WO2024032715A1

WO2024032715A1 - Hydrazide compound and preparation method therefor and use thereof

Info

Publication number: WO2024032715A1
Application number: PCT/CN2023/112217
Authority: WO
Inventors: 王伟; 孙晓阳; 曾宏; 巩晓明; 王英; 李森林; 潘德思; 鲁先平
Original assignee: 深圳微芯生物科技股份有限公司; 成都微芯药业有限公司
Priority date: 2022-08-12
Filing date: 2023-08-10
Publication date: 2024-02-15
Also published as: CN116730995A; CN116730995B

Abstract

Disclosed is a compound having a structure represented by formula (I). The compound has excellent antiviral activity against orthopoxvirus, has multiple advantages compared with a marketed drug Tecovirimat, and has important development significance and use prospects. Further provided are a preparation method for the compound represented by formula (I) and a use of the compound in the treatment of related diseases caused by orthopoxvirus related viruses such as smallpox virus, monkeypox virus, cowpox virus, camelpox virus, and horsepox virus.

Description

A kind of hydrazide compound, its preparation method and its application

Technical field

The present invention relates to the field of medicinal chemistry, specifically to a class of hydrazide compounds, their preparation methods, and their application in the treatment of poxvirus infections.

Background technique

Poxviruses belong to the Poxviridae family. They are a family of double-stranded DNA viruses that multiply in cells after infection. Under an electron microscope, they have a brick-like or oval structure. Poxviruses are also called ancient viruses because they once Found in organisms such as insects, reptiles, birds and mammals. Poxviruses include two subfamilies: Spinopoxvirinae and Entomopoxvirinae. Among them, the subfamily Spinopoxvirinae includes the genus Orthopoxvirus, whose virions are large and brick-shaped (the same is true for the virions of Atapoxvirus and Molpoxvirus). The length ranges from 220-450nM, mainly including 12 kinds of viruses such as monkeypox, smallpox, cowpox, horsepox and camelpox (Fenner F, Henderson DA, Arita I, et al., Smallpox and its Eradication), all of which can infect humans.

Smallpox virus is highly contagious and causes severe disease in humans, resulting in high mortality (JAMA, 1999, 281, 2127-2137). In addition, there is historical precedent for the use of variola virus as a biological weapon, so concerns about the use of variola virus as a biological weapon in recent years have emphasized the need to develop drugs against orthopoxviruses.

Monkeypox is a zoonotic viral disease caused by infection with monkeypox virus (MPXV). The main clinical manifestations are fever, rash, and swollen lymph nodes. The disease is mainly prevalent in Central and West Africa. Since May 2022, monkeypox cases have also been reported in some non-endemic countries, and community transmission exists. On July 23, 2022, the World Health Organization (WHO) declared that the monkeypox epidemic in many countries constituted a "global health emergency", which was the highest alert issued by the organization. As of August 9, 2022, the number of confirmed monkeypox infections globally has rapidly exceeded 27,000. Only the United States has a high number of confirmed cases of monkeypox, with 9,492 confirmed cases, including 1,424 new confirmed cases on the 8th. Monkeypox virus is expanding at an unprecedented rate, prompting the World Health Organization (WHO) to implement a series of new emergency actions to respond to the epidemic, including the release of new monkeypox vaccination guidelines.

Currently, the small molecule drug Tecovirimat has been granted expanded use (EA-IND) by the US CDC and can be used during monkeypox outbreaks. However, Tecovirimat has neurotoxic side effects during use and has poor drugability.

Clearly, there is a need for new therapies for the treatment and/or prevention of diseases caused by orthopoxvirus infections.

Contents of the invention

Problems to be solved by the invention:

In view of the fact that Tecovirimat, a drug used for orthopoxviruses in the prior art, has neurotoxic side effects during use and has problems with poor drugability, the present invention aims to find a drug for treating and/or preventing infections caused by orthopoxviruses. New small molecule drugs for diseases caused by smallpox, monkeypox, and cowpox viruses, It can reduce the amount of drug entering the brain to improve drug safety and better drug quality.

Solutions used to solve the problem:

In order to solve the above problems, the inventor of the present application conducted in-depth research and found that specific hydrazide compounds can achieve the desired purpose, and as a result, the present invention was completed.

The present invention relates to the following hydrazide compounds.

The present invention protects the following specific embodiments:

A compound represented by formula (I), or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or its pharmaceutically acceptable Salt accepted:

in,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from hydrogen, deuterium or halogen;

R ^a is selected from the group consisting of 5 or 6-membered aryl and 4- to 7-membered heterocyclyl, 5- or 6-membered aryl and 4- to 7-membered carbocyclyl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclyl, A 5- or 6-membered heteroaryl group and a 4- to 7-membered carbocyclyl group, each of the 5- or 6-membered heteroaryl group and the 4- to 7-membered heterocyclyl group independently contains 1-4 heterocyclic groups selected from N, O, or S. Atom; the aryl group, heteroaryl group, carbocyclyl group and heterocyclyl group are each independently and optionally substituted by one or more substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n ;

Each R ⁹ , R ¹⁰ , R ¹³ , and R _n are each independently selected from hydrogen, deuterium, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl;

------ is a single key or does not exist.

In some embodiments, R ^a is selected from the group consisting of 5-membered aryl and 4- to 7-membered heterocyclyl, 5-membered aryl and 4- to 7-membered carbocyclyl, 5-membered heteroaryl and 4- to 7-membered heterocyclyl , 5-membered heteroaryl and 4- to 7-membered carbocyclyl, the 5-membered heteroaryl and 4- to 7-membered heterocyclyl each independently contain 1-4 heteroatoms selected from N, O or S; The aryl group, heteroaryl group, carbocyclic group and heterocyclic group are each independently and optionally substituted by one or more R _n .

In some embodiments, R ^a is selected from the group consisting of 5-membered aryl and 5- to 6-membered heterocyclyl, 5-membered aryl and 5- to 6-membered carbocyclyl, 5-membered heteroaryl and 5- to 6-membered heterocyclyl , 5-membered heteroaryl and 5- to 6-membered carbocyclyl, the 5-membered heteroaryl and 5- to 6-membered heterocyclyl each independently contain 1-2 heteroatoms selected from N, O or S; the The aryl group, heteroaryl group, carbocyclic group and heterocyclic group are each independently and optionally substituted by one or more R _n .

In some embodiments, R ^a is selected from 5-membered aryl and 5- to 6-membered heterocyclyl, 5-membered aryl and 5-membered heterocyclyl to a 6-membered carbocyclyl group, a 5-membered heteroaryl group and a 5- to 6-membered heterocyclyl group, a 5-membered heteroaryl group and a 5- to 6-membered carbocyclyl group, and the 5-membered heteroaryl group and the 5- to 6-membered heterocyclyl group Each independently contains 1-3 heteroatoms selected from N, O or S; the aryl, heteroaryl, carbocyclyl and heterocyclyl are each independently and optionally substituted by 1 or more Rn .

In some embodiments, R ^a is selected from the group consisting of 5-membered aryl and 6-membered heterocyclyl, 5-membered aryl and 6-membered carbocyclyl, 5-membered heteroaryl and 6-membered heterocyclyl, 5-membered heteroaryl and 6-membered carbocyclyl, the 5-membered heteroaryl and 5 to 6-membered heterocyclyl each independently contain 1-3 heteroatoms selected from N, O or S; the aryl, heteroaryl, The carbocyclic group and the heterocyclic group are each independently and optionally substituted by one or more R _n .

In some embodiments, ^R has any structure selected from the group consisting of: thienopyridyl, thienophenol, thienopyrimidinyl, thienopyridazinyl, furanopyridazinyl, furophenyl, furan Pyridyl, furopyrimidinyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrrolophenyl, pyrrolopyrazinyl, pyrrolopyridazinyl, imidazopyridinyl, imidazophenyl, imidazopyrimidinyl , imidazopyrazinyl, imidazopyridazinyl, thiazolopyridinyl, thiazolophenyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, triazolopyrazinyl, triazolo Phenyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyridinyl; each of them is independently and optionally substituted by 1, 2 or 3 R _n .

In some specific embodiments, ^R has any structure selected from: thienopyridyl, thienopyridyl, thienopyridazinyl, furopyridazinyl, furophenyl, furopyridyl, pyrrole Pyridyl, imidazopyridyl, thiazolopyridyl, imidazopyrazinyl, triazolopyrazinyl; each of them is independently and optionally substituted by 1, 2 or 3 R _n .

In some specific embodiments, ^Ra has any structure selected from the following:

where p=0,1,2 or 3.

In some specific embodiments, each R _n is independently selected from deuterium, halogen, C _1-6 alkyl, or haloC _1-6 alkyl.

In some specific embodiments, each _Rn is independently selected from deuterium, halogen, C _1-4 alkyl, or haloC _1-4 alkyl.

In some specific embodiments, each _Rn is independently selected from hydrogen, deuterium, halogen, C _5-6 alkyl, or haloC _5-6 alkyl.

In some embodiments, each _Rn is independently selected from deuterium, halogen, methyl, halomethyl, ethyl, haloethyl, propyl, halopropyl, isopropyl, halo Isopropyl, C ₄ alkyl, halogenated C ₄ alkyl.

In some embodiments, each _Rn is independently selected from F, Cl, Br, methyl, fluoromethyl, ethyl, fluorine- or chlorine-substituted ethyl, propyl, fluorine- or chlorine-substituted propyl base, isopropyl, fluorine or chlorine substituted isopropyl, C ₄ alkyl or fluorine, chlorine substituted C ₄ alkyl.

In some specific embodiments, each R _n is independently selected from F, Cl, Br, methyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F.

In some specific embodiments, each _Rn is independently selected from F, Cl, Br, methyl, _-CF3 .

In some embodiments, in Formula I, ------ is a single bond.

In some embodiments, in Formula I, ------ is absent.

In some embodiments, R ^a is selected from the group consisting of 6-membered aryl and 4- to 7-membered heterocyclyl, 6-membered aryl and 4- to 7-membered carbocyclyl, 6-membered heteroaryl and 4- to 7-membered heterocyclyl , 6-membered heteroaryl and 4- to 7-membered carbocyclyl, the 6-membered heteroaryl and 4- to 7-membered heterocyclyl each independently contain 1-4 heteroatoms selected from N, O or S; The aryl group, heteroaryl group, carbocyclic group and heterocyclic group are each independently and optionally substituted by one or more substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from the group consisting of 6-membered aryl and 5- to 6-membered heterocyclyl, 6-membered aryl and 4- to 6-membered carbocyclyl, 6-membered heteroaryl and 5- to 6-membered heterocyclyl , 6-membered heteroaryl and 4- to 6-membered carbocyclyl, the 6-membered heteroaryl and 5- to 6-membered heterocyclyl each independently contain 1-3 heteroatoms selected from N, O or S; The aryl group, heteroaryl group, carbocyclic group and heterocyclic group are each independently and optionally substituted by one or more substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from Wherein Y and Z are each independently selected from N or C; V is N, NR ⁹ or CR ⁹ ; X is N, NR ¹⁰ or CR ¹⁰ ; W is N, NR ¹³ or CR ¹³ ; Ring A is selected from 4-7 1-membered carbocyclyl or heterocyclyl, the 4-7 heterocyclyl contains 1-3 heteroatoms selected from N, O or S, 1 or more H atoms in ring A are optionally replaced by 1-3 3 R _n substitutions; among them, ------ is a single bond or does not exist.

In some specific embodiments, each R ⁹ , R ¹⁰ , R ¹³ , R _n is each independently selected from hydrogen, deuterium, halogen, or C _1-6 alkyl.

In some specific embodiments, each R ⁹ , R ¹⁰ , R ¹³ , R _n is each independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, tert-butyl or C _5-6 alkyl.

In some specific embodiments, each R ⁹ , R ¹⁰ , R ¹³ , R _n is each independently selected from hydrogen, deuterium, F, Cl, or methyl.

In some embodiments, Ring A is selected from 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 5- or 6-membered heteroaryl, C _4-6 cycloalkyl, or phenyl ; 1 or more H atoms in Ring A are optionally substituted by 1-3 R _n .

In some specific embodiments, Ring A is selected from It is fused to the 6-membered ring where X, Y, and Z are located through any connectable position; wherein 1 or more H atoms in ring A are optionally replaced by 1-3 R _n .

In some specific embodiments, each R _n is independently selected from deuterium, F, Cl, Br, I, C _1-4 alkyl, C _5-6 alkyl.

In some specific embodiments, each R _n is independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, C _{5 -6} alkyl.

In some embodiments, each _Rn is independently selected from deuterium, methyl, F, Cl.

In some specific embodiments, Ring A is selected from It is fused to the 6-membered ring where X, Y, and Z are located through any connectable position.

In some specific embodiments, R ^a has a structure selected from the following groups:

In some specific embodiments, R ^a has a structure selected from the following groups:

where r=0,1,2 or 3.

In some specific embodiments, each of R ⁹ , R ¹⁰ , and R ¹³ is independently selected from hydrogen, deuterium, halogen, or C _1-6 alkyl.

In some embodiments, R ⁹ , R ¹⁰ , and R ¹³ are each independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Base, C _5-6 alkyl.

In some specific embodiments, each of R ⁹ , R ¹⁰ , and R ¹³ is independently selected from hydrogen, deuterium, F, Cl, Br, or methyl.

In some embodiments, one of R ⁹ , R ¹⁰ , and R ¹³ is selected from hydrogen, deuterium, F, Cl, Br, or methyl, and the other two are each independently selected from hydrogen or deuterium.

In some specific embodiments, each of R ⁹ , R ¹⁰ , and R ¹³ is independently selected from hydrogen or deuterium.

In some embodiments, R ^a is selected from 5 or 6 membered aryl and 4 to 7 membered heterocyclyl, 5 or 6 membered heteroaryl and 4 to 7 membered heterocyclyl, the 5 or 6 membered heteroaryl The aryl group and the 4- to 7-membered heterocyclyl group each independently contain 1-4 heteroatoms selected from N, O or S; the aryl group, heteroaryl group, and heterocyclyl group are each independently and optionally substituted by 1 Or substituted with multiple substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from the group consisting of phenyl 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl 4- to 7-membered heterocyclyl, the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, The 7-membered heterocyclyl group each independently contains 1-4 heteroatoms selected from N, O or S; the phenyl group, heteroaryl group and heterocyclyl group are each independently and optionally selected from 1 or more Substituted from a substituent of R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from the group consisting of phenyl 5- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl 5- to 6-membered heterocyclyl, said 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclyl The 6-membered heterocyclyl group each independently contains 1-3 heteroatoms selected from N, O or S; the phenyl group, heteroaryl group and heterocyclyl group are each independently and optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n are substituted.

In some embodiments, R ^is selected from the group consisting of phenyl 5-membered heterocycloalkyl, phenyl 5-membered heteroaryl, phenyl 6-membered heteroaryl, 5-membered heteroaryl 6-membered heteroaryl , the 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heterocycloalkyl each independently contain 1-3 heteroatoms selected from N, O or S; the phenyl, heteroaryl, hetero Each cycloalkyl group is independently optionally substituted with 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^is selected from the group consisting of phenyloxadiazolyl, phenyldioxolyl, phenylpyridyl, thienopyridyl, and pyridylimidazolyl; the phenyl Each of the oxadiazolyl, phenyldioxolyl, phenylpyridinyl, thienopyridyl, and pyridinoimidazolyl groups is independently optionally substituted by 1, 2, or 3 Substituted with a substituent selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, each R ⁹ , R ¹⁰ , R ¹³ , R _n is each independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, iso Butyl or tert-butyl.

In some specific embodiments, each R ⁹ , R ¹⁰ , R ¹³ , R _n is each independently selected from deuterium, F, Cl, Br, or methyl.

In some specific embodiments, Ra ^is selected from:

In some embodiments, R ^a is selected from the group consisting of phenyl 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, the 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl, The cycloalkyl groups each independently contain 1-2 heteroatoms selected from N, O or S; the phenyl, heteroaryl and heterocycloalkyl groups are each independently and optionally substituted by 1, 2 or 3 Substitute with a substituent selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from the group consisting of phenyldioxolyl and thienopyridinyl; each of the phenyldioxolyl and thienopyridinyl groups is independently, optionally is substituted with 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, Ra ^is selected from:

In some embodiments, R ^a is selected from 5 or 6 membered heteroaryl and 4 to 7 membered heterocyclyl, each of the 5 or 6 membered heteroaryl and 4 to 7 membered heterocyclyl independently contains 1- 4 heteroatoms selected from N, O or S; the heteroaryl and heterocyclic groups are each independently and optionally substituted by 1 or more selected from R ⁹ , R ¹⁰ , R ¹³ or R _n base substitution.

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 4- to 7-membered heterocyclyl, each of the 5-membered heteroaryl and 4- to 7-membered heterocyclyl independently contains 1-4 selected from Heteroatom of N, O or S; the heteroaryl group and heterocyclyl group are each independently and optionally substituted by one or more R _n .

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 5- to 6-membered heterocyclyl, each of the 5-membered heteroaryl and 5- to 6-membered heterocyclyl independently contains 1-2 selected from Heteroatom of N, O or S; the heteroaryl group and heterocyclyl group are each independently and optionally substituted by one or more R _n .

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 6-membered heterocyclyl, each of the 5-membered heteroaryl and 6-membered heterocyclyl independently contains 1-2 selected from N, O or Heteroatom of S; the heteroaryl and heterocyclic groups are each independently and optionally substituted by one or more R _n .

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 6-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1 selected from N, O or S Heteroatom; the 5-membered heteroaryl, Each 6-membered heteroaryl group is independently optionally substituted by 1, 2 or 3 _Rn .

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 6-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1 heteroatom selected from N or S ; The 5-membered heteroaryl group and the 6-membered heteroaryl group are each independently and optionally substituted by 1, 2 or 3 R _n .

In some specific embodiments, Ra ^is selected from thienopyridyl, which is optionally substituted with 1, 2, or 3 _Rn .

where p=0,1,2 or 3.

In some specific embodiments, each R _n is independently selected from deuterium, halogen, or C _1-6 alkyl.

In some specific embodiments, each R _n is independently selected from deuterium, halogen, or C _1-4 alkyl.

In some embodiments, each _Rn is independently selected from F, Cl, Br, methyl, ethyl, or propyl.

In some embodiments, each _Rn is independently selected from F, Cl, Br, methyl.

In some specific embodiments, Ra ^is selected from:

In some embodiments, R ^a is selected from phenyl 4- to 7-membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O, or S; the benzene group and heterocyclyl group are each independently optionally substituted by one or more substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from phenyl 5- to 6-membered heterocyclyl groups containing 1-3 heteroatoms selected from N, O, or S; the benzene group and heterocyclyl group are each independently optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from phenyl 5- or 6-membered heteroaryl, the 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S; the benzene group and heteroaryl group are each independently optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from phenyl 5-membered heteroaryl, and the 5-membered heteroaryl contains 1-3 heteroatoms selected from N or O; each of the phenyl and heteroaryl groups Independently, optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from Wherein, ring A is selected from a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains 1-3 heteroatoms selected from N or O, and the Each is independently optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, Ring A is selected from It is fused to the benzene ring through any attachable position.

In some specific embodiments, R ^a is selected from Each is independently optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from Each is independently, optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br or methyl.

In some specific embodiments, Ra ^is selected from:

In some embodiments, R ^a is selected from phenyl 5- to 6-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O, or S; The phenyl group and heterocycloalkyl group are each independently and optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some embodiments, R ^a is selected from phenyl and 6-membered heterocycloalkyl, and the 6-membered heterocycloalkyl contains 2 heteroatoms selected from N or O; the phenyl, heterocycloalkyl Each is independently optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from phenyl 6-membered heterocycloalkyl, the 6-membered heterocycloalkyl contains 2 oxygen heteroatoms; the phenyl and heterocycloalkyl are each independently, optionally Optionally substituted by 1, 2 or 3 substituents selected from ^R9 , ^R10 , ^R13 or _Rn .

In some specific embodiments, R ^a is selected from Each is independently and optionally substituted by one or more substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from Each is independently optionally substituted by 1, 2 or 3 substituents selected from F or deuterium.

In some specific embodiments, R ^a is selected from Each is independently optionally substituted by 1, 2 or 3 F's.

In some specific embodiments, Ra ^is selected from:

In some embodiments, R ^a is selected from an 8-10 membered heteroaryl group, which contains 1-3 heteroatoms selected from N, O, or S; the 8-10 membered heteroaryl group contains Heteroaryl is optionally substituted with 1 or more ^R9 , ^R10 , ^R13 or _Rn .

In some specific embodiments, R ^a is selected from an 8-10 membered bicyclic heteroaryl group containing 1-3 heteroatoms selected from N, O or S; the 8- The 10-membered bicyclic heteroaryl is optionally substituted with 1 or more R ⁹ , R ¹⁰ , R ¹³ or R _n .

In some specific embodiments, R ^a is selected from 5-membered heteroaryl and 6-membered heteroaryl, benzo 5-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1- 3 heteroatoms selected from N, O or S; the phenyl, 5-membered heteroaryl and 6-membered heteroaryl are each independently and optionally substituted by 1, 2 or 3 R ⁹ , R ¹⁰ , R ¹³ or R _n substituted.

Preferably, R ^a is selected from the group consisting of thienopyridyl and benzoxadiazolyl, each of which is independently and optionally replaced by 1, 2 or 3 R ⁹ , R ¹⁰ , R ¹³ or R _n substitution;

Preferably, R ^a is selected from:

Each of them is independently, optionally substituted by 1, 2 or 3 substituents selected from R ⁹ , R ¹⁰ , R ¹³ or R _n ;

Preferably, each R ⁹ , R ¹⁰ , R ¹³ or R _n is independently selected from deuterium, halogen or C _1-6 alkyl;

Preferably, each R ⁹ , R ¹⁰ , R ¹³ or R _n is independently selected from deuterium, halogen or C _1-4 alkyl.

Preferably, each R ⁹ , R ¹⁰ , R ¹³ or R _n is independently selected from F, Cl, Br, methyl, ethyl or propyl;

Preferably, each R ⁹ , R ¹⁰ , R ¹³ or R _n is independently selected from F, Cl, Br, methyl;

Or preferably, R ^a is selected from:

Or preferably, R ^a has any structure selected from the following:

Preferably, R ^a is selected from:

In some specific embodiments, formula (I) has the structure shown in formula (I'):

Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^a are each defined as described in formula (I).

In some specific embodiments, formula (I) has the structure shown in formula (I'-A):

In some specific embodiments, formula (I) has the structure shown in formula (I'-B):

Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^a are respectively defined as described in formula (I).

As exemplary compounds of formula (I), the present invention provides specific compounds selected from the following structures:

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

The term "prodrug" refers to the derivatives of the compound represented by formula (I) found in the present invention to have specific substituents. They themselves may have weak or even no activity, but after administration, under physiological conditions (such as (through metabolism, solvolysis or other means) are converted into compounds with specific substituents found in the present invention, producing corresponding biological activities in the body.

The term "metabolite" refers to the product obtained by metabolism in the body of the compound represented by formula (I) found to have a specific substituent in the present invention. The metabolites of a compound can be determined by techniques well known in the art. The activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, etc. Accordingly, the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so.

The term "deuterated compound" means that the compound of the present invention includes at least one deuterium atom, specifically means that one or more hydrogen atoms in the compound of the present invention may be replaced or substituted by a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

Preparation:

The invention also provides methods of preparing said compounds. The preparation of the compound described in general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way. The compounds described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the methods described in the present invention can be used. The product obtained in each reaction step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be routinely synthesized according to literature (such as those provided by Scifinder) or purchased.

The compound described in the general formula (I') of the present invention can be synthesized according to the route described in the following method:

1) Diels-Alder reaction occurs between raw material I-a and raw material I-b to obtain intermediate I-c;

Among them, when the ------ between the carbon atoms connected to R ⁷ and R ⁸ in formula I' does not exist, further reduce Ic to I-c' I-c' can be converted into intermediate Ic"

2) The intermediate Ic/I-c'/Ic" is condensed with hydrazide Id or I-d' to obtain product I';

Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{a are} defined as described in Formula I.

Similarly, the compound of formula I can be obtained by referring to the above synthetic route.

pharmaceutical composition

The present invention also provides a pharmaceutical composition, which contains the aforementioned compound, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, Prodrugs, deuterated compounds, pharmaceutically acceptable salts, and pharmaceutical adjuvants.

In some embodiments, the pharmaceutical composition may also include other drugs for treating and/or preventing related diseases caused by orthopoxvirus infection.

Methods for preparing various pharmaceutical compositions containing amounts of active ingredients are known or will be apparent to those skilled in the art in light of the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), the method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

medicinal purposes

In another aspect, the invention also provides the compound, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, The use of a pharmaceutically acceptable salt, or the pharmaceutical composition, in the preparation of a medicament for the treatment and/or prevention of related diseases caused by orthopoxvirus infection.

In another aspect, the invention also provides the compound, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, Use of a pharmaceutically acceptable salt, or the pharmaceutical composition, in the treatment and/or prevention of related diseases caused by orthopoxvirus infection.

In another aspect, the invention also provides the compound, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, Pharmaceutically acceptable salts, or said pharmaceutical compositions, are used to treat and/or prevent related diseases caused by orthopoxvirus infection.

In another aspect, the present invention also provides a method for treating and/or preventing related diseases caused by orthopoxvirus infection, which includes: administering to a subject/individual in need thereof a therapeutically and/or preventively effective amount of the Compounds, or their tautomers, stereoisomers, polymorphs, co-crystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or pharmaceutical combinations thereof things.

In some embodiments, orthopoxviruses described herein include, but are not limited to, variola virus, monkeypox virus, camelpox virus, vaccinia virus, lepox virus, and murine pox virus.

The related diseases caused by orthopoxvirus infection as mentioned herein refer to diseases caused by one, two or more types selected from the group consisting of variola virus, monkeypox virus, camelpox virus, cowpox virus, lepox virus and mousepox virus. Related diseases caused by orthopoxviruses.

In the present invention, "treating" generally means obtaining the desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. "Treatment" as used herein covers any treatment of a disease in a patient, including: (a) prevention of a disease or condition in a patient who has not been diagnosed with the disease; A disease or symptom that occurs in a patient; (b) inhibits the symptoms of the disease, i.e., prevents their progression; or (c) alleviates the symptoms of the disease, i.e., causes the regression of the disease or symptoms.

In the present invention, "subject" or "individual in need thereof" refers to a vertebrate animal. In certain embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human.

In the present invention, "effective amount" refers to an amount effective in the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount of the substance/molecule in which the therapeutically beneficial effects outweigh any toxic or harmful consequences. "Prophylactically effective amount" refers to an amount effective in the dosage and time necessary to achieve the desired preventive effect. Often, but not necessarily, the prophylactically effective amount will be less than the therapeutically effective amount because the prophylactic dose is administered to the subject prior to the onset of disease or in the early stages of the disease.

Definition of Terms:

According to common practice in this field, The bonds used in the structural formulas herein describe the point of attachment of the moiety or substituent to the parent core or main structure.

A dash "-" that does not appear between two letters or symbols is used to indicate the point of attachment of a substituent. For example, _-CF3 is attached through a carbon atom. As used herein, the term "substituted" means that any one or more hydrogens on a specified atom or group are replaced by a selected selection of the specified group, provided that the normal valence of the specified atom is not exceeded.

The term "1 or more H atoms in XXX may be further substituted by 1-3 YYY" means that the H atoms in XXX may be substituted by YYY or not substituted by YYY; when substituted, XXX may be substituted by 1 It can be replaced by one YYY or multiple YYY, and each YYY can be the same or different.

In various parts of this specification, substituents of the compounds disclosed herein are disclosed according to group type or range. In particular, the present invention includes each and every individual subcombination of the individual members of these radical classes and ranges. For example, the term "C _1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl, or the independently disclosed "C _1-6 alkyl" ₄ alkyl”, or independently disclosed “C _1-3 alkyl”.

The term "alkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, "C ₁ _-6 alkyl" refers to C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ . In addition, for example, "C _1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted such that one or more of its hydrogens are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-butyl Pentyl, isopentyl, neopentyl), etc.

The term "halogenated C _1-6 alkyl" means that one or more (such as 2, 3) hydrogen atoms in the alkyl group are replaced by halogen atoms, such as fluorine, chlorine, bromine. The alkyl group is as defined above. In some embodiments, the term "halo C _1-6 alkyl" is preferably fluorinated, for example, it can be -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ etc.

The term "cycloalkyl" refers to cyclized alkyl groups, including monocyclic, bicyclic or polycyclic ring systems. When the cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or carbocyclic residue. The possible connection methods for each two rings of the bicyclic or polycyclic cycloalkyl group include bridging and fusion. Or screw connection. For example, C _3-10 cycloalkyl refers to C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The terms "carbocycle" and "carbocyclyl" are interchangeable and refer to any stable 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic or bicyclic or tricyclic ring, in which any One can be saturated, partially saturated, unsaturated or aromatic. Herein, the 4-7 membered carbocyclic ring is especially a 4-7 membered cycloalkyl group, including but not limited to cyclobutyl, cyclopentyl, and cyclohexyl.

The terms "heterocycle" and "heterocyclyl" are interchangeable and refer to substituted and unsubstituted 4- to 7-membered monocyclic groups or bicyclic groups, 8- to 10-membered bicyclic groups group or tricyclic group; wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing group preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, And a further restriction is that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatoms refer only to N or O, and the total number thereof does not exceed 3, preferably only 1-2 heteroatoms. Carbon and sulfur atoms can be optionally oxidized, nitrogen atoms can be optionally quaternized, and when the valence allows, ring atoms on the heterocyclic ring can be optionally substituted with =O (oxo). (For example: ). Heterocyclic groups can be attached at any available nitrogen or carbon atom. The term "heterocycle" can be aromatic or non-aromatic, saturated, unsaturated or partially unsaturated; in this article, 4-7 membered heterocycle especially refers to 4-7 membered heterocycloalkyl, 4-7 membered heterocycle Alkenyl, 4-7 membered heteroaryl, exemplary 4-7 membered heterocycles include but are not limited to

The term "heterocycloalkyl" refers to a heterocyclic group as defined above in which all ring atoms are fully saturated, e.g.

The term "heterocycloalkenyl" refers to a heterocyclic group with at least one carbon-carbon double bond in the heterocyclic ring as defined above, for example

The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group with 5 to 14 carbon atoms in the ring part. When the "aryl" is a bicyclic or tricyclic ring, each of its rings is an aromatic ring. . The possible connection methods for each two rings of a bicyclic or tricyclic aryl group include bridging, fusion, and spiro connection. Examples include phenyl and naphthyl, each of which may be substituted.

The term "heteroaryl" refers to the above-mentioned substituted and unsubstituted aryl groups having at least one heteroatom (O, N or S) in at least one ring, including aromatic 5-8 membered monocyclic groups, 8-10 membered bicyclic groups and 10-14 membered tricyclic group, the heteroatom-containing ring preferably has 1, 2 or 3 heterocyclic atoms selected from O, N or S. Each heteroatom-containing ring of a heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each A ring has at least one carbon atom. Carbon and sulfur atoms may optionally be oxidized and nitrogen atoms may be optionally quaternized. Each ring of a bicyclic or tricyclic heteroaryl group is an aromatic ring.

The term "optional" means that it may or may not be selected. For _example , "C _1-6 alkyl optionally substituted by 1 to 3 R ^d " means that the C _1-6 alkyl group may be substituted by 1 to 3 R ^d or may not be substituted by 1 to 3 R d 3 R ^d replaced. Other similar definitions can be understood with reference to the foregoing content.

In this article, unless otherwise expressly stated, the description "... each independently selected from" used throughout this article may refer to one of the specific options expressed between the same or different symbols in different groups. do not affect each other, it can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

Throughout the specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds useful as pharmaceutically acceptable compounds and/or as intermediates useful in the preparation of pharmaceutically acceptable compounds. compound.

In this specification, when the compound structure is inconsistent with the compound name, the compound structure shall prevail.

Invention effect:

The compound of the present invention has multiple advantages compared with the marketed drug Tecovirimat:

1. The compound of the present invention has excellent antiviral activity against orthopoxviruses and has no obvious toxicity to cells, and can be used as a drug to treat or prevent diseases related to this effect;

2. Compared with Tecovirimat, the compound of the present invention has lower brain exposure and exposure ratio, smaller risk of drug entering the brain and higher drug safety;

3. The compound of the present invention not only has better antiviral activity than Tecovirimat, but also has a greater improvement in solubility. Compared with Tecovirimat, it has a huge improvement in drug potential, which has important development significance.

4. The compound of the present invention has excellent blood exposure performance (both C _max and AUC are significantly better than Tecovirimat), and has better drug effect and medication safety than Tecovirimat.

5. The compound of the present invention shows excellent performance in the stability test of human liver microsomes and has good application prospects in the field of medicine.

Detailed ways

It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. Additionally, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

The structure of a compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker ASCENA-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was tetrahydrofuran. Methylsilane (TMS), chemical shift is in 10 ^- ⁶ (ppm) is given as unit.

Reaction monitoring and MS measurement used a Thermofisher ESQ (ESI) mass spectrometer.

HPLC was measured using a Thermo Fisher U3000DAD high-pressure liquid chromatograph (GL Sciences ODS-HL HP 3μm 3.0*100mm column).

The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15~0.2mm. The specification of the thin layer chromatography separation and purification product is 0.9~1.0mm. Thin layer chromatography preparation plates. Column chromatography uses Qingdao Ocean 200-300 mesh silica gel as the carrier. The systems used as developing agents are A: methylene chloride and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is different according to the polarity of the compound. And make adjustments. For medium-pressure preparative liquid phase purification, biotage isera one type preparative liquid phase is used.

In the following examples, unless otherwise specified, all reaction raw materials can be obtained from Sarn Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical R&D Co., Ltd., Shanghai Bi It can be purchased from manufacturers such as De Medical Technology Co., Ltd.

In the following examples, unless otherwise specified, concentrated sulfuric acid refers to concentrated sulfuric acid with a mass percentage of 98%; unless otherwise specified, all reagents used are of analytical grade.

abbreviation

Example 1

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-2,2-difluorobenzo[d][1,3]dioxolane-5-carboxamide

Step 1: Add 2,2-difluorobenzo[d][1,3]dioxolane-5-carboxylic acid methyl to a 50ml single-neck bottle. Ester (1-a, 200 mg, 93 mmol), hydrazine hydrate (2 ml) and methanol (15 ml) were stirred and refluxed at 80°C for 2 hr. No raw materials remained under TLC monitoring. The reaction solution was spun to dryness under reduced pressure, 20 ml of DCM was added, washed with 3*5 ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by prep-TLC (DCM:MeOH=30:1) to obtain 2,2-difluorobenzo. [d][1,3]dioxolane-5-carboxylic acid hydrazide (1-b, 185mg, 0.86mmol, 92% yield).MS Calcd: 216.03; MS Found: 217.04 ([M+H] ⁺ ) .

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[ f]Isobenzofuran-1,3(3aH)-dione (1-c, 105 mg, 0.56 mmol), 2,2-difluorobenzo[d][1,3]dioxolane-5- Formyl hydrazide (1-b, 100 mg, 0.46 mmol), DIPEA (59 mg, 0.46 mmol) and solvent ethanol (20 ml) were stirred at 80°C for 12 hr. LCMS monitored that the reaction was complete. The reaction solution was spin-dried under reduced pressure, 20 ml DCM was added, washed with 3*5 ml saturated brine, the organic phase was dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a ,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2,2-difluorobenzo[d][1 , 3] Dioxolane-5-carboxamide (1, 60 mg, 0.15 mmol, 33% yield). MS Calcd: 388.09; MS Found: 389.06 ([M+H] ⁺ ). ¹ H NMR (600MHz, DMSO -d6)δ11.06(s,1H),7.95–7.77(m,2H),7.59(d,J＝8.4Hz,1H),5.84–5.71(m,2H),3.31–3.22(m,4H) ,1.23-1.19(m,2H),0.29-0.26(m,1H),0.08-0.06(m,1H).

Example 2

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)thieno[2,3-c]pyridine-2-carboxamide

Step 1: Add thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (2-a, 100 mg, 0.53 mmol) and MeOH (10 mL) to a 100 mL eggplant-shaped flask, and then add hydrazine hydrate solution to it (0.36mL, 11.35mmol). Stir at 80°C for 14 hours. TLC monitored the completion of the raw material reaction, and the reaction solution was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:MeOH=40:1) to obtain thieno[2,3-c]pyridine-2-carboxylic acid hydrazide (2-b ,80mg, 0.41mmol, 80% yield). MS Calcd:193.03; MS Found:194.11([M+H] ⁺ ).

Step 2: Combine thieno[2,3-c]pyridine-2-carboxylic acid hydrazide (2-b, 80 mg, 0.41 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5 ,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 94.5mg, 0.50mmol) Place in a 25mL eggplant-shaped flask, add 10mL ethanol solution, and reflux at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)thieno[2,3-c] Pyridine-2-carboxamide (2,120 mg, 0.33 mmol, 79.3% yield). MS Calcd: 365.08; MS Found: 366.12 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.70 (s, 1H), 9.39 (s, 1H), 8.58 (d, J ＝5.6Hz,1H),8.29(s,1H),8.02(dd,J＝5.6,1.2Hz,1H),5.84-5.73(m,2H),3.32-3.18(m,4H),1.25-1.14( m,2H),0.32-0.27(m,1H),0.11-0.07(m,1H).

Example 3

N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ya Ethylenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolyl[4,3-a]pyrazine-3-carboxamide

Step 1: Weigh [1,2,4]triazole[4,3-a]pyrazine-3-carboxylic acid ethyl ester (3-a, 100mg, 0.52mmol) into a 10ml microwave reaction tube, and add ethanol ( 2mL), then add hydrazine hydrate (0.08mL, 1.56mmol), react at room temperature after addition, and monitor at any time. After adding hydrazine hydrate, a large amount of solid precipitated, and LC-MS detected that the reaction was complete after 10 minutes. The reaction solution was filtered to obtain the crude product [1,2,4]triazole[4,3-a]pyrazine-3-carboxylic acid hydrazide (3-b, 80 mg, 0.40 mmol, 77.7% Yeild). MS Calcd: 178.06; MS Found: 179.08 ([M+H] ⁺ ).

Step 2: Weigh [1,2,4]triazole[4,3-a]pyrazine-3-carboxyhydrazide (3-b, 80mg, 0.40mmol), (3aR, 4R, 4aR, 5aS, 6S ,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione(1 -c, 92.2 mg, 0.48 mmol) into a 25 ml single-neck bottle, add ethanol (2 mL), then add DIPEA (0.16 mL, 0.97 mmol), and react at 80 degrees Celsius for 2 hours after the addition is complete. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and then pulped with methanol to obtain the title product: N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a, 5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolyl[4,3- a] Pyrazine-3-carboxamide (3,80 mg, 0.23 mmol, 47.1% Yeild). MS Calcd: 350.11; MS Found: 351.07 ([M+H] ⁺ ). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.00(s,1H),9.66(d,J＝1.6Hz,1H),8.98(dd,J＝4.4,1.6Hz,1H),8.19(d,J＝4.4Hz,1H),5.82- 5.80(m,2H),3.32–3.18(m,4H),1.21-1.18(m,2H),0.32-0.26(m,1H),0.12-0.08(m,1H).

Example 4

N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ya Vinylcyclopropa[f]isoindole-2(1H)-yl)imidazo[1,2-a]pyrazine-2-carboxamide

Step 1: Weigh imidazole [1,2-a]pyrazine-2-carboxylic acid ethyl ester (4-a, 100mg, 0.52mmol) into a 25ml single-neck bottle, add ethanol (2mL), and then add hydrazine hydrate (0.13 mL, 2.62 mmol), and after the addition was completed, the reaction was carried out at room temperature overnight. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain crude imidazole [3,2-a]pyrazine-2-carboxylic acid hydrazide (4-b, 107 mg, 0.48 mmol, 92.3% Yeild). MS Calcd: 177.07; MS Found: 178.04 ([M+H] ⁺ ).

Step 2: Weigh imidazole [3,2-a]pyrazine-2-carboxylic acid hydrazide (4-b, 107mg, 0.48mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 110.3mg, 0.58mmol ) into a 25ml single-neck bottle, add ethanol (2mL), then add DIPEA (0.16mL, 0.97mmol), and react at 70 degrees Celsius for 2 hours after the addition is complete. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and then slurried with methanol to obtain the title compound: N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a, 5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)imidazo[1,2-a]pyrazine-2-methyl Amide (4,123 mg, 0.35 mmol, 72.1% Yeild). MS Calcd: 349.12; MS Found: 350.01 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.14 (s, 1H) ,9.20(s,1H),8.66(dd,J＝4.4,1.6Hz,1H),8.64(s,1H),8.02(d,J＝4.4Hz,1H),5.80-5.76(m,2H), 3.32-3.23(m,4H),1.20-1.17(m,2H),0.31-0.26(m,1H),0.11-0.08(m,1H).

Example 5

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-2(1H)-yl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide

Step 1: Add 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (5-a, 100mg, 0.53mmol) and solvent methanol (10ml) to a 50ml single-neck bottle in sequence, and add hydration to the reaction solution Hydrazine (0.08ml), stir at 80°C for 2 hr. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. 100 ml DCM and 3*30 ml saturated saline were added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure to obtain 1H-pyrrolo[3,2-c ] Crude pyridine-2-carboxylic acid hydrazide (5-b, 102 mg, 0.58 mmol). MS Calcd: 176.07; MS Found: 177.10 ([M+H] ⁺ ).

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 130mg, 0.68mmol), 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid hydrazide (5-b , 100mg, 0.57mmol) and solvent ethanol (10ml), stir at 80°C for 12hr. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure and purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5, 5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2(1H)-yl)-1H-pyrrolo[3,2 -c]pyridine-2-carboxamide (5, 136mg, 1.38mmol, 67% yield). MS Calcd: 348.12; MS Found: 349.20 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.23 (brs, 1H), 11.30 ( brs,1H),9.01(d,J＝1.2Hz,1H),8.28(d,J＝5.6Hz,1H),7.44–7.40(m,2H),5.85–5.78(m,2H),3.32-3.26 (m,4H),1.22-1.18(m,2H),0.32-0.27(m,1H),0.11–0.07(m,1H).

Example 12

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropo[f]isoindole-2(1H)-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide

Step 1: Add compound benzo[c][1,2,5]oxadiazole-5-carboxylic acid (12-a, 200 mg, 1.22 mmol) and solvent methanol (10 mL) into a 50 mL eggplant-shaped flask. Then concentrated sulfuric acid (0.03 mL, 0.61 mmol) was added dropwise, and the mixture was stirred and refluxed at 80°C for 4 hours. TLC detected that the reaction of the raw materials was complete, and then hydrazine hydrate (1 mL, 24.38 mmol) was added, and the mixture was continued to reflux for 0.5 hours. Spin the reaction solution to dryness under reduced pressure, add 50 ml of DCM, wash the organic phase with 2 × 20 ml of saturated brine, dry over anhydrous sodium sulfate, and spin to dryness under reduced pressure to obtain the target compound: benzo[c][1,2,5]oxodi Azole-5-carboxylic hydrazide (12-b, 71.8 mg, 0.4 mmol, 33.1% yield) MS Calcd: 178.15; MS Found: 179.10 ([M+H] ⁺ ).

Step 2: Combine the compound benzo[c][1,2,5]oxadiazole-5-carboxylic acid hydrazide (12-b, 71.8mg, 0.4mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS )-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione(1-c , 92 mg, 0.48 mmol) was placed in a 25 mL eggplant-shaped flask, added with 10 mL of ethanol solution, and refluxed at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by flash column chromatography (DCM:MeOH=33:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4 ,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)benzo[c][1,2,5] Oxadiazole-5-carboxamide (12,95 mg, 0.27 mmol, 67.3% yield). MS Calcd:350.10; MS Found:351.09([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.59(s,1H),8.62(s,1H),8.22(dd,J ＝9.2,1.2Hz,1H),7.92(d,J＝9.2Hz,1H),5.83-5.78(m,2H),3.31-3.25(m,4H),1.23-1.19(m,2H),0.30- 0.25(m,1H),0.07(brs,1H).

Example 24

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide

Step 1: Add compound 1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxylic acid to a 50mL eggplant-shaped bottle (24-a, 200 mg, 1.13 mmol) and solvent methanol (10 mL). Then concentrated sulfuric acid (0.02 mL, 0.56 mmol) was added dropwise, and the mixture was stirred and refluxed at 80°C for 4 hours. TLC detected that the reaction of the raw materials was complete, and then hydrazine hydrate (1.2 mL, 22.57 mmol) was added, and the mixture was continued to reflux for 0.5 hours. Spin the reaction solution to dryness under reduced pressure, add 50 mL of DCM, wash the organic phase with 2 × 20 mL of saturated brine, dry over anhydrous sodium sulfate, and spin to dryness under reduced pressure to obtain the target compound: 1-methyl-1H-benzo[d][1, 2,3]Triazole-5-carbohydrazide (24-b, 120 mg, 0.63 mmol, 55.5% yield). MS Calcd:191.08; MS Found:192.12([M+H] ⁺ ).

Step 2: Combine compound 1-methyl-1H-benzo[d][1,2,3]triazole-5-carbohydrazide (24-b, 120mg, 0.63mmol) and (3aR, 4R, 4aR, 5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropo[f]isobenzofuran-1,3(3aH)-di The ketone (1-c, 143 mg, 0.75 mmol) was placed in a 25 mL eggplant-shaped flask, added with 10 mL of ethanol solution, and refluxed at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-TLC (DCM:MeOH=20:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-1-methyl-1H-benzo[d] [1,2,3]Triazole-5-carboxamide (24,150 mg, 0.41 mmol, 65.6% yield). MS Calcd:363.13; MS Found:364.11([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.29(brs,1H),8.65-8.62(m,1H),8.09–8.00 (m,2H),5.88–5.81(m,2H),4.38(s,3H),3.32-3.26(m,4H),1.26-1.18(m,2H),0.33-0.27(m,1H),0.11 –0.06(m,1H).

Example 27

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide

Step 1: Add [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (27-a, 100mg, 0.37mmol) and hydrazine hydrate (0.2 ml) and solvent methanol (5 ml), stir and reflux at 80°C for 4 hours, TLC monitors that no raw materials remain. The reaction solution is spin-dried under reduced pressure, added with 20 ml DCM, washed with 3*5 ml saturated brine, and the organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. Spin to dryness to obtain [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid hydrazide (27-b, 80mg, 0.45mmol, 80% yield). MS Calcd: 177.07; MS Found: 178.11([M+H] ⁺ ).

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 103mg, 0.54mmol), [1,2,4]triazolo[1,5-a]pyridine-6-methyl Hydrazide (27-b, 80mg, 0.45mmol), DIPEA (116mg, 0.9mmol) and solvent ethanol (10ml) were stirred at 80°C for 12hr. LCMS monitored that the reaction was complete. The reaction solution was spin-dried under reduced pressure, and 20ml DCM was added, 3* Wash with 5 ml saturated brine, dry the organic phase over anhydrous sodium sulfate, and spin dry under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound: N- ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene ring Propano[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (27, 60 mg, 0.17 mmol, 38% yield).MS Calcd:349.12; MS Found:350.14([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.44(brs,1H),9.51(s,1H),8.69( s,1H),8.08–7.99(m,2H),5.84-5.80(m,2H),3.32-3.26(m,4H),1.25-1.17(m,2H),0.32-0.26(m,1H), 0.10-0.07(m,1H).

Example 31

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

Step 1: Add compound [1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (31-a, 200mg, 1.23mmol) and solvent methanol (10mL) into a 50mL eggplant-shaped flask. . Then concentrated sulfuric acid (0.5 mL, 9.38 mmol) was added dropwise, and the mixture was stirred and refluxed at 80°C for 4 hours. TLC detected that the reaction of the raw materials was complete, and then hydrazine hydrate (2 mL, 41.12 mmol) was added to it, and the mixture was continued to reflux overnight. Spin the reaction solution to dryness under reduced pressure, add 50 mL of DCM, wash the organic phase with 2×20 mL of saturated brine, dry over anhydrous sodium sulfate, and spin to dryness under reduced pressure to obtain [1,2,4]triazolo[4,3-a]pyridine -6-Carbohydrazide (31-b, 120 mg, 0.68 mmol, 55.3% yield). MS Calcd:177.17; MS Found:178.03([M+H] ⁺ ).

Step 2: Combine [1,2,4]triazolo[4,3-a]pyridine-6-carbohydrazide (31-b, 100mg, 0.56mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione(1- c, 107 mg, 0.56 mmol) was placed in a 25 mL eggplant-shaped flask, added with 10 mL of ethanol solution, and refluxed at 85°C overnight. LC-MS monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a -Otahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[4,3-a]pyridine-6- Formamide (31, 20.3 mg, 0.06 mmol, 10.1% yield). MS Calcd:349.35; MS Found:350.07([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.34(s,1H),9.50(s,1H),8.68(s,1H ),8.07(d,J＝9.2Hz,1H),7.99(d,J＝9.2Hz,1H),5.84-5.81(m,2H),3.31–3.18(m,4H),1.21–1.17(m, 2H),0.31-0.27(m,1H),0.10-0.07(m,1H).

Example 32

N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxoctahydro-4,6-vinylidenecyclopropo[f]isoindol-2(1H)-yl )-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

Step 1: Combine N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4, 6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (31, 10 mg ,0.03mmol) was placed in a 25mL eggplant-shaped flask, and then 2mL MeOH and palladium carbon (15mg) were added to it, and the reaction was stirred at 40°C for 48h under a hydrogen atmosphere. LC-MS detects that the reaction of the raw materials is complete, and the organic phase is filtered and concentrated to obtain a crude product. The crude product is prepared by Pre-HPLC to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo Octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-methyl Amide (32, 3.4 mg, 0.01 mmol, 33.7% yield). MS Calcd:351.37; MS Found:352.17([M+H] ⁺ ). ¹ H NMR(400MHz,Chloroform-d)δ9.34(s,1H),8.49(s,1H),8.18–7.95(d, J＝9.2Hz,1H),7.85(d,J＝9.2Hz,1H),3.17(brs,2H),2.66(brs,2H),1.65-1.53(m,2H),1.399–1.16(m,4H ),0.93–0.89(m,2H).

Example 33

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)isoquinoline-7-carboxamide

Step 1: Add isoquinoline-7-carboxylic acid methyl ester (33-a, 100 mg, 0.53 mmol) and solvent methanol (7 mL) into a 50 mL eggplant-shaped flask. Then, hydrazine hydrate (0.5 mL, 10.28 mmol) was added, and the mixture was refluxed at 70° C. overnight. LC-MS monitors the completion of the raw material reaction. The reaction solution is spin-dried under reduced pressure, 50 mL of DCM is added, the organic phase is washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain isoquinoline-7-formyl. Hydrazine (33-b, 60 mg, 0.32 mmol, 60.0% yield) MS Calcd: 187.20; MS Found: 188.10 ([M+H] ⁺ ).

Step 2: Combine the compounds isoquinoline-7-carboxyhydrazide (33-b, 60mg, 0.32mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a -Hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 59 mg, 0.32 mmol) was placed in a 25 mL eggplant-shaped bottle , add 10 mL of ethanol solution, and reflux at 85°C overnight. LCMS monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a - Octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)isoquinoline-7-carboxamide (33, 45.1 mg, 0.13 mmol, 39.7% yield). MS Calcd:359.39; MS Found:360.19([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.32(s,1H),9.47(s,1H),8.74(s,1H ),8.65(d,J＝5.6Hz,1H),8.20(d,J＝8.8Hz,1H),8.13(d,J＝8.8Hz,1H),7.95(d,J＝5.6Hz,1H), 5.85-5.82(m,2H),3.35–3.31(m,4H),1.25-1.19(m,2H),0.32-0.27(m,1H),0.11–0.06(m,1H).

Example 34

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropano[f]isoindole-2(1H)-yl)-1-methyl-1H-indazole-5-carboxamide

Step 1: Add 1-methyl-1H-indazole-5-carboxylic acid methyl ester (34-a, 200 mg, 1.05 mmol) and solvent methanol (7 mL) into a 50 mL eggplant-shaped flask. Then, hydrazine hydrate (0.5 mL, 10.28 mmol) was added, and the mixture was refluxed at 70° C. overnight. LC-MS monitors the completion of the raw material reaction. Spin the reaction solution to dryness under reduced pressure. Add 50 mL of DCM and 2 × 20 mL of saturated brine to wash the organic phase. Dry over anhydrous sodium sulfate and spin to dryness under reduced pressure to obtain 1-methyl-1H-indazole. -5-Formyl hydrazide (34-b, 150 mg, 0.79 mmol, 75.0% yield). MS Calcd:190.21; MS Found:191.15([M+H] ⁺ ).

Step 2: Combine 1-methyl-1H-indazole-5-carboxylic hydrazide (34-b, 100mg, 0.53mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4, 4a, 5, 5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 100 mg, 0.53 mmol) was placed In a 25 mL eggplant-shaped flask, add 10 mL of ethanol solution and reflux at 85°C overnight. LC-MS monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a -Otahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-1-methyl-1H-indazole-5-carboxamide (34, 70.2 mg, 0.19 mmol, 36.7% yield). MS Calcd: 362.39; MS Found: 363.25 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.13 (s, 1H), 8.26 (d, J = 1.2Hz, 1H), 8.18(d,J＝1.2Hz,1H),7.89(d,J＝8.8Hz,1H),7.65(d,J＝8.8Hz,1H),5.88–5.82(m,2H),4.13(s,3H ),3.41–3.26(m,4H),1.25–1.13(m,2H),0.33-0.27(m,1H),0.11–0.05(m,1H).

Example 35

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropa[f]isoindole-2(1H)-yl)isoquinoline-6-carboxamide

Step 1: Add isoquinoline-6-carboxylic acid (35-a, 1000 mg, 5.77 mmol) and solvent methanol (30 ml) to a 50 ml single-mouth bottle in sequence, slowly add concentrated sulfuric acid (4 ml) dropwise, stir and reflux at 80°C for 2 hours. TLC monitored that there was no remaining raw material. Add hydrazine hydrate (16 ml) to the reaction solution and keep stirring at 80°C for 2 hours. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. Add 100ml DCM and 3*30ml saturated food. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain isoquinoline-6-carboxylic hydrazide (35-b, 980 mg, 5.24 mmol, 90% yield). MS Calcd: 187.07; MS Found: 188.14([M+H] ⁺ )..

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f] Isobenzofuran-1,3(3aH)-dione (1-c, 207mg, 1.09mmol), isoquinoline-6-carboxyhydrazide (35-b, 170mg, 0.91mmol) and solvent ethanol (15ml), stirred at 80°C for 12hr. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, 60 ml DCM was added, washed with 3*10 ml saturated saline, the organic phase was dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. The title compound was crudely purified by column chromatography (DCM:MeOH=30:1): N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)isoquinoline-6-carboxamide (35, 230mg, 0.64mmol, 70% yield). MS Calcd: 359.13; MS Found: 360.16 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.43 (s, 1H), 9.46 (s, 1H),8.64(d,J＝5.6Hz,1H),8.56(d,J＝7.2Hz,1H),8.30(d,J＝8.4Hz,1H),8.09(d,J＝8.4Hz,1H) ,8.00(d,J＝5.6Hz,1H),5.85–5.80(m,2H),3.32-3.27(m,4H),1.25-1.17(m,2H),0.32–0.27(m,1H),0.11 –0.06(m,1H).

Example 36

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropo[f]isoindole-2(1H)-yl)-2,2-difluorobenzo[d][1,3]dioxol-4-carboxamide

Step 1: Add 2,2-difluoro-1,3-benzodioxin-4-carboxylic acid (36-a, 500mg, 2.47mmol) and solvent methanol (20ml) into a 50ml single-neck bottle, and slowly drip Add concentrated sulfuric acid (1 ml), stir and reflux at 80°C for 2 hours. TLC monitored that there was no remaining raw material. Add hydrazine hydrate (4 ml) to the reaction solution and keep stirring at 80°C for 2 hours. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. 100 ml DCM and 3*30 ml saturated brine were added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure to obtain 2,2-difluorobenzo[d ][1,3]Dioxal-4-carboxyhydrazide (36-b, 510 mg, 2.36 mmol, 95% yield). MS Calcd: 216.03; MS Found: 217.10 ([M+H] ⁺ ).

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 158 mg, 0.83 mmol), 2,2-difluorobenzo[d][1,3]dioxin-4- Formyl hydrazide (36-b, 150 mg, 0.69 mmol) and solvent ethanol (10 ml) were stirred at 80°C for 12 hours. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure and purified by column chromatography (DCM:MeOH=25:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo -3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2,2-di Fluorobenzo[d][1,3]dioxin-4-carboxamide (36, 247 mg, 0.64 mmol, 92% yield). MS Calcd: 388.09; MS Found: 389.20 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.23 (s, 1H), 7.68 (dd, J = 8.0, 1.2Hz, 1H), 7.58 (dd, J＝8.0,1.2Hz,1H),7.37(t,J＝8.0Hz,1H),5.82–7.79(m,2H),3.32-3.27(m,4H),1.21–1.17(m,2H),0.32 -0.27(m,1H),0.10-0.07(m,1H).

Example 37

N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a, 4,4a, 5,5a, 6,6a-octahydro-4,6-ethene ring Propane[f]isoindol-2(1H)-yl)-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxamide

Step 1: Add benzo-1,4-dioxane-6-carboxylic acid (37-a, 500mg, 2.47mmol) and solvent methanol (20ml) to a 50ml single-neck bottle in sequence, and slowly add concentrated sulfuric acid (1ml) dropwise , stir and reflux at 80°C for 2 hours. TLC monitored that there was no remaining raw material. Add hydrazine hydrate (4 ml) to the reaction solution and keep stirring at 80°C for 2 hours. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. 100 ml DCM and 3*30 ml saturated brine were added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure to obtain 2,3-dihydrobenzo[b ][1,4]dioxane-6-carboxylhydrazide (37-b, 510 mg, 2.36 mmol, 95% yield). MS Calcd: 194.07; MS Found: 195.12 ([M+H] ⁺ ).

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 100mg, 0.51mmol), 2,3-dihydrobenzo[b][1,4]dioxane-6- Formyl hydrazide (37-b, 100 mg, 0.51 mmol) and solvent ethanol (10 ml) were stirred at 70°C for 12 hours. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, and the crude product was purified by reverse-phase column chromatography using a scraper to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a ,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2,3-dihydrobenzo[ b] [1,4]dioxane-6-carboxamide (37, 11 mg, 0.03 mmol, 5.8% yield). MS Calcd: 366.12; MS Found: 367.22 ([M+H] ⁺ ). ¹ H NMR ( 400MHz, DMSO-d ₆ )δ11.96(s,1H),7.41-7.37(m,2H),6.99(d,J＝9.2Hz,1H),5.79–5.71(m,2H),4.32–4.26( m,4H),3.28-3.17(m,4H),1.21–1.15(m,2H),0.29-0.23(m,1H),0.09-0.05(m,1H).

Example 38

6-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)carbamoyl)isoquinoline 2-oxide

Step 1: Add N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a- to a 50ml single-neck bottle Octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)isoquinoline-6-carboxamide (35, 35 mg, 0.10 mmol), add DCM (1 ml) to dissolve, then add mCPBA (20.2 mg, 0.12 mmol), and stir at room temperature overnight. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, and the crude product was purified by Prep-HPLC to obtain the title compound: 6-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a, 5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)carbamoyl)isoquinoline 2-oxide (38,25 mg , 0.07mmol, 68.3%). MS Calcd: 375.12; MS Found: 376.19 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.26 (s, 1H), 9.05 (d, J＝1.6Hz,1H),8.52(s,1H),8.26(dd,J＝7.2,1.6Hz,1H),8.10–7.99(m,3H),5.84-5.81(m,2H),3.33-3.25 (m,4H),1.26–1.20(m,2H),0.32-0.27(m,1H),0.10-0.06(m,1H).

Example 39

4-Chloro-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4, 6-vinylidenecyclopropa[f]isoindole-2(1H)-yl)isoquinoline-6-carboxamide

Step 1: Add N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a- to a 50ml single-neck bottle Octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)isoquinoline-6-carboxamide (35, 35 mg, 0.10 mmol), add DCM (1 ml) to dissolve Then add iodobenzene acetate (47.0 mg, 0.15 mmol), add acetyl chloride (0.03 ml, 0.49 mmol) dropwise at room temperature, and place under reflux at 50°C for 3 hours. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, and the crude product was purified by Prep-HPLC to obtain the title compound: 4-chloro-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a, 4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)isoquinoline-6-carboxamide (39, 8mg, 0.02mmol, 20.8%). MS Calcd: 393.09; MS Found: 394.18 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.58 (brs, 1H), 9.45 (s ,1H),8.79(s,1H),8.74(s,1H),8.42(d,J＝8.4Hz,1H),8.21(d,J＝8.4Hz,1H),5.84(brs,2H),3.32 -3.27(m,4H),1.25-1.21(m,2H),0.32-0.27(m,1H),0.10-0.07(m,1H).

Example 40

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropo[f]isoindole-2(1H)-yl)benzo[c][1,2,5]thiadiazole-5-carboxamide

Step 1: Add benzo[c][1,2,5]thiadiazole-5-carboxylic acid methyl ester (40-a, 100mg, 0.51mmol) and MeOH (10mL) to a 100mL eggplant-shaped flask, and then add Add hydrazine hydrate solution (0.33 mL, 10.3 mmol). 80℃ Stir for 14 hours at low temperature. TLC monitors the completion of the raw material reaction. The reaction solution is concentrated under reduced pressure, and the crude product is purified by flash column chromatography (DCM:MeOH=40:1) to obtain benzo[c][1,2,5]thiadiazole. -5-Formyl hydrazide (40-b, 90 mg, 0.46 mmol, 90% yield). MS Calcd:194.03; MS Found:195.11([M+H] ⁺ ).

Step 2: Combine benzo[c][1,2,5]thiadiazole-5-carboxylic acid hydrazide (40-b, 90mg, 0.46mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)- 4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c,105.8 mg, 0.56 mmol) was placed in a 25 mL eggplant-shaped flask, added with 10 mL of ethanol solution, and refluxed at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)benzo[c][1,2,5]thithi Diazole-5-carboxamide (40, 120 mg, 0.33 mmol, 70% yield). MS Calcd: 366.08; MS Found: 367.09 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.51 (s, 1H), 8.63 (s, 1H), 8.22 (d, J ＝8.8Hz,1H),8.08(d,J＝8.8Hz,1H),5.81-5.77(m,2H),3.31–3.23(m,4H),1.22-1.17(m,2H),0.30–0.25( m,1H),0.10-0.06(m,1H).

Example 41

N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ya Vinylcyclopropo[f]isoindole-2(1H)-yl)imidazo[1,2-b]pyridazine-6-carboxamide

Step 1: Weigh imidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester (41-a, 100 mg, 0.56 mmol) into a 10 ml single-neck bottle, add methanol (1 mL), and then add hydrazine hydrate ( 0.14mL, 2.82mmol), after addition, react at 80°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain crude imidazole [1,2-b]pyridazine-6-carboxylic hydrazide (41-b, 108 mg, 0.55 mmol, 97.2% Yeild). MS Calcd: 177.07; MS Found: 178.08 ([M+H] ⁺ ).

Step 2: Weigh imidazole [1,2-b]pyridazine-6-carbohydrazide (41-b, 108mg, 0.55mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 125.2mg, 0.66mmol ) into a 10 ml microwave reaction tube, add ethanol (2 mL), and react at 80°C for 2 hours. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and slurried with methanol to obtain the title compound: N-(((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3, 3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)imidazo[1,2-b] Pyridazine-6-carboxamide (41,122 mg, 0.34 mmol, 62.4% Yeild). MS Calcd: 349.12; MS Found: 350.1 ([M+H] ⁺ ). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11. 50(s,1H),8.39(s,1H),8.33(d,J＝9.2Hz,1H),8.02(d,J＝1.6Hz,1H),7.68(dd,J＝9.2,1.6Hz,1H ),5.81-5.75(m,2H),3.33-3.27(m,4H),1.22–1.18(m,2H),0.31-0.26(m,1H),0.11–0.07(m,1H).

Example 42

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropano[f]isoindole-2(1H)-yl)-1-methyl-1H-indazole-6-carboxamide

Step 1: Weigh 1-methyl-1H-indazole-6-carboxylic acid methyl ester (42-a, 100mg, 0.53mmol) into a 10ml single-neck bottle, add methanol (1mL), and then add hydrazine hydrate (0.14mL ,2.82mmol), after addition, react at 80°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain crude product 1-methyl-1H-indazole-6-carboxylic hydrazide (42-b, 97 mg, 0.48 mmol, 92.1% Yeild). used directly in the next step. MS Calcd: 190.09; MS Found: 191.17 ([M+H] ⁺ ).

Step 2: Weigh 1-methyl-1H-indazole-6-carboxylic hydrazide (42-b, 97mg, 0.48mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4, 4a, 5 ,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 110mg, 0.58mmol) to In a 10 ml microwave reaction tube, add ethanol (2 mL), finally add DIPEA (0.24 mL, 1.45 mmol), and react at 80°C for 2 hours. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. The title compound was prepared by pre-HPLC: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo- 3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-1-methyl-1H -Indazole-6-carboxamide (42, 112 mg, 0.30 mmol, 62.5% Yeild). MS Calcd:362.14; MS Found:363.22([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.17(s,1H),8.26(d,J＝5.2Hz,1H),8.18(s,1H),7.90(d,J＝8.4Hz,1H) ,7.64(d,J＝8.4Hz,1H),5.85–5.80(m,2H),4.13(s,3H),3.33-3.25(m,4H),1.23-1.19(m,2H),0.32-0.27 (m,1H),0.11-0.07(m,1H).

Example 43

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1: Weigh pyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (43-a, 100mg, 0.57mmol) into a 10ml single-neck bottle, add methanol (2mL), and then add hydrazine hydrate ( 0.08mL, 1.56mmol), after addition, react at 60°C for 2 hours. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure to obtain crude pyrazolo[1,5-a]pyridine-5-carboxylic acid hydrazide (43-b , 98mg, 0.56mmol, 98% Yeild). MS Calcd: 176.07; MS Found: 177.17 ([M+H] ⁺ ).

Step 2: Weigh pyrazolo[1,5-a]pyridine-5-carboxylic acid hydrazide (43-b, 98mg, 0.56mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a ,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 120.6mg, 0.63 mmol) into a 25 ml single-neck bottle, add ethanol (2 mL), then add DIPEA (0.26 mL, 1.59 mmol), and react at 80°C for 2 hours after the addition is complete. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and then pulped with methanol to obtain the title product: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5 ,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (43,101 mg, 0.28 mmol, 53.2% Yeild). MS Calcd: 348.12; MS Found: 349.14 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.33 (s, 1H), 8.84 (d, J = 8.0Hz, 1H), 8.34 (d, J = 11.2Hz, 1H), 8.16 (d, J = 2.4Hz,1H),7.29-7.25(m,1H),6.93(d,J＝2.4Hz,1H),5.84-5.79(m,2H),3.32–3.25(m,4H),1.22-1.17(m ,2H),0.32-0.26(m,1H),0.11-0.06(m,1H).

Example 44

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxoctahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl )-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide

Step 1: Add N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a- to a 25ml single-neck bottle Octahydro-4,6-vinylidenecyclopropa[f]isoindole-2(1H)-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (27, 50 mg, 0.14 mmol), Pd/C (30%) (6 mg) and solvent methanol (5 ml), replaced with hydrogen three times, and stirred at room temperature for 2 hr under a hydrogen atmosphere. LCMS monitored that the reaction was complete, and the reaction solution was diatomaceous earth. Filter, wash the filter cake with 2*5ml methanol, and spin dry the organic phase under reduced pressure to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxoctahydro-4,6 -Vinylidenecyclopropa[f]isoindol-2(1H)-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (44, 8 mg, 0.02mmol, 15% yield,).MS Calcd: 351.13; MS Found: 352.20 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.70 (s, 1H),8.12(d,J＝9.2Hz,1H),8.01(d,J＝9.2Hz,1H),3.24-3.19(brs,2H),2.42(brs,2H),1.56–1.06(m,6H ),0.86-0.83(m,1H),0.59-0.53(m,1H).

Example 45

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxoctahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl )-2,2-difluorobenzo[d][1,3]dioxin-5-carboxamide

Step 1: Add N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a- to a 25ml single-neck bottle Octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2,2-difluorobenzo [d][1,3]dioxin-5-carboxamide (1, 30 mg, 0.08 mmol), Pd/C (30%) (2 mg) and solvent methanol (5 ml), replaced with hydrogen 3 times, and incubated in hydrogen Stir at room temperature for 2 hr. LC-MS monitored that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 2*5ml methanol. The organic phase was spin-dried under reduced pressure and then prepared by pre-HPLC to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S,6aS)-1,3-dioxoctahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-2,2-difluorobenzo[d ] [1,3] Dioxol-5-carboxamide (45, 25 mg, 0.06 mmol, 82% yield,). MS Calcd: 390.34; MS Found: 391.09 ([M+H]). ¹ H NMR (400MHz ,DMSO-d ₆ )δ11.20(s,1H),7.93–7.84(m,2H),7.63(d,J＝8.4Hz,1H),3.25-3.22(m,2H),2.52-2.50(m ,2H),1.49–1.29(m,2H),1.22-1.11(m,4H),0.85-0.81(m,1H),0.57–0.52(m,1H).

Example 46

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropano[f]isoindole-2(1H)-yl)imidazo[1,5-a]pyridine-6-carboxamide

Step 1: Add imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (46-a, 100 mg, 0.57 mmol) and MeOH (10 mL) to a 100 mL eggplant-shaped flask, and then add hydrazine hydrate solution thereto (0.36mL, 11.35mmol). Stir for 14 hours at 80°C. TLC monitors the completion of the raw material reaction. The reaction solution is concentrated under reduced pressure, and the crude product is purified by flash column chromatography (DCM:MeOH=40:1) to obtain imidazo[1,5-a]pyridine-6- Formyl hydrazide (46-b, 90 mg, 0.51 mmol, 90% yield). MS Calcd:176.07; MS Found:177.14([M+H] ⁺ ).

Step 2: Combine imidazo[1,5-a]pyridine-6-carboxylic acid hydrazide (46-b, 90mg, 0.51mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5 ,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 116.6mg, 0.61mmol) Place in a 25mL eggplant-shaped flask, add 10mL ethanol solution, and reflux at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)imidazo[1,5-a]pyridine-6- Formamide (46, 47 mg, 0.13 mmol, 26.4%, yield). MS Calcd:348.12; MS Found:349.15([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.15(s,1H),9.01(s,1H),8.58(s,1H ),7.66(d,J＝10.0Hz,1H),7.46(s,1H),7.15(d,J＝10.0Hz,1H),5.82-5.78(m,2H),3.32–3.18(m,4H) ,1.25-1.15(m,2H),0.32-0.26(m,1H),0.10-0.06(m,1H).

Example 47

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxaoctahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl )benzo[c][1,2,5]oxadiazole-5-carboxamide

Step 1: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidene ring to a 100mL eggplant-shaped bottle Propano[f]isobenzofuran-1,3(3aH)-dione (1-c, 500mg, 2.63mmol) and MeOH (5mL), add 10% palladium on carbon (50mg), and replace hydrogen three times . The reaction was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was collected. After concentration, methanol solution (10 mL) was added to redissolve, and excess hydrazine hydrate solution was added and the reaction was refluxed at 80°C for 2 hours. LC-MS monitors the completion of the raw material reaction. The reaction solution is concentrated under reduced pressure, and the crude product is purified by Prep-HPLC to obtain (3aR, 4R, 4aR, 5aS, 6S, 6aS)-2-aminohexahydro-4,6-ethylidene. Cyclopropo[f]isoindole-1,3(2H,3aH)-dione (47-a, 200 mg, 0.97 mmol, 36.9% yield). MS Calcd:206.11; MS Found:207.17([M+H] ⁺ ).

Step 2: Place compound 47-b (100 mg, 0.61 mmol) in a 25 mL eggplant-shaped flask, add 3 mL of dry dichloromethane to dissolve, and add a drop of DMF. Oxalyl chloride (0.1 mL, 1.22 mmol) was slowly added dropwise thereto, and the reaction was stirred at room temperature. TLC monitored the completion of the raw material reaction, and the reaction solution was concentrated under reduced pressure to obtain crude compound 47-c (100 mg, 0.55 mmol, 89.8% yield), which was directly used in the next step.

Step 3: Combine compound 47-c (100 mg, 0.55 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-2-aminohexahydro-4,6-ethylenecyclopropa[f]isoindole Indole-1,3(2H,3aH)-dione (47-a, 113.4 mg, 0.55 mmol) was placed in a 25 mL eggplant-shaped flask, and dry dichloromethane solution (3 mL) was added, followed by anhydrous potassium carbonate ( 303.6 mg, 2.20 mmol), stirred at room temperature for 1 hour. TLC monitors the completion of the raw material reaction, filters the reaction solution, and concentrates the filtrate under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxaoctahydro-4,6- Vinylidene cyclopropa[f]isoindol-2(1H)-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide (47, 66 mg, 0.19 mmol, 34.1% )MS Calcd:352.12; MS Found:353.10([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.58(s,1H),8.70(s,1H),8.25(d, J＝9.2Hz,1H),7.97(dd,J＝9.2,1.6Hz,1H),3.29-3.23(m,2H),2.43(s,2H),1.51–1.13(m,6H),0.86-0.82 (m,1H),0.58-0.53(m,1H).

Example 48

N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxhexahydro-4,6-ethylcyclopropane[f]isoindol-2(1H)-yl) Isoquinoline-6-carboxamide

Step 1: Place the compound isoquinoline-6-carboxylic acid (48-a, 100 mg, 0.58 mmol) in a 25 mL eggplant-shaped flask, add 3 mL of dry dichloromethane to dissolve, and add a drop of DMF. Oxalyl chloride (0.1 mL, 1.15 mmol) was slowly added dropwise thereto, and the reaction was stirred at room temperature. TLC monitored the completion of the raw material reaction, and the reaction solution was concentrated under reduced pressure to obtain the target compound isoquinoline-6-carboxyl chloride (48-b, 100 mg, 0.52 mmol, 90.4% yield), which was directly used in the next step.

Step 2: Combine the compound isoquinoline-6-acyl chloride (48-b, 90.6mg, 0.47mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-2-aminohexahydro-4,6-ethylene Cyclopropa[f]isoindole-1,3(2H,3aH)-dione (47-a, 65 mg, 0.32 mmol) was placed in a 25 mL eggplant-shaped flask, and dry dichloromethane solution (3 mL) was added , add anhydrous potassium carbonate (175 mg, 1.26 mmol), and stir at room temperature for 1 hour. TLC monitors the completion of the raw material reaction, filters the reaction solution, and concentrates the filtrate under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxohexadecahydro-4,6 -Ethylcyclopropane[f]isoindol-2(1H)-yl)isoquinoline-6-carboxamide (46, 80 mg, 0.22 mmol, 70.2% yield) MS Calcd: 361.14; MS Found: 362.17 ([ M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.43 (s, 1H), 9.47 (s, 1H), 8.66 (d, J = 5.6Hz, 1H), 8.60 (d, J＝7.2Hz,1H),8.32(d,J＝8.4Hz,1H),8.11(dd,J＝8.4,1.6Hz,1H),8.03(d,J＝5.6Hz,1H),3.29-3.23( m,2H),2.44(s,2H),1.56–1.13(m,6H),0.87-0.83(m,1H),0.59-0.54(m,1H).

Example 49

5-Bromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4, 6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)benzo[b]thiophene-2-carboxamide

Step 1: Add 5-bromobenzo[b]thiophene-2-carboxylic acid methyl ester (49-a, 300mg, 1.17mmol) and solvent methanol (20ml) to a 50ml single-neck bottle in sequence, and slowly add concentrated sulfuric acid (0.5 ml), stir and reflux at 80°C for 2 hours. TLC monitored that there was no remaining raw material. Add hydrazine hydrate (1 ml) to the reaction solution and keep stirring at 80°C for 2 hours. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. 100 ml DCM and 3*30 ml saturated brine were added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure to obtain 5-bromobenzo[b]thiophene- 2-Formyl hydrazide (49-b, 143.6 mg, 0.53 mmol, 45.4% yield). MS Calcd: 269.95; MS Found: 272.93 ([M+H] ⁺ ).

Step 2: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 25ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 35.1mg, 0.18mmol), 5-bromobenzo[b]thiophene-2-carboxylic hydrazide (49-b, 50mg ,0.18mmol) and solvent ethanol (3ml), stir at 70°C overnight. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, and the crude product was dissolved in methanol and purified by a scraper (DCM:MeOH=20:1) to obtain the title compound: 5-bromo-N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1, 3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropo[f]isoindol-2(1H)-yl)benzene And [b] thiophene-2-carboxamide (49, 47.6 mg, 0.11 mmol, 58.6% yield). MS Calcd: 442.00; MS Found: 445.09 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO- d ₆ ) δ11.57(s,1H),8.33(s,1H),8.21(d,J＝8.0Hz,1H),8.08(d,J＝8.8Hz,1H),7.68(d,J＝8.0 Hz,1H),5.83-5.77(m,2H),3.28-3.18(m,4H),1.29-1.19(m,2H),0.32-0.27(m,1H),0.11-0.07(m,1H).

Example 50

3-Chloro-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4, 6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1: Add pyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (43-a, 110 mg, 0.62 mmol) and N-chlorosuccinimide (125.0 mg) to a 50 ml single-neck bottle in sequence. ,0.94mmol), glacial acetic acid (0.06ml) and solvent acetonitrile (2ml), stir and reflux at 40°C for 2hr. LC-MS monitoring showed no raw material remaining. The reaction solution was lowered to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM and subjected to flash column chromatography (DCM) to obtain 3-chloropyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (50-a, 104.1 mg, 0.49 mmol, 79.2% yield). MS Calcd: 210.02; MS Found: 211.04 ([M+H] ⁺ ).

Step 2: Add 3-chloropyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (50-a, 90mg, 0.43mmol) and solvent methanol (2ml) to the 50ml single-neck bottle in sequence, and add to the reaction solution Add hydrazine hydrate (0.5 ml), place it at 80°C and continue stirring for 2 hours. LC-MS monitoring showed no raw material remaining. The reaction solution was brought to room temperature, and the reaction solution was spin-dried under reduced pressure. 100 ml DCM and 3*30 ml saturated brine were added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure to obtain crude 3-chloropyrazole [1,5- a] Pyridine-5-carboxylic hydrazide (50-b, 78.3mg, 0.37mmol, 87.0% yield).MS Calcd: 210.03; MS Found: 211.07 ([M+H] ⁺ )

Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa to a 50ml single-neck bottle [f]Isobenzofuran-1,3(3aH)-dione (1-c, 86.7mg, 0.46mmol), 3-chloropyrazole[1,5-a]pyridine-6-carboxylic acid hydrazide (50 -b, 80 mg, 0.38 mmol) and solvent ethanol (4 ml), stirred at 70°C overnight. LC-MS monitored the reaction to be complete. The reaction solution was spin-dried under reduced pressure, and the crude product was dissolved in methanol and purified by a scraper (DCM:MeOH=20:1) before being sent to prep-HPLC for purification to obtain the title compound: 3-chloro-N-((3aR, 4R, 4aR, 5aS, 6S ,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane And[f]isoindol-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (50, 47.6 mg, 0.11 mmol, 58.6% yield). MS Calcd: 382.08; MS Found: 383.14 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.41 (s, 1H), 8.86 (d, J = 7.2Hz, 1H), 8.35 (s, 1H ),8.31(s,1H),7.35(d,J＝7.2Hz,1H),5.84-5.81(m,2H),3.32-3.28(m,4H),1.22-1.19(m,2H),0.32- 0.27(m,1H),0.11-0.07(m,1H).

Example 51

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxoctanoic acid-4,6-ethylcyclopropyl[f]isoindol-2(1H)-yl)pyra Azolo[1,5-a]pyridine-5-carboxamide

Step 1: Weigh N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4 , 6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (43,101mg, 0.28mmol) to 25ml single-mouth bottle , add methanol (2 ml) and DCM (0.5 ml), then add 10% palladium on carbon (20 mg), replace with hydrogen three times, and react at 30°C overnight. LC-MS detected that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by pre-HPLC to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxoctanoic acid- 4,6-Ethylcyclopropyl[f]isoindol-2(1H)-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (51,22mg, 0.06mmol, 22.1% Yeild). MS Calcd: 350.14; MS Found: 351.16 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.34 (s, 1H), 8.86 (d, J = 7.6Hz, 1H), 8.38 (d, J = 6.4Hz, 1H), 8.17 (d, J = 2.0Hz,1H),7.30(dd,J＝7.6,2.0Hz,1H),6.95(d,J＝2.0Hz,1H),3.26-3.21(m,2H),2.42-2.34(m,2H), 1.50–1.27(m,6H),0.86-0.82(m,1H),0.58-0.53(m,1H).

Example 52

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropa[f]isoindole-2(1H)-yl)quinoline-7-carboxamide

Step 1: Weigh quinoline-7-carboxylic acid methyl ester (52-a, 50mg, 0.27mmol) into a 25ml single-neck bottle, add methanol (2mL), then add hydrazine hydrate (0.04mL, 0.81mmol), after the addition is complete Reaction was carried out at 80°C overnight. LC-MS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to dryness to obtain quinoline-7-carbohydrazide (52-b, 46 mg, 0.23 mmol, 87.4% Yeild). MS Calcd: 187.07; MS Found: 188.17 ([M+H] ⁺ ).

Step 2: Weigh (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]iso Benzofuran-1,3(3aH)-dione (1-c, 53.3mg, 0.28mmol), quinoline-7-carbohydrazide (52- b, 46 mg, 0.23 mmol) into a 25 ml single-neck bottle, add ethanol (2 mL), then add DIPEA (0.08 mL, 0.47 mmol), and react overnight at 80°C after addition. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and then slurried with methanol to obtain N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4 ,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)quinoline-7-carboxamide (52,44mg, 0.12mmol, 51.4% Yeild). MS Calcd: 359.13; MS Found: 360.21 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.45 (s, 1H), 9.05 (dd, J = 4.0, 1.0 Hz, 1H), 8.63 (d, J = 12.0 Hz, 1H), 8.49 (dd, J＝8.4,2.0Hz,1H),8.16(d,J＝8.4Hz,1H),8.05(d,J＝8.4Hz,1H),7.69(dd,J＝8.4,4.0Hz,1H),5.85- 5.80(m,2H),3.33-3.26(m,4H),1.23-1.18(m,2H),0.32-0.27(m,1H),0.11–0.07(m,1H).

Example 53

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropo[f]isoindole-2(1H)-yl)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxamide

Step 1: Weigh 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid methyl ester (53-a, 50mg, 0.19mmol) into a 25ml single-neck bottle, add methanol (1mL), and then add hydration Hydrazine (0.02 mL, 0.38 mmol), after addition, react at 50°C for 2 hours. LC-MS detected that the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to obtain 5-(trifluoromethyl)benzo[b]thiophene-2-carbohydrazide (53-b, 47 mg, 0.16 mmol, 84.6% Yeild) . MS Calcd: 260.02; MS Found: 261.09 ([M+H] ⁺ ).

Step 2: Weigh (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]iso Benzofuran-1,3(3aH)-dione (1-c, 37.1mg, 0.20mmol), 5-(trifluoromethyl)benzo[b]thiophene-2-carbohydrazide (53-b, 47mg, 0.16mmol) into a 25ml single-neck bottle, add ethanol (2mL), then add DIPEA (0.05mL, 0.33mmol), and react at 80°C for 2 hours after addition. LC-MS detects that the reaction is complete. The reaction solution is concentrated to dryness under reduced pressure and sent for preparation and purification to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3, 3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-5-(trifluoromethyl) Benzo[b]thiophene-2-carboxamide (53, 30 mg, 0.08 mmol, 41.8% Yeild). MS Calcd: 432.08; MS Found: 433.10 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.65 (s, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.36 (d, J = 8.4Hz, 2H), 7.83 (dd, J = 8.4,2.0Hz,1H),5.84-5.79(m,2H),3.34-3.26(m,4H),1.25-1.21(m,2H),0.32-0.27(m,1H),0.10-0.07(m, 1H).

Example 54

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

Step 1: Add compound 1-H ethyl pyrrolo[3,2-b]pyridine-2-acetate (54-a, 500mg, 2.63mmol) and solvent ethanol (10mL) into a 50mL eggplant-shaped flask, and then add Add hydrazine hydrate (0.5 mL, 10.28 mmol) and continue refluxing overnight. Spin the reaction solution to dryness under reduced pressure, add 50 mL of DCM, wash the organic phase with 2×20 mL of saturated brine, dry over anhydrous sodium sulfate, and spin to dryness under reduced pressure to obtain the target compound: 1H-pyrrolo[3,2-b]pyridine-2 -Formyl hydrazide (54-b, 400 mg, 2.27 mmol, 86.4% yield) MS Calcd: 176.18; MS Found: 177.15 ([M+H] ⁺ ).

Step 2: Combine compound 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid hydrazide (54-b, 100mg, 0.57mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4, 4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 108 mg, 0.57 mmol) into a 25 mL eggplant-shaped flask, add 10 mL ethanol solution, and reflux at 85°C overnight. LCMS monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a -Otahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (54,100.17 mg, 0.29mmol, 50.6% yield). MS Calcd: 348.36; MS Found: 349.21 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.04 (s, 1H), 11.29 (s, 1H), 8.46 (dd, J ＝4.4,1.6Hz,1H),7.84(d,J＝8.4Hz,1H),7.41(d,J＝18.0Hz,1H),7.27(dd,J＝8.4,4.6Hz,1H),5.85–5.80 (m,2H),3.32-3.26(m,4H),1.25-1.17(m,2H),0.32-0.27(m,1H),0.10-0.07(m,1H).

Example 55

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropa[f]isoindole-2(1H)-yl)-6-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide

Step 1: Place compound 4-acetamido-2-methylbenzoic acid (55-a, 3.0g, 15.53mmol) in a 100mL eggplant-shaped flask, add 15mL H ₂ SO ₄ to it under ice bath, and then add ice in sequence. Acetic acid (10 mL) and concentrated nitric acid (1.5 mL) were stirred at room temperature for 2 hours. LCMS detected that the raw material reaction was completed. The reaction solution was slowly poured into ice and filtered to obtain 4-acetamido-2-methyl-5-nitrobenzoic acid (55-b, 1.2g, 5.04mmol, 32.4% yield). MS Calcd:238.20; MS Found:237.09([MH] ^- ).

Step 2: Add compound 4-acetamido-2-methyl-5-nitrobenzoic acid (55-b, 1.2g, 5.04mmol) and solvent glacial acetic acid (30mL) into a 100mL eggplant-shaped flask. Then concentrated hydrochloric acid (10 mL) was added thereto, and the mixture was refluxed at 100° C. for 2 hours. LCMS monitored the completion of the reaction of the raw materials, added 30 mL of water, solid precipitated, filtered to obtain 4-amino-2-methyl-5-nitrobenzoic acid (55-c, 700 mg, 3.57 mmol, 70.08% yield) MS Calcd: 196.16; MS Found:195.11([MH] ^- ).

Step 3: Place compound 4-amino-2-methyl-5-nitrobenzoic acid (55-c, 600mg, 3.63mmol) and 10mL ethanol in a 100mL eggplant-shaped bottle, and add potassium hydroxide (490mg, 8.72mmol) , saturated solution), reflux at 85°C for 30 minutes. The reaction solution was cooled to 0°C, and sodium hypochlorite solution (648.5 mg, 8.72 mmol) was added, and the reaction was continued at this temperature for 1 hour. LCMS monitors the completion of the raw material reaction. Use concentrated hydrochloric acid to adjust the pH to about 1. If a solid precipitates, filter it. Spin the filtrate dry and add 20 ml of water. If a solid precipitates, filter to obtain 6-carboxy-5-methylbenzo[c]. [1,2,5] Oxadiazole-1-oxide (55-d, 430 mg, 2.22 mmol, 61.0% yield). MS Calcd:194.15; MS Found:193.11([MH] ^- ).

Step 4: Add compound 6-carboxy-5-methylbenzo[c][1,2,5]oxadiazole-1-oxide (55-d, 400mg, 2.06mmol) and Solvent ethanol (7 mL). Then, ethyl phosphite (1.77 mL, 10.30 mmol) was added thereto, and the mixture was refluxed at 85° C. for 30 minutes. LCMS monitors the completion of the raw material reaction. Spin the solvent dry and add 30 ml of water. Extract with ethyl acetate. Concentrate the organic phase. Adjust the pH of the remaining oil to 9-10 with saturated sodium bicarbonate solution and wash it twice with ethyl acetate. , then adjust the pH to 1 with concentrated hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and spin dry under reduced pressure to obtain the target compound 6-methylbenzo[c][1, 2,5]oxadiazole-5-carboxylic acid (55-e, 270 mg, 1.52 mmol, 73.6% yield) MS Calcd: 178.15; MS Found: 177.11 ([M+H] ⁺ ).

Step 5: Add compound 6-methylbenzo[c][1,2,5]oxadiazole-5-carboxylic acid (55-e, 270mg, 1.52mmol) and solvent ethanol (5mL) into a 50mL eggplant-shaped flask. ). Then concentrated sulfuric acid (0.5 mL, 9.38 mmol) was added dropwise, and the mixture was stirred and refluxed at 80°C for 4 hours. TLC detected that the reaction of the raw materials was complete, and then hydrazine hydrate (2 mL, 41.12 mmol) was added to it, and the mixture was continued to reflux overnight. Spin the reaction solution to dryness under reduced pressure, add 50 mL of DCM, wash the organic phase with 2×20 mL of saturated brine, dry over anhydrous sodium sulfate, and spin to dryness under reduced pressure to obtain the target compound 6-methylbenzo[c][1,2,5] Oxadiazole-5-carboxyhydrazide (55-f, 250mg, 1.30mmol, 85.8% yield) MS Calcd: 192.18; MS Found: 191.13 ([M+H] ⁺ ).

Step 6: Combine compound 6-methylbenzo[c][1,2,5]oxadiazole-5-carboxyhydrazide (55-f, 250mg, 1.30mmol) and (3aR, 4R, 4aR, 5aS, 6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione ( 1-c, 297 mg, 1.56 mmol) was placed in a 50 mL eggplant-shaped flask, added with 7 mL of ethanol solution, and refluxed at 85°C overnight. LCMS monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a -Otahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-6-methylbenzo[c][1,2,5]oxadiazole-5 -Formamide (55, 45.3 mg, 0.12 mmol, 9.5% yield). MS Calcd:364.36; MS Found:365.14([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.40(s,1H),8.11(s, 1H),8.01(s,1H),5.83-5.78(m,2H),3.32-3.27(m,4H),2.47(s,3H),1.22–1.19(m,2H),0.32-0.27(m, 1H),0.10-0.07(m,1H).

Example 56

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidene Cyclopropro[f]isoindole-2(1H)-yl)-4-fluorothieno[2,3-c]pyridine-2-carboxamide

Step 1: Weigh 4-fluorothio[2,3-c]pyridine-2-carboxylic acid (56-a, 100mg, 0.51mmol) and HATU (578.4mg, 1.52mmol) into a 25ml single-neck bottle, add DCM ( 2 mL) and DIPEA (0.25 mL, 1.52 mmol), stir at room temperature for 5 minutes after addition, add tert-butyl carbazate (80.4 mg, 0.61 mmol), and finally react at room temperature for 1 hour. LC-MS detected that the reaction was complete. The reaction solution was washed twice with water, and then concentrated to dryness under reduced pressure to obtain crude product tert-butyl 2-(4-fluorothieno[2,3-c]pyridine-2-carbonyl)hydrazine-1-carboxylate. Ester (56-b, 122 mg, 0.31 mmol, 61.8% Yeild). MS Calcd: 311.07; MS Found: 312.11 ([M+H] ⁺ ).

Step 2: Weigh 2-(4-fluorothio[2,3-c]pyridine-2-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester (56-b, 122mg, 0.31mmol) into a 25ml single-neck bottle, Then add hydrogen chloride-ethyl acetate solution (3mL), stir for 10 minutes and concentrate to dryness under reduced pressure to obtain crude 4-fluorothio[2,3-c]pyridine-2-carboxylic acid hydrazide (56-c, 74mg, 0.28mmol, 89.4% Yeild). MS Calcd: 211.02; MS Found: 212.07 ([M+H] ⁺ ).

Step 3: Weigh 4-fluorothio[2,3-c]pyridine-2-carboxylic hydrazide (56-c, 74 mg, 0.28 mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4 ,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 53.3mg , 0.28mmol) into a 25ml single-neck bottle, add ethanol (2mL), then add DIPEA (0.14mL, 0.84mmol), and react at 85°C for 2 hours. LC-MS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness and purified by pre-TLC to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3 ,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-4-fluorothieno[2 ,3-c]pyridine-2-carboxamide (56,84 mg, 0.21 mmol, 74.3% Yeild). MS Calcd: 383.07; MS Found: 384.08 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.65 (s, 1H), 9.27 (d, J = 2.0Hz, 1H), 8.57 (d, J = 2.0Hz, 1H), 8.39 (s, 1H) ,5.87–5.83(m,2H),3.33-3.30(m,4H),1.20–1.16(m,2H),0.31-0.26(m,1H),0.11–0.06(m,1H).

Example 57

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxoctahydro-ethylenecyclopropano[f]isoindol-2(1H)-yl)thieno[ 2,3-c]pyridine-2-carboxamide

Step 1: Dissolve thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (57-a, 300mg, 1.45mmol) in 5mL THF, add 1mL of lithium hydroxide (173mg, 7.24mmol) aqueous solution, Reaction was carried out overnight at 40°C. TLC monitors the completion of the reaction of the raw materials. Concentrate the reaction solution, add 5 mL of water, adjust the pH to acidic with dilute hydrochloric acid, and a solid will precipitate. Directly filter and collect the filter cake to obtain thieno[2,3-c]pyridine-2-carboxylic acid (57 -b, 200 mg, 1.12 mmol, 77% yield) MS Calcd: 179.00; MS Found: 180.06 ([M+H] ⁺ ).

Step 2: Place thieno[2,3-c]pyridine-2-carboxylic acid (57-b, 75 mg, 0.42 mmol) in a 25 mL eggplant-shaped flask, add 3 mL of dry dichloromethane to dissolve, and add a drop of DMF. Oxalyl chloride (0.1 mL, 1.15 mmol) was slowly added dropwise thereto, and the reaction was stirred at room temperature. TLC monitored the completion of the raw material reaction, and the reaction solution was concentrated under reduced pressure to obtain thieno[2,3-c]pyridine-2-carboxylic acid chloride (57-c, 70 mg, 0.35 mmol, 84% yield), which was directly used in the next step.

Step 3: Combine thieno[2,3-c]pyridine-2-carboxyl chloride (57-c, 70 mg, 0.35 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-2-aminohexahydro- 4,6-Ethylenecyclopropa[f]isoindole-1,3(2H,3aH)-dione (47-a, 70mg, 0.34mmol) was placed in a 25mL eggplant-shaped bottle, and dry diacetyl was added. Methyl chloride solution (3 mL), then add anhydrous potassium carbonate (140 mg, 1.02 mmol), and stir at room temperature for 1 hour. TLC monitors the completion of the raw material reaction, filters the reaction solution, and concentrates the filtrate under reduced pressure. The crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxooctahydro-ethylenecyclopropa[f]isoindole- 2(1H)-yl)thieno[2,3-c]pyridine-2-carboxamide (57, 50 mg, 0.14 mmol, 40% yield) MS Calcd: 367.10; MS Found: 368.17 ([M+H] ⁺ ). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.68 (s, 1H), 9.41 (s, 1H), 8.60 (d, J = 5.6Hz, 1H), 8.34 (s, 1H), 8.05 ( d,J＝5.6Hz,1H),3.29-3.23(m,2H),2.42(s,2H),1.47–1.27(m,6H),0.86-0.82(m,1H),0.58-0.53(m, 1H).

Example 58

N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropane And[f]isoindole-2(1H)-yl)thieno[3,2-c]pyridine-2-carboxamide

Step 1: Dissolve 4-chloropyridine-3-carbaldehyde (58-a, 900mg, 6.36mmol) in N,N-dimethylformamide (5mL), and add potassium carbonate (1.3g, 9.53 mmol) and ethyl thioglycolate (0.8 mL, 9.53 mmol) and stirred for 15 minutes, then warmed to room temperature and continued stirring for 24 hours. TLC monitors that the reaction of raw materials is completed, and the reaction solution is Add 30 mL of water, if a white solid precipitates, filter directly and collect the filter cake. Thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (58-b, 1.3g, 6.27mmol, 98% yield) was obtained. MS Calcd:207.04; MS Found:208.09([M+H] ⁺ ).

Step 2: Add thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (58-b, 300 mg, 1.44 mmol) and MeOH (20 mL) to a 100 mL eggplant-shaped flask, and add hydrazine hydrate solution ( 0.46mL, 14.4mmol). Stir for 14 hours at 80°C. TLC monitors the completion of the raw material reaction. The reaction solution is concentrated under reduced pressure, and the crude product is purified by flash column chromatography (DCM:MeOH=30:1) to obtain thieno[3,2-c]pyridine-2- Formyl hydrazide (58-c, 250 mg, 1.29 mmol, 89% yield). MS Calcd:193.03; MS Found:194.11([M+H] ⁺ ).

Step 3: Combine thieno[3,2-c]pyridine-2-carboxylic acid hydrazide (58-c, 250 mg, 1.29 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5 ,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 369mg, 1.94mmol) In a 25 mL eggplant-shaped flask, add 20 mL ethanol solution and reflux at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by column chromatography (DCM:MeOH=40:1) to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4, 4a,5,5a,6,6a-octahydro-4,6-cyclopropa[f]isoindol-2(1H)-yl)thieno[3,2-c]pyridine-2-carboxamide ( 58,422mg, 1.15mmol, 89% yield). MS Calcd:365.08; MS Found:366.14([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.64(s,1H),9.26(s,1H),8.52(d,J ＝5.6Hz,1H),8.35-8.30(m,1H),8.13(d,J＝5.6Hz,1H),5.80-5.73(m,2H),3.30-3.22(m,4H),1.21-1.16( m,2H),0.29–0.24(m,1H),0.08-0.03(m,1H).

Example 59

4-Bromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4, 6-Ethylcyclopropano[f]isoindol-2(1H)-yl)thieno[2,3-c]pyridine-2-carboxamide

Step 1: Add the reactants 4-bromothieno[2,3-c]pyridine-2-carboxylic acid methyl ester (59-a, 200 mg, 0.74 mmol) and MeOH (10 mL) into a 100 mL eggplant-shaped flask, and then add Add hydrazine hydrate solution (0.47 mL, 14.7 mmol). Stir for 14 hours at 80°C. TLC monitors the completion of the raw material reaction. The reaction solution is concentrated under reduced pressure, and the crude product is purified by flash column chromatography (DCM:MeOH=30:1) to obtain 4-bromothieno[2,3-c]pyridine. -2-Formyl hydrazide (59-b, 180 mg, 0.66 mmol, 90% yield). MS Calcd:272.94; MS Found:273.95([M+H] ⁺ ).

Step 2: Combine 4-bromothieno[2,3-c]pyridine-2-carboxylic acid hydrazide (59-b, 180 mg, 0.66 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4, 4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropa[f]isobenzofuran-1,3(3aH)-dione (1-c, 188 mg, 0.99 mmol) into a 25 mL eggplant-shaped flask, add 10 mL ethanol solution, and reflux at 85°C overnight. TLC monitors the completion of the raw material reaction, and directly concentrates the reaction solution. The crude product was purified by Prep-TLC (DCM:MeOH=40:1) to obtain the title compound: 4-bromo-N-((3aR,4R,4aR,5aS,6S,6aS)- 1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethylcyclopropano[f]isoindol-2(1H)-yl) Thieno[2,3-c]pyridine-2-carboxamide (59, 100 mg, 0.23 mmol, 34% yield). MS Calcd:444.99; MS Found:445.98([M+H] ⁺ ). ¹ H NMR(400MHz, DMSO-d ₆ )δ11.98(s,1H),9.24(s,1H),8.65(s,1H ),8.31-8.25(m,1H),5.77–5.72(m,2H),3.27–3.22(m,4H),1.18-1.15(m,2H),0.27-0.22(m,1H),0.08-0.03 (m,1H).

Test Example 1: Inhibitory activity of the compound of the present invention on the cytopathic effect of HFF caused by vaccinia virus

1) Compound dilution: First use DMSO to dilute the 2000 μM compound stock solution 5 times to 8 concentration points to obtain 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 μM compounds, and then dilute the compounds 50 times with culture medium. times to the final concentrations of 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0.000512 μM.

2) Experimental steps: ① Cytopathy experiment: On the first day, inoculate HFF-1 cells (purchased from American Type Culture Collection, ATCC, Cat. No. SCRC-1041 ^TM ) at a density of 6,000 cells per well and 100 μL per well. in a 96-well plate and cultured overnight in a 5% CO ₂ , 37°C incubator. The next day, add 50 μL of the diluted compound in (1) (double wells) and 50 μL of Vaccinia Virus VP13 virus strain (purchased from China Type Culture Collection Center, CCTCC, Cat. No. GDV088) per well. The virus inoculum volume is 0.1 pfu/cell (i.e. MOI=0.1). Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (culture medium only). The total volume of cell culture medium in each well was 200 μL, and the final concentration of DMSO in the culture medium was 0.5%. The cells were cultured in a 5% CO ₂ and 37°C incubator for 4 days to detect the cytopathic effects caused by the virus. ②Cytotoxicity experiment: The simultaneous compound cytotoxicity experiment does not include virus infection, and other conditions are the same as those for the cytotoxicity experiment. On the sixth day, both experiments used a cell viability CCK8 detection kit (Shanghai Liji Biotechnology Co., Ltd., Cat. No. AC11L057) to detect cell viability.

3) Data analysis:

The antiviral activity and cytotoxicity of the test compound were expressed by the inhibition rate (%) and cell viability (%) of the cytopathic effect caused by the virus at different concentrations, respectively. Calculated as follows:

Cytopathic effect inhibition rate (%) = (compound test well reading value - virus control average value) / (cell control average value - virus control average value) × 100;

Cell viability (%) = (test well reading value - average value of culture medium control) / (average value of cell control - average value of culture medium control) × 100;

Use GraphPad Prism to perform nonlinear fitting analysis on the inhibition rate and cell viability of the sample, and calculate the half effective concentration (EC ₅₀ ) and half cytotoxic concentration (CC ₅₀ ) values of the sample. The inhibition curve fitting method is log(inhibitor) vs. response--Variable slope.

4) Experimental results:

Table 1. Inhibition of cytopathic effects caused by vaccinia virus by compounds of the present invention activity and cell viability

Conclusion: According to Table 1, it can be seen that the compound of the present invention has excellent antiviral activity against vaccinia virus of the genus Orthopoxvirus, and has no obvious toxicity to cells.

Test Example 2 In vivo pharmacokinetic experiment in mice

Main principles of the experiment:

The LC-MS/MS method was used to measure the drug concentration in the plasma of BALB/C mice at different time points after a single oral administration of the example compounds, and the relevant pharmacokinetic parameters were calculated by Winnonlin to study the pharmacokinetics of the compounds of the present invention in mice. kinetic behavior and evaluate its pharmacokinetic characteristics.

Experimental materials, plans and result analysis:

The experimental animals were healthy adult BALB/c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

Dosing method and sample collection: BALB/c female mice were orally administered (10 mg/kg, 0.5% Tween 80 + 99.5% 1% HPMC) at 0.083, 0.25, 0.5, 1, respectively after administration. Collect 60 μL of whole blood from the mouse orbital venous plexus at 2, 4, 6, 8, and 24 hours into EDTA-K2 anticoagulant tubes (Jiangsu Kangjian, Cat. No.: KJ202), centrifuge at 4000 rpm, 4°C for 6 min, and collect plasma;

Sample analysis: Take 10 μL of mouse plasma sample, add 290 μL of acetonitrile solution containing internal standard to precipitate the protein, vortex for 10 min, then centrifuge at 4000 rpm for 10 min, and take 200 μL of supernatant in a 96-well plate. Place it for LC-MS/MS detection and analysis, and the injection volume is 1 μL.

Under the same dosage and administration mode, the pharmacokinetic properties parameters of the compounds of the present invention in mice are shown in Table 2 below:

Table 2 Pharmacokinetic parameters of the compounds of the present invention in mice

Conclusion: According to Table 2, it can be seen that the compound of the present invention has better in vivo pharmacokinetic properties than Tecovirimat, and C _max , AUC _last and bioavailability are all improved to varying degrees.

Test Example 3: Mouse tissue distribution experiment

Main principles of the experiment:

The LC-MS/MS method was used to measure the drug concentrations in the plasma and brain tissue of BALB/C mice at different time points after a single oral administration of the example compounds, and the relevant pharmacokinetic parameters were calculated by Winnonlin to study the effects of the compounds of the present invention on the mouse brain. The distribution of the organization.

Experimental materials, plans and result analysis:

Administration method and sample collection: BALB/c female mice were orally administered (100 mg/kg, 99.5% 1% HPMC + 0.5% Tween80) at 0.5, 1, 3, 5, and 8 hours after administration. Collect individual tissue samples. Take 60 μL of whole blood through the orbital venous plexus of the mouse into an EDTA-K2 anticoagulant tube, centrifuge at 4000 rpm for 6 minutes at 4°C, and collect the plasma. The animals are anesthetized and sacrificed. The abdominal cavity is opened and the heart is perfused with physiological saline. The brain tissue is removed and the water is wiped off with filter paper. , weigh and add a certain amount of physiological saline in proportion, and collect the homogenate;

Sample analysis: Take 10 μL of mouse plasma and brain samples, add 290 μL of acetonitrile solution containing internal standard to precipitate the protein, vortex for 10 min, then centrifuge at 4000 rpm for 10 min, and take 200 μL of supernatant in a 96-well plate. Place it for LC-MS/MS detection and analysis, and the injection volume is 1 μL.

Under the same dosage and administration method, the exposure ratio of mouse brain tissue to plasma of the compound of the present invention is shown in Table 3 below:

Table 3 Exposure ratios of compounds in mouse brain tissue and plasma

Conclusion: Neurotoxicity is mainly caused by drugs entering the brain. According to Table 3, compound 2 and compound 12 of the present invention have lower brain exposure and exposure ratio, which can reduce the risk of drugs entering the brain and improve drug safety. .

Test Example 4: Kinetic Solubility

principle:

Since suspended particles in turbid liquids are proportional to the intensity of scattered light, the intensity of scattered light can be used to evaluate the degree of turbidity of the solution and thereby evaluate the kinetic solubility of the drug.

Solution preparation:

1) pH 6.8 phosphate buffer: Weigh 6.805g of potassium dihydrogen phosphate, then weigh 0.896g of sodium hydroxide, put it in a 1000ml volumetric flask, add water to dissolve and dilute to the mark, shake well, and you have it;

2) pH 2.0 hydrochloric acid solution: measure 1.17mL of hydrochloric acid, place it in a 1000mL volumetric flask, add water to dilute to the mark, shake well, and it is ready;

Stock solution: Dissolve the compound of the present invention (test product) in DMSO and dilute it to a compound solution of 5000 μg/ml.

operate:

Pipette 15 μL of the stock solution into a 96-row well plate, add 285 μL of pH 2.0/6.8 dissolution medium to dilute the test product concentration to 250 μg/mL, and then gradually dilute the test solution to 125, 62.5, 31.3, 15.6, and 7.8 μg. /mL (take 150μL from the previous concentration sample, add 150μL dissolution medium and mix well). Then take 190 μL of the two dissolution media and 10 μL of DMSO and mix well to serve as a blank control. After configuration, shake for 10 minutes. Use a multifunctional microplate reader (manufacturer: TECAN model: Spark) to measure the absorbance at 633nm.

Solubility limit: Insoluble: <10μg/mL; Slightly soluble: 10~100μg/mL; Soluble: >100μg/mL

Table 4 Kinetic solubility of compounds at different pH

Conclusion: According to Table 4, the solubility of the compound of the present invention is significantly improved compared with Tecovirimat. Combining Table 1, it can be seen that the compound of the present invention not only has better antiviral activity than Tecovirimat, but also has a greater improvement in solubility. Compared with Tecovirimat, it has a huge improvement in drugability, which has important development significance.

Test Example 5: Liver microsome stability

Reagent preparation:

_PBS : 0.1M _KH2PO4 _and _K2HPO4 buffer, pH 7.4.

MgCl ₂ : Weigh a certain amount of MgCl ₂ and prepare a 16mM MgCl ₂ solution with PBS.

NADPH (Sigma, Cat. No. 481973-500mg): Weigh a certain amount of NADPH, use 16mM _MgCl2 solution to prepare NADPH to 4mM, and the final incubation concentration is 1mM.

Compound: Use PBS to prepare the compound to be tested to 4 μM, and the final incubation concentration is 1 μM.

Human liver microsomes (BIOIVT): Dilute liver microsomes to 1 mg/mL with PBS, giving a final incubation concentration of 0.5 mg/mL.

Experimental steps:

Add the compound to be tested into the test tube, then add the prepared NADPH and mix evenly. Place it in an incubator at 37°C and 220 rpm for pre-incubation. After pre-incubation for 5 minutes, add liver microsomes to start the reaction.

Set up parallel experimental groups. At 0 min, 5 min, 15 min, 30 min, and 60 min respectively, add a certain volume of ice-cold acetonitrile solution containing internal standard to precipitate the protein, vortex for 5 min, and then centrifuge at 4000 rpm for 10 min. Take the supernatant in a 96-well plate. Put into LC-MS/MS for analysis.

The concentration (peak area) of the example compound was measured by LC-MS/MS, and the rate constant was obtained by plotting "Ln (compound residual amount %)" against "incubation time" in Excel to calculate the half-life and intrinsic clearance rate of the drug. .

data analysis:

CL _int = (0.693/T _1/2 , microsomes) × [incubation liquid volume (ml)/microsomal protein mass (mg)] × [microsomal protein mass (mg)/liver mass (g)] × [liver Mass (g)/Body weight (kg)] ^[1]

CL _H =CL _int × _fu ×Q _h /(CL _int × _fu +Q _h )

in the formula

CL _int --intrinsic clearance rate (ml/min/kg)

CL _H --hepatic clearance (ml/min/kg)

f _u --plasma protein binding rate 1

Q _h --hepatic blood flow

Reference ^[1] : Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993; 10:1093-5.

Table 5 Stability of compounds in human liver microsomes

Conclusion: According to Table 5, it can be seen that the compound of the present invention has good stability in human liver microsomes.

Industrial applicability

Compared with the already marketed drug Tecovirimat, the compound of the present invention has multiple advantages and has important development significance and application prospects.

The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.

Claims

A compound represented by formula (I), or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or its pharmaceutically acceptable Salt accepted:

in,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium or halogen;

R a is selected from the group consisting of 5 or 6-membered aryl and 4- to 7-membered heterocyclyl, 5- or 6-membered aryl and 4- to 7-membered carbocyclyl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclyl, A 5- or 6-membered heteroaryl group and a 4- to 7-membered carbocyclyl group, each of the 5- or 6-membered heteroaryl group and the 4- to 7-membered heterocyclyl group independently contains 1-4 heterocyclic groups selected from N, O, or S. Atom; the aryl group, heteroaryl group, carbocyclyl group and heterocyclyl group are each independently and optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Each R 9 , R 10 , R 13 , and R n are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

is a single key or does not exist.
The compound of claim 1, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt :

R a is selected from the group consisting of 5-membered aryl and 4- to 7-membered heterocyclyl, 5-membered aryl and 4- to 7-membered carbocyclyl, 5-membered heteroaryl and 4- to 7-membered heterocyclyl, 5-membered heteroaryl and 4 to 7-membered carbocyclyl, the 5-membered heteroaryl and 4 to 7-membered heterocyclyl each independently contain 1-4 heteroatoms selected from N, O or S; the aryl and heteroaryl , carbocyclyl, and heterocyclyl are each independently and optionally substituted by one or more R n ;

Preferably, R a is selected from the group consisting of 5-membered aryl and 5- to 6-membered heterocyclyl, 5-membered aryl and 5- to 6-membered carbocyclyl, 5-membered heteroaryl and 5- to 6-membered heterocyclyl, 5-membered heterocyclic Aryl and 5- to 6-membered carbocyclyl, the 5-membered heteroaryl and 5- to 6-membered heterocyclyl each independently contain 1-2 heteroatoms selected from N, O or S; the aryl, Heteroaryl, carbocyclyl, and heterocyclyl are each independently and optionally substituted by 1 or more R n ;

Or preferably, R a is selected from the group consisting of 5-membered aryl and 5- to 6-membered heterocyclyl, 5-membered aryl and 5- to 6-membered carbocyclyl, 5-membered heteroaryl and 5- to 6-membered heterocyclyl, 5-membered aryl and 5- to 6-membered heterocyclyl, Heteroaryl and 5- to 6-membered carbocyclyl groups, the 5-membered heteroaryl group and the 5- to 6-membered heterocyclyl group independently contain 1-3 heteroatoms selected from N, O or S; the aryl group , heteroaryl, carbocyclyl, and heterocyclyl are each independently and optionally substituted by one or more R n ;

Preferably, R a is selected from the group consisting of 5-membered aryl and 6-membered heterocyclyl, 5-membered aryl and 6-membered carbocyclyl, 5-membered heteroaryl and 6-membered heterocyclyl, 5-membered heteroaryl and 6-membered carbon. Cyclic group, the 5-membered heteroaryl group, 5 to 6-membered heterocyclyl group Each independently contains 1-3 heteroatoms selected from N, O or S; the aryl, heteroaryl, carbocyclyl and heterocyclyl are each independently and optionally substituted by 1 or more R n replace;

Preferably, R a has any structure selected from the following: thienopyridyl, thienophenyls, thienopyrimidinyl, thienopyridazinyl, furanopyridazinyl, furophenyl, furopyridyl, Furopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolophenyl, pyrrolopyrazinyl, pyrrolopyridazinyl, imidazopyridinyl, imidazophenyl, imidazopyrimidinyl, imidazopyridyl Azinyl, imidazopyridazinyl, thiazolopyridyl, thiazolophenyl, thiazolopyrimidinyl, thiazolopyridazinyl, thiazolopyridazinyl, triazolopyrazinyl, triazolophenyl, triazolopyridazinyl Azolopyrimidinyl, triazolopyridazinyl, triazolopyridinyl; each of them is independently and optionally substituted by 1, 2 or 3 R n ;

Preferably, R a has any structure selected from the following: thienopyridyl, thienopyridyl, thienopyridazinyl, furopyridazinyl, furophenyl, furopyridyl, pyrrolopyridyl, Imidazopyridyl, thiazolopyridyl, imidazopyrazinyl, triazolopyrazinyl; each of which is independently and optionally substituted by 1, 2 or 3 R n ;

Preferably, R a has any structure selected from the following:

where p=0,1,2 or 3;

Each Rn is independently selected from deuterium, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

Preferably, each R n is independently selected from deuterium, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;

Or preferably, each R n is independently selected from hydrogen, deuterium, halogen, C 5-6 alkyl or halo C 5-6 alkyl;

Preferably, each R n is independently selected from deuterium, halogen, methyl, halomethyl, ethyl, haloethyl, propyl, halopropyl, isopropyl, haloisopropyl, C 4 alkyl, halogenated C 4 alkyl;

Preferably, each R n is independently selected from F, Cl, Br, methyl, fluoromethyl, ethyl, fluorine or chlorine substituted ethyl, propyl, fluorine or chlorine substituted propyl, isopropyl base, fluorine or chlorine substituted isopropyl, C 4 alkyl or fluorine, chlorine substituted C 4 alkyl;

Preferably, each R n is independently selected from F, Cl, Br, methyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2F ;

Preferably, each R n is independently selected from F, Cl, Br, methyl, -CF 3 ;

Preferably, R a has any structure selected from the following:
The compound of claim 1, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt :

R a is selected from the group consisting of 6-membered aryl and 4- to 7-membered heterocyclyl, 6-membered aryl and 4- to 7-membered carbocyclyl, 6-membered heteroaryl and 4- to 7-membered heterocyclyl, and 6-membered heteroaryl. 4 to 7-membered carbocyclyl, the 6-membered heteroaryl and 4- to 7-membered heterocyclyl each independently contain 1-4 heteroatoms selected from N, O or S; the aryl and heteroaryl , carbocyclyl and heterocyclyl are each independently and optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from the group consisting of 6-membered aryl and 5- to 6-membered heterocyclyl, 6-membered aryl and 4- to 6-membered carbocyclyl, 6-membered heteroaryl and 5- to 6-membered heterocyclyl, 6-membered heterocyclyl. Aryl and 4 to 6-membered carbocyclyl, the 6-membered heteroaryl and 5- to 6-membered heterocyclyl each independently contain 1-3 heteroatoms selected from N, O or S; the aryl, Heteroaryl, carbocyclyl, and heterocyclyl are each independently and optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from Wherein Y and Z are each independently selected from N or C; V is N, NR 9 or CR 9 ; X is N, NR 10 or CR 10 ; W is N, NR 13 or CR 13 ; Ring A is selected from 4-7 1-membered carbocyclyl or heterocyclyl, the 4-7 heterocyclyl contains 1-3 heteroatoms selected from N, O or S, 1 or more H atoms in ring A are optionally replaced by 1-3 3 R n substitutions; where, Is a single key or does not exist;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl or C 5-6 alkyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from hydrogen, deuterium, F, Cl or methyl;

Preferably, Ring A is selected from 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 5- or 6-membered heteroaryl, C 4-6 cycloalkyl or phenyl; in Ring A 1 or more H atoms are optionally substituted by 1-3 R n ;

Preferably, Ring A is selected from It is fused to the 6-membered ring where X, Y, and Z are located through any connectable position; wherein 1 or more H atoms in ring A are optionally replaced by 1-3 R n ;

Preferably, each R n is independently selected from deuterium, F, Cl, Br, I, C 1-4 alkyl, C 5-6 alkyl;

Preferably, each R n is independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, C 5-6 alkyl ;

Preferably, each R n is independently selected from deuterium, methyl, F, and Cl;

Preferably, Ring A is selected from It is fused to the 6-membered ring where X, Y, and Z are located through any connectable position;

Preferably, R a is selected from any of the following structures:

Preferably, R a is selected from any of the following structures:

where r=0,1,2 or 3;

Preferably, R a is selected from any of the following structures:

Preferably, R 9 , R 10 , and R 13 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Preferably, R 9 , R 10 , and R 13 are each independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, C 5 -6 alkyl;

Preferably, R 9 , R 10 , and R 13 are each independently selected from hydrogen, deuterium, F, Cl, Br or methyl;

Preferably, one of R 9 , R 10 , and R 13 is selected from hydrogen, deuterium, F, Cl, Br or methyl, and the other two are each independently selected from hydrogen or deuterium;

Preferably, R a is selected from any of the following structures:
The compound of claim 1, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt , which is characterized by:

R a is selected from the group consisting of 5 or 6-membered aryl and 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclyl, and the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl The ring groups each independently contain 1-4 heteroatoms selected from N, O or S; the aryl group, heteroaryl group and heterocyclyl group are each independently and optionally substituted by 1 or more heteroatoms selected from R 9 , R 10 , R 13 or R n substituent substitution;

Preferably, R a is selected from phenyl 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl 4- to 7-membered heterocyclyl, and the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl The groups each independently contain 1-4 heteroatoms selected from N, O or S; the phenyl, heteroaryl and heterocyclic groups are each independently and optionally substituted by 1 or more selected from R 9 , R 10 , R 13 or R n is substituted by a substituent;

Preferably, R a is selected from the group consisting of phenyl and 5- to 6-membered heterocyclyl groups, 5- and 6-membered heteroaryl and 5- to 6-membered heterocyclyl groups, and the 5- and 6-membered heteroaryl and 5- to 6-membered heterocyclic groups are Each group independently contains 1-3 heteroatoms selected from N, O or S; the phenyl, heteroaryl and heterocyclyl groups are each independently and optionally selected from 1, 2 or 3 R 9 , R 10 , R 13 or R n is substituted by a substituent;

Preferably, R a is selected from the group consisting of phenyl 5-membered heterocycloalkyl, phenyl 5-membered heteroaryl, phenyl 6-membered heteroaryl, 5-membered heteroaryl 6-membered heteroaryl, and the 5 The one-membered heteroaryl group, the 6-membered heteroaryl group, and the 5-membered heterocycloalkyl group each independently contain 1-3 heteroatoms selected from N, O, or S; the phenyl group, heteroaryl group, and heterocycloalkyl group each independently contain 1-3 heteroatoms selected from N, O, or S. Independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from phenyloxadiazolyl, phenyldioxolyl, phenylpyridyl, thienopyridyl, pyridylimidazolyl; the phenyloxadiazolyl Azolyl, phenyldioxolyl, phenylpyridyl, thienopyridyl, and pyridylimidazolyl are each independently, optionally, selected from R 9 by 1, 2, or 3 , R 10 , R 13 or R n substituent substitution;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br or methyl;

Or preferably, R a is selected from:

Preferably, R a is selected from:

or preferably,

R a is selected from the group consisting of phenyl 5-membered heterocycloalkyl and 5-membered heteroaryl 6-membered heteroaryl. The 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heterocycloalkyl each independently contain 1-2 heteroatoms selected from N, O or S; the phenyl, heteroaryl and heterocycloalkyl groups are each independently and optionally substituted by 1, 2 or 3 selected from R 9 , R 10 , R 13 or R n is substituted by a substituent;

Preferably, R a is selected from phenyldioxolanyl and thienopyridinyl; the phenyldioxa Cyclopentyl and thienopyridyl are each independently and optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br or methyl;

Preferably, R a is selected from:

Preferably, R a is selected from:

or,

Preferably, R a is selected from a 5- or 6-membered heteroaryl group and a 4- to 7-membered heterocyclyl group, and each of the 5- or 6-membered heteroaryl group and the 4- to 7-membered heterocyclyl group independently contains 1 to 4 members selected from Heteroatom of N, O or S; the heteroaryl group and heterocyclyl group are each independently and optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from 5-membered heteroaryl and 4- to 7-membered heterocyclyl, and each of the 5-membered heteroaryl and 4- to 7-membered heterocyclyl independently contains 1-4 selected from N, O or Heteroatom of S; the heteroaryl group and heterocyclyl group are each independently and optionally substituted by one or more R n ;

Preferably, R a is selected from 5-membered heteroaryl and 5- to 6-membered heterocyclyl, and each of the 5-membered heteroaryl and 5- to 6-membered heterocyclyl independently contains 1-2 selected from N, O or Heteroatom of S; the heteroaryl group and heterocyclyl group are each independently and optionally substituted by one or more R n ;

Preferably, R a is selected from 5-membered heteroaryl and 6-membered heterocyclyl, and each of the 5-membered heteroaryl and 6-membered heterocyclyl independently contains 1-2 heteroatoms selected from N, O or S ; The heteroaryl and heterocyclic groups are each independently and optionally substituted by one or more R n ;

Preferably, R a is selected from 5-membered heteroaryl and 6-membered heteroaryl, and the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1 heteroatom selected from N, O or S; Each of the 5-membered heteroaryl and 6-membered heteroaryl Independently, optionally substituted by 1, 2 or 3 R n ;

Preferably, R a is selected from 5-membered heteroaryl and 6-membered heteroaryl, and the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1 heteroatom selected from N or S; the 5 The one-membered heteroaryl group and the six-membered heteroaryl group are each independently and optionally substituted by 1, 2 or 3 R n ;

Preferably, R a is selected from thienopyridyl, which is optionally substituted by 1, 2 or 3 R n ;

Preferably, R a has any structure selected from the following:

where p=0,1,2 or 3;

Preferably, each R n is independently selected from deuterium, halogen or C 1-6 alkyl;

Preferably, each R n is independently selected from deuterium, halogen or C 1-4 alkyl

Preferably, each R n is independently selected from F, Cl, Br, methyl, ethyl or propyl;

Preferably, each R n is independently selected from F, Cl, Br, and methyl;

Or preferably, R a is selected from:

Or preferably, R a has any structure selected from the following:

Preferably, R a is selected from:

Preferably, R a is selected from:

Or preferably, R a is selected from phenyl 4- to 7-membered heterocyclyl groups, and the 4- to 7-membered heterocyclyl groups contain 1-4 heteroatoms selected from N, O, or S; the phenyl, heterocyclic groups Each ring group is independently and optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from phenyl and 5- to 6-membered heterocyclic groups, and the 5- to 6-membered heterocyclic groups contain 1-3 heteroatoms selected from N, O, or S; the phenyl, heterocyclic groups Each group is independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from phenyl 5- or 6-membered heteroaryl, and the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from N, O, or S; the phenyl, heteroaryl The bases are each independently optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n are substituted;

Preferably, R a is selected from phenyl 5-membered heteroaryl, and the 5-membered heteroaryl contains 1-3 heteroatoms selected from N or O; the phenyl and heteroaryl groups are each independently, optionally. Optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from Wherein, ring A is selected from a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains 1-3 heteroatoms selected from N or O, and the Each is independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, Ring A is selected from It is fused to the benzene ring through any attachable position;

Preferably, Ring A is selected from It is fused to the benzene ring through any attachable position;

Preferably, R a is selected from Each is independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Or preferably, R a is selected from phenyl 5- to 6-membered heterocycloalkyl, and the 5- to 6-membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O or S; the phenyl , Heterocycloalkyl groups are each independently and optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from phenyl 6-membered heterocycloalkyl, and the 6-membered heterocycloalkyl contains 2 heteroatoms selected from N or O; the phenyl and heterocycloalkyl are each independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from phenyl 6-membered heterocycloalkyl, and the 6-membered heterocycloalkyl contains 2 oxygen heteroatoms; the phenyl and heterocycloalkyl are each independently and optionally substituted by 1 Substituted with one, two or three substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from Each is independently, optionally substituted by one or more substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl;

Preferably, each R 9 , R 10 , R 13 and R n are independently selected from deuterium, F, Cl, Br or methyl;

Preferably, R a is selected from Each is independently, optionally substituted by 1, 2 or 3 substituents selected from F or deuterium;

Preferably, R a is selected from Each independently, optionally replaced by 1, 2 or 3 F;

Preferably, R a is selected from:

Further preferably, R a is selected from:

Or preferably, R a is selected from Each is independently and optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br or methyl;

Preferably, R a is selected from:

Further preferably, R a is selected from:

or,

Preferably, R a is selected from an 8-10-membered heteroaryl group, and the 8-10-membered heteroaryl group contains 1-3 heteroatoms selected from N, O or S; the 8-10-membered heteroaryl group is optionally Optionally substituted by 1 or more R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from an 8-10-membered bicyclic heteroaryl group, and the 8-10-membered bicyclic heteroaryl group contains 1-3 heteroatoms selected from N, O or S; the 8-10-membered bicyclic heteroaryl group is Aryl is optionally substituted by 1 or more R 9 , R 10 , R 13 or R n ;

Preferably, R a is selected from 5-membered heteroaryl and 6-membered heteroaryl, benzo 5-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1 to 3 members selected from Heteroatom of N, O or S; the phenyl, 5-membered heteroaryl and 6-membered heteroaryl are each independently and optionally substituted by 1, 2 or 3 R 9 , R 10 , R 13 or R n substitution;

Preferably, R a is selected from the group consisting of thienopyridyl and benzoxadiazolyl, each of which is independently and optionally replaced by 1, 2 or 3 R 9 , R 10 , R 13 or R n substitution;

Preferably, R a is selected from:

Each of them is independently, optionally substituted by 1, 2 or 3 substituents selected from R 9 , R 10 , R 13 or R n ;

Preferably, each R 9 , R 10 , R 13 or R n is independently selected from deuterium, halogen or C 1-6 alkyl;

Preferably, each R 9 , R 10 , R 13 or R n is independently selected from deuterium, halogen or C 1-4 alkyl.

Preferably, each R 9 , R 10 , R 13 or R n is independently selected from F, Cl, Br, methyl, ethyl or propyl;

Preferably, each R 9 , R 10 , R 13 or R n is independently selected from F, Cl, Br, methyl;

Or preferably, R a is selected from:

Or preferably, R a has any structure selected from the following:

Preferably, R a is selected from:
The compound according to any one of claims 1 to 4, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutical The above acceptable salt is characterized in that: formula (I) has the structure shown in formula (I'):

Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R a are each defined as described in formula (I);

Preferably, formula (I) has the structure shown in formula (I'-A) or formula (I'-B):

Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R a are each defined as described in formula (I).
The compound of claim 1, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt , the compound represented by formula (I) is selected from the following specific compounds:
A pharmaceutical composition, characterized in that it includes the compound described in any one of claims 1 to 6, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, Metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and pharmaceutical excipients.
The compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutical The above acceptable salt, or the use of the composition according to claim 7 in the preparation of a medicament for the treatment of related diseases caused by orthopoxvirus infection;

Preferably, the orthopoxvirus includes but is not limited to variola virus, monkeypox virus, camelpox virus, vaccinia virus, lepox virus and murine pox virus.
The compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutical The above acceptable salt, or the use of the pharmaceutical composition according to claim 7 in the treatment of related diseases caused by orthopoxvirus infection way;

Preferably, the orthopoxvirus includes but is not limited to variola virus, monkeypox virus, camelpox virus, vaccinia virus, lepox virus and murine pox virus.
The compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutical The above acceptable salt, or the pharmaceutical composition of claim 7, which is used to treat and/or prevent related diseases caused by orthopoxvirus infection;

Preferably, the orthopoxvirus includes but is not limited to variola virus, monkeypox virus, camelpox virus, vaccinia virus, lepox virus and murine pox virus.
A method for treating and/or preventing related diseases caused by orthopoxvirus infection, comprising administering to a subject/individual in need a therapeutically and/or preventively effective amount of a compound according to any one of claims 1-6 , or its tautomers, stereoisomers, polymorphs, co-crystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or as claimed in claim 7 Pharmaceutical compositions;

Preferably, the orthopoxvirus includes but is not limited to variola virus, monkeypox virus, camelpox virus, vaccinia virus, lepox virus and murine pox virus.