, concentrated hydrochloric acid (30 mL) was slowly added dropwise, stirred for 10 min, and then ethyl acetate (200 mL) was added and washed with water (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by gel column chromatography (PE: EtOAc (V:V) = 10:1) afforded 4.0 g of yellow oil.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (t, J = 7.6Hz, 1H), 7.61 (d, J = 8.2Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 3.90 (s , 3H), 3.06 (t, J = 12.3 Hz, 2H) ppm.

Step 2) Synthesis of Compound 34-2

Compound 34-1 (4.0 g, 20 mmol, 1 eq), triethyl decane (11.6 g, 100 mmol, 5 eq), TFA (40 mL) was added to a two-necked flask and refluxed. The reaction was monitored by TLC. After the reaction was completed, it was poured into ice water and extracted with EtOAc (40 mL×2). The organic phase was neutralized with sodium hydrogen carbonate aqueous solution, washed with water, dried, and dried, and then purified by silica gel column chromatography (PE) to give product 3.35 g. The rate is 91%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.20 (t, J = 7.8Hz, 1H), 6.93 (d, J = 7.4Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 3.90 (s , 3H), 3.23 (t, J = 12.3, 4H) ppm.

Step 3) Synthesis of Compound 34-3

Acetyl chloride (1.7 g, 21.6 mmol, 1.2 eq) was slowly added dropwise to compound 34-2 (3.32 g, 18 mmol, 1 eq), aluminum trichloride (3.11 g, 23.4 mmol, 1.3 eq. In a solution of DCM (20 mL), the reaction was continued at room temperature after completion of the reaction. After the reaction was completed, it was poured into ice water, extracted with DCM (2×20 mL), dried, dried, and purified by silica gel column chromatography (PE: DCM) (V: V) = 5:1), the product was obtained 3.38 g, yield 83%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.72 (d, J = 8.2Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 3.90 (s, 3H), 3.23 (t, J = 12.3, 4H), 2.55 (s, 3H) ppm.

Step 4) Synthesis of Compound 34-4

Boron tribromide (4.51 g, 18 mmol, 1.2 eq) was slowly added dropwise to a solution of compound 34-3 (3.38 g, 15 mmol, 1 eq) in DCM (50 mL). After the reaction was completed, it was poured into EtOAc (EtOAc (EtOAc) (EtOAc) The rate is 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.72 (d, J = 8.2Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 3.23 (t, J = 12.3,4H), 2.55 (s, 3H) ppm.

Step 5) Synthesis of Compound 34-5

Trifluoromethanesulfonic anhydride (3.4 g, 12 mmol, 1.2 eq) was added dropwise to compound 34-4 (2.12 g, 10 mmol, 1 eq), pyridine (1.96 g, 20 mmol, 2 eq. 40mL) mixture, after the addition, room temperature reaction, TLC monitoring reaction, after the reaction is complete, add water (10mL) wash, saturated sodium chloride wash, dry, organic phase drying, spin dry, gel column chromatography purification (PE) The product was obtained 3.27 g, yield 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.82 (d, J = 8.2Hz, 1H), 7.11 (d, J = 8.4Hz, 1H), 3.23 (t, J = 12.3,2H), 3.03 (t, J = 12.3, 2H), 2.55 (s, 3H) ppm.

Step 6) Synthesis of Compound 34-6

Compound 34-5 (1.84 g, 5.33 mmol, 1 eq), copper bromide (2.38 g, 10.7 mmol, 2 eq) was added to EtOH (20 mL) solvent for 2 h at 60 ° C. After completion of the reaction, the mixture was filtered over Celite. The mixture was dried with EtOAc EtOAc (EtOAc) (EtOAc) The red oil was 1.38 g, and the yield was 85%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J = 12.3Hz , 2H), 3.07 (t, J = 12.3 Hz, 2H) ppm.

Step 7) Synthesis of Compound 34-7

Triethylamine (0.6 g, 6 mmol, 1.5 eq) was added dropwise to compound 34-6 (1.52 g, 3.6 mmol, 1 eq), L- Boc-valine (1.0 g, 4.6 mmol, 1.3). Eq) in dichloromethane (20 mL) mixture, after the addition, the reaction was carried out at room temperature. The reaction was monitored by TLC. After the reaction was completed, it was washed with water (10 mL), washed with saturated sodium chloride, dried with organic phase, dried and dried. Purification by chromatography (PE: EtOAc (V:V) = 6:1)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.78 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 5.13 (m, 1H), 4.43 (s, 2H), 3.36 (m, 2H), 3.16 (m, 2H), 3.07 (m, 4H), 2.29 (m, 2H), 1.36 (t, 9H) ppm; MS-ESI, m/z : 558.1 [M+H] ⁺ .

Step 8) Synthesis of Compound 34-8

Compound 34-7 (1.45 g, 2.6 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.33 g of a pale yellow solid was obtained, yield 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (s, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz, 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J =15.0, 7.1 Hz, 4H), 2.85-2.59 (m, 2H), 1.52 (s, 9H) ppm; MS-ESI, m/z : 538.2 [M+H] ⁺ .

Step 9) Synthesis of Compound 34-9

Compound 34-8 (1.29 g, 2.4 mmol, 1.0 eq), EtOAc (0.63 g, 2.5 mmol, 1.05 eq), potassium acetate (0.71 g, 7.2 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water, and then filtered to afford white crystals (yield: EtOAc (V:V) = 5:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48 (dd, J = 35.4, 12.0 Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m , 2H), 1.52 (s, 9H), 1.36 (s, 12H) ppm; MS-ESI, m/z : 516.4 [M+H] ⁺ .

Step 10) Synthesis of Compound 34-10

Compound 34-9 (567 mg, 1.1 mmol, 1.0 eq), Compound 7-7A (460 mg, 1.1 mmol, 1.0 eq), potassium carbonate (0.30 g, 2.2 mmol, 2.0 eq), tetratriphenylphosphine palladium (38 mg) , 0.033 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.757 g was obtained in a yield of 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.14 (dd, J = 20.9, 13.7 Hz) , 5H), 2.81-2.62 (m, 2H), 2.44 - 2.21 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J = 6.7 Hz, 18H) ppm; MS-ESI, m/ z : 725.4 [M+H] ⁺ .

Step 11) Synthesis of Compound 34-11

Compound 34-10 (0.725 g, 1.0 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 92%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.21 (m, 2H), 3.15-2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 2H) pm; MS-ESI, m/z : 525.4 [M+H] ⁺ .

Step 12) Synthesis of Compound 34

Compound 34-11 (263 mg, 0.5 mmol, 1.0 eq), Compound 1-14 (193 mg, 1.1 mmol, 2.2 eq), ethyl 2- cyanoacetate (57 mg, 0.4 mmol, 0.8 eq) and DIPEA (32 mg) , 0.25 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 239 mg of a white solid product was obtained in a yield of 57%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J = 26.7, 14.6) Hz, 2H), 2.59-2.07 (m, 3H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J = 16.3, 5.8 Hz, 12H) ppm; MS-ESI, m/z : 839.3 [M+H] ⁺ .

Example 17

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 35-2

Compound 1-6 (1.2 g, 3.1 mmol, 1.0 eq) and compound 35-1 (0.82 g, 0.34 mmol, 1.1 eq) were added to acetonitrile (10 mL) and triethylamine (0.47 g) was added dropwise at 0 °C , 4.6 mmol, 1.5 eq), and allowed to react at room temperature for 2 h. The solvent was evaporated, and water (20 mL) was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (d, J = 8.5Hz, 1H), 7.20 (d, J = 8.2Hz, 1H), 5.45 (dd, J = 63.1,16.2Hz, 1H), 5.12 (dd, J = 55.0, 16.2 Hz, 1H), 4.58 (ddd, J = 26.2, 8.5, 3.4 Hz, 1H), 3.51-3.34 (m, 2H), 3.32 (d, J = 7.0 Hz, 2H), 3.05 (t, J = 7.1 Hz, 2H), 2.39 (dd, J = 12.6, 8.8 Hz, 1H), 2.26-2.12 (m, 2H), 2.09 (d, J = 12.7 Hz, 1H), 1.46 (d) , J = 3.4 Hz, 9H), 0.63 (dd, J = 13.4, 8.3 Hz, 4H) ppm.

Step 2) Synthesis of Compound 35-3

Compound 35-2 (1.70 g, 3.1 mmol, 1.0 eq) and ammonium acetate (1.4 g, 19 mmol, 6.0 eq) were added to toluene (10 mL) and reacted at 115 ° C for 15 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.33 g of a pale yellow solid was obtained, yield 81%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.88 (d, J = 214.7Hz, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.18 (s, 1H), 7.11 (d, J = 8.5Hz , 1H), 5.13 (s, 1H), 3.53 (d, J = 10.0 Hz, 1H), 3.20-3.07 (m, 5H), 2.80 (d, J = 10.6 Hz, 1H), 2.37 (s, 1H) , 2.21 (d, J = 6.8 Hz, 2H), 1.52 (s, 9H), 0.89 (dd, J = 9.6, 5.4 Hz, 1H), 0.63 (ddd, J = 18.6, 11.0, 4.9 Hz, 3H) ppm ;MS-ESI, m/z : 528.20 [M+H] ⁺ .

Step 3) Synthesis of Compound 35-4

Compound 35-3 (1.25 g, 2.37 mmol, 1.0 eq), EtOAc (0.63 g, 2.49 mmol, 1.05 eq), potassium acetate (0.69 g, 7.11 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (52 mg, 0.071 mmol, 0.03 eq), was added to DMF (10 mL). The reaction mixture was poured into water, and then filtered to afford white crystals (yield: EtOAc (V:V) = 5:1).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.83 (d, J = 222.3Hz, 1H), 7.81 (s, 1H), 7.66 (d, J = 7.5Hz, 1H), 7.22 (s, 1H), 5.14 (d, J = 6.2 Hz, 1H), 3.52 (d, J = 10.3 Hz, 1H), 3.38-2.97 (m, 5H), 2.79 (s, 1H), 2.56-2.28 (m, 1H), 2.21 2.08 (m, 2H), 1.52 (s, 9H), 1.36 (s, 12H), 0.90 (s, 1H), 0.73-0.52 (m, 3H) ppm; MS-ESI, m/z : 506.4 [M+ H] ⁺ .

Step 4) Synthesis of Compound 35-5

Compound 35-4 (600 mg, 1.19 mmol, 1.0 eq), Compound 7-7A (494 g, 1.19 mmol, 1.0 eq), potassium carbonate (0.33 g, 2.37 mmol, 2.0 eq), tetratriphenylphosphine palladium (41 mg) , 0.035 mmol, 0.03 eq) was added to ethanol (10 mL) and water (3 mL). The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.80 g was obtained in a yield of 94%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.56-10.55 (m, 2H), 8.68 (d, J = 13.5Hz, 1H), 8.00 (s, 1H), 7.87 (d, J = 7.1Hz, 1H) , 7.72 (d, J = 25.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 5.32-5.09 (m, 2H), 3.56 ( Dd, J = 37.5, 26.4 Hz, 3H), 3.15 (dd, J = 26.7, 3.2 Hz, 4H), 2.84 (dd, J = 13.4, 10.1 Hz, 1H), 2.46-2.25 (m, 2H), 2.20 -2.08 (m, 2H), 1.79-170 (m, 4H), 1.61-1.44 (m, 18H), 0.86 (d, J = 2.9 Hz, 1H), 0.79-0.43 (m, 3H) ppm; ESI, m/z : 715.4 [M+H] ⁺ .

Step 5) Synthesis of Compound 35-6

Compound 35-5 (0.80 g, 1.1 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 100%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 8.48 (d, J = 8.4Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.69 (d, J = 11.0Hz, 3H) , 7.34 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 4.43 (dt, J = 14.8, 7.2 Hz, 2H), 3.45 (d, J = 7.0 Hz, 2H), 3.09 (dd, J =16.1, 7.5 Hz, 4H), 3.01-2.90 (m, 2H), 2.82 (d, J = 9.9 Hz, 1H), 2.21 (dt, J = 14.2, 7.8 Hz, 1H), 2.12-1.98 (m) , 4H), 1.81 (dd, J = 14.0, 7.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 1H), 0.56 (t, J = 13.3 Hz, 3H) ppm; MS-ESI, m/z :515.2[M+H] ⁺ .

Step 6) Synthesis of Compound 35

Compound 35-6 (280 mg, 0.54 mmol, 1.0 eq), Compound 1-14 (209 mg, 1.20 mmol, 2.2 eq), ethyl 2- cyanoacetate (61 mg, 0.43 mmol, 0.8 eq) and DIPEA (35 mg) , 0.27 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 5:10:1), 243 mg of a white solid product was obtained in a yield of 53.88%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.97-10.31 (m, 2H), 8.63 (d, J = 7.6Hz, 1H), 7.90 (dd, J = 45.6,19.8Hz, 2H), 7.68 (dd, J = 21.5, 8.3 Hz, 2H), 7.39 (d, J = 32.9 Hz, 2H), 7.19 (s, 1H), 5.64 (dd, J = 83.6, 38.2 Hz, 4H), 4.48-4.26 (m, 1H) ), 4.15 (dd, J = 6.0, 4.1 Hz, 1H), 4.00-3.87 (m, 1H), 3.83 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 3.13 (dd, J =18.7, 11.1 Hz, 4H), 2.51 (dd, J = 27.9, 23.1 Hz, 2H), 2.40-2.26 (m, 1H), 2.26-1.96 (m, 5H), 1.79-1.69 (m, 1H) , 1.69-1.58 (m, 1H), 1.05-0.83 (m, 12H), 0.84-0.56 (m, 4H) ppm; MS-ESI, m/z : 829.4 [M+H] ⁺ .

Example 18

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 36-2

5-methoxy-3,4-tetrahydronaphthalene-1( 2H )-one 36-1 (12 g, 68 mmol), triethyldecane (26.3 g, 272 mmol), ammonium fluoride (8.3 g, 272 mmol) Dissolved in trifluoroacetic acid (100 mL) and reacted at 72 ° C for 6 h. The solvent was spun off, the residue was dissolved with ethyl acetate (300 mL×2), the organic phase was neutralized with sodium hydrogen carbonate solution, washed with water, dried, and dried, and the residue was purified by column chromatography (PE) to give colorless oil. 10 g, yield 90%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.15 (t, J = 7.9Hz, 1H), 6.75 (dd, J = 21.5,7.9Hz, 2H), 3.88 (s, 3H), 2.84 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 5.9 Hz, 2H), 1.91-1.80 (m, 4H) ppm; MS (ESI, pos.ion) m/z : 163.2 [M+H] ⁺ .

Step 2) Synthesis of Compound 36-3

Compound 36-2 (11 g, 67.8 mmol), aluminum trichloride (13.7 g, 100 mmol) was dissolved in DCM (100 mL), and ethyl acetate (7 g, 88 mmol) was added dropwise at 0 ° C. The reaction was carried out at room temperature for 24 h. The reaction mixture was poured into ice water, extracted with ethyl acetate (200 mL×2), washed with water, dried and evaporated to dryness.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.63 (d, J = 8.6Hz, 1H), 6.69 (d, J = 8.6Hz, 1H), 3.87 (s, 3H), 3.04 (t, J = 5.8Hz , 2H), 2.75-2.57 (m, 2H), 2.55 (s, 3H), 1.75 (td, J = 7.3, 3.6 Hz, 4H) ppm; MS (ESI, pos.ion) m/z : 205.1 [M +H] ⁺ .

Step 3) Synthesis of Compound 36-4

Compound 36-3 (9 g, 44 mmol) was dissolved in N -methylpyrrolidone (90 mL), pyridine hydrobromide (28 g, 176 mmol) was added, and the reaction was carried out at 180 ° C for 4 h. The reaction mixture was poured into water (400 mL), EtOAc (EtOAc m. V) = 10:1) gave 4 g of a white solid, yield 47.7%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.58 (d, J = 8.4Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 3.10 (t, J = 6.1Hz, 2H), 2.82-2.60 (m, 2H), 2.57 (s, 3H), 1.98-1.70 (m, 4H) ppm; MS (ESI, pos.ion) m/z : 191.2 [M+H] ⁺ .

Step 4) Synthesis of Compound 36-5

Trifluoromethanesulfonic anhydride (6.5 g, 23 mmol) was added dropwise to a mixture of compound 36-4 (4 g, 21 mmol), pyridine (2.2 g, 27 mmol) in dichloromethane (120 mL) at 0 ° C. After the reaction at room temperature for 3 h. The reaction was washed with water (30 mL), EtOAcjjjjjjjjjjjj .

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.58 (d, J = 8.4Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 3.10 (t, J = 6.1Hz, 2H), 2.82-2.60 (m, 2H), 2.57 (s, 3H), 1.98-1.70 (m, 4H) ppm; MS (ESI, pos.ion) m/z : 323.2 [M+H] ⁺ .

Step 5) Synthesis of Compound 36-6

Compound 36-5 (2.6 g, 8 mmol) and copper bromide (3.6 g, 16 mmol) were added to ethanol (50 mL) and reacted at 60 ° C for 2 h. The reaction mixture was filtered over EtOAc EtOAc (EtOAc)EtOAc.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.60 (d, J = 8.4Hz, 1H), 6.99 (d, J = 8.4Hz, 1H), 4.66 (s, 2H), 3.10 (t, J = 6.1Hz , 2H), 2.82-2.60 (m, 2H), 1.98-1.70 (m, 4H) ppm; MS (ESI, pos.ion) m/z : 401.3 [M+H] ⁺ .

Step 6) Synthesis of Compound 36-7

Triethylamine (1.1 g, 10 mmol) was added dropwise to the compound 36-6 (2.8 g, 7 mmol), N -tert-butoxycarbonyl- L -valine (2.0 g, 9 mmol) of dichloride at 0 °C. In methane (60 mL), the mixture was reacted at room temperature for 8 h after the addition. The reaction mixture was washed with EtOAc EtOAc m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.40 (d, J = 8.5Hz, 1H), 7.16 (d, J = 8.4Hz, 1H), 5.05 (ddd, J = 63.0,51.9,16.7Hz, 2H) , 4.48-4.26 (m, 1H), 3.64-3.22 (m, 2H), 2.98-2.65 (m, 4H), 2.13-1.67 (m, 8H), 1.43 (d, J = 13.2 Hz, 9H) ppm; MS (ESI, pos.ion) m / z: 536.0 [m + H] +.

Step 7 Synthesis) of compound 36-8

Compound 36-7 (3 g, 5.6 mmol) and ammonium acetate (2.6 g, 33 mmol) were added to toluene (60 mL) and reacted at 110 ° C for 12 h. After completion of the reaction, water (20 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated. = 4:1) gave a brownish yellow oil, 0.8 g, yield 30%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.43 (s, 1H), 7.21-7.07 (m, 1H), 7.04 (s, 1H), 4.99 (d, J = 5.2Hz, 1H), 3.43 (s, 2H), 3.00-2.75 (m, 4H), 2.24-1.95 (m, 5H), 1.78 (dt, J = 48.8, 24.0 Hz, 4H), 1.58-1.41 (m, 9H) ppm; MS (ESI, pos .ion) m/z : 516.1 [M+H] ⁺ .

Step 8) Synthesis of Compound 36-9

Compound 36-8 (0.8 g, 1.6 mmol), pinacol borate (0.5 g, 1.9 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (0.25 g, 0.3 mmol), AcOK (0.5 g, 4.7 mmol) was suspended in DMF (20 mL). The reaction solution was cooled to room temperature, water (60 mL) was added, and the mixture was filtered. The oil was 0.65 g, and the yield was 80%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.76 (s, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.03 (s, 2H), 5.00 (d, J = 5.4Hz, 1H), 3.43 (d, J = 5.3 Hz, 2H), 2.84 (s, 3H), 2.10 (dd, J = 60.9, 20.7 Hz, 3H), 1.86-1.69 (m, 6H), 1.51 (s, 9H), 1.36 ( s, 12H) ppm; MS (ESI, pos.) m/z : 494.3 [M+H] ⁺ .

Step 9) Synthesis of Compound 36-10

Compound 36-9 (0.65 g, 1.3 mmol), compound 4-9 (0.64 g, 1.03 mmol), Pd(PPh ₃ ) ₄ (0.23 g, 0.2 mmol), K ₂ CO ₃ (0.54 g, 4 mmol) In ethanol (16 mL) and water (4 mL), the mixture was reacted at 90 ° C for 3 h under nitrogen. The solvent was evaporated, the residue was evaporated mjjjjjjjjjjjjjjjjjjjj :V) = 2:1) gave 0.7 g of a yellow solid, yield 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 13.87-9.99 (m, 2H), 8.62 (d, J = 8.5Hz, 1H), 8.05-7.77 (m, 2H), 7.68 (t, J = 8.6Hz, 1H), 7.63-7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J = 45.6, 22.5 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H) ), 4.29 (s, 1H), 3.98-3.68 (m, 3H), 3.57-3.38 (m, 3H), 2.94 (t, J = 30.7 Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90- 1.66 (m, 9H), 1.52 (s, 9H), 1.34-1.22 (m, 4H), 1.19-1.09 (m, 5H) ppm; MS (ESI, pos .ion) m/z : 774.6 [M+H] ⁺ .

Step 10) Synthesis of Compound 36-11

To a solution of compound 36-10 (0.7 g, 0.9 mmol) in dichloromethane (16 mL), EtOAc (EtOAc) The reaction mixture was spun and the residue was purified with ethyl acetate and filtered. The filter cake was dissolved with water (10 mL), and the mixture was adjusted to pH -8.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 13.87-9.99 (m, 2H), 8.62 (d, J = 8.5Hz, 1H), 8.05-7.77 (m, 2H), 7.68 (t, J = 8.6Hz, 1H), 7.63-7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J = 45.6, 22.5 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H) ), 4.29 (s, 1H), 3.98-3.68 (m, 3H), 3.57-3.38 (m, 4H), 2.94 (t, J = 30.7 Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90- 1.66 (m, 9H), 1.34-1.22 (m, 4H), 1.19-1.09 (m, 5H) ppm; MS (ESI, pos.ion) m/z : 674.3 [M+H] ⁺ .

Step 11) Synthesis of Compound 36

Compound 36-11 (0.28 g, 0.41 mmol), ( S )-2-((methoxymethylhydrazino)amino)-3-methylbutyric acid 1-14 (0.09 g, 0.5 mmol). Ethyl acetate (0.024 g, 0.165 mmol) was dissolved in DCM (10 mL). The reaction was quenched with water, EtOAc (EtOAc) (EtOAc)EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (10 mL), EtOAc (3 mL, dry. 60%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.80 (m, 2H), 8.78-8.40 (m, 1H), 8.02-7.80 (m, 2H), 7.73-7.48 (m, 3H), 7.19 (m, 2H ), 7.05 (s, 1H), 5.63-5.38 (m, 3H), 5.32 (s, 1H), 4.48-4.24 (m, 3H), 3.94 (s, 1H), 3.85 (s, 1H), 3.77- 3.63 (m, 4H), 3.50-3.22 (m, 2H), 3.09-2.78 (m, 4H), 2.69 (s, 1H), 2.52-2.25 (m, 1H), 2.20 (s, 1H), 2.04 ( s, 3H), 1.45 (s, 1H), 1.28 (t, J = 7.1 Hz, 4H), 1.18 (d, J = 6.0 Hz, 2H), 1.12 (m, 4H), 1.02-0.76 (m, 11H) MS (ESI, pos.ion) m/z : 831.6 [M+H] ⁺ .

Example 19

synthetic route:

Synthesis steps:

Compound 36-11 (0.28 g, 0.41 mmol), ( S )-2-cyclohexyl-2-((methoxymethylhydrazino)amino)acetic acid 37-1 (0.102 g, 0.46 mmol), 2-cyanide Ethyl acetate (0.024 g, 0.16 mmol) was dissolved in DCM (10 mL). The reaction was quenched with water, EtOAc (EtOAc) (EtOAc)EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (10 mL), EtOAc (EtOAc m. m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.82-10.07 (m, 2H), 8.86-8.40 (m, 1H), 7.86 (dd, J = 22.5,12.4Hz, 2H), 7.53 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 5.65-5.41 (m, 3H), 5.31 (d, J = 6.7 Hz, 1H), 4.32 (m, 3H), 3.97-3.80 (m, 3H) , 3.78-3.61 (m, 6H), 2.87 (m, 6H), 2.48-2.15 (m, 4H), 2.06 (s, 1H), 1.45 (s, 3H), 1.28 (m, 6H), 1.21-1.07 (m, 6H), 0.99 (t, J = 6.7 Hz, 3H), 0.95 - 0.78 (m, 6H) ppm; MS (ESI, pos.ion) m/z : 871.8 [M+H] ⁺ .

Example 20

synthetic route:

Synthesis steps: Step 1) Synthesis of Compound 38-2

Compound 38-1 (0.664 g, 2.73 mmol, 1.05 eq) and compound 1-6 (1.0 g, 2.6 mmol, 1.0 eq) were added to acetonitrile (10 mL) and triethylamine (0.39 g) was added dropwise at 0 °C. , 3.9 mmol, 1.5 eq), and reacted at room temperature for 2 h. The solvent was evaporated, and water (20 mL) was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (d, J = 8.5Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 5.54-5.35 (m, 1H), 5.20 (dd, J = 25.2, 13.6 Hz, 1H), 4.62 (dt, J = 21.6, 8.3 Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 2H), 3.06 (t, J = 7.5 Hz, 2H) ), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J = 14.2, 7.3 Hz, 2H), 1.48 (m, 12H), 0.9 (t, J = 5.6 Hz, 3H) ppm.

Step 2) Synthesis of Compound 38-3

Compound 38-2 (1.42 g, 2.6 mmol, 1.0 eq) and ammonium acetate (1.2 g, 15.6 mmol, 6.0 eq) were added to toluene (15 mL) and reacted at 115 ° C for 20 h. The toluene was added to EtOAc (V:V) = 5:1. ), 1.28 g of a pale yellow solid was obtained, yield 93%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.97 (d, J = 188.0Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.5Hz , 1H), 5.33 (d, J = 52.9 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 3.98 (dd, J = 21.0, 13.0 Hz, 1H), 3.61-3.22 (m, 2H) , 3.12 (dt, J = 15.0, 7.1 Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (m, 11H), 0.9 (t, J = 5.6 Hz, 3H) ) ppm; MS-ESI, m/z : 530.2 [M+H] ⁺ .

Step 3) Synthesis of Compound 38-4

Compound 38-3 (1.26 g, 2.37 mmol, 1.0 eq), EtOAc (0.63 g, 2.49 mmol, 1.05 eq), potassium acetate (0.70 g, 7.1 mmol, 3.0 eq), Pd (dppf) ₂ Cl ₂ (69 mg, 0.094 mmol, 0.04 eq), was added to DMF (15 mL) and reacted at 100 ° C for 10 h under nitrogen atmosphere. The reaction mixture was poured into water (60 mL).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 10.89 (d, J = 186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J = 42.7, 30.3 Hz, 2H), 3.97 (dd, J = 20.7, 13.3 Hz, 1H), 3.48 (dd, J = 35.4, 12.0 Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m, 1H), 2.19-2.07 (m, 2H), 1.52 (m, 11H), 1.36 (s, 12H), 0.9 (t, J = 5.6 Hz, 3H) ppm; MS-ESI, m /z :508.3[M+H] ⁺ .

Step 4) Synthesis of Compound 38-5

Compound 38-4 (558 mg, 1.10 mmol, 1.0 eq), Compound 15-5 (473 g, 1.10 mmol, 1.0 eq), potassium carbonate (0.30 g, 2.21 mmol, 2.0 eq), tetratriphenylphosphine palladium (38 mg) , 0.033 mmol, o.03 eq) was added to ethanol (10 mL) and water (3 mL), and the mixture was reacted at 90 ° C for 6 h under nitrogen. The reaction mixture was poured into water (50 mL), EtOAc (EtOAc m. 1) A white solid product of 0.75 g was obtained in a yield of 93%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 11.88-10.35 (m, 2H), 8.67 (d, J = 8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J = 23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J = 21.1, 13.2 Hz, 1H), 3.57 (dd, J = 32.1, 9.6 Hz, 3H), 3.30-3.11 (m, 5H), 2.44 -2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (m, 20H), 1.32-1.18 (m, 3H), 0.9 (t, J = 5.6 Hz , 3H) ppm; MS-ESI, m/z : 731.3 [M+H] ⁺ .

Synthesis Step 5) Compound 38-6

Compound 38-5 (0.75 g, 1.03 mmol, 1.0 eq) was added to EtOAc (EtOAc)EtOAc. The solvent was added to EtOAc (20 mL), EtOAc (EtOAc)EtOAc. The rate is 92%.

^{1 H NMR (400MHz, DMSO- d} 6): δ 12.10 (s, 2H), 8.48 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45- 7.08 (m, 2H), 5.37 (d, J = 55.4 Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.15 (m, 2H), 3.15-2.85 (m, 6H), 2.28 (ddd, J = 39.8, 14.5, 9.4 Hz, 3H), 2.04 (d, J = 5.5 Hz, 2H), 1.94-1.65 (m, 4H), 1.32-1.18 (m, 3H), 0.9 (t, J = 5.6 Hz) , 3H) ppm; MS-ESI, m/z : 531.4 [M+H] ⁺ .

Step 6) Synthesis of Compound 38

Compound 38-6 (265 mg, 0.5 mmol, 1.0 eq), Compound 1-14 (193 mg, 1.1 mmol, 2.2 eq), ethyl 2- cyanoacetate (57 mg, 0.4 mmol, 0.8 eq) and DIPEA (32 mg) , 0.25 mmol, 0.5 eq) was added to DCM (15 mL). The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. 296 mg of a white solid product was obtained in a yield of 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 12.09-10.24 (m, 2H), 8.63 (s, 1H), 8.19-7.54 (m, 4H), 7.42 (d, J = 39.2Hz, 1H), 7.13 ( Dd, J = 75.7, 30.2 Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J = 23.1, 15.4 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.76 (d, J = 27.7 Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J = 26.7, 14.6) Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J = 1.3 Hz, 2H), 1.80-1.58 (m, 3H), 1.32-1.18 (m, 3H) 0.89 (m, 15H) ppm ;MS-ESI, m/z : 845.4 [M+H] ⁺ .

Biological experiments Biological Example 1: HCV subgenomic replicon analysis Purpose:

The compounds were evaluated for their inhibitory effects on HCV wild-type replicons GT1a, GT1b and GT2a, and HCV replicon chimeras GT3a, GT 4a, GT5a and GT6a, and GT1b L31V, GT1b Y93H resistant strains.

experimental method:

GT1a, GT1b and GT2a replicon activity assays: RNA clicks of the HCV GT 1a H77 replicon, GT1b Con1b replicon and GT2a JFH1 replicon with the G418 resistance gene NEO and luciferase reporter gene were transiently transduced Huh-7 cells were stained and added to G418 for 3~4 weeks to construct stable transfected cell lines. The Huh7-H77 and Huh7-JFH1 stable cell lines were diluted to 5×10 ⁴ /mL, inoculated into 200 μL to 96-well plates, and the Huh7-Con1b stable cell line was diluted to 1×10 ⁵ /mL, and inoculated with 50 μL to 384 wells. board. After 16-24h, using 3-fold serial dilution, dilution method in 11 dilution points were diluted to a suitable concentration of the compound, the compound POD ^TM 810 was added to microplate preprocessing system was diluted 96-well plate, each well of The final concentration of DMSO was 0.5%. After incubating for 72 h in 37 ° C, 5% CO ₂ in CO ₂ constant temperature culture, 40 μL of luciferase assay reagent (Promega Bright-Glo) was added to each well, and after 5 min, the chemiluminescence detection system (Envision) was used. Detection. The experimental results were processed using GraphPad Prism software to calculate the EC50 of compound inhibition of HCV replicons.

GT3a, GT4a, GT5a, GT6a chimeric replicon and GT1b L31V, GT1b Y93H resistant strain activity test: HCV GT1b/GT3a-NS5A, HCV GT1b/GT4a-NS5A, HCV GT1b/GT5a-NS5A, HCV by electric shock method GT1b/GT6a-NS5A chimeric replicon RNA and HCV GT1b L31V, HCV GT1b Y93H resistant replicon RNA were transferred into Huh7 cells, respectively, and then cells were seeded at a density of 10,000 per well to 96-well assay plates containing the corresponding concentrations of compounds. in. The compound DMSO stock solution was diluted and added to a 96-well assay plate with a final DMSO concentration of 0.5%. The cells were cultured for 72 hours at 37 ° C in 5% CO ₂ . The luciferase luminescent substrate Bright-Glo was added to the cell well, and the Luminescence signal value was detected by a chemiluminescence detection system Envision after 5 minutes, and the original data (RLU) was used to calculate the compound inhibitory activity. The percent inhibition was introduced into the GraphPad Prism software for nonlinear fitting calculation to obtain the corresponding curve of the compound and its inhibitory activity (EC50) value for the hepatitis C virus replicon.

The EC50 results for compounds for HCV genotype replicons are shown in Table 2.

Conclusion: The results in the table show that the compounds of the present invention have good inhibitory activities against HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a replicons, and also have good inhibitory activity against HCVGT1b L31V, GT1b Y93H resistant strains. That is, the compound of the present invention is a full-type HCV inhibitor resistant to drug resistance.

Biological Example 2: SD Rat PK Screening Test experimental method:

Male Sprague-Dawley rats were divided into two groups, three in each group, one group was intravenously injected with the compound of the present invention at a dose of 1.0 mg/kg, and the other group was orally administered with the compound at 5.0 mg/kg. Blood was collected for 8-9 time points within 24 hours after administration. A standard curve of the appropriate range was established based on the sample concentration, and the concentration of the compound in the plasma sample was determined in the MRM mode using AB SCIEX API4000 type LC-MS/MS. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated using the WinNonLin 6.3 software non-compartmental model method. The results are shown in Table 3.

Conclusion: The results in Table 3 show that the compounds of the invention have good bioavailability.

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. Therefore, the various embodiments are to be considered in all respects as illustrative and not restrictive, And all changes within the scope are included in this article.

In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" and the like means a specific feature described in connection with the embodiment or example, A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms does not necessarily mean the same embodiment or example. Moreover, the particular features, structures, materials, or characteristics described can be implemented in any one or more The examples or examples are combined in a suitable manner.

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 (21)

a compound which is a stereoisomer, a geometric isomer, a tautomer, an enantiomer, an oxynitride, a hydrate, or a compound of the formula (I). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug, Wherein, A is _{^{- (CR 7 R 7a) m}} -, - CR 7 = CR 7a -, - (CH 2) n O -, - N = CR 7 -, - NR 7 -CR 7 R 7a -, - CR ⁷ R ^7a -NR ⁷ -, -O(CH ₂ ) _n -, -CR ⁷ =N-, -S(CH ₂ ) _n -, -(CH ₂ ) _n S- or -NR ^9a -; X and X ¹ each independently N or CR ^7b ; Y and Y ¹ are each independently H, oxime, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, -C(=O -(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ or α-amino acid group; wherein the α -amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, styrene Amino acid, threonine, tryptophan, valine, alanine, aspartame, aspartic acid, glutamic acid, glutamine, valine, serine, tyrosine, arginine Acid, histidine, cysteine, glycine, sarcosine, N , N -dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, high a group formed by phenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline; R ¹ , R ² , R ³ and R ⁴ are each independently H, oxime, alkyl , arylalkyl, cycloalkyl, heterocyclic, An aryl group or an aryl group; or R ^1, R ² form a 3-8 membered heterocycle optionally X-CH, 3-8 membered carbocyclic ring, fused bicyclic, fused bicyclic heteroaryl, or spiro bicyclic spiro bicyclic heteroaryl; or R ³ , R ⁴ and X ¹ -CH optionally form a 3-8 membered heterocyclic ring, a 3-8 membered carbocyclic ring, a fused bicyclic ring, a fused heterobicyclic ring, a spiro bicyclo or a spiro bicyclo ring; each R ⁵ and R ^{6 are} independently Is H, anthracene, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, decyl, Nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, alkoxy, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy , heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl fluorenyl, alkyl decyloxy, alkane Oxidyl, heterocyclylalkyl or aryloxy; each R ⁷ , R ^7a , R ^7b , R ⁸ , R ^8a and R ^{9a are} independently H, oxime, oxo (=O), hydroxy, amino , F, Cl, Br, I, cyano, haloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, hetero Base, cycloalkyl, decyl, nitro, aryl, heteroaryl, arylalkyl, alkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylamino , heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, hetero Cycloamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbachol, alkyl-OS(=O) _r -, alkyl-S(=O) _r O - alkyl-OS(=O) _r O-, alkyl-S(=O) _r -, heterocyclylalkylamino or aryloxy; each R ⁹ and R ^{10 are} independently H, hydrazine, alkyl , cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, alkyl-OC(=O)-, alkyl-C(=O)-, carbamoyl, alkyl-OS (=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O) _r - or aminosulfonyl; each f, n and t are independently 0, 1, 2 3 or 4; m is 1, 2, 3 or 4; and each r is independently 0, 1 or 2; each of the following groups: alkyl, alkoxy, cycloalkyl, heterocyclic, aryl , heteroaryl, arylalkyl, -C(=O)-(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ , α-amino acid group, 3-8 Aromatic heterocyclic ring, 3-8 membered carbocyclic ring, fused bicyclic ring, fused heterobicyclic ring, spirobicyclo, spirobicyclo, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, heteroarylalkyl, naphthenic Alkyl, heterocyclylalkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkyl Oxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkyl-OC(=O)-, alkyl-C(=O)-, carbamoyl, alkyl-OS (=O) _r -, alkyl-S(=O) _r O-, alkyl-S(=O)r- or aminosulfonyl is independently optionally 1, 2, 3 or 4 selected from hydroxyl groups , anthracene, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkyne Base, cycloalkyl, heterocyclic, fluorenyl, nitro, aryloxy, arylamino, heteroaryloxy, heteroarylalkyl, 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)- Substituted by a substituent of a hydroxy-substituted alkyl-S(=O) ₂ - or carboxy-substituted alkoxy group. The compound of claim 1, wherein each of R ¹ , R ² , R ³ and R ^{4 is} independently H, C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl a C _3-10 cycloalkyl group, a C _2-10 heterocyclic group, a C _1-9 heteroaryl group or a C _6-10 aryl group; or R ¹ , R ² and X-CH are optionally formed into a 3-8 membered hetero Ring, 3-8 membered carbocyclic ring, C _5-12 fused bicyclic ring, C _5-12 fused heterobicyclic ring, C _5-12 spiro bicyclo or C _5-12 spiro bicyclo ring; or R ³ , R ⁴ and X ¹ -CH optionally forms a 3-8 membered heterocyclic ring, 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. Wherein the 3-8 membered heterocyclic ring, 3-8 membered carbocyclic ring, C _5-12 fused bicyclic ring, C _5-12 fused heterobicyclic ring, C _5-12 spiro bicyclic ring or C _5-12 spiro bicyclo ring Optionally, 1, 2, 3 or 4 are selected from the group consisting of H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 Alkylthio, C _6-10 arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkane group, C _3-8 cycloalkyl Substituted C _2-10 heterocyclyl group or a substituted group. The compound according to claim ¹ , wherein the heterocyclic ring, fused ring or spiro ring system formed by R ¹ , R ² and YX-CH is selected from the following substructures: The heterocyclic ring, fused ring or spiro ring system formed by R ³ , R ⁴ and Y ¹ -X ¹ -CH is selected from the following substructures: Wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 haloalkoxy C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylthio, C _{6- 10} arylamino, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 ring An alkyl group or a C _2-10 heterocyclic group; each R ^{9b 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 a -6} 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 cycloalkyl group; and each of n ₁ and n _{2 is} independently 1, 2 3 or 4. The compound of claim 3, wherein each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _1-3 alkyl , C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 haloalkoxy C _1-3 alkyl, 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 _1-9 heteroaryl C _1-3 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclic; and each R ^{9b 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 -3} alkyl, C _6-10 aryl C _1-3 alkyl, C _1-9 heteroaryl, C _6-10 aryl, C _2-10 heterocyclyl or C _3-8 cycloalkyl. The compound according to claim 3, wherein each R ^{15 is} independently H, hydrazine, oxo (=O), F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, Propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxy Methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or pyridazinyl; and each R ^{9b is} independently Hydrogen, hydrazine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxymethyl, ethoxymethyl, phenylmethyl, phenyl, Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The compound according to claim 1, wherein each of R ⁷ , R ^7a , R ^7b and R ^{9a is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, fluorenyl , nitro, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 Heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 arylamino, C _1-9 Heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _{1 -6} alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _2-10 heterocyclooxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 Heterocyclylamino, 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-OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy; and each r is independently 0, 1 or 2. The compound according to claim 1, wherein Y and Y ¹ are each independently H, oxime, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, -C(=O)-(CR ⁸ R ^8a ) _t -N(R ⁹ )-R ¹⁰ Each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkane , C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl, decyl, nitro, C _6-10 a C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a C _1-9 heteroaryl C _1-6 alkyl group, a C _3-8 cycloalkyl C _1-6 alkyl group, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl a C _1-6 alkylamino group, a C _1-9 heteroaryloxy group, a C _6-10 aryl C _1-6 alkoxy group, a C _1-9 heteroaryl C _1-6 alkoxy group, a C _{2 - 10} heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclic group, 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 alkane base- OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy; R ⁹ and R ¹⁰ each independently H, 氘, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclic, C _6-10 aryl, C _1-9 heteroaryl, C _{6- 10} aryl C _1-6 alkyl, 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; t is 0, 1, 2, 3 or 4; and each r is independently 0, 1 or 2. The compound of claim 7, wherein R ⁹ and R ¹⁰ are each independently H, hydrazine, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. Butyl, methyl-OC(=O)-, ethyl-OC(=O)-, propyl-OC(=O)-, isopropyl-OC(=O)-, tert-butyl-OC ( =O)-, methyl-C(=O)-, ethyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, isobutyl -C(=O)-, carbamidyl, methylaminomethyl hydrazino, ethylaminomethyl hydrazino, methyl-OS(=O) ₂ -, cyclopropyl-OS(=O) ₂ -, methyl -S(=O) ₂ O-, cyclopropyl-S(=O) ₂ O- or aminosulfonyl. The compound according to claim 1, wherein the compound has a structure represented by formula (II), (IIa), (IIb) or (III), or formula (II), (IIa), (IIb) Or a structural stereoisomer, geometric isomer, tautomer, enantiomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Prodrug: Wherein A is -O-, -S-, -NH-, -CH ₂ -S-, -CH ₂ -O-, -CH ₂ -NH-, -O-CH ₂ -, -NH-CH ₂ - , -S-CH ₂ - or -CH ₂ -CH ₂ -; wherein each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, C _{1 -3} alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkyl, C _1-3 haloalkoxy C _1-3 alkyl, 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- 9} heteroaryl C _1-3 alkyl, C _3-8 cycloalkyl or C _2-10 heterocyclyl; and each of n ₁ and n ₂ are independently 2, 3 or 4. The compound of claim 9, wherein each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 ring Alkyl, fluorenyl, nitro, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclic C _1-6 alkyl, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _6-10 aryl C _1-6 alkoxy, C _1-9 Aryl C _1-6 alkoxy, C _2-10 heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, 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-OS(=O) _r O-, C _1-6 alkyl-S(=O) _r -, C _2-10 heterocyclic C _1-6 Alkylamino or C _6-10 aryloxy. The compound of claim 9, wherein each R ^{15 is} independently H, oxime, oxo (=O), F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, Propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxy Methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or pyridazinyl. The compound according to any one of claims 1 to 11, wherein each of R ⁵ and R ^{6 is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-10 heterocyclyl, C _3-8 cycloalkyl , mercapto, nitro, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _{1 -6} alkoxy, C _6-10 arylamino, C _1-9 heteroarylamino, C _6-10 aryl C _1-6 alkylamino, C _1-9 heteroaryl C _1-6 alkylamino, C _1-9 heteroaryloxy, C _1-9 heteroaryl C _1-6 alkyl, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkane Oxy, C _2-10 heterocyclyloxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _2-10 heterocyclylamino, C _1-6 alkyl fluorenyl, C _1-6 Alkyl methoxy, C _1-6 alkoxy fluorenyl, C _2-10 heterocyclyl C _1-6 alkylamino or C _6-10 aryloxy. The compound of claim 12, wherein each of R ⁵ and R ^{6 is} independently H, oxime, oxo (=O), hydroxy, amino, F, Cl, Br, I, cyano, A Base, ethyl, propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxymethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyloxy, phenylamino, fluorenyl or nitro. The compound according to any one of claims 1 to 11, wherein each of R ⁸ and R ^{8a is} independently H, hydrazine, hydroxy, amino, F, Cl, Br, I, cyano, Methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy , ethoxy, isopropoxy, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3- Methoxypropyl, phenyl, pyranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, vinyl, allyl, ethynyl, morpholinyl, fluorenyl, nitrate Base, benzyl, anilino. The compound according to claim 1, wherein the compound has a structure shown below or a stereoisomer, a geometric isomer, a tautomer, an enantiomer, or the structure shown below. Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs: A pharmaceutical composition comprising the compound of any one of claims 1 to 15, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition further comprises other anti-HCV drugs. The pharmaceutical composition according to claim 17, wherein the other anti-HCV drug is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, and promotes a type 1 helper T cell response. Compound, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavirizumab, hepatitis C immunoglobulin, Civacir ^TM , boceprevir, telaprevir, erlotinib, dacaviride, simipiride, anapyvir, vaniprevir, faldaprevir, paritaprevir, danpoprovir, sovaprevir, grazoprevir, vedroprevir, BZF -961, GS-9256, narlaprevir, ANA975, ombitasvir, EDP239, ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, cilostry, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX -184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir , HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Ray Dipavir, odalasvir, ritonavir, furaprevir, setrobuvir, alistorivir, BIT-225, AV-4025, ACH-3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD-6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, alispor, MK-3682, MK -8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB-5300, miravirsen, chronvac-C , MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ -47910382, AL-704, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12 or a combination thereof; the interferon is interferon alpha-2b, PEGylated Interferon alpha, interferon alpha-2a, PEGylated Interferon α-2a, interferon α- complex, interferon-γ, or combinations thereof. The pharmaceutical composition according to claim 17, wherein the other anti-HCV drug is for inhibiting the HCV replication process and/or inhibiting the function of the HCV viral protein; the HCV replication process comprises HCV entry, HCV removal Shell, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome entry point required for HCV viral replication ( IRES) and inosine monophosphate dehydrogenase (IMPDH). The use of the pharmaceutical composition according to any one of claims 1 to 15 or the pharmaceutical composition according to any one of claims 16 to 19 for the preparation of a medicament, Wherein the medicament is for inhibiting the HCV replication process and/or inhibiting the function of an HCV viral protein; the HCV replication process comprises HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; said HCV virus The protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, as well as the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. The use of the pharmaceutical composition according to any one of claims 1 to 15 or the pharmaceutical composition according to any one of claims 16 to 19 for the preparation of a medicament, Wherein the medicament is for preventing, treating, treating or ameliorating HCV infection or hepatitis C disease.