TW202106677A - Dicarbamate inhibitors of ns5a for the treatment of hepatitis c virus infections - Google Patents

Abstract

Dicarbamate compounds as inhibitors of NS5A, and therapeutic uses and methods of preparation thereof, are disclosed. These compounds, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs, and pharmaceutical compositions thereof, are useful in treating diseases and disorders caused by the hepatitis C virus in humans, including cirrhosis and liver cancer.

Description

Dicarbamate inhibitor of NS5A for the treatment of hepatitis C virus infection

The present invention relates to novel dicarbamate compounds, compositions and methods for treating or preventing diseases, disorders or medical conditions (including liver cirrhosis and liver cancer) in humans caused by hepatitis C virus.

Hepatitis C is a liver disease caused by hepatitis C virus (HCV). HCV can cause acute and chronic hepatitis, and its severity ranges from a mild infection that lasts only a few weeks to a serious lifelong disease. According to WHO estimates, 71 million people worldwide suffered from chronic hepatitis C in 2018. A large proportion of these chronically infected individuals will eventually develop cirrhosis and/or liver cancer, causing approximately 399,000 deaths worldwide each year.

Hepatitis C virus (HCV) is a member of the Flaviviridae family of enveloped ortho-strand RNA viruses. There is currently no clinically proven vaccine. For decades, antiviral treatments for chronic hepatitis C have been based on the combination of interferon (IFN)-α and ribavirin, and have been associated with suboptimal response rates and/or high incidence of side effects (Bassetti, M. et al., W World J. Gastroenterol. 2015 , 21(38), 10760-10775). The highly complex and incompletely understood nature of the virus life cycle complicates the discovery of novel HCV therapies. The HCV genome consists of a single-stranded RNA of approximately 9600 nucleotides, which encodes a polypeptide precursor of approximately 3000 amino acids. Co-translation and post-translational proteolytic cleavage of this precursor by cells and viral enzymes will produce non-structural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, which are required for membrane-associated RNA replication (Kim , CW, Chang, K.-M., Clin. Mol. Hepatol. 2013 , 19, 17-25).

The non-structural protein NS5A has been identified as a promising drug target for antiviral therapeutic intervention because it plays a functionally essential role in regulating HCV replication, assembly and escape (Pawlotsky, J.-M., J. Hepatol) . 2013 , 59, 375–382). It is a proline-rich hydrophilic phosphoprotein of 447 residues with three domains. Although there is no clear enzymatic function assigned to NS5A, it seems to work through interaction with other HCV proteins and host cell factors. In a cell culture-based model, the inhibitory effect of NS5A at picomolar concentrations is associated with a significant decrease in HCV RNA content. Clinically, small molecule inhibitors of NS5A have been shown to be effective when administered in combination therapy (Schinazi, RF, Infect. Drug Resist. 2014 , 7, 41-56).

Daclatasvir (WO2008021927A2) and ledipasvir (WO2010132601A1) are representative examples of dicarbamate-based NS5A inhibitors, and are currently used clinically as approved drugs. Other clinically successful examples include elbasvir (WO2012040923A1), odalasvir (WO2012166716A2), vepadasvir (WO2013075029A1) and ruzasvir (WO2016004899A1) ).

However, despite the clinical success of NS5A inhibitors, they still have certain limitations. Although many commercially available NS5A inhibitors show potent activity against HCV genotypes 1a and 1b, their relative antiviral effects against HCV genotypes 2-6 can vary greatly from one structural motif to another. Great (Gao, M., Curr. Opin. Virol. 2013 , 3 , 514-520). In addition, the emergence of antiviral resistance in the form of resistance-related variants (RAV) is still a problem and can invalidate existing clinical NS5A inhibitors (Chayama, K., Biochem. Biophys. Res. Commun. 2018 , 500 , 152-157). Obviously, there is still a need to develop novel small molecule NS5A inhibitors with pan-genotypic activity and/or potent RAV.

The present invention relates to the diurethane compound of the following general formula I, wherein the dash "-" represents a covalent bond.

或其醫藥上可接受之鹽、立體異構體、互變異構體、溶劑化物或前藥，其中： M係選自式II、III及IV，其中R¹ 在每次出現時獨立地為C₁ -C₆ 烷基：

P¹ 及P² 係相同或不同且獨立地不存在(直接鍵)或選自下式：

其中X為CH或N，L¹ 為與Q¹ 或Q² 之直接鍵，L² 為與M之直接鍵； Q¹ 及Q² 獨立地不存在(直接鍵)、

或

，其中L¹ 係與A¹ 或A² 之直接鍵，及L² 係與P¹ 或P² 之直接鍵；然而，條件為P¹ 及Q¹ 並非同時不存在，及P² 及Q² 並非同時不存在；當M為II時，P¹ 及P² 不為

； A¹ 及A² 係相同或不同且獨立地選自下式：

其中L³ 在每次出現時獨立地係與B¹ 或B² 之直接鍵；L⁴ 在每次出現時獨立地係與Q¹ 或Q² 之直接鍵；R² 及R³ 在每次出現時相同或不同，且獨立地選自H及視需要經取代之C₁ -C₆ 烷基，或與其所連接之碳原子一起形成視需要經取代之C₃ -C₆ 環烷基； B¹ 及B² 係相同或不同且獨立地選自下式：

， 其中R⁴ 係C₁ -C₆ 烷基或芳基-(C₁ -C₃ )烷基，各視需要經取代；及R⁵ 係C₁ -C₆ 烷基、芳基、雜芳基、經取代之C₁ -C₆ 烷基、芳基-(C₁ -C₃ )烷基、經取代之芳基-(C₁ -C₃ )烷基、雜芳基-(C₁ -C₃ )烷基、經取代之雜芳基-(C₁ -C₃ )烷基、經取代之芳基或經取代之雜芳基；及L⁵ 係與A¹ 或A² 之直接鍵。In one aspect, the present invention provides a compound of formula I :

Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein: M is selected from formula II, III and IV, wherein R ¹ is independently C at each occurrence _1- C ₆ alkyl:

P ¹ and P ² are the same or different and independently do not exist (direct bond) or are selected from the following formulas:

Where X is CH or N, L ¹ is a direct bond ^{with Q 1} or Q ^{2 and L 2} is a direct bond with M; Q ¹ and Q ² independently do not exist (direct bond),

or

, Where L ¹ is a direct bond ^{with A 1} or A ^{2 and L 2} is a ^{direct bond with P 1} or P ² ; however, the condition is that P ¹ and Q ¹ do not exist at the same time, and P ² and Q ^{2 are} not Does not exist at the same time; when M is II, P ¹ and P ^{2 are} not

; A ¹ and A ² are the same or different and are independently selected from the following formulas:

Wherein L ³ is independently a direct bond ^{with B 1} or B ² in each occurrence ^{; L 4} is independently a direct bond ^{with Q 1} or Q ² in each occurrence ^{; R 2} and R ^{3 are in each occurrence} When are the same or different, and are independently selected from H and optionally substituted C ₁ -C ₆ alkyl, or together with the carbon atom to which it is attached, form optionally substituted C ₃ -C ₆ cycloalkyl; B ¹ And B ² are the same or different and are independently selected from the following formulas:

, Wherein R ⁴ is a C ₁ -C ₆ alkyl group or an aryl-(C ₁ -C ₃ ) alkyl group, each of which is optionally substituted; and R ⁵ is a C ₁ -C ₆ alkyl group, an aryl group, or a heteroaryl group , Substituted C ₁ -C ₆ alkyl, aryl-(C ₁ -C ₃ )alkyl, substituted aryl-(C ₁ -C ₃ )alkyl, heteroaryl-(C ₁ -C ₃ ) Alkyl, substituted heteroaryl-(C ₁ -C ₃ )alkyl, substituted aryl or substituted heteroaryl; and L ⁵ is a direct bond ^{with A 1} or A ^2.

Another aspect of the present invention relates to a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof and one or more pharmaceutically acceptable salts. Acceptable excipients such as adjuvants, diluents and/or carriers.

Another aspect of the present invention relates to a method for inhibiting the function of HCV NS5A protein, which comprises combining a biological sample containing HCV NS5A protein with a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer Body, solvate, prodrug contact.

Another aspect of the present invention relates to a method for treating or preventing a disease, disorder or medical condition caused by HCV in a patient, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable Accepted salts, stereoisomers, tautomers, solvates or prodrugs.

In one embodiment, the disease, disorder, or medical condition caused by HCV may include liver cirrhosis, liver cancer, or hepatitis C infection.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug or combination thereof according to any embodiment described herein It is used to prepare drugs for the treatment of related diseases or disorders caused by HCV.

The compounds according to the present invention can generally be prepared by combining the known knowledge of those skilled in synthetic organic chemistry according to a series of steps of the synthetic methods described herein.

In view of the following detailed description and the scope of patent application, combined with the generally known knowledge and skills in this technology, those who are familiar with this technology will know other aspects or advantages of the present invention.

Cross reference of related applications This application claims the priority of the U.S. Provisional Application Serial No. 62/838,925 filed on April 25, 2019, the disclosure of which is incorporated herein by reference in its entirety.

The present invention provides novel dicarbamate compounds, which can be used as inhibitors of NS5A to treat hepatitis C virus (HCV) infection and diseases or disorders associated with HCV infection.

或其醫藥上可接受之鹽、立體異構體、互變異構體、溶劑化物或前藥，其中： M係選自式II、III及IV，其中R¹ 在每次出現時獨立地為C₁ -C₆ 烷基：

P¹ 及P² 係相同或不同且獨立地不存在(直接鍵)或選自下式：

其中X為CH或N，L¹ 為與Q¹ 或Q² 之直接鍵，L² 為與M之直接鍵； Q¹ 及Q² 獨立地不存在(直接鍵)、

或

，其中L¹ 係與A¹ 或A² 之直接鍵，及L² 係與P¹ 或P² 之直接鍵；然而，條件為P¹ 及Q¹ 並非同時不存在，及P² 及Q² 並非同時不存在；當M為II時，P¹ 及P² 不為

； A¹ 及A² 係相同或不同且獨立地選自下式：

其中L³ 在每次出現時獨立地係與B¹ 或B² 之直接鍵；L⁴ 在每次出現時獨立地係與Q¹ 或Q² 之直接鍵；R² 及R³ 在每次出現時相同或不同，且獨立地選自H及視需要經取代之C₁ -C₆ 烷基，或與其所連接之碳原子一起形成視需要經取代之C₃ -C₆ 環烷基； B¹ 及B² 係相同或不同且獨立地選自下式：

， 其中R⁴ 係C₁ -C₆ 烷基或芳基-(C₁ -C₃ )烷基，各視需要經取代；及R⁵ 係C₁ -C₆ 烷基、芳基、雜芳基、經取代之C₁ -C₆ 烷基、芳基-(C₁ -C₃ )烷基、經取代之芳基-(C₁ -C₃ )烷基、雜芳基-(C₁ -C₃ )烷基、經取代之雜芳基-(C₁ -C₃ )烷基、經取代之芳基或經取代之雜芳基；及L⁵ 係與A¹ 或A² 之直接鍵。In one aspect, the present invention provides a compound of formula I :

Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein: M is selected from formula II, III and IV, wherein R ¹ is independently C at each occurrence _1- C ₆ alkyl:

P ¹ and P ² are the same or different and independently do not exist (direct bond) or are selected from the following formulas:

Where X is CH or N, L ¹ is a direct bond ^{with Q 1} or Q ^{2 and L 2} is a direct bond with M; Q ¹ and Q ² independently do not exist (direct bond),

or

, Where L ¹ is a direct bond ^{with A 1} or A ^{2 and L 2} is a ^{direct bond with P 1} or P ² ; however, the condition is that P ¹ and Q ¹ do not exist at the same time, and P ² and Q ^{2 are} not Does not exist at the same time; when M is II, P ¹ and P ^{2 are} not

; A ¹ and A ² are the same or different and are independently selected from the following formulas:

Wherein L ³ is independently a direct bond ^{with B 1} or B ² in each occurrence ^{; L 4} is independently a direct bond ^{with Q 1} or Q ² in each occurrence ^{; R 2} and R ^{3 are in each occurrence} When are the same or different, and are independently selected from H and optionally substituted C ₁ -C ₆ alkyl, or together with the carbon atom to which it is attached, form optionally substituted C ₃ -C ₆ cycloalkyl; B ¹ And B ² are the same or different and are independently selected from the following formulas:

, Wherein R ⁴ is a C ₁ -C ₆ alkyl group or an aryl-(C ₁ -C ₃ ) alkyl group, each of which is optionally substituted; and R ⁵ is a C ₁ -C ₆ alkyl group, an aryl group, or a heteroaryl group , Substituted C ₁ -C ₆ alkyl, aryl-(C ₁ -C ₃ )alkyl, substituted aryl-(C ₁ -C ₃ )alkyl, heteroaryl-(C ₁ -C ₃ ) Alkyl, substituted heteroaryl-(C ₁ -C ₃ )alkyl, substituted aryl or substituted heteroaryl; and L ⁵ is a direct bond ^{with A 1} or A ^2.

；Q¹ 及Q² 不存在；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；及R⁵ 為視需要經取代之C₁ -C₆ 烷基。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is II; P ¹ and P ^{2 for} each

; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₁ -C ₆ alkyl.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, each X is CH; and R ² And R ^{3 is} independently hydrogen, methyl, ethyl, or together with the carbon atom to which it is attached to form an optionally substituted C ₃ -C ₆ cycloalkyl group.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ² and R ^{3 are} independently Hydrogen or methyl; R ⁴ is methyl or ethyl; R ⁵ is isopropyl.

；Q¹ 及Q² 不存在；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；R⁵ 為視需要經取代之C₁ -C₆ 烷基。In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is III; P ¹ and P ^{2 for} each

; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; R ⁵ is optionally substituted C ₁ -C ₆ alkyl.

；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；R⁵ 為視需要經取代之C₁ -C₆ 烷基。In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is III; P ¹ and P ^{2 does} not exist; Q ¹ and Q ^{2 are} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; R ⁵ is optionally substituted C ₁ -C ₆ alkyl.

；P² 為

；Q² 不存在；A¹ 為

；A² 為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；R⁵ 為視需要經取代之C₁ -C₆ 烷基。In one example of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is III; P ^{1 is} not present ; Q ¹ is

; P ² is

；Q ² does not exist; A ¹ is

; A ² is

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; R ⁵ is optionally substituted C ₁ -C ₆ alkyl.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, each X is CH; R ² And R ^{3 is} independently hydrogen, methyl, ethyl, or together with the carbon atom to which it is attached to form an optionally substituted C ₃ -C ₆ cycloalkyl group.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ² and R ^{3 are} independently Hydrogen or methyl; R ⁴ is methyl or ethyl, each optionally substituted; and R ⁵ is optionally substituted isopropyl.

，其中X為CH；Q¹ 及Q² 不存在；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；R⁵ 為C₁ -C₆ 烷基或C₆ -C₁₀ 芳基，各視需要經取代。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is IV; P ¹ and P ^{2 for} each

, Where X is CH; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; R ⁵ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, each of which is optionally substituted.

，其中X為N；Q¹ 及Q² 不存在；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；且R⁵ 為C₁ -C₆ 烷基或芳基，各視需要經取代。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is IV; P ¹ and P ^{2 for} each

, Where X is N; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is C ₁ -C ₆ alkyl or aryl, each of which is optionally substituted.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ⁵ is isopropyl or benzene The bases are each substituted as necessary.

，其中X為CH或N；Q¹ 及Q² 不存在；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；且R⁵ 為C₆ -C₁₀ 芳基，各視需要經取代。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is IV; P ¹ and P ^{2 for} each

, Where X is CH or N; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is C ₆ -C ₁₀ aryl, each optionally substituted.

；Q¹ 及Q² 各為

；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；且R⁵ 為視需要經取代之C₆ -C₁₀ 芳基。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is IV; P ¹ and P ^{2 for} each

; Q ¹ and Q ^{2 are} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₆ -C ₁₀ aryl.

；Q¹ 及Q² 各為

；A¹ 及A² 各為

；R⁴ 為視需要經取代之C₁ -C₆ 烷基；且R⁵ 為視需要經取代之C₆ -C₁₀ 芳基。In an embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, M is IV; P ¹ and P ^{2 for} each

; Q ¹ and Q ^{2 are} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₆ -C ₁₀ aryl.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ⁵ is optionally substituted Phenyl.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ² and R ^{3 are} independently Hydrogen, methyl, ethyl, or together with the carbon atom to which it is attached form an optionally substituted C ₃ -C ₆ cycloalkyl; and R ⁴ is an optionally substituted C ₁ -C ₄ alkyl.

In one embodiment of this aspect, in the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, R ² and R ^{3 are} independently Hydrogen or methyl; R ⁴ is methyl or ethyl.

In other embodiments, the present invention covers any and all possible combinations of the embodiments disclosed herein.

In one embodiment of this aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, which is selected from the following composition The group:

4,12-雙-[N -(甲氧基羰基)-L -纈胺醯基-L -脯胺醯基-N -(3-胺基苯基)]-[2.2]對環芳烴；

((S )-1-((S )-2-(5-(9,9-二氟-7-(3-((S )-1-((甲氧羰基)-L -纈胺醯基)吡咯啶-2-甲醯胺基)苯基)-9H -茀-2-基)-1H-咪唑-2-基)吡咯啶-1-基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸甲酯；

((2S ,2'S )-((2S ,2'S )-((((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯-4,8-二基)雙(3,1-伸苯基))雙(氮二基))雙(羰基))雙(吡咯啶-2,1-二基))雙(3-甲基-1-側氧基丁烷-1,2-二基))二胺甲酸二甲酯；

((1R ,1'R )-((2S ,2'S )-((((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯-4,8-二基)雙(3,1-伸苯基)雙(氮二基))雙(羰基))雙(吡咯啶-2,1-二基))雙(2-側氧基-1-苯基乙烷-2,1-二基))二胺甲酸二甲酯；

((1R ,1'R )-((2S ,2'S )-((((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯-4,8-二基)雙(吡啶-5,3-二基))雙(氮二基))雙(羰基))雙(吡咯啶-2,1-二基))雙(2-側氧基-1-苯基乙烷-2,1-二基))二胺甲酸二甲酯；

((1R ,1'R )-((2S ,2'S )-((((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯-4,8-二基)雙(3,1-伸苯基))雙(1H-咪唑-5,2-二基))雙(吡咯啶-2,1-二基))雙(2-側氧基-1-苯基乙烷-2,1-二基))二胺甲酸二甲酯；及

((1R ,1'R )-((2S ,2'S )-(((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯-4,8-二基)雙(4,1-伸苯基))雙(1H-咪唑-5,2-二基))雙(吡咯啶-2,1-二基))雙(2-側氧基-1-苯基乙烷-2,1-二基))二胺甲酸二甲酯。In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, which is selected from the group consisting of:

4,12-Bis-[ N -(methoxycarbonyl) -L - valinyl-L -proline- N -(3-aminophenyl)]-[2.2]paracyclic aromatic hydrocarbon;

(( S )-1-(( S )-2-(5-(9,9-Difluoro-7-(3-(( S )-1-((methoxycarbonyl) -L -valinyl ) pyrrolidine-2-acyl) phenyl) -9 H - fluorenyl-2-yl) lH-imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxo-side Butan-2-yl) methyl carbamate;

((2 S ,2' S )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro -s -Dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(azadiyl))bis(carbonyl))bis(pyrrolidine-2,1- Diyl)) dimethyl bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate;

((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro -s -Dicyclopentacene-4,8-diyl)bis(3,1-phenylene)bis(azadiyl))bis(carbonyl))bis(pyrrolidine-2,1-di )) Dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;

((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro -s -Dicyclopentacene-4,8-diyl)bis(pyridine-5,3-diyl))bis(azadiyl))bis(carbonyl))bis(pyrrolidine-2,1 -Diyl)) dimethyl bis(2-oxo-1-phenylethane-2,1-diyl)) dicarbamate;

((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro -s -Dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2, 1-diyl)) dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate; and

((1 R ,1' R )-((2 S ,2' S )-(((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro- s -Dicyclopentacene-4,8-diyl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1 -Diyl)) dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, and solvent according to any embodiment disclosed herein Compounds or prodrugs, and one or more pharmaceutically acceptable excipients such as adjuvants, diluents and/or carriers.

In one embodiment of this aspect, the pharmaceutical composition additionally includes a second agent having anti-HCV activity.

In one embodiment of this aspect, in the pharmaceutical composition, the second agent having anti-HCV activity is selected from the group consisting of: recombinant human interferon alpha, nucleoside analogs, direct-acting antiviral agents, NS3 /4A protease inhibitor, nucleotide NS5B polymerase inhibitor, NS5A inhibitor, non-nucleoside NS5B polymerase inhibitor, and combinations thereof.

In an embodiment of this aspect, in the pharmaceutical composition, the second agent is selected from the group consisting of: pegylated interferon, ribavirin, dacatavir, boceprevir (boceprevir) ), telapravir, simeprevir, sofosbuvir, dasabuvir, ombitasvir, velpatasvir , Redipavir, paritaprevir, ritonavir, elbavir, grazoprevir, asunaprevir, beclabuvir And its combination.

In another aspect, the present invention provides a method for inhibiting the function of HCV NS5A protein, which comprises combining a biological sample containing HCV NS5A protein with a compound or a salt, stereoisomer, or tautomer according to any embodiment disclosed herein. Contact with a conformer, solvate, or prodrug.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug or combination thereof according to any embodiment described herein It is used to prepare drugs for the treatment of related diseases or disorders caused by HCV.

In another aspect, the present invention provides a method for treating or preventing a disease, disorder, or medical condition associated with HCV activity in an individual, which comprises administering to the individual a therapeutically effective amount of any of the embodiments disclosed herein The compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, or its pharmaceutically acceptable salt, solvate or prodrug.

In one embodiment of this aspect, the method is additionally combined with the administration of a second agent having anti-HCV activity to the individual.

In an embodiment of this aspect, the second agent is selected from the group consisting of: recombinant human interferon alpha, nucleoside analogs, direct-acting antiviral agents, NS3/4A protease inhibitors, nucleotide NS5B polymerization Enzyme inhibitors, NS5A inhibitors, non-nucleoside NS5B polymerase inhibitors, including but not limited to pegylated interferon, ribavirin, dacatavir, bosiprevir, telapravir, cyme Previr, sofosbuvir, dalsabvir, obetavir, vipatavir, redipavir, palitaprevir, ritonavir, elbavir, glazoprevir, assu Navir, Bekrabuvir and their combinations.

In another embodiment, a method for treating or preventing a disease, disorder, or medical condition associated with HCV activity in an individual comprises administering to the individual a therapeutically effective amount of the pharmaceutical composition according to any of the embodiments disclosed herein .

Diseases, disorders, or medical conditions associated with HCV activity include, but are not limited to, hepatitis C infection, chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), liver cancer, mixed cryoglobulinemia, and delayed skin lesions Porphyria, leukocytosis vasculitis, lichen planus (LP), sicca syndrome, urticaria, pruritus, thrombocytopenic purpura and psoriasis.

In one embodiment, diseases, disorders, or medical conditions caused by HCV may include liver cirrhosis, liver cancer, and hepatitis C infection.

In one embodiment, the disease is liver cirrhosis.

In one embodiment, the disease is liver cancer.

In one embodiment, the disease is hepatitis C infection.

Unless otherwise specified, the term "alkyl" as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups containing 1 to 8 carbons, preferably 1 to 6, more preferably 1 to 4 carbons. The term includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, or the like.

Unless otherwise specified, the term "alkylene" as used herein refers to a divalent saturated aliphatic group derived from an alkane by removing two hydrogen atoms. Examples include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), _{ethylene (-CH 2} CH ₂ CH ₂ -), or the like.

Unless otherwise specified, the term "cycloalkyl" as used herein alone or as part of another group includes saturated cyclic hydrocarbon groups of 3 to 8 carbons that form a ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Unless otherwise specified, the term "aryl" as used herein alone or as part of another group refers to a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion (such as phenyl and naphthalene). Group, including 1-naphthyl and 2-naphthyl).

As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more (preferably 1 to 4, sometimes preferably 1 to 3) independently selected from nitrogen (N), oxygen (O ) And sulfur (S) heteroatoms are 5 to 14 membered monocyclic, bicyclic or tricyclic, and sometimes preferably 5 to 10 membered monocyclic or bicyclic aromatic groups. As is well known to those skilled in the art, heteroaryl rings have fewer aromatic properties than their all-carbon counterparts. Therefore, for the purposes of the present invention, a heteroaryl group only needs to have a certain degree of aromatic character.

As used herein, "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

When any group such as alkyl, alkenyl, "cycloalkyl", "aryl", "heterocyclyl" or "heteroaryl" is considered to be "optionally substituted", unless explicitly defined otherwise It means that the group is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _1- C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxyl, pendant oxy, C ₁ -C ₆ acyl, cyano, nitro and NR ^a R ^b (R ^a and R ^{b are} each independently H Or C ₁ -C ₄ alkyl) or similar substituents, provided that such substitution does not violate the conventional bonding principle known to those skilled in the art. When the phrase "substituted as needed" is used before the list of groups, it means that the listed groups can be substituted as needed.

Those familiar with the art should understand that when an aryl, heteroaryl, cycloalkyl, heterocyclyl or the like is between two or more groups, it should be interpreted as having the appropriate name "extension". A divalent group of "aryl", "heteroaryl", "cycloalkylene", "heterocyclylene" or the like. However, sometimes such a distinction is not made. For example, "aryl" should be interpreted as "aryl extension", and those who are familiar with this technology should understand.

The term "substitution as necessary" means that the substitution may or may not occur, and includes the case where the substitution occurs and the case where the substitution does not occur. Those of ordinary skill should understand that any molecule described as containing one or more substituents is only intended to include sterically feasible and/or synthetically feasible compounds. Unless otherwise stated in this specification, when it is said that a variable is substituted by a substituent or substituted by a substituent as necessary, it should be understood that the substitution is by replacing a hydrogen covalently bonded to the variable with one of these substituents And happen.

As used herein, the term "pharmaceutically acceptable salt" refers to within the scope of reasonable medical judgment, suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and with reasonable benefits/risks Comparable to their salt. Pharmaceutically acceptable salts are well known in the art. See, for example, SM Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and organic acids. Examples of pharmaceutically acceptable non-toxic acid addition salts are amine groups and inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, Citric acid, succinic acid, or malonic acid) or salts formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate , Camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, grape enanthate, glycerophosphoric acid Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, apple salt, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin ester Acid salt, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Salt, undecanoate, valerate, etc.

The stereochemical definitions and conventions used herein generally follow the McGraw-Hill Dictionary of Chemical Terms, edited by SP Parker, McGraw-Hill Book Company, New York (1984) and Stereochemistry of Organic Compounds, Eliel, E. and Wilen, S., John Wiley & Sons, Inc., New York (1994). Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its opposing center. The prefixes d and 1 or (+) and (-) are used to indicate the rotation symbol of the plane-polarized light of the compound, where (-) or 1 means that the compound is levorotatory, and (+) or d means that the compound is dextrorotatory Spin. For a given chemical structure, these compounds (called stereoisomers) are the same, but the differences are mirror images of each other. A specific stereoisomer of a mirror image pair can also be called an enantiomer, and a mixture of such isomers is usually called an enantiomeric mixture. Regarding the use of ( R ) or ( S ), the absolute configuration of the substituents is specified in the context of the entire compound rather than in the context of individual substituents.

化合物9 之互變異構

化合物17 之互變異構The term "tautomer" refers to a molecule in which a proton can shift from one atom to another in the same molecule, for example in amide and urethane linkages or heterocycles such as imidazole. The compounds proposed in this article may exist in the form of tautomers. In the case of possible tautomerism, there will be a chemical equilibrium of tautomers, and the exact ratio of tautomers can depend on several factors, including physical state, temperature, solvent, and pH. For illustrative purposes, some examples (not exhaustive) of tautomer equilibrium may include:

Tautomerism of Compound 9

Tautomerism of Compound 17

The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances, which has no optical activity.

The term "enantiomerically pure" or "enantiomerically pure" means a pure stereoisomer that is not contaminated by its enantiomer. "Enantiomeric enrichment" means a compound in which one of two (or more) enantiomers is found in a given sample at a higher concentration than the other enantiomer.

As used herein, the term "substituted" is intended to include all permitted substituents of organic compounds. In a broad sense, the permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permitted substituents of the organic compounds described herein that satisfy the valence of the heteroatoms. The present invention is not intended to be limited in any way by the permitted substituents of organic compounds.

As used herein, the term "solvate" means the physical association of a compound of the invention with a stoichiometric or non-stoichiometric amount of solvent molecules. For example, one molecule of the compound is associated with one or more (preferably 1-3) solvent molecules. It is also possible that multiple (for example, 1.5 or 2) molecules of the compound share one solvent molecule. This physical association may include hydrogen bonding. In some cases, the solvate will be able to isolate as a crystalline solid. The solvent molecules in the solvate can be arranged in regular and/or disordered arrangements. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

As used herein, the term "prodrug" refers to a derivative of the compound of the present invention, which has a chemically or metabolically cleavable group, and becomes pharmacologically active in vivo by solvolysis or under physiological conditions. Compounds of the invention. A compound prodrug can be formed in a conventional manner with the functional group (when present) of the compound, for example, with an amine group, a hydroxyl group, or a carboxyl group. The prodrug derivative form usually has the advantages of solubility, histocompatibility or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pages 7 to 9, pages 21 to 24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reacting a parent acid compound with a suitable alcohol, or amides prepared by reacting a parent acid compound with a suitable amine.

When used in therapy, when a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can be administered as a chemical raw material, the active ingredient can be presented as a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition, which includes any compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and one or more, preferably 1 to 3 pharmaceutically acceptable carriers and diluents Or other excipients. The carrier(s), diluent or other excipients must be acceptable in the sense that they are compatible with the other ingredients of the formulation and not harmful to the individual being treated.

The composition of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphoric acid). Salt), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g. glutenamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc Salt, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block Polymers, polyethylene glycol and lanolin.

As used herein, the term "pharmaceutically acceptable" refers to the properties of their compounds, materials, compositions and/or dosage forms, which are suitable for contact with the patient’s tissues within the scope of reasonable medical judgment without excessive toxicity or irritation. Sex, allergic reactions or other problems or complications with a reasonable benefit/risk ratio, and can be effectively used for its intended use.

The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, transrectally, nasally, transbuccally, transvaginally, or via implanted reservoirs. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

Pharmaceutical formulations suitable for oral administration can exist in discrete units, such as capsules or lozenges; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foaming agents; Or oil-in-water liquid emulsion or water-in-oil emulsion.

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

In addition, when needed or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, etc. . Lubricants used in these dosage forms include sodium oleate, sodium chloride and so on. Disintegrants include but are not limited to starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing, adding a lubricant and disintegrant, and pressing into a tablet. The powder mixture is prepared by mixing the appropriately pulverized compound with the above diluent or alkali, and if necessary, with a binder such as carboxymethyl cellulose, alginate, gelling agent or polyvinylpyrrolidone, solution retarder For example, it is prepared by paraffin wax, reabsorption promoters such as quaternary salts and/or absorbents such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or a solution of cellulose or polymer materials and forcing it through a sieve. As an alternative to granulation, the powder mixture can be run through a lozenge machine, and as a result the imperfect lumps that are formed will break into granules. The granules can be lubricated by adding stearic acid, stearate, talc or mineral oil to prevent sticking to the tablet mold. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with free-flowing inert carriers and directly compressed into tablets without undergoing granulation or dry pressing steps. A transparent or opaque protective coating consisting of a seal coating of shellac, a coating of sugar or polymer materials, and a polishing coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit doses.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs are prepared by using a non-toxic carrier. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners can also be added.

Where appropriate, the dosage unit formulation for oral administration can be microencapsulated. The formulation can also be prepared for extended or sustained release, for example by coating or embedding particulate material in a polymer, wax or the like.

It should be understood that, in addition to the ingredients specifically mentioned above, considering the type of formulation in question, the formulation may include other agents known in the art, for example, a formulation suitable for oral administration may include flavoring agents.

The term "individual" or "patient" includes humans and other mammals, including but not limited to horses, cats, dogs, monkeys, and cows, and preferably humans.

The term "treatment" includes the partial or full inhibition of human diseases, disorders or medical conditions caused by the hepatitis C virus, including liver cirrhosis and liver cancer. The term "prevention" includes in general the prevention of the onset of hepatitis C infection or the prevention of the onset of hepatitis C infection in individuals at risk.

In view of the following detailed description and the scope of the patent application, combined with the generally known knowledge and skills in this technology, those who are familiar with this technology will know other aspects or advantages of the present invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

It should be noted here that as used in this specification and the scope of the appended application, the singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. Unless otherwise indicated, the terms "including", "including", "containing" or "having" and their variants are intended to cover the items listed thereafter and their equivalents and other subject matter.

Chemical synthesis The compounds described herein and/or their pharmaceutically acceptable salts and solvates can be synthesized from commercially available starting materials by methods well known to those skilled in the art. The following general synthesis reaction diagram illustrates the preparation of most compounds. In each of these reaction diagrams, G ¹ and G ² are leaving groups, which are the same or different and are exemplified by, but not limited to, halogen, methanesulfonate, tosylate, or trifluoromethanesulfonate. In addition, reagents, solvents, temperatures, catalysts, and ligands are not limited to those described for illustrative purposes. For the sake of clarity, some abbreviations and initials that are familiar to those familiar with the technology used in the reaction diagram are listed below.

Abbreviations and initials The following abbreviations and initials can be used in this application: anhyd.=anhydrous aq.=aqueous; br=broad salt water=saturated NaCl aqueous solution; B ₂ pin ₂ =bis(pinacol radical) diboron; n -Bu ₃ P = tri-n-butyl phosphine; CAS# = Chemical Abstract Service registration number; Compd = compound; Concd. = concentration d = day; DCM = dichloromethane; DIEA = DIPEA = N , N -diisopropyl Ethylamine; DMF = N , N -dimethylformamide; DMSO = dimethyl sulfide; DMA = N , N -dimethylacetamide; dppf = 1,1'-bis(diphenyl Phosphonyl) ferrocene; EtOAc = ethyl acetate; Ex = example; FCC = fast column chromatography using silica gel; h = hour; HATU = hexafluorophosphate 1-[bis(dimethylamino) Methyl]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide; IBCF = isobutyl chloroformate; KOAc = potassium acetate; LDA = diisopropyl acetonitrile Lithium amide; LiHMDS = lithium bis(trimethylsilyl) amide [LiN(SiMe ₃ ) ₂ ]; MeOH = methanol; min. = minutes; NMM = N -methylmorpholine; Pd ₂ (dba) ₃ = Ref. (dibenzylideneacetone)dipalladium(0); Pd(PPh ₃ ) ₂ Cl ₂ = bis(triphenylphosphine) palladium(II); Pd(dppf)Cl ₂ = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ = [1,1'-bis(diphenylphosphino)ferrocene] The complex of dichloropalladium(II) and dichloromethane rt = room temperature; satd. = saturated; T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxo Heterotriphosphorane-2,4,6-trioxide; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; wt. = weight; wt.% = weight percentage; w/v = Weight-to-volume ratio; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XtalFluor-E = tetrafluoroborate (diethylamino) difluorosulfonium.

酸或酯2 偶合。或者，

酸或酯3 可在相似條件下與4 偶合以提供式I化合物5 。能夠形成P¹ -M及M-P² 鍵但採用替代之偶合搭配物及試劑之其他過渡金屬介導之交叉偶合反應包括但不限於根岸(Negishi)、熊田(Kumada)、薗頭(Sonagasira)及施蒂勒(Stille)反應。反應圖 1 ：具有對稱結構之式I化合物之代表性合成

General synthesis reaction diagram Reaction diagram 1 shows the general synthesis of the compound of formula I of the present invention when the compound has a symmetrical structure of formula 5 , in which transition metal-mediated cross-coupling reactions are used to construct P ¹ -M and MP ² bonds. For illustration purposes, a palladium catalyst such as Pd(dppf) ₂ Cl _{2 is} used, and a Suzuki reaction is used to make the intermediates G ¹ -MG ² 1 (where G ¹ and G ^{2 are the} same or different) and

Acid or ester 2 coupling. or,

Acid or ester 3 can be coupled with 4 under similar conditions to provide compound 5 of formula I. Other transition metal-mediated cross-coupling reactions capable of forming P ¹ -M and MP ² bonds but using alternative coupling partners and reagents include, but are not limited to, Negishi, Kumada, Sonagasira, and Shi Stille reacted. Reaction Figure 1 : Representative synthesis of a compound of formula I with a symmetric structure

Reaction Figure 2 shows the synthesis of the compound of formula I of the present invention containing a carboxyamide bond. The carboxylic acid 6 is coupled with the amine 7 using a peptide coupling reagent (such as HATU) to obtain the carboxyamide 8 of formula I. Alternatively, the reaction of the corresponding carboxylic acid halide, activated ester or mixed acid anhydride derivative of amine 7 and 6 can also provide formula I carboxyamide 8 reaction Figure 2

反應圖 4

反應圖 5

反應圖 6

反應圖 7

反應圖 8

Other general reaction diagrams for the synthesis of compounds of formula I include but are not limited to the following reaction diagrams 3 to 8. Response Figure 3

Response Figure 4

Response Figure 5

Response Figure 6

Response Figure 7

Response Figure 8

These general reaction diagrams are provided for illustrative purposes. In any synthesis reaction diagram provided, any one of X, X ¹ , X ² , X ³ , Y, Y ¹ , Y ² , Y ³ , G, G ¹ , G ² and G ³ can be selected as required It is preferable to have good selectivity from various coupling, leaving or protecting groups. If necessary, protection and deprotection of certain functional groups such as hydroxyl (-OH), amino (-NH ₂ ) and carboxyl (-CO _{2 H) can be implemented.}

The compound thus obtained can be additionally modified at its peripheral positions to provide the desired compound. Synthetic chemical transformations are described in, for example, R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , third edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and edited by L. Paquette, Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions. The compound of formula I described herein and/or its pharmaceutically acceptable salts and solvates can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

Examples The following non-limiting examples further illustrate certain aspects of the invention. These compounds were prepared according to the general synthesis scheme described above.

化合物9 係根據反應圖9製備。反應圖 9

Example 1 (±)-4,12-bis-[N-(methoxycarbonyl)-L-valinyl-L-proline-N-(3-aminophenyl)]-[2.2] Paracyclic aromatic hydrocarbons ( 9 )

Compound 9 was prepared according to reaction diagram 9. Response Figure 9

( ± )-4,12 -bis- (3 -aminophenyl )-[2.2] paracyclic aromatic hydrocarbon (12). (±)-4,12-dibromo[2.2]-paracyclic aromatic hydrocarbon(10) (100 mg, 0.2732 mmol; CAS#23927-40-4), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ( 11 ) (239 mg, 1.09 mmol; CAS#210907-84-9) and K ₃ PO ₄ (476 mg, 2.24 mmol) and 10.6 mL of 1,4-dioxane and water (v/v) 10 :1 The mixture is combined in a microwave reaction tube. The resulting white slurry was _{degassed via N 2} bubbling for 30 minutes, treated with Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (22 mg, 0.0273 mmol), and heated on a microwave reactor at 80°C with vigorous stirring for 2 hours . The reaction mixture was cooled to room temperature and partitioned between water and CH ₂ Cl ₂ /MeOH (19:1). The aqueous layer was _{extracted twice more with CH 2} Cl ₂ /MeOH (19:1), and the combined organic extracts were washed twice with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 5-30% EtOAc in hexane to obtain 22 mg (21%) of (±)-4,12-bis-(3-amine) as a white foam Phenylphenyl)-[2.2] paracyclic aromatic hydrocarbon ( 12 ): MS ( m/z ) MH ⁺ 391.

( ± )-4,12 -bis- [N-( tertiary butoxycarbonyl )-L- proline- N-(3 -aminophenyl ))-[2.2] paracyclic aromatic hydrocarbon (14). Dissolve N-(tertiary butoxycarbonyl)-L-proline ( 13 ) (27 mg, 0.126 mmol) and DIEA (30 µL, 0.1713 mmol) in DMF (1.0 mL), and use HATU (65 mg, 0.1713 mmol) treatment. The reaction mixture was placed under a nitrogen atmosphere, stirred at room temperature for 30 minutes, and then treated with (±)-4,12-bis-(3-aminophenyl)-[2.2] paracyclic aromatic hydrocarbon ( 12 ) (22 mg , 0.0571 mmol) in DMF (1.5 mL) solution treatment. After 18 hours, the reaction mixture was quenched by adding water (5 mL), diluted with brine (5 mL), and extracted 3 times with 5 mL EtOAc. The combined EtOAc layer was _{washed twice with 5 mL of a 1:1 mixture of saturated aqueous NaHCO 3} and brine (v/v), then washed twice with 5 mL of 10% aqueous citric acid, dried (Na ₂ SO ₄ ), and filtered And concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 10-50% EtOAc in hexane to obtain 37 mg (83%) of (±)-4,12-bis-[N-(section) as a beige solid Tributoxycarbonyl)-L-proline-N-(3-aminophenyl)]-[2.2] paracyclic aromatic hydrocarbon ( 14 ): MS (m/z) MH ⁺ 785 (weak).

(±)-4,12 -bis- [L- proline- N-(3 -aminophenyl )]-[2.2] paracyclic aromatic hydrocarbon (15). Will (±)-4,12-bis -[N-(tertiary butoxycarbonyl)-L-proline-N-(3-aminophenyl)]-[2.2] paracyclic aromatic hydrocarbon (14 ) (37 mg, 0.0471 mmol) dissolved in In CH ₂ Cl ₂ (1.0 mL) and treated with trifluoroacetic acid (1.0 mL) at room temperature under a nitrogen atmosphere while stirring. After 25 hours, the reaction mixture was concentrated in vacuo, and the residue was partitioned between 1 N aqueous NaOH (10 mL) and CH ₂ Cl ₂ (5 mL). The alkaline aqueous layer was _{extracted twice more with CH 2} Cl ₂ (5 mL), and the combined organic extracts were washed twice with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 5-30% MeOH/NH 4} OH (49:1) in CH ₂ Cl ₂ solution to obtain 11.4 mg (41%) of (±)-4 as a white solid ,12-Bis-[L-proline-N-(3-aminophenyl)]-[2.2] paracyclic aromatic hydrocarbon ( 15 ): MS ( m/z ) MH ⁺ 585.

(±) -4,12- bis - [N-(methoxycarbonyl) -L- valinamide -L-proline acyl acyl amine -N- (3- aminophenyl)] - [2.2] on the ring Aromatics (9). Dissolve N-(methoxycarbonyl)-L-valine ( 16 ) (8.5 mg (0.0487 mmol)) and DIEA (10 μL, 0.0585 mmol) in DMF (2.0 mL), and Treat with HATU (18.5 mg, 0.0487 mmol) at room temperature under nitrogen atmosphere while stirring. After 30 minutes, add (±)-4,12-bis-[L-proline-N-(3-aminophenyl)]-[2.2] paracyclic aromatic hydrocarbon ( 15 ) (11.4 mg, 0.0195 mmol ), and the resulting slurry was stirred at room temperature for 16 hours. The reaction was stopped by adding water (5 mL), diluted with brine (5 mL), and _{extracted 3 times with CH 2} Cl ₂ (5 mL). The combined layers were extracted twice with 10% citric acid aqueous solution (5 mL), twice with brine (5 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed The silica gel was purified by gradient elution with 0-5% MeOH in CH ₂ Cl ₂ solution to obtain 13.8 mg (78%) of (±)-4,12-bis-[N-(methoxycarbonyl)- as a white solid L-valinyl-L-proline-N-(3-aminophenyl)]-[2.2] paracyclic aromatic hydrocarbon ( 9 ): MS (m/z) MH ⁺ 899; ¹ H NMR ( 300 MHz, CD3OD): δ 7.98 (br s, 0.2H), 7.95 (br s, 0.8H), 7.90 (br s, 0.2H), 7.88 (br s, 0.8H), 7.60-7.49 (m, 2H) ), 7.40 (dd, J = 7.8, 7.9 Hz, 2H), 7.27-7.17 (m, 2H), 6.81-6.57 (m, 6H), 4.66-4.56 (m, 2H), 4.28-4.18 (m, 2H) ), 4.06-3.92 (m, 2H), 3.98-3.71 (m, 2H), 3.65 (s, 6H), 3.60-3.39 (m, 2H), 3.11-2.91 (m, 2H), 2.91-2.76 (m , 2H), 2.76-2.61 (m, 1.6H), 2.61-2.47 (m, 0.4 H), 2.43-2.26 (m, 2H), 2.26-1.91 (m, 8H), 1.12-0.81 (m, 12H) .

化合物17 係根據反應圖10製備。反應圖 10

Example 2 ((S)-1-((S)-2-(5-(9,9-difluoro-7-(3-((S)-1-((methoxycarbonyl)-L-valine) (Pyrrolidine-2-carboxamido)phenyl)-9H-茀-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-side Oxybutan-2-yl)carbamate ( 17 )

Compound 17 was prepared according to Reaction Figure 10. Response Figure 10

酸頻哪醇酯(19 ) (85 mg，0.3873 mmol)、K₃ PO₄ (123 mg，0.5808 mmol)、水(0.25 mL)及1,4-二噁烷(2.5 mL)在微波反應管中組合。將所得混合物經由N₂ 鼓泡且同時攪拌下用脫氣，然後添加Pd(dppf)Cl₂ (14.2 mg，0.0194 mmol)。將所得混合物在CEM Discover SP微波反應器中在PowerMax模式下在80℃劇烈攪拌下加熱2小時。將反應冷卻至室溫，用EtOAc (15 mL)稀釋，用15 mL之飽和NaHCO₃ 水溶液及鹽水(v/v)之1:1混合物萃取兩次，用15 mL鹽水洗兩次，乾燥(Na₂ SO₄ )，過濾並真空濃縮。殘餘物藉由層析法於矽膠上用10-40%EtOAc之CH₂ Cl₂ 溶液梯度溶離純化，得到100 mg (98%)呈淺橙色固體之(S)-2-(5-(7-(3-胺基苯基)-9,9-二氟-9H-茀-2-基)-1H-咪唑-2-基)吡咯啶-1-甲酸第三丁酯(20 )：MS (m/z) MH⁺ 529。 (S)-2-(5-(7-(3 -aminophenyl )-9,9 -difluoro -9H- 茀 -2- yl )-1H- imidazol -2- yl ) pyrrolidine- 1- Tertiary butyl formate (20) . (S)-2-(5-(7-bromo-9,9-difluoro-9H-茀-2-yl)-1H-imidazol-2-yl)pyrrolidine Tert-butyl-1-carboxylate ( 18 ) (100 mg, 0.1936 mmol; CAS#1256388-03-0; J. Med. Chem. 2014, 57(5), 2033-2046), 3-aminophenyl

Pinacol ester ( 19 ) (85 mg, 0.3873 mmol), K ₃ PO ₄ (123 mg, 0.5808 mmol), water (0.25 mL) and 1,4-dioxane (2.5 mL) in a microwave reaction tube combination. The resulting mixture _{was degassed with bubbling through N 2} while stirring, and then Pd(dppf)Cl ₂ (14.2 mg, 0.0194 mmol) was added. The resulting mixture was heated in a CEM Discover SP microwave reactor in PowerMax mode at 80°C with vigorous stirring for 2 hours. The reaction was cooled to room temperature, diluted with EtOAc (15 mL), _{extracted twice with 15 mL of a 1:1 mixture of saturated aqueous NaHCO 3} and brine (v/v), washed twice with 15 mL brine, and dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 10-40% EtOAc in CH 2} Cl _{2 to} obtain 100 mg (98%) of (S)-2-(5-(7- (3-Aminophenyl)-9,9-difluoro-9H-茀-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate ( 20 ): MS (m /z) MH ⁺ 529.

(S)-2-(5-(9,9 -Difluoro -7-(3-((S)-1-(( Methoxycarbonyl )-L- valinyl ) pyrrolidine -2 -methan (Amino ) phenyl )-9H- 茀 -2- yl )-1H- imidazol -2- yl ) pyrrolidine- 1- carboxylate (22) . (Methoxycarbonyl)-L-valine A solution of L-L-proline ( 21 ) (66 mg, 0.2435 mmol; CAS#181827-47-4) and DIEA (98 µL, 0.5619 mmol) in DMF (2.0 mL) at room temperature and nitrogen atmosphere Treat with HATU (93 mg, 0.2435 mmol) while stirring. After 30 minutes, add (S)-2-(5-(7-(3-aminophenyl)-9,9-difluoro-9H-茀-2-yl)-1H-imidazol-2-yl) A solution of tert-butyl pyrrolidine-1-carboxylate (20) (99 mg, 0.1873 mmol) in DMF (1.0 mL). After 15 hours, the reaction was diluted with EtOAc (15 mL), _{extracted twice with 15 mL of a 1:1 mixture of saturated aqueous NaHCO 3} and brine (v/v), washed twice with 15 mL brine, and dried (Na ₂ SO ₄ ), filter and concentrate in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 10-60% EtOAc in CH 2} Cl ₂ solution to obtain 97 mg (66%) of (S)-2-(5-(9, 9-Difluoro-7-(3-((S)-1-((methoxycarbonyl)-L-valinyl)pyrrolidine-2-carboxamido)phenyl)-9H-茀-2 -Yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (22): MS (m/z) MH ⁺ 783.

((S)-1-((S)-2-((3-(9,9 -Difluoro -7-(2-((S) -pyrrolidin -2- yl )-1H- imidazole -5- yl) -9H- fluorene-2-yl) phenyl) methyl acyl group) pyrrolidin-1-yl) -3-methyl-1-oxo-2-yl) methyl amine three Fluoroacetate (1:2) (23) . (S)-2-(5-(9,9-Difluoro-7-(3-((S)-1-((methoxycarbonyl)-L- Valinyl)pyrrolidine-2-carboxamido)phenyl-9H-phen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate ( 22 ) (94 mg, 0.1196 mmol) in CH ₂ Cl ₂ (3.0 mL) was treated with trifluoroacetic acid (1.0 mL) at room temperature under nitrogen atmosphere while stirring. After 2 hours, the reaction mixture was concentrated in vacuo and used Et ₂ O was wet-milled twice, and the obtained solid was vacuum dried to obtain 101 mg (92%) of ((S)-1-((S)-2-((3-(9,9-difluoro-)) as a beige solid 7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-茀-2-yl)phenyl)aminomethanyl)pyrrolidin-1-yl ) Methyl-3-methyl-1-oxobutan-2-yl)carbamate trifluoroacetate (1:2) ( 23 ): MS (m/z) MH ⁺ 683.

((S)-1-((S)-2-(5-(9,9 -difluoro -7-(3-((S)-1-(( methoxycarbonyl )-L- valinyl ) -Pyrrolidine -2- carboxamido ) phenyl )-9H- 茀 -2- yl )-1H- imidazol -2- yl ) pyrrolidin- 1 -yl )-3 -methyl- 1 -oxo Methyl butane -2- yl ) carbamate (17) . Combine N-(methoxycarbonyl)-L-valine acid ( 16 ) (29 mg, 0.1630 mmol) and DIEA (76 µL, 0.4348 mmol) The solution was dissolved in DMF (2.0 mL) and treated with HATU (62 mg, 0.1630 mmol) at room temperature under nitrogen atmosphere while stirring. After 30 minutes, add (S)-2-(5-(7-(3-aminophenyl)-9,9-difluoro-9H-茀-2-yl)-1H-imidazol-2-yl) A solution of tert-butyl pyrrolidine-1-carboxylate ( 20 ) (99 mg, 0.1873 mmol) in DMF (1.0 mL). After 18 hours, the reaction mixture was diluted with EtOAc (15 mL), _{extracted twice with 15 mL of a 1:1 mixture of saturated aqueous NaHCO 3} and brine (v/v), washed twice with brine (15 mL), and dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 0-5% MeOH in CH 2} Cl ₂ solution to obtain 67 mg (73%) of -((S)-1-((S)-) as a beige solid 2-(5-(9,9-Difluoro-7-(3-((S)-1-((Methoxycarbonyl)-L-valinyl)-pyrrolidine-2-methanyl) (Phenyl)-9H-茀-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)methyl carbamate ( 17 ): MS (m/z) MH ⁺ 840; ¹ H NMR (300 MHz, CD ₃ OD): 8.11-7.23 (m, 11H), 5.19-5.17 (m, 1H), 4.65-4.51 (m, 1H ), 4.27-4.16 (m, 2H), 4.14 to 3.71 (m, 4H), 3.65 (s, 3H), 3.64 (s, 3H), 2.44-2.07 (m, 10H), 1.11 to 0.88 (m, 12H) ).

化合物24 係根據反應圖11製備。反應圖 11

Example 3 ((2S,2'S)-((2S,2'S)-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-two Cyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(azadiyl)bis(carbonyl)bis(pyrrolidine-2,1-diyl))bis( 3-Methyl-1-oxobutane-1,2-diyl)) dimethyl dicarbamate ( 24 ).

Compound 24 was prepared according to Reaction Figure 11. Response Figure 11

4,4'-(2,5 -Dibromo -1,4- phenylene ) bis (2 -methylbut- 3- yn -2- ol ) (27) . Add triethylamine (125 mL) To 1,4-dibromo-2,5-diiodobenzene (25) (12.2 g, 25.0 mmol), cuprous (I) iodide (49.6 mg, 0.260 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ ( 354 mg, 0.504 mmol) in a mixture. The resulting suspension was placed under an N ₂ atmosphere and degassed by 5 evacuation/N ₂ coating cycles, and 2-methyl-3-butyn-2-ol ( 26 ) (6.1 mL, 62.9 mmol) ). The reaction mixture was degassed again, and then heated to reflux with stirring _{under N 2 for 17 hours.} The cooled reaction mixture was concentrated in vacuo, wet milled several times with ethyl acetate, and filtered. The filtrate was washed with brine, dried (CaSO ₄ ), filtered and concentrated in vacuo. The residue was recrystallized from boiling heptane to obtain 9.3 g of 4,4'-(2,5-dibromo-1,4-phenylene)bis(2-methylbut-3-yne) as off-white powder -2-ol) ( 27 ): MS (m/z) (MH ₂ O) H ⁺ = 382; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.49 (s, 12H), 5.60 (s, 2H), 7.79 (s, 2H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 31.7, 64.3, 78.3, 104.0, 123.9, 126.2, 136.3.

酸(28 ) (1.43 g，8.57 mmol)、碳酸鈉(7.55 g，71.3 mmol)、Pd(dppf)Cl₂ ·CH₂ Cl₂ (250 mg，0.31 mmol)及水合四丁基氯化銨(84.1 mg，0.30 mmol)在室溫下於THF及H₂ O之1:1混合物(v/v) (58 mL)中合併。經由5個抽空/N₂ 包覆循環將所得懸浮液脫氣並在室溫及N₂ 下攪拌。2.5小時後，反應混合物用鹽水洗及有機層真空濃縮並藉由層析法於矽膠上用0-10% MeOH之CH₂ Cl₂ 溶液的梯度溶離純化，得到1.61 g淺棕色固體。將該物質自沸騰之乙酸乙酯重結晶，得到1.09 g呈白色粉末之4,4'-(3,3''-二硝基-[1,1':4',1''-聯三苯]-2',5'-二基)雙(2-甲基丁-3-炔-2-醇) (29 )：MS(m/z) (M-H₂ O)H⁺ = 467；¹ H NMR (300 MHz，DMSO-d₆ )：δ 1.34 (s，12H)，5.40 (s，2H)，7.69 (s，2H)，7.80 (dd，J = 8.0，8.0 Hz，2H)，8.13 (d ，J = 8.3 Hz，2H)，8.32 (m，2H)，8.49 (t，J = 1.9 Hz，2H) ppm；¹³ C NMR (75 MHz，DMSO-d₆ ) δ 31.5，64.1，79.1，102.1，121.7，123.4，124.1，130.4，134.1，136.2，140.0，140.6，147.9。 4,4'-(3,3''- Dinitro- [1,1':4',1''- terphenyl ]-2',5' -diyl ) bis (2 -methylbutyl 3-yn-2-ol) (29) 4,4 '- (2,5-dibromo-1,4-phenylene) bis (2-methylbut-3-yn-2-ol ) (27) (1.14 g, 2.85 mmol), 3-nitrophenyl

Acid ( 28 ) (1.43 g, 8.57 mmol), sodium carbonate (7.55 g, 71.3 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (250 mg, 0.31 mmol) and hydrated tetrabutylammonium chloride (84.1 mg, 0.30 mmol) were combined in a 1:1 mixture (v/v) of _{THF and H 2 O (58 mL) at room temperature.} The resulting suspension was degassed via 5 evacuation/N ₂ coating cycles and stirred at room temperature under _{N 2.} After 2.5 hours, the reaction mixture was washed with brine and the organic layer was concentrated in vacuo and _{purified by chromatography on silica gel with a gradient of 0-10% MeOH in CH 2} Cl ₂ solution to obtain 1.61 g of a light brown solid. This material was recrystallized from boiling ethyl acetate to obtain 1.09 g of 4,4'-(3,3''-dinitro-[1,1':4',1''-on-three as a white powder Benzene]-2',5'-diyl)bis(2-methylbut-3-yn-2-ol) ( 29 ): MS (m/z) (MH ₂ O) H ⁺ = 467; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.34 (s, 12H), 5.40 (s, 2H), 7.69 (s, 2H), 7.80 (dd, J = 8.0, 8.0 Hz, 2H), 8.13 (d , J = 8.3 Hz, 2H), 8.32 (m, 2H), 8.49 (t, J = 1.9 Hz, 2H) ppm; ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 31.5, 64.1, 79.1, 102.1, 121.7, 123.4, 124.1, 130.4, 134.1, 136.2, 140.0, 140.6, 147.9.

4,4'-(3,3''- diamino- [1,1':4',1''- terphenyl ]-2',5' -diyl ) bis (2 -methylbutyl -2- ol ) (30). Add 10% by weight of carbon-supported Pd (311 mg dry basis; 50% by weight H ₂ O; Degussa E101 type) to 4,4'-(3 ,3''-Dinitro-[1,1':4',1''-terphenyl]-2',5'-diyl)bis(2-methylbut-3-yne-2- Alcohol) ( 29 ) (1.09 g, 2.25 mmol) quickly stirred suspension in EtOAc (200 mL). The suspension was then bubbled with hydrogen gas for 5 minutes, and then stirred under a hydrogen atmosphere for 7 hours. The reaction was evacuated, flushed with N _2, filtered through diatomaceous earth, and the filtrate concentrated in vacuo. The solid residue was recrystallized from boiling EtOAc/heptane to obtain 885 mg of 4,4'-(3,3''-diamino-[1,1':4',1''- as a white powder Terphenyl]-2',5'-diyl)bis(2-methylbutan-2-ol) ( 30 ): MS (m/z) (MH ₂ O) H ⁺ = 415, MH ⁺ = 433 (Weak), MNa ⁺ = 455 (weak): ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.98 (s, 12H), 1.54 (m, 2H), 2.56 (m, 2H), 4.09 (s , 2H), 5.10 (s, 4H), 6.46 (d, J = 7.5 Hz, 2H), 6.54 (m, 4H), 6.99 (s, 2H), 7.05 (m, 2H); ¹³ C NMR (75 MHz , DMSO-d ₆ ) 27.6, 29.5, 46.4, 69.2, 112.8, 115.1, 117.1, 128.9, 130.7, 137.3, 141.2, 142.3, 148.9.

3,3'-(1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene- 4,8 -diyl ) Diphenylamine (31). 4,4'-(3,3''-diamino-[1,1':4',1''-terphenyl]-2',5'-diyl) Bis(2-methylbutan-2-ol) ( 30 ) (187 mg, 0.43 mmol) was added as a solid to trifluoroacetic acid (4.3 mL, 56.2 mmol) in batches while stirring _{at room temperature under N 2.} The reaction mixture was heated to reflux for 4 days, cooled to room temperature, _{carefully basified with saturated aqueous NaHCO 3} and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 10-25% EtOAc in hexane to obtain 181 mg of white solid. The solid was recrystallized from EtOAc/heptane to obtain 131 mg of 3,3'-(1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro as a fine white powder -s-Dicyclopentacene-4,8-diyl)diphenylamine ( 31 ): MS (m/z) MH ⁺ = 397; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.95 (d, J = 0.9 Hz, 6H), 0.99 (d, J = 1.4 Hz, 6H), 1.66 (t, J = 7.0 Hz, 4H), 2.36 (t, J = 7.0, 4H), 5.03 (s, 4H), 6.35 (dd, J = 7.4, 1.0 Hz, 2H), 6.41 (d, J = 1.7 Hz, 2H), 6.53 (dd, J = 8.0, 1.4 Hz, 2H), 7.03 (t, J = 7.7 Hz, 2H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 28.8, 28.9, 43.4, 45.5, 112.7, 115.4, 117.4, 128.6, 135.2, 140.7, 140.9, 145.6, 148.5.

2,2'-(((((1,1,5,5 -Tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene- 4,8- diyl) bis (3, l-phenylene)) bis (N-diyl)) bis (carbonyl)) (2S, 2'S) - bis (1-carboxylic acid) di tert-butyl ester pyrrolidine (32). 3,3'-(1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl) Diphenylamine (31) (121 mg, 0.31 mmol), (tertiary butoxycarbonyl)-L-proline ( 13 ) (139 mg, 0.64 mmol), HATU (248 mg, 0.65 mmol) in THF (20 mL The mixture in) was treated with DIEA (0.3 mL, 1.72 mmol) at room temperature under nitrogen while stirring. After 17 hours, the resulting suspension was then partitioned between saturated aqueous NaCl and EtOAc. The organic extract was shown as a suspension, which was concentrated in vacuo to obtain 536 mg of 2,2'-((((1,1,5,5-tetramethyl-1,2,3,5,6 ,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(azadiyl)-bis(carbonyl)) (2S,2'S )-Bis(Di-tert-butylpyrrolidine-1-carboxylate) ( 32 ), can be used without further purification: MS (m/z) MH ⁺ = 791.

(2S, 2'S) -N, N '- ((1,1,5,5- tetramethyl-1, 2,3,5,6,7-hexahydro-benzene and dicyclopentadiene -s- - 4,8-diyl) bis (3, l-phenylene)) bis (pyrrolidine-2-acyl-amine) dihydrochloride (33) via syringe at 0 deg.] C, the acetyl chloride (2.2 mL, 30.9 mmol) was slowly added to methanol (200 mL) while stirring. After 10 minutes, add 2,2'-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene -4,8-Diyl)bis(3,1-phenylene)bis(azadiyl))bis(carbonyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid) di-tertiary butyl ester ( 32 ) (536 mg, 0.68 mmol) in methanol (50 mL), and the resulting suspension was heated under reflux for 2 hours. The slightly turbid reaction mixture was filtered while it was hot and the volume of the filtrate was reduced. Dilution. The precipitated product obtained was separated by filtration to obtain 410 mg of (2S,2'S)-N,N'-((1,1,5,5-tetramethyl-1,2,3,5, 6,7-hexahydro-s-dicyclopentacene-4,8-diylbis(3,1-phenylene))bis(pyrrolidine-2-methamide) dihydrochloride ( 33 ): MS (m/z) MH ⁺ = 591.

((2S,2'S)-((2S,2'S)-(((((1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopenta Dienacene- 4,8 -diyl ) bis (3,1 -phenylene )) bis ( azadiyl ) bis ( carbonyl ) bis ( pyrrolidine- 2,1 -diyl )) bis (3- Methyl- 1 -oxobutane- 1,2 -diyl )) dimethyl dicarbamate (24) . Add DIEA (0.6 mL, 3.44 mmol) to (2S,2'S)-N,N' -((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(3 ,1-phenylene)) bis(pyrrolidine-2-carboxamide) dihydrochloride ( 33 ) (203 mg, 0.31 mmol) and (methoxycarbonyl)-L-valine (118 mg, A suspension of 0.67 mmol) in THF (6.2 mL) was stirred at room temperature for 1 hour, and then treated with a 50% by weight solution of T3P in EtOAc (0.6 mL, 1.01 mmol). After 17 hours at room temperature, The reaction mixture was partitioned between 5% aqueous NaHCO ₃ (w/v) and EtOAc. The organic extract was washed with brine, dried (CaSO ₄ ) and concentrated in vacuo, and the residue was chromatographed on silica gel with 50- 100% EtOAc in hexane solution gradient elution purification. The obtained material was recrystallized from EtOAc/heptane to obtain 66.4 mg of white powder ((2S,2'S)-((2S,2'S)-((((1,1 ,5,5-5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(3,1-extension (Phenyl)) bis(azadiyl))bis(carbonyl)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl) Dimethyl dicarbamate ( 24 ): MS (m/z) MH ⁺ =905; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.81-1.05 (m, 24 H), 1.68 (t, J = 6.5 Hz, 4H), 1.82-2.06 (m, 8H), 2.09-2.23 (m, 2H) ), 2.24-2.50 (m, 4H), 3.52 (s, 6H), 3.57-3.69 (m, 2H) , 3.75-3.88 (m, 2H), 4.04 (t, J = 8.2 Hz, 2H), 4.41-4.51 (m, 2H), 6.92 (t, J = 5.5 Hz, 2H), 7.32-7.68 (m, 8H) ), 10.05 (s, 2H); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 18.9, 19.1, 19.3, 25 .1, 28.8, 29.9, 30.3, 43.4, 45.4, 47.6, 51.9, 58.4, 60.7, 117.7, 120.1, 124.6, 128.7, 134.6, 139.2, 140.7, 141.1, 146.0, 157.3, 170.

化合物34 係根據反應圖12製備。反應圖 12

Example 4 ((1R,1'R)-((2S,2'S)-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s -Dicyclopentacene-4,8-diyl)bis(3,1-phenylene)bis(azadiyl))bis(carbonyl)bis(pyrrolidine-2,1-diyl)) Dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 34 ).

Compound 34 was prepared according to reaction diagram 12. Response Figure 12

((1R,1'R)-((2S,2'S)-((((1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s -two and cyclopenta-4,8-phenylene) bis (3,1-phenylene) bis (N-diyl)) bis (carbonyl) bis (pyrrolidin-2,1-diyl)) bis ( 2 -Phenyl oxy- 1 -phenylethane- 2,1 -diyl )) dimethyl dicarbamate (34) . At room temperature, DIEA (0.6mL, 3.44mmol) was added to (2S, 2'S )-N,N'-((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8- Diyl)bis(3,1-phenylene))bis(pyrrolidine-2-carboxamide) dihydrochloride ( 33 ) (207 mg, 0.31 mmol) and (R)-2-((methoxy A stirred suspension of carbonyl)amino)-2-phenylacetic acid ( 35 ) (229 mg, 1.09 mmol; CAS#50890-96-5) in THF (6.2 mL) was stirred at room temperature for 1 hour, And then treated with a 50% by weight solution of T3P in EtOAc (0.6 mL, 1.01 mmol). After 17 hours at room temperature, the reaction mixture was partitioned between 5% aqueous NaHCO ₃ (w/v) and EtOAc. Organic The extract was washed with brine, dried (CaSO ₄ ) and concentrated in vacuo, and the residue was purified by chromatography on silica gel with a gradient of 50-100% EtOAc in hexane. The resulting material was recrystallized from EtOAc/heptane , Obtain 74 mg of white fine powder ((1R,1'R)-((2S,2'S)-(((((1,1,5,5-tetramethyl-1,2,3,5,6 ,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(azadiyl))bis-(carbonyl))bis-( Dimethyl pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 34 ): MS (m/z) MH ⁺ = 973; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.94 (d, J = 3.0 Hz, 6H), 1.00 (d, J = 5.6 Hz, 6H), 1.70 (t, J = 6.9 Hz, 4H), 1.75-1.83 (m, 2H), 1.88-2.10 (m, 6H), 2.26-2.44 (m, 4H), 3.18 (br s, 2H), 3.49-3.55 (m, 6H), 3.82 (br s, 2H), 4.41 (d, J = 6.7 Hz, 2H), 5.34-5.51 (m, 2H), 6.94 (d, J = 7.5 Hz, 2H), 7.04-7.11 ( m, 2H), 7.24-7.52 (m, 12H), 7.59-7.80 (m, 4H), 9.99 (s, 2H); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 22.6, 24.7, 28.9, 29.7, 43.3, 45.5, 47.4, 52.0, 57.2, 61.2, 118.0, 118.2, 120.6, 124.8, 128.2, 128.5, 128.7, 129.1, 134.6, 137.5, 139.0, 140.7, 141.0, 145.9, 156.6, 168.9, 170.7.

化合物36係根據反應圖13製備。反應圖 13

Example 5 ((1R,1'R)-((2S,2'S)-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s -Dicyclopentacene-4,8-diyl)bis(pyridine-5,3-diyl)bis(azadiyl)bis(carbonyl)bis(pyrrolidine-2,1-diyl)) Dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 36 ).

Compound 36 was prepared according to reaction scheme 13. Response Figure 13

4,4'-(1,4- phenylene ) bis (2 -methylbut- 3- yn -2- ol ) (38) . Combine triethylamine (172 mL) with 1,4-diiodobenzene ( 37 ) (11.4 g, 34.4 mmol), copper(I) iodide (329 mg, 1.7 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (1.2 g, 1.7 mmol) in combination. The resulting suspension was degassed by 5 evacuation/N _{2 coating cycles while stirring.} 2-methyl-3-butyn-2-ol (6.1 mL, 62.9 mmol), and the reaction mixture was degassed again as described above, then heated to reflux while stirring under N _2. After 3 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo and wet triturated with hot EtOAc. The combined wet grinds were filtered through Celite, and the filtrate was washed with 0.1N aqueous HCl, brine, dried (CaSO ₄ ), heated to boiling, and then diluted with heptane to precipitate the crude product. The precipitate was separated by filtration and recrystallized from boiling heptane to obtain 7.3 g of 4,4'-(1,4-phenylene)bis(2-methylbut-3-yne-2) as a brown powder -Alcohol) ( 38 ): MS (m/z) (MH ₂ O) H ⁺ = 225; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.36 (s, 4H), 5.51 (s, 2H) , 1.47 (s, 12H).

4,4'-(1,4- phenylene ) bis (2 -methylbutan -2- ol ) (39) . At room temperature and nitrogen atmosphere, 10% by weight of carbon-supported Pd (619 g dry basis; 50% by weight H ₂ O; Degussa E101 type) was added to 4,4'-(1,4-phenylene) bis( A rapidly stirred suspension of 2-methylbut-3-yn-2-ol) ( 38 ) (4.1 g, 17.0 mmol) in MeOH (200 mL). The suspension was then bubbled with hydrogen for 5 minutes and then stirred under a hydrogen atmosphere for about 1 week. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 10-40% EtOAc in hexane, and then recrystallized from EtOAc/hexane to obtain 805 mg of 4,4'-(1,4) as a white powder. -Phenyl)bis(2-methylbutan-2-ol) ( 39 ): ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.07 (s, 4H), 4.23 (s, 2H), 2.59 -2.50 (m, 4H), 1.63-1.57 (m, 4H), 1.13 (s, 12H); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 140.4, 128.5, 69.1, 46.3, 30.3, 29.7.

1,1,5,5 -Tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene (40). Methanesulfonic acid (10.4 mL, 160 mmol) was quickly added to 4,4'-(1,4-phenylene) bis(2-methylbutan-2-ol) ( 39 ) (804 mg, 3.2 mmol) in CH ₂ Cl ₂ ( The stirred solution in 160 mL) and the solution immediately turned red-brown. After 17 hours, the reaction mixture was successively extracted with water, 5% (w/v) NaHCO ₃ aqueous solution, dried (CaSO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with 100% hexane to obtain 370 mg of 1,1,5,5-tetramethyl-1,2,3,5,6,7-hexa as a white solid Hydrogen-s-Dicyclopentacene ( 40 ): ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.95 (s, 2H), 2.84 (t, J = 7.1 Hz, 4H), 1.91 (t, J = 7.1 Hz, 4H), 1.24 (s, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 150.7, 141.0, 117.9, 43.4, 41.9, 29.9, 28.8.

4,8 -Dibromo- 1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene (41). At room temperature Next, pure bromine (32 □L, 0.6 mmol) was added to 1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentadieno A stirred solution of benzene ( 40 ) (51 mg, 0.2 mmol) and iodine (12.3 mg, 0.1 mmol) in anhydrous CH ₂ Cl ₂ (2.4 mL) was stirred in the dark for 1 hour. The reaction was _diluted with additional ₂ Cl CH, washed with aqueous 5M NaOH, and the resulting colorless CH ₂ Cl ₂ extract was concentrated in vacuo. The residue was dissolved in EtOAc, filtered through Celite, and the filtrate was evaporated to obtain 65 mg of 4,8-dibromo-1,1,5,5-tetramethyl-1,2,3,5 as a white solid ,6,7-hexahydro-s-dicyclopentacene ( 41 ): ¹ H NMR (300 MHz, CDCl ₃ ): δ 2.87 (t, J = 7.5 Hz, 4H), 1.94 (t, J = 7.5 Hz, 4H), 1.41 (s, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 148.3, 145.2, 116.2, 48.2, 41.8, 31.8, 26.9.

(S)-2-((5 -Bromopyridyl - 3 -yl ) aminomethanyl) pyrrolidine- 1- carboxylic acid tert-butyl ester (42) . Under nitrogen and 0℃, isobutyl chloroformate Ester (4.5 mL, 34.7 mmol) was slowly added to (tert-butoxycarbonyl)-L-proline ( 13 ) (6.8 g, 31.6 mmol) and NMM (7.7 mL, 70 mmol) in EtOAc (160 mL) The solution while stirring. After 1 hour, the resulting suspension was slowly treated with a solution of 5-bromopyridin-3-amine (5.5 g, 31.6 mmol) in EtOAc (20 mL) at 0°C, and then slowly warmed to room temperature overnight. The reaction mixture was extracted with water followed by 5% NaHCO ₃ aqueous solution, which caused the product to precipitate in the EtOAc phase. The EtOAc phase containing the precipitated product was concentrated in vacuo, and the solid residue was wet-milled with boiling EtOAc and separated by filtration to provide 7.6 g of (S)-2-((5-bromopyridine-3- (4)aminomethanyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( 42 ): MS (m/z) MH ⁺ =370.

酸 (43) . 將(S)-2-((5-溴吡啶基-3-基)胺基甲醯基)吡咯啶-1-甲酸第三丁酯(42 ) (2.0 g，5.4 mmol)、雙(頻哪醇根基)二硼(1.5 g，6.0 mmol)、乙酸鉀(1.6 g，16.3 mmol)及Pd(dppf)Cl₂ ·CH₂ Cl₂ (224 mg，0.3 mmol)組合在無水DMSO (54 mL)中及然後脫氣。將反應混合物在80℃及N₂ 下加熱17小時，同時攪拌，冷卻至室溫並分配在H₂ O水與EtOAc之間。水層用EtOAc萃取幾次並將合併之有機萃取物乾燥(CaSO₄ )，過濾並真空濃縮，得到3.5 g呈黑色焦油之(S)-(5-(1-(第三丁氧基羰基)吡咯啶-2-甲醯胺基)吡啶-3-基)

酸(43 )：MS (m/z) MH⁺ = 336。 (S)-(5-(1-( Third-butoxycarbonyl ) pyrrolidine -2- carboxamido ) pyridin- 3 -yl )

Acid (43) . (S)-2-((5-Bromopyridin-3-yl)aminomethanyl)pyrrolidine-1-carboxylate ( 42 ) (2.0 g, 5.4 mmol) , Bis(pinacol radical) diboron (1.5 g, 6.0 mmol), potassium acetate (1.6 g, 16.3 mmol) and Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (224 mg, 0.3 mmol) combined in anhydrous DMSO (54 mL) neutralize and then degas. The reaction mixture was heated at 80°C _{under N 2} for 17 hours while stirring, cooled to room temperature and partitioned between H ₂ O water and EtOAc. The aqueous layer was extracted several times with EtOAc and the combined organic extracts were dried (CaSO ₄ ), filtered and concentrated in vacuo to obtain 3.5 g of (S)-(5-(1-(tertiary butoxycarbonyl) as a black tar) Pyrrolidine-2-carboxamido)pyridin-3-yl)

Acid ( 43 ): MS (m/z) MH ⁺ =336.

酸(43 ) (892 mg，2.7 mmol)、Na₂ CO₃ (1.6 g，14.7 mmol) 、Pd(dppf)Cl₂ ·CH₂ Cl₂ (49mg，0.1mmol)及水合四丁基氯化銨(20 mg，0.1 mmol)組合在20 mL之THF及H₂ O (v/v)之1:1混合物中。所得懸浮液經由5個抽空/N₂ 包覆循環脫氣，及然後在回流下加熱3小時，同時在N₂ 下攪拌。將反應混合物冷卻至室溫，用另外之THF稀釋並用鹽水萃取。將有機層真空濃縮及殘餘物藉由層析法於矽膠上用30-100% EtOAc之己烷溶液梯度溶離純化，得到144 mg呈灰白色固體之2,2'-((((1,1,5,5-四甲基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4,8-二基)雙(吡啶-5,3-二基))雙(氮二基))雙(羰基))(2S,2'S)-雙(吡咯啶-1-甲酸二第三丁酯) (44 )：MS (m/z) MH⁺ = 794。 2,2'-(((((1,1,5,5 -Tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene- 4,8- diyl) bis (pyridin -5,3- diyl) bis (N) bis (carbonyl)) (2S, 2'S) -. bis (pyrrolidin-l-carboxylic acid tert-butyl ester) (44) 4 ,8-Dibromo-1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene ( 41 ) (221 mg, 0.6 mmol), (S)-(5-(1-(Third-butoxycarbonyl)pyrrolidine-2-carboxamido)pyridin-3-yl)

Acid ( 43 ) (892 mg, 2.7 mmol), Na ₂ CO ₃ (1.6 g, 14.7 mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (49 mg, 0.1 mmol) and hydrated tetrabutylammonium chloride ( 20 mg, 0.1 mmol) in 20 mL _{of a 1:1 mixture of THF and H 2} O (v/v). The resulting suspension was degassed via 5 evacuation/N ₂ coating cycles, and then heated under reflux for 3 hours while stirring under _{N 2.} The reaction mixture was cooled to room temperature, diluted with additional THF and extracted with brine. The organic layer was concentrated in vacuo and the residue was purified by chromatography on silica gel with a gradient of 30-100% EtOAc in hexane to obtain 144 mg of 2,2'-((((1,1, 5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(pyridine-5,3-diyl) )) Bis(azadiyl))bis(carbonyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid di-tert-butyl ester) ( 44 ): MS (m/z) MH ⁺ = 794.

(2S, 2'S) -N, N '- ((1,1,5,5- tetramethyl-1, 2,3,5,6,7-hexahydro-benzene and dicyclopentadiene -s- - 4,8 - Diyl) bis ( pyridine- 5 , 3 -diyl ) bis ( pyrrolidine -2- carboxamide ) tetrahydrochloride (1 : 4) (45) . Heat under reflux 2,2' -((((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-bis(yl) Bis(pyridine-5,3-diyl)bis(azadiyl))bis(carbonyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid di-tert-butyl ester) ( 44 ) (144 mg, 0.2 mmol) and a stirred solution of concentrated aqueous HCl (2.0 mL) in methanol (90 mL). After 2 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo to obtain 160 mg of (2S, 2'S) as a light brown solid )-N,N'-((((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8 -Diyl)bis(pyridine-5,3-diyl)bis(pyrrolidine-2-carboxamide) tetrahydrochloride (1:4) ( 45 ): MS (m/z) MH ⁺ = 593.

((1R,1'R)-((2S,2'S)-((((1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s -two and cyclopenta-4,8-phenylene) bis (pyridin -5,3- diyl) bis (N) bis (carbonyl) bis (pyrrolidin-2,1-diyl)) bis ( 2 -Phenyl oxy- 1 -phenylethane- 2,1 -diyl )) dimethyl dicarbamate (36) . At room temperature, DIEA (0.5mL, 2.9mmol) was added to (2S, 2'S)-N,N'-((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8 -Diyl)bis(pyridine-5,3-dipyridine))bis(pyrrolidine-2-carboxamide) tetrahydrochloride (1:4) ( 45 ) (160 mg, 0.2 mmol) (207 mg, 0.31 mmol) and a stirred solution of (R)-2-((methoxycarbonyl)amino)-2-phenylacetic acid ( 35 ) (202 mg, 1.0 mmol) in EtOAc (85 mL), in the room Stir at warm for 1 hour, and then use a 50% by weight solution of T3P in EtOAc (0.6 mL, 1.01 mmol). After 17 hours at room temperature, the reaction mixture was partitioned between 5% aqueous NaHCO ₃ (w/v) and EtOAc Between. The organic extract was washed with brine, dried (CaSO ₄ ) and concentrated in vacuo, and the residue was purified by chromatography on silica gel with a _{gradient of 0-10% MeOH in CH 2} Cl ₂ solution. The resulting material was obtained from EtOAc /Heptane was recrystallized to obtain 94 mg of white solid ((1R,1'R)-((2S,2'S)-(((((1,1,5,5-tetramethyl-1,2,3 ,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(pyridine-5,3-diyl))bis(azadiyl))bis(carbonyl) )Dimethyl bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 36 ): MS (m /z) MH ⁺ = 976; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.18 (s, 2H), 8.83-8.82 (m, 2H), 7.93-7.92 (m, 2H), 7.75 (t , J = 7.8 Hz, 2H), 7.43-7.32 (m, 12H), 3.87-3.80 (m, 2H), 3.52-3.51 (m, 6H), 3.25-3.15 (m, 2H), 2.41-2.32 (m , 4H), 2.09-1.96 (m, 8H), 1.81-1.73 (m, 8H), 1.01-0.99 (m, 6H), 0.96-0.93 (m, 6H).

化合物46 係根據反應圖14製備。反應圖 14

Example 6 ((1R,1'R)-((2S,2'S)-(((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s- Dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-di Yl)) Dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 46 ).

Compound 46 was prepared according to reaction scheme 14. Response Figure 14

((R)-2-((( Methoxycarbonylcarbonyl ) amino )-2- phenylacetyl )-L- proline benzyl ester (48). At room temperature and under N ₂ , (R) -2-((Methoxycarbonyl)amino)-2-phenylacetic acid (35) (2.5 g, 12.1 mmol) and L-proline benzyl ester hydrochloride ( 47 ) (2.9 g, 12.1 mmol) The suspension in EtOAc (120 mL) was treated with a 50% by weight solution of T3P in EtOAc (7.2 mL, 12.2 mmol) and then DIEA (6.3 mL, 36.2 mmol). After 1 hour, the reaction mixture was partitioned between Between water and EtOAc, and extracted with additional EtOAc. The combined organic extracts were washed with 5% aqueous NaHCO ₃ (w/v) brine, dried (CaSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed Purified by gradient elution with 10-50% EtOAc on silica gel to obtain 2.2 g of ((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-L-proline as a pale yellow solid Benzyl amino acid ( 48 ): MS (m/z) MH ⁺ =397.

((R)-2-(( Methoxycarbonyl ) amino )-2- phenylacetyl )-L- proline (49) . Under N ₂ and room temperature, 10% by weight of carbon is loaded with Pd (890 mg dry basis; 50% by weight H ₂ O; Degussa E101 type) added to ((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-L-proline A rapidly stirred suspension of the ester ( 48 ) (2.2 g, 5.5 mmol) in EtOAc (175 mL). The suspension was then bubbled with hydrogen for 5 minutes and then stirred under a hydrogen atmosphere for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to obtain 2.4 g of ((R)-2-((methoxycarbonyl)amino)-2-phenylacetinyl)-L-proline as a colorless oil Amino acid ( 49 ): MS (m/z) MH ⁺ =307.

((R)-2-(( Methoxycarbonyl ) amino )-2- phenylacetyl )-L- proline acid 2-(3- bromophenyl )-2 -oxoethyl ester (51) at room temperature, 2-bromo-1- (3-bromophenyl) ethan-l-one (50) (2.2 g, 7.7 mmol) and ((R) -2 -. ( ( methoxycarbonyl )Amino)-2-phenylacetyl)-L-proline ( 49 ) (2.4 g, 7.7 mmol) in acetonitrile (80 mL) was treated with TEA (2.2 mL, 15.8 mmol) dropwise . After 1 hour, the reaction mixture was partitioned between brine and EtOAc. The organic extract was dried (CaSO ₄ ), filtered and concentrated in vacuo to obtain 3.4 g of ((R)-2-((methoxycarbonyl)amino)-2-phenylacetinyl)- as a white foam L-Proline acid 2-(3-bromophenyl)-2-oxoethyl ester ( 51 ): MS (m/z) MH ⁺ =503.

((R)-2-((S)-2-(5-(3- Bromophenyl )-1H- imidazole -2- carbonyl ) pyrrolidin- 1 -yl )-2 -oxo- 1 -benzene ethyl) -2-amine-carboxylate (52) ((R.) - ((methoxycarbonyl carbonyl) amino) -2-phenyl-acetylamino-yl) -L- proline 2- (3-bromo A mixture of phenyl)-2-oxoethyl ( 51 ) (3.3 g, 6.5 mmol) and ammonium acetate (2.5 g, 32.6 mmol) was heated under reflux in toluene (110 mL) while under N ₂ Stir. After 17 hours, the reaction mixture was cooled to room temperature, and partitioned between EtOAc in water, and the organic extracts were dried (CaSO _4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 10-80% EtOAc in hexane to obtain 2.0 g of ((R)-2-((S)-2-(5) as a light yellow foam -(3-Bromophenyl)-1H-imidazole-2-carbonylpyrrolidin-1-yl)-2-oxo-1-phenethyl)carbamate ( 52 ): MS (m/z) MH ⁺ = 483.

((R)-2- Pendant oxy- 1 -phenyl -2-((S)-2-(5-(3-(4,4,5,5 -tetramethyl -1,3,2- Dioxaborolan- 2- yl ) phenyl )-1H- imidazole -2- carbonyl ) pyrrolidin- 1 -yl ) ethyl ) carbamate (53) . Make ((R)-2 -((S)-2-(5-(3-Bromophenyl)-1H-imidazole-2-carbonyl)pyrrolidin-1-yl)-2-oxo-1-phenethyl)carbamate Ester ( 52 ) (2.0 g, 4.1 mmol), bis(pinacol radical) diboron (1.3 g, 5.0 mmol), KOAc (970 mg, 9.9 mmol) and Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ ( A stirred mixture of 338 mg, 0.4 mmol) in anhydrous DMSO (21 mL) was degassed and then heated at 80°C under _{N 2 for 1 hour.} The cooled reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted with EtOAc, and the combined extracts were dried (CaSO ₄ ), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 0-10% methanol in CH 2} Cl ₂ solution, and then recrystallized from EtOAc/hexane to obtain 970 mg of tan foam ((R) -2-Pendant oxy-1-phenyl-2-((S)-2-(5-(3-(4-(4,4,5,5-tetramethyl-1,3,2-di Oxaloborolan-2-yl)phenyl)-1H-imidazole-2-carbonyl)-pyrrolidin-1-yl)ethyl)carbamate ( 53 ): MS (m/z) MH ⁺ = 531.

((1R,1'R)-((2S,2'S)-(((1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s- bicyclic -4-pentadiene and benzene, 8-diyl) bis (3,1-phenylene)) bis (lH-imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl) ) Bis (2- side oxy- 1 -phenylethane- 2,1 -diyl )) dimethyl dicarbamate (46) . 4,8-dibromo-1,1,5,5- Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene ( 41 ) (196 mg, 0.5 mmol), ((R)-2-oxo- 1-Phenyl-2-((S)-2-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Phenyl)-1H-imidazole-2-carbonyl)pyrrolidin-1-yl)ethyl)carbamate ( 53 ) (823 mg, 1.6 mmol), NaCO ₃ (1.4 g, 13.1 mmol), Pd( dppf) Cl ₂ ·CH ₂ Cl ₂ (87 mg, 0.1 mmol) and tetrabutylammonium chloride hydrate (32.4 mg, 0.1 mmol) combined in 20 mL of THF/H ₂ O (v/v) 1:1 In the mixture. The resulting suspension was degassed via 5 evacuation/N ₂ coating cycles, and then heated under reflux for 3 hours while stirring under _{N 2.} The reaction mixture was cooled to room temperature, diluted with additional THF and washed with brine. The organic layer was concentrated in vacuo, and the residue was purified by chromatography on silica gel with 0-10% MeOH in CH ₂ Cl ₂ solution, and then recrystallized from EtOAc/hexane to obtain 189 mg of white powder (( 1R,1'R)-((2S,2'S)-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentadi Alkenene-4,8-diyl)bis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis (2-side oxy-1-phenylethane-2,1-diyl)) dimethyl dicarbamate ( 46 ): MS (m/z) MH ⁺ = 1020; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.94-11.74 (m, 2H), 7.98-6.89 (m, 22H), 5.50-5.06 (m, 4H), 3.88-3.11 (m, 10H), 4.08 (br s, 4H) , 2.00 (br s, 4H), 1.73-1.71 (m, 4H), 1.00-0.96 (m, 12H).

化合物54 係根據反應圖15製備。反應圖 15

Example 7 ((1R,1'R)-((2S,2'S)-(((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s- Dicyclopentacene-4,8-diyl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-di Yl)) Dimethyl bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate ( 54 ).

Compound 54 was prepared according to reaction scheme 15. Response Figure 15

(S) -. Pyrrolidine- 1,2-dicarboxylic acid 2- (2- (4-bromophenyl) -2-oxo-ethyl) 1- (tert-butyl ester) (56) at room temperature , Et ₃ N (6.0 mL, 43 mmol) was slowly added to 2-bromo-1-(4-bromophenyl)ethan-1-one ( 55 ) (5.7 g, 21 mmol) and (the third butoxycarbonyl )-L-Proline acid (13) (5.2 g, 24.2 mmol) in a stirred slightly turbid solution in acetonitrile (69 mL). After 2 hours, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (CaSO ₄ ), filtered and concentrated in vacuo to obtain 7.8 g of (S)-pyrrolidine-1,2-dicarboxylic acid 2-(2) as a clear yellow oil -(4-Bromophenyl)-2-oxoethyl ester) 1-(tert-butyl ester) ( 56 ): MS (m/z) MNa ⁺ 434, (M-Boc) H ⁺ = 312.

(S)-2-(5-(4- Bromophenyl )-1H- imidazol -2- yl ) pyrrolidine- 1- carboxylic acid tert-butyl ester (57) . Under reflux, heat ammonium acetate (7.3 g, 94.2 mmol) and (S)-pyrrolidine-1,2-dicarboxylic acid 2-(2-(4-bromophenyl)-2-oxoethyl ester) 1-(tert-butyl ester) ( 56 ) ( A mixture of 7.8 g, 18.9 mmol) in toluene (125 mL). After 17 hours, the reaction mixture was cooled to room temperature and partitioned between brine and EtOAc. The organic extract was dried (CaSO ₄ ), filtered, and concentrated in vacuo. The obtained light yellow foam was crystallized from ethyl acetate/hexane to obtain 3.9 g of (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine- as a white powder Tertiary butyl 1-formate ( 57 ): MS (m/z) MH ⁺ =392.

(S)-2-(5-(4-(4,4,5,5 -tetramethyl -1,3,2- dioxaborolan- 2- yl ) phenyl )-1H- imidazole -2- yl ) pyrrolidine- 1- carboxylate (58) . (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1- Tertiary butyl formate ( 57 ) (3.8 g, 9.7 mmol), bis(pinacol radical) diboron (3.0 g, 11.7 mmol), potassium acetate (2.4 g, 24.3 mmol) and Pd(dppf)Cl ₂ · A mixture of CH ₂ Cl ₂ (795 mg, 1.0 mmol) in anhydrous DMSO (49 mL) was degassed and heated at 80° C. for 17 hours while stirring under a nitrogen atmosphere. The cooled reaction mixture was diluted with brine and extracted several times with EtOAc. The combined organic extracts were dried (CaSO ₄ ), filtered, and concentrated in vacuo. The dark brown solid residue was recrystallized from boiling EtOAc/heptane to obtain 1.3 g of (S)-2-(5-(4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate ( 58 ): MS (m/z) MH ⁺ = 440.

2,2'-(((1,1,5,5 -Tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene- 4,8 -di yl) bis (4, l-phenylene)) bis (lH-imidazole-5,2-diyl)) (2S, 2'S) - bis (pyrrolidin-l-carboxylic acid) di tert-butyl ester (59) The title compound ( 59 ) is derived from 4,8-dibromo-1,1,5,5-tetramethyl-1,2,3,5,6 in a manner similar to that described for Example 6 ( 46) ,7-hexahydro-s-dicyclopentacene ( 41 ) (437 mg, 1.2 mmol), (S)-2-(5-(4-(4,4,5,5-tetramethyl -1,3,2-Dioxolidine-2-phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate ( 58 ) (2.2 g, 5.1 mmol), Sodium carbonate (3.1 g, 29 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (192 mg, 0.2 mmol) and tetrabutylammonium chloride hydrate (66 mg, 0.2 mmol) in 1:1 of THF and water: 1 The mixture (v/v) (47 mL) was prepared. The product was purified by chromatography on silica gel with a _{gradient of 0-10% MeOH in CH 2} Cl ₂ solution, and then recrystallized from EtOAc/hexane to obtain 167 mg 2,2'-(((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-di Yl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid) di-tertiary butyl ester ( 59 ) : MS(m/z) MH ⁺ = 838.

5,5'-((1,1,5,5 -Tetramethyl -1,2,3,5,6,7 -hexahydro- s -dicyclopentacene- 4,8 -diyl ) Bis (4,1 -phenylene )) bis (2-((S) -pyrrolidin -2- yl )-1H- imidazole ) dihydrochloride (60) . Heating under reflux 2,2'- (((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(4 ,1-phenylene)) bis(1H-imidazole-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid di-tert-butyl ester) ( 59 ) (117 mg, 0.2 mmol) and concentrated HCl (1.0 mL) in methanol (4.0 mL) were stirred for 0.5 hours, cooled, and the precipitated product was separated by filtration to provide 138 mg of 5,5'-((1,1, 5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4,8-diyl)bis(4,1-phenylene) ) Bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole) dihydrochloride ( 60 ): MS (m/z) MH ⁺ =637.

((1R,1'R)-((2S,2'S)-(((1,1,5,5 -tetramethyl -1,2,3,5,6,7 -hexahydro- s- bicyclic Pentacene- 4,8 -diyl ) bis (4,1 -phenylene )) bis (1H- imidazole- 5,2 -diyl )) bis ( pyrrolidine- 2,1 -diyl ) ) Dimethyl bis (2 -oxo- 1 -phenylethane- 2,1 -diyl )) dicarbamate (54) . Add DIEA (0.2 mL, 1.0 mmol) to 5,5'-((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopenta Dienacene-4,8-diyl)bis(4,1-phenylene))bis(2-((S)-pyrrolidinyl-2-yl)-1H-imidazole) dihydrochloride ( 60 ) (138 mg, 0.2 mmol) and (R)-2-((methoxycarbonyl)amino)-2-phenylacetic acid ( 35 ) in a THF (19 mL) suspension, at room temperature and Stir under N _2. After 0.5 hour, the reaction mixture was treated with a 50% by weight solution of T3P in EtOAc (0.5 mL, 0.8 mmol), stirred for 10 minutes, and then diluted with brine. The layers were separated, and the aqueous layer was extracted with additional THF. The combined THF extracts were washed with saturated aqueous NaHCO ₃ solution, filtered, dried (CaSO ₄ ), and concentrated in vacuo. The residue was purified by chromatography on silica gel with a _{gradient of 0-10% MeOH in CH 2} Cl ₂ solution, and then recrystallized from EtOAc/heptane to obtain 102 mg of ((1R,1'R) as a white solid -((2S,2'S)-((((1,1,5,5-Tetramethyl-1,2,3,5,6,7-hexahydro-s-dicyclopentacene-4, 8-diyl)bis(4,1-phenylene)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-side oxy- 1-phenylethane-2,1-diyl)) dimethyl dicarbamate ( 54 ): MS (m/z) MH ⁺ = 1020; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.97-11.75 (m, 2H), 8.03-7.00 (m, 22H), 5.51-5.08 (m, 4H), 3.90 (br s, 1H), 3.62-3.54 (m, 6H), 3.16 (br s, 1H) ), 2.41-2.37 (m, 4H), 2.03 (br s, 4H), 1.99-1.84 (m, 2H), 1.71 (br s, 4H), 0.97 (br s, 12H).

Biological analysis The compound and standard (STD) control compounds dacatavir and sofosbuvir were determined side by side for the selected HCV genotype. Both control compounds are FDA-approved anti-hepatitis C virus (HCV) direct-acting antiviral agents for the treatment of chronic HCV infection, and the HCV genotype selectivity and potency values have been published, and the analysis can be inferred from it Reliability and compare it with the profile of the test compound analysis.

GT1b-Luc (Con-1) replicon analysis . HCV GT1b (Con-1) replicon analysis (luciferase end point) was performed in Huh Luc/Neo cells by Southern Research, Frederick, Maryland, USA. The HCV GT1b (Con-1) replicon analysis evaluated the antiviral activity of six serially diluted compounds in triplicate. Sofosbuvir was included as a reference standard in each run. Huh Luc/Neo replicon cells were plated at 5,000 cells/well into a separate 96-well plate to analyze cell viability or antiviral activity. On the second day, add the diluted test sample to the appropriate well. After 72 hours, when the cells are still at subconfluence, the cells are processed. HCV replicon content is quantified by the luciferase activity derived from the replicon. Use curve fitting software to generate EC ₅₀ values (concentration that inhibits HCV replicon by 50%).

GT1a WT replicon, GT1b/3a NS5a and GT1b/6a NS5a chimeric replicon and cytotoxicity (CC ₅₀ ) analysis . These analyses were performed and used in Huh7 cells by WuXi Apptec Co. Ltd. (Shanghai, China) Dacatavir is used as a reference standard. The chimeric replicons GT1b/3a and GT1b/6a are constructed using GT1b replicon as the main chain. Replicon Strains/ Clinical 1a-wt H77 1b/3a-NS5A chimera S52 strain (GU814263) 1b/6a-NS5A chimera 1b/6a NS5A DQ480516-clinical

Test the compounds according to the following procedures: 1) Add the compounds to the Echo 96-well plate at 9 concentrations of serial 3-fold dilutions in duplicate. The final concentration of DMSO in the cell culture medium is 0.5%. 2) Use the replicon plasmid DNA to transcribe the replicon RNA in vitro. 3) Huh7 cells were transiently transfected with replicon RNA by electroporation, and seeded in a 96-well plate at a density of 10,000 cells/well. The cells were cultured and treated with compounds at 37°C and 5% CO ₂ for 3 days. 4) According to the protocol provided by the supplier, use the CellTiter-Fluor kit to determine the cell survival rate in the cells analyzed by the GT1a replicon. 5) Remove the supernatant from the wells. According to the solution provided by the supplier, the antiviral activity is determined by using Bright-Glo to monitor the replicon reporter gene firefly luciferase. The raw data (RLU) is used to calculate the antiviral activity (inhibition %) of the compound. Inhibition %=(CPD-ZPE)/(HPE-ZPE)*100% *CPD: signal from the well containing the test compound. ZPE: average signal from DMSO control wells. HPE: Mean value of signal from medium control wells.

Use GraphPad Prism software to calculate 50% effective concentration (EC ₅₀ ) and 50% cytotoxic concentration (CC ₅₀ ) values. The results of Examples 1 to 7 are shown in Table 1.

Efforts are made to design the structure claimed in this application to develop improvements in selectivity and efficacy characteristics superior to the currently approved drugs. The favorable comparison between the genotype selectivity, potency and cytotoxicity of the proposed structure and the genotype selectivity, potency and cytotoxicity of dacatavir and dofosbuvir provides a basis for further development of these compounds.

70,000 (102,000)* NT NT NT NT STD 達卡他韋

NT    (4.0)* 39    (20)* 105    (150)* 47    (54)* ＞500 1 9

80 471 ＞500 ＞500 ＞500 2 17

＜50 44 ＞500 275 ＞500 3 24

＜50 ＞500 ＞500 ＞500 ＞500 4 34

＜50 ＞500 28 92 ＞500 5 36

NT ＞500 56 ＞500 ＞500 6 46

NT ＞500 53 ＞500 ＞500 7 54

NT ＞500 128 ＞500 ＞500 STD=參考標準；WT=野生型；GT1b-Luc (Con 1)分析係在Huh Luc/Neo細胞中進行；Gt1a-wt，Gt1b/3a NS5a及Gt1b/6a NS5a係暫態轉染之複製子分析且在Huh7細胞中進行；NT=未測試；* = Solvaldi包裝插頁(修訂版03/2015)及Gao, M.，Curr . Opin. in Virology 2013 , 3, 514-520中之文獻值。Those skilled in the art should understand that various modifications can be made to the compounds, compositions and/or methods of the present invention without departing from the spirit of the present invention. Therefore, the various examples and embodiments of the present invention described herein are only illustrative and are not intended to limit the scope of the present invention in any way. All references cited in this article are incorporated into this article by reference in their entirety. Table 1. Anti- HCV activity of Examples 1 to 7 Instance structure Anti- HCV activity EC ₅₀ (pM) Cytotoxicity CC ₅₀ (pM) in Huh7 cell Gt1a-WT structure GT1b-Luc (Con-1) Gt1a-WT Gt1b/3a NS5a Gt1b/6a NS5a STD Sofosbuvir

70,000 (102,000)* NT NT NT NT STD Dacatavir

NT (4.0)* 39 (20)* 105 (150)* 47 (54)* ＞500 1 9

80 471 ＞500 ＞500 ＞500 2 17

＜50 44 ＞500 275 ＞500 3 twenty four

＜50 ＞500 ＞500 ＞500 ＞500 4 34

＜50 ＞500 28 92 ＞500 5 36

NT ＞500 56 ＞500 ＞500 6 46

NT ＞500 53 ＞500 ＞500 7 54

NT ＞500 128 ＞500 ＞500 STD=reference standard; WT=wild type; GT1b-Luc (Con 1) analysis was performed in Huh Luc/Neo cells; Gt1a-wt, Gt1b/3a NS5a and Gt1b/6a NS5a transient transfection replicon analysis And it was performed in Huh7 cells; NT=not tested; *=Solvaldi package insert (revision 03/2015) and literature value in Gao, M., Curr . Opin. in Virology 2013 , 3, 514-520.

Claims (33)

A compound of formula I :

Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein: M is selected from formula II, III and IV, wherein R ¹ is independently C at each occurrence _1- C ₆ alkyl:

P ¹ and P ² are the same or different and independently do not exist (direct bond) or are selected from the following formulas:

,

,

,

,

and

, Where X is CH or N, L ¹ is a direct bond ^{with Q 1} or Q ^{2 and L 2} is a direct bond with M; Q ¹ and Q ² independently do not exist (direct bond),

or

, Where L ¹ is a direct bond ^{with A 1} or A ^{2 and L 2} is a ^{direct bond with P 1} or P ² ; however, the condition is that P ¹ and Q ¹ do not exist at the same time, and P ² and Q ^{2 are} not Does not exist at the same time; and when M is II, P ¹ and P ^{2 are} not

; A ¹ and A ² are the same or different and are independently selected from the following formulas:

Wherein L ³ is independently a direct bond ^{with B 1} or B ² in each occurrence ^{; L 4 is independently a direct bond with Q 1} or Q ² in each occurrence; and R ² and R ^{3 are} in each occurrence When they appear, they are the same or different, and are independently selected from H and optionally substituted C ₁ -C _{6 alkyl groups, or form optionally substituted C 3} -C ₆ cycloalkyl groups together with the carbon atom to which they are attached; B ¹ and B ² are the same or different and are independently selected from the following formulas:

, Wherein R ⁴ is C ₁ -C ₆ alkyl or aryl-(C ₁ -C ₃ ) alkyl, each of which is optionally substituted; and R ⁵ is C ₁ -C ₆ alkyl, aryl, heteroaryl , Substituted C ₁ -C ₆ alkyl, aryl-(C ₁ -C ₃ )alkyl, substituted aryl-(C ₁ -C ₃ )alkyl, heteroaryl-(C ₁ -C ₃ ) Alkyl, substituted heteroaryl-(C ₁ -C ₃ )alkyl, substituted aryl or substituted heteroaryl; and L ⁵ is a direct bond ^{with A 1} or A ^2. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is II; P ¹ and P ^{2 are} each

; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₁ -C ₆ alkyl. Such as the compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein each X is CH; R ² and R ^{3 are} independently hydrogen and methyl , Ethyl, or together with the carbon atom to which it is attached, form an optionally substituted C ₃ -C ₆ cycloalkyl group. Such as the compound of claim 2 or 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein R ² and R ^{3 are} independently hydrogen or methyl; R ⁴ Is methyl or ethyl; and R ⁵ is isopropyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is III; P ¹ and P ^{2 are} each

; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₁ -C ₆ alkyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is III; P ¹ and P ^{2 are} not present; Q ¹ and Q ^{2 for} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₁ -C ₆ alkyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is III; P ¹ does not exist; Q ¹ is

; P ² is

；Q ² does not exist; A ¹ is

; A ² is

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₁ -C ₆ alkyl. The compound of any one of claims 5 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein each X is CH; R ² and R ^{3 are} independent Ground is hydrogen, methyl, ethyl, or together with the carbon atom to which it is attached to form an optionally substituted C ₃ -C ₆ cycloalkyl group. Such as the compound of any one of claims 5 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein R ² and R ^{3 are} independently hydrogen or methyl R ⁴ is methyl or ethyl, each optionally substituted; and R ⁵ is optionally substituted isopropyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is IV; P ¹ and P ^{2 are} each

, Where X is CH; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, each optionally substituted. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is IV; P ¹ and P ^{2 are} each

, Where X is N; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is C ₁ -C ₆ alkyl or aryl, each of which is optionally substituted. Such as the compound of claim 10 or 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein R ⁵ is isopropyl or phenyl, each of which is optionally substituted . Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is IV; P ¹ and P ^{2 are} each

, Where X is CH or N; Q ¹ and Q ² do not exist; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is C ₆ -C ₁₀ aryl, each optionally substituted. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is IV; P ¹ and P ^{2 are} each

; Q ¹ and Q ^{2 are} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₆ -C ₁₀ aryl. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug, wherein M is IV; P ¹ and P ^{2 are} each

; Q ¹ and Q ^{2 are} each

; A ¹ and A ^{2 are} each

; R ⁴ is optionally substituted C ₁ -C ₆ alkyl; and R ⁵ is optionally substituted C ₆ -C ₁₀ aryl. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein R ⁵ is optionally substituted phenyl. Such as the compound of any one of claims 10 to 16, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein R ² and R ^{3 are} independently hydrogen, methyl Group, ethyl group, or together with the carbon atom to which it is connected, form an optionally substituted C ₃ -C ₆ cycloalkyl group; and R ⁴ is an optionally substituted C ₁ -C ₄ alkyl group. Such as the compound of any one of claims 10 to 16, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, wherein R ² and R ^{3 are} independently hydrogen or methyl Group; R ⁴ is a methyl group or an ethyl group. Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, which is selected from the group consisting of:

Such as the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, which is selected from the group consisting of 4,12-bis-[ N -( Methoxycarbonyl) -L -valinyl- L -proline- N- (3-aminophenyl)]-[2.2]paracyclic aromatic hydrocarbon; (( S )-1-(( S ) -2-(5-(9,9-Difluoro-7-(3-(( S )-1-((Methoxycarbonyl)-L-valinyl)pyrrolidine-2-carboxamide) phenyl) -9H- fluorene-2-yl) -1 H - imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxo-2-yl) amine carboxylic acid Esters; ((2 S ,2' S )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7- Hexahydro- s -dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(azadiyl))bis(carbonyl))bis(pyrrolidine-2, 1-Diyl)) bis(3-methyl-1-oxobutane-1,2-diyl)) dimethyl dicarbamate; ((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro- s -dicyclopentacene-4,8 -Diyl)bis(3,1-phenylene)bis(azadiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-side oxy-1-benzene Ethane-2,1-diyl)) dimethyl dicarbamate; ((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5 -Tetramethyl-1,2,3,5,6,7-hexahydro- s -dicyclopentacene-4,8-diyl)bis(pyridine-5,3-diyl))bis (Azodiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamic acid Dimethyl ester; ((1 R ,1' R )-((2 S ,2' S )-((((1,1,5,5-tetramethyl-1,2,3,5,6, 7-hexahydro- s -dicyclopentacene-4,8-diyl)bis(3,1-phenylene))bis(1 H -imidazole-5,2-diyl))bis( Pyrrolidine-2,1-diyl)) bis(2-oxo-1-phenylethane-2,1-diyl)) dimethyl dicarbamate; and ((1 R ,1' R )-((2 S ,2' S )-(((1,1,5,5-tetramethyl-1,2,3,5,6,7-hexahydro- s -dicyclopentadieno Benzene-4,8-diyl)bis(4,1-phenylene))bis(1 H -imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis( 2-Pendant oxy-1-phenylethane-2,1-diyl)) dimethyl dicarbamate. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof according to any one of claims 1 to 20, and a Or multiple pharmaceutically acceptable excipients, such as adjuvants, diluents and/or carriers. The composition of claim 21, which additionally comprises a second agent having anti-HCV activity. The composition of claim 22, wherein the second agent having anti-HCV activity is selected from the group consisting of: recombinant human interferon alpha, nucleoside analogs, direct-acting antiviral agents, NS3/4A protease inhibitors, Nucleotide NS5B polymerase inhibitor, NS5A inhibitor, non-nucleoside NS5B polymerase inhibitor, and combinations thereof. Such as the composition of claim 22, wherein the second agent is selected from the group consisting of pegylated interferon, ribavirin, daclatasvir, boceprevir ), telapravir, simeprevir, sofosbuvir, dasabuvir, ombitasvir, velpatasvir , Ledipasvir, paritaprevir, ritonavir, elbasvir, grazoprevir, asunaprevir, baker Beclabuvir and combinations thereof. A method for inhibiting the function of HCV NS5A protein, which comprises combining a biological sample containing the HCV NS5A protein with a compound or a salt, stereoisomer, tautomer, solvate, or salt thereof according to any one of claims 1 to 20 Pro-drug exposure. A method for treating or preventing a disease, disorder or medical condition associated with HCV activity in an individual, which comprises administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 20 or its pharmaceutically acceptable Accepted salts, stereoisomers, tautomers, solvates or prodrugs, or pharmaceutically acceptable salts, solvates or prodrugs thereof. Such as the method of claim 26, which additionally combines the administration of a second agent with anti-HCV activity to the individual. The method of claim 27, wherein the second agent is selected from the group consisting of: recombinant human interferon alpha, nucleoside analogs, direct-acting antiviral agents, NS3/4A protease inhibitors, nucleotide NS5B polymerase Inhibitors, NS5A inhibitors, non-nucleoside NS5B polymerase inhibitors, including but not limited to pegylated interferon, ribavirin, dacatavir, bosiprevir, telapravir, simapril Weir, Sofosbuvir, Dasabvir, Obitavir, Vipatavir, Redipavir, Palitaprevir, Ritonavir, Elbavir, Glazoprevir, Ashuna Wei, beclabwe and their combination. A method for treating or preventing a disease, disorder or medical condition associated with HCV activity in an individual, comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition according to any one of claims 21 to 24. The method according to any one of claims 26 to 29, wherein the disease, disorder or medical condition is selected from the group consisting of hepatitis C infection, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), liver cancer, Mixed cryoglobulinemia, delayed skin lesion purpura, leukocytosis vasculitis, lichen planus (LP), sicca syndrome, urticaria, pruritus, thrombocytopenic purpura and psoriasis. The method according to any one of claims 26 to 29, wherein the disease or condition is liver cirrhosis. The method according to any one of claims 26 to 29, wherein the disease or condition is liver cancer. The method according to any one of claims 26 to 29, wherein the disease is hepatitis C infection.