CN114057769A - Macrocyclic pyridazine compound and application thereof - Google Patents

Abstract

The present disclosure relates to macrocyclic pyridazine compounds and uses thereof. Specifically, the compound shown as the formula I or pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer and deuteron thereof are provided, wherein R is¹～R⁷、X¹～X⁹As defined herein. Further, the compounds of formula I can be used for preventing or treating infections caused by viruses.

Description

Macrocyclic pyridazine compound and application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a macrocyclic pyridazine compound and application thereof.

Background

Influenza viruses share three types: A. b and C. Influenza a viruses are the most common form and can be transmitted in dairy animals and birds. Subtypes of influenza a are named by the type of surface proteins hemagglutinin (H) and neuraminidase (N). Seasonal influenza viruses currently found in humans are mainly of the H1N1 and H3N2 subtypes. Influenza b viruses are generally found only in humans. They are not divided into subtypes, but can be further subdivided into different strains. Yearly epidemics of influenza viruses vary widely, and influenza a and b cause seasonal epidemics around the world. The symptoms of influenza c virus are much milder and do not cause epidemics.

Common anti-influenza drugs are: such a virus inhibitor is exemplified by a virus inhibitor, such as, for example, benomyl (Symmetrel, trade name: Amantadine) or Rimantadine hydrochloride (Flumadine, trade name: Rimantadine), Oseltamivir (Oseltamivir, trade name: Tamiflu) or Zanamivir (Zanamivir, trade name: Relenza (renza)) which inhibits the uncoating process of viruses. However, there is a need for the development of anti-influenza drugs having a novel mechanism, because of the problems of the occurrence and side effects of drug-resistant strains and the concern about the worldwide pandemic of a novel influenza virus having high pathogenicity or lethality.

On the other hand, cap-dependent endonucleases derived from influenza viruses are essential for virus propagation and have virus-specific enzymatic activities not possessed by the host, and therefore are suitable as targets for anti-influenza drugs.

WO2010147068 discloses a class of substituted polycyclic carbamoylpyridone derivatives having HIV integrase inhibitory activity and inhibiting influenza virus proliferation by having cap-dependent endonuclease inhibitory activity.

The following references may be used as background information:

CN109721615A, CN103228653A, WO2017104691, WO2017221869 disclose a series of pyridone derivatives or quinolizine derivatives, respectively, which can be used for inhibiting influenza virus proliferation and have lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties.

In addition, WO2020075080 discloses macrocyclic pyridotriazine derivatives useful as therapeutics or prophylactics for viral infections caused by viruses of the orthomyxoviridae family.

Disclosure of Invention

The disclosure provides compounds of formula I,

or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron thereof,

wherein R is¹Selected from alkylene (e.g. C)_1-6Alkylene, including but not limited to methylene, ethylene, propylene or isopropylene), alkylene-O-, alkylene-N-, cycloalkylene (e.g. C)_3-12Cycloalkylene radicals including, but not limited to, cyclopropylene, cyclopentylene, cyclohexylene) or heterocycloalkylene (e.g., 3-to 12-membered heterocycloalkyl, including, but not limited to, oxetane) optionally substituted with one or more groups selected from halogen (e.g., fluorine, chlorine, bromine), deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with A (e.g., C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), optionally substituted with ACycloalkyl (e.g. C)_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with a (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), SR ', NR' (R "), COOR 'or CONR' (R");

R²selected from O, alkylene (e.g. C)_1-6Alkylene, including but not limited to methylene, ethylene, propylene or isopropylene), cycloalkylene (e.g. C)_3-12Cycloalkylene groups, including but not limited to cyclopropylene, cyclopentylene, cyclohexylene), heterocycloalkylene groups (e.g., 3-to 12-membered heterocycloalkylene groups, including but not limited to oxetane, oxetane), alkylene-O-, alkylene-N-, alkenylene-O-, or alkenylene-N-, said alkylene, cycloalkylene, heterocycloalkylene, alkylene-O-, alkylene-N-, alkenylene-O-, or alkenylene-N-groups being optionally substituted with one or more groups selected from halogen (e.g., fluorine, chlorine, bromine), deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with A (e.g., C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl optionally substituted with A (e.g., C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with A (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), aryl optionally substituted with A (e.g., C_6-12Aryl including but not limited to phenyl or naphthyl), heteroaryl optionally substituted with a (e.g., 5-12 membered heteroaryl including but not limited to pyridyl or pyrrolyl), SR ', NR' (R "), COOR 'or CONR' (R");

R³selected from O, alkylene (e.g. C)_1-6Alkyl including but not limited to methylene, ethylene, propylene or isopropylene) or NH, optionally substituted with one or more groups independently selected from halogen (e.g. fluorine, chlorine, bromine), deuterium, oxo, nitrile, nitro, alkyl optionally substituted with A(s) ((s)Such as C_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g. C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl) or heterocycloalkyl (such as 3-to 12-membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl) optionally substituted with a;

or, R²And R³Together form an alkenylene group optionally substituted with one or more groups selected from halogen (e.g., fluorine, chlorine, bromine), deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with A (e.g., C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g. C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl) or heterocycloalkyl (such as 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl) optionally substituted with a;

X¹to X⁹Each independently selected from N or C, and X¹To X⁹Any one of which is selected from C, optionally substituted with one or more substituents independently selected from halogen (e.g. fluoro, chloro, bromo), deuterium, hydroxy, nitro, cyano, alkyl optionally substituted with A (e.g. C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g., C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with A (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), alkenyl optionally substituted with A, alkynyl optionally substituted with AAryl, optionally substituted with A (e.g. C)_6-12Aryl, including but not limited to phenyl or naphthyl), heteroaryl optionally substituted with A (e.g., 5-12 membered heteroaryl, including but not limited to pyridyl or pyrrolyl), SR ', SOR', SO₂R'、SO₂NR '(R "), COOR' or CONR '(R');

the dotted lines are each an optional bond;

R⁴is absent or selected from-CH₂-CH₂-、-O-CH₂-、-S-CH₂-、-S(O)-CH₂-、-S(O)₂-CH₂-or cycloalkyl, -said-CH₂-CH₂-、-O-CH₂-、-S-CH₂-、-S(O)-CH₂-、-S(O)₂-CH₂-or cycloalkyl optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with a (e.g. C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl optionally substituted with A (e.g., C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with A (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), aryl optionally substituted with A (e.g., C_6-12Aryl including but not limited to phenyl or naphthyl), heteroaryl optionally substituted with a (e.g., 5-12 membered heteroaryl including but not limited to pyridyl or pyrrolyl);

R⁵selected from hydrogen, alkyl (e.g. C)_1-6Alkyl including, but not limited to, methyl, ethyl, propyl, or isopropyl), cycloalkyl (e.g., C)_3-12Cycloalkyl groups including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl (e.g., 3-to 12-membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), aryl (e.g., C)_6-12Aryl, including but not limited to phenyl or naphthyl) or heteroaryl (e.g. 5-12 membered heteroaryl, including but not limited to pyridyl or pyrazinylPyrrolyl), said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', NR ' (R "), COR ', OCOR ', OCOOR ', COOR ', CONR ' (R"), OCONR ' (R ") or oc (o) alkyl NR ' (R");

R⁶or R⁷Each independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), alkyl (e.g. C)_1-6Alkyl including, but not limited to, methyl, ethyl, propyl, or isopropyl), cycloalkyl (e.g., C)_3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl (such as 3-to 12-membered heterocycloalkyl, including but not limited to oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), said alkyl, cycloalkyl or heterocyclyl being optionally substituted with one or more groups selected from halo (such as fluoro, chloro, bromo), deuterium, hydroxy, nitro, cyano, alkyl optionally substituted with A (such as C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g., C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with a (such as 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), alkenyl optionally substituted with a, alkynyl optionally substituted with a, aryl optionally substituted with a, heteroaryl optionally substituted with a, SR ', NR' (R "), COOR ', or CONR' (R"); or R⁶Or R⁷Together with their adjacent carbon atoms form a 3-to 12-membered carbocyclic or heterocyclic ring, preferably a 3-to 8-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more groups selected from halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl optionally substituted by A (e.g. C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), optionally substituted withA substituted cycloalkyl (e.g. C)_3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl (such as 3 to 12 membered heterocycloalkyl, including but not limited to oxetane, tetrahydropyrrolyl, tetrahydrofuryl) optionally substituted with a, alkenyl optionally substituted with a, alkynyl optionally substituted with a, aryl (such as C) optionally substituted with a_6-12Aryl including but not limited to phenyl or naphthyl), heteroaryl optionally substituted with a (e.g., 5-12 membered heteroaryl including but not limited to pyridyl or pyrrolyl);

each R ', R ' or R ' is independently selected from hydrogen, deuterium, hydroxyl, alkyl (e.g., C)_1-20Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)_3-12Cycloalkyl groups including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl (e.g., 3-to 12-membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), aryl (e.g., C)_6-12Aryl, including but not limited to phenyl or naphthyl) or heteroaryl (e.g., 5-12 membered heteroaryl, including but not limited to pyridyl or pyrrolyl), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with A (e.g., C)_1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy optionally substituted with A (e.g. C_1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl optionally substituted with A (e.g., C_3-12Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with A (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, oxetane, tetrahydropyrrolyl, tetrahydrofuranyl), aryl optionally substituted with A (e.g., C_6-12Aryl including but not limited to phenyl or naphthyl), heteroaryl optionally substituted with a (e.g., 5-12 membered heteroaryl including but not limited to pyridyl or pyrrolyl);

a is selected from halogen (such as fluorine, chlorine, bromine), deuterium, hydroxyl, oxo, nitro, cyano, C_1-6Alkyl (including but not limited to methyl, ethyl, propyl or isopropyl), C_1-6Alkoxy (including but not limited to methoxy, ethoxy, propoxy or isopropoxy), C_3-7Cycloalkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), 3-12 membered heterocyclyl (including but not limited to oxetane, tetrahydropyrrolyl, tetrahydrofuryl), 6-12 membered aryl (including but not limited to phenyl or naphthyl), 5-12 membered heteroaryl (including but not limited to pyridinyl or pyrrolyl), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen (e.g., fluoro, chloro, bromo), deuterium, hydroxy, oxo, nitro, cyano.

In some embodiments, R in the compound of formula I¹Is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene or 3-to 7-membered heterocycloalkylene, C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene N-is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl.

In some embodiments, R in the compound of formula I²Is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-C_2-6Alkenylene N-with said C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene radicalN-is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl;

R³selected from O, C_1-6Alkylene or NH, said C_1-6Alkylene is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo, nitrile, nitro or C_1-6Alkyl substituted;

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen, hydroxy, deuterium, oxo, nitrile, nitro or C_1-6Alkyl groups are substituted.

In some embodiments, X in the compound of formula I¹To X⁹Each independently selected from N or C, and X¹To X⁹Is selected from C, said C is optionally substituted by one or more substituents independently selected from halogen, deuterium, hydroxy, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂Said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl) or-SO₂N(C_1-6Alkyl radical)₂Optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, oxo, nitro or cyano.

In another aspect, the dashed lines in the compounds of formula I are each optional bonds; r⁴Is absent or selected from-CH₂CH₂-、-OCH₂-、-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-CH₂CH₂-、 -OCH₂-、-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with a, alkoxy optionally substituted with a, cycloalkyl optionally substituted with a, heterocycloalkyl optionally substituted with a, a being as defined for compounds of formula I.

In some embodiments, R in the compound of formula I⁵Selected from hydrogen, deuterium, or C_1-6Alkyl optionally substituted with one or more groups selected from deuterium, COR ', OCOR ', OCOOR ', COOR ', CONR ' (R "), OCONR ' (R") or OC (O) C (R ') NR "(R '"), each R ' or R "being independently selected from C optionally substituted with A_1-6Alkyl, C optionally substituted by A_3-7Cycloalkyl, 3-to 7-membered heterocycloalkyl optionally substituted by A, C optionally substituted by A_6-12Aryl, 5-to 12-membered heteroaryl optionally substituted with A as defined in compounds of formula I.

Some embodiments provide compounds of formula I wherein a is selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

Further, some embodiments provide R in the compound of formula I⁵Selected from hydrogen or-C (O) R', -C_1-6Alkyl O (CO) R', -C_1-6Alkyl O (CO) OR', -C_1-6Alkyl O (CO) NHR', -C_1-6Alkyl O (CO) C (R ') NR', R 'and R' are independently selected from hydrogen or C_1-6An alkyl group.

In some embodiments, R in the compound of formula I⁶Or R⁷Each independently selected from hydrogen, deuterium, halogen, hydroxy, C_1-6Alkyl radical, C_3-7Cycloalkyl, 3-to 7-membered heterocycloalkyl, said C_1-6Alkyl radical, C_3-7Cycloalkyl or 3-to 7-membered heterocycloalkyl optionally substituted by one or more groups selected from nitro, nitrile, hydroxy, deuterium, halogen, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy substituted; or R⁶Or R⁷Together with adjacent carbon atoms thereof form C_3-7Cycloalkyl, or 3 to 7 membered heterocycloalkyl, said C_3-7Cycloalkyl or 3-to 7-membered heterocycloalkyl optionally substituted with one or more substituents selected from nitroRadical, deuterium, nitrile radical, hydroxyl radical, halogen, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy groups.

In some embodiments, R in the compounds of formula I of the present disclosure¹Is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene or 3-to 7-membered heterocycloalkylene, C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene or 3-to 7-membered heterocycloalkylene optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl;

R²is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene N-with said C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene N-is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl;

R³is selected from-O-, C_1-6Alkylene or NH, said C_1-6Alkylene is optionally substituted with one or more substituents independently selected from halogen, deuterium, oxo, nitrile, nitro or C_1-6Alkyl substituted;

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen, hydroxy, deuterium, oxo, nitrile, nitro or C_1-6Alkyl substituted;

X¹to X⁹Each independently selected from N or C, and X¹To X⁹Is selected from C, said C is optionally substituted by one or more substituents independently selected from halogen, deuterium, hydroxy, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂C is said_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl) or-SO₂N(C_1-6Alkyl radical)₂Optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, oxo, nitro or cyano; the dotted lines are each an optional bond; r⁴Is absent or selected from-CH₂CH₂-、-OCH₂-、 -SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-CH₂CH₂-、-OCH₂-、-SCH₂-、 -S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with a, alkoxy optionally substituted with a, cycloalkyl optionally substituted with a, heterocycloalkyl optionally substituted with a;

R⁵selected from hydrogen OR-C (O) R ', - (C) O (CO) OR ', - (C) O (CO) NHR ', - (C) O (CO) C (R ') NH (R ' "), R ' and R '" are independently selected from hydrogen OR C (O) R ', - (C) O (CO) NH (R ' "), R ' and R '" are independently selected from hydrogen OR C_1-20An alkyl group;

R⁶or R⁷Each independently selected from hydrogen, deuterium, C_1-6Alkyl or C_3-7Cycloalkyl radical, said C_1-6Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷Together with their adjacent carbon atoms form C_3-7Cycloalkyl or C_4-7A heterocycloalkyl group;

a is selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

In other embodiments, R in the compound of formula I¹Is selected from C_1-4Alkylene radical, C_1-4alkylene-O-, C_1-4alkylene-N-, C_3-6Cycloalkylene or 3-to 6-membered heterocycloalkylene, C_1-4Alkylene radical, C_1-4alkylene-O-C_1-4alkylene-N-, C_3-6Cycloalkylene or 4-to 6-membered heterocycloalkylene optionally substituted with one or more groups selected from halogen, deuterium, oxo, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7Cycloalkyl groups are substituted.

Further, in some embodiments, R in the compound of formula I¹Is selected from-CH₂-、-CH₂CH₂-、 -CH(CH₃)-、-CH(CH₂CH₃)-、

Optionally substituted with one or more groups selected from halogen (e.g. fluoro), deuterium, oxo, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7Cycloalkyl groups are substituted.

Further, some embodiments provide R in the compound of formula I²Is selected from C_1-6Alkylene radical, C_3-6Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6alkenylene-O-, C_2-6alkenylene-N-, said C_1-6Alkylene radical, C_3-6Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6alkenylene-O-or C_2-6alkenylene-N-optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted;

R³selected from O, C_1-6Alkylene radical of the formula C_1-6Alkylene is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo or C_1-4Alkyl substituted;

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen, deuterium, oxo or C_1-4Alkyl groups are substituted.

In other embodiments, X in the compound of formula I¹To X⁹Each independently selected from N or C, and X¹To X⁹Is selected from C, said C being optionally substituted by one or more groups independently selected from halogen, deuterium, hydroxy, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy, C optionally substituted by halogen_3-7Cycloalkyl, -SCF₃、-SCH₃、-SCH₃、-SO₂CH₃or-SO₂CF₃And (4) substituting.

In certain embodiments, the dashed lines in the compounds of formula I are each an optional bond; r⁴Is absent or selected from-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-SCH₂-、-S(O)CH₂-、 -S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy groups.

Further, R in the compound shown in the formula I⁵Selected from hydrogen OR-C (O) R ', - (C) O (CO) OR ', - (C) O (CO) NHR ', - (C) O (CO) C (R ') NH (R ' "), R ' and R '" are independently selected from hydrogen OR C (O) R ', - (C) O (CO) NH (R ' "), R ' and R '" are independently selected from hydrogen OR C_1-20Alkyl (e.g. C)_1-6Alkyl groups including, but not limited to, methyl, ethyl, or propyl).

In other embodiments, R in the compound of formula I⁶Or R⁷Each independently selected from hydrogen, deuterium, C_1-6Alkyl or C_3-7Cycloalkyl radical, said C_1-6Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷To its adjacent carbon atom oneForm C_3-7Cycloalkyl radical, C_4-7A heterocycloalkyl group.

Further, in some embodiments, R in the compound of formula I⁶Or R⁷Each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷Together with adjacent carbon atoms thereof form

Further, the present disclosure provides R in the compound of formula I¹Is selected from C_1-4Alkylene (including but not limited to methylene, ethylene or propylene), C_1-4alkylene-O- (including but not limited to-CH)₂O-、 -CH₂CH₂O-、-CH₂CH₂CH₂O-)、C_1-4alkylene-N- (including but not limited to-CH)₂NH-、-CH₂CH₂NH-、 -CH₂CH₂CH₂NH-)、C_3-6Cycloalkylene (including but not limited to cyclobutyl, cyclopropylene, cyclohexylene) or 3-to 6-membered heterocycloalkylene (including but not limited to oxetane, oxetane), C_1-4Alkylene radical, C_1-4alkylene-O-, C_1-4alkylene-N-, C_3-6Cycloalkylene or 3-to 6-membered heterocycloalkylene optionally substituted with one or more substituents selected from halogen (including but not limited to fluoro or chloro), deuterium, oxo, C_1-6Alkyl (including but not limited to methyl, ethyl, propyl or isopropyl), C_1-6Alkoxy (including but not limited to methoxy, ethoxy, propoxy or isopropoxy) or C_3-7Cycloalkyl groups (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl);

R²is selected from C_1-6Alkylene (including but not limited to methylene, ethylene or propylene), C_3-6Cycloalkylene radicals (including but not limited to cyclobutyl, cyclopropyleneAlkyl, cyclohexylidene), C_2-6Alkenylene (including but not limited to ethenylene, propenylene), C_2-6alkenylene-O-, C_2-6alkenylene-N-, said C_1-6Alkylene radical, C_3-6Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6alkenylene-O-or C_2-6alkenylene-N-optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl (including but not limited to methyl, ethyl or propyl), C_1-4Alkoxy (including but not limited to methoxy, ethoxy, propoxy, or isopropoxy);

R³selected from O, C_1-6Alkylene (including but not limited to methylene, ethylene or propylene), said C_1-6Alkylene is optionally substituted by one or more substituents independently selected from halogen (e.g. fluoro or chloro), deuterium, oxo or C_1-4Alkyl (including but not limited to methyl, ethyl or propyl);

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen (e.g. fluoro or chloro), deuterium, oxo or C_1-4Alkyl (including but not limited to methyl, ethyl, or propyl);

the dotted lines are each an optional bond; r⁴Is absent or selected from-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy substituted;

R⁵selected from hydrogen OR-C (O) R ', - (C) O (CO) OR ', - (C) O (CO) NHR ', - (C) O (CO) C (R ') NH (R ' "), R ' and R '" are independently selected from hydrogen OR C (O) R ', - (C) O (CO) NH (R ' "), R ' and R '" are independently selected from hydrogen OR C_1-4Alkyl (including but not limited to methyl, ethyl, or propyl);

R⁶or R⁷Each independently selected from hydrogen, deuterium, C_1-6Alkyl (including but not limited to methyl,Ethyl or propyl) or C_3-7Cycloalkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), said C_1-6Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷Together with their adjacent carbon atoms form C_3-7Cycloalkyl or C_4-7A heterocycloalkyl group;

X¹to X⁹Each independently selected from N or C, and X¹To X⁹Any one of which is selected from C, said C being optionally substituted by one or more groups independently selected from halogen (e.g. fluoro or chloro), deuterium, hydroxy, C optionally substituted by halogen_1-4Alkyl (including but not limited to methyl, ethyl or propyl), C optionally substituted with halogen_1-4Alkoxy (including but not limited to methoxy, ethoxy, propoxy or isopropoxy), C optionally substituted with halogen_3-7Cycloalkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), -SCF₃、-SCH₃、-SCH₃、-SO₂CH₃or-SO₂CF₃And (4) substituting.

Typical compounds of formula I include, but are not limited to:

or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron thereof.

The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron, and pharmaceutically acceptable excipient thereof.

In some embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000 mg.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of the compound of formula I, or a pharmaceutically acceptable salt thereof, as described above, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of a compound of formula I as described above or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises from 0.5% to 99.5% of a compound of formula I as described above or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a compound of formula I as described above or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises from 2% to 98% of a compound of formula I as described above or a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

In another aspect, the present disclosure also provides a method for preventing or treating a viral infection by administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron, or a pharmaceutical composition of the foregoing.

The present disclosure also relates to the use of a compound represented by formula I as described in the above schemes, or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prevention or treatment of a patient suffering from a viral infection.

In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.

In another aspect, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure.

In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations.

The disclosed compounds may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.

All compounds in this disclosure can be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、 ¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and³⁶cl, and the like.

The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C)³H) The deuterium-substituted drug can be formed by replacing hydrogen with deuterium, the bond formed by deuterium and carbon is firmer than the bond formed by common hydrogen and carbon, and compared with the non-deuterated drug, the deuterium-substituted drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)²H) Substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life)Phase or reduced dosage requirements) and thus may be preferred in certain circumstances where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

Interpretation of terms:

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

"monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "alkylene" means a compound that "formally" eliminates two monovalent or one divalent formed atoms or groups of atoms. Examples "alkyl" refers to the moiety remaining after removal of 1 hydrogen atom from an alkane molecule, and includes straight and branched chain monovalent groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independentlySelected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkylene (-CH)₂- "then denotes the remaining part of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. Alkylene having 1 to 6 carbon atoms, non-limiting examples of which include methylene (-CH)₂-), ethylene (e.g. -CH)₂CH₂-or-CH (CH)₃) -), propylene (e.g. -CH)₂CH₂CH₂-or-CH (CH)₂CH₃) -) butylene (e.g., -CH₂CH₂CH₂CH₂-). The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

Similarly, "alkyleneoxy", "alkenylene", "alkyleneoxy", "cycloalkylene", "heterocycloalkylene" are as defined for "alkylene".

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C_2-6Alkenyl "denotes alkenyl having 2,3,4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl groups.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heteroCyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

and so on.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

and the like.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, orC is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, preferably phenyl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

and so on.

The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "hydroxy" refers to an-OH group.

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

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to the ═ O substituent.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the case where the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

Which are known in the art to protect reactive groups (including, without limitation, hydroxyl and amino groups) from side reactions during the synthetic process. Hydroxy and amino groups protected with protecting groups are referred to herein as "protected hydroxy" and "protected amino", respectively. Protecting groups are typically used selectively and/or orthogonally to protect sites during reaction of other reactive sites and can then be removed while leaving the unprotected group intact or taking part in further reactions. Protecting Groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of "hydroxy protecting groups" include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl (TBDPS). Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1- (4-biphenyl) -ethoxy-carbonyl (Bpoc), tert-Butoxycarbonyl (BOC), and benzyloxycarbonyl (Cbz).

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS). The spatial configuration of the optical isomers (isomers) of the compounds can be further confirmed by measuring parameters of the single crystal.

HPLC measurements were performed using Waters ACQUITY ultra high Performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatography (ACQUITY UPLC BEH C181.7UM 2.1.1X 50MM column, Ultimate XB-C183.0. 150mm column or xtmate C182.1. 30mm column).

MS is measured by a Waters SQD2 mass spectrometer, scanning is carried out in a positive/negative ion mode, and the mass scanning range is 100-1200.

Chiral HPLC analysis and determination using Chiralpak IC-3100 × 4.6mm I.D., 3um, Chiralpak AD-3150 × 4.6mm I.D., 3um, Chiralpak AD-350 × 4.6mm I.D., 3um, Chiralpak AS-3150 × 4.6mm I.D., 3um, Chiralpak AS-4.6 mm I.D., 3 μm, Chiralcel OD-3150 × 4.6mm I.D., 3um, Chiralcel OD- × 4.6mm I.D., 3 μm, Chiralcel OJ-H150 × 4.6mm I.D., 5um, Chiralcel OJ-3150 × 4.6mm I.D., 3um chromatographic column;

the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The flash column purification system used either Combiflash Rf150(TELEDYNE ISCO) or Isolara one (Biotage).

The forward column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel of the Titan yellow sea silica gel as a carrier, or uses a hyperpure normal phase silica gel column (40-63 μm, 60, 12g, 25g, 40g, 80g or other specifications) pre-filled by Santai in Changzhou.

Reverse phase column chromatography typically uses a column of ultrapure C18 silica gel (20-45 μm,

40g, 80g, 120g, 220g or other specifications).

The high pressure Column purification system used Waters AutoP in combination with Waters Xbridge BEH C18 OBD Prep Column,

5 μm, 19mm X150 mm or Atlantis T3 OBD Prep Column,

5μm，19mm X 150mm。

the chiral preparative column used DAICEL CHIRALPAK IC (250 mm. times.30 mm,10um) or Phenomenex-Amylose-1(250 mm. times.30 mm,5 um).

Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoshi Chemicals (Accela ChemBio Inc), Darri Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC).

Example 1

(E) -24, 25-difluoro-12-hydroxy-2, 6,9,17 a-tetrahydro-3, 4- (cyclopropyl1-en [1] yl [3] ylidene) -10, 17-methylenebenzo [6,7] thiepino [4,5-c ] pyridinylazao [1,6-f ] [1] oxa [5,6,9] triazacyclotridecyne-11, 13-

Diketones 1

First step of

3, 4-difluoro-2-methylbenzoic acid ethyl ester 1b

Thionyl chloride (11.4mL,156.85mmol) was added slowly to ethanol (90mL) at 0 deg.C and 3, 4-difluoro-2-methylbenzoic acid 1a (9g,52.28mmol) was added to the reaction. After the reaction was substantially completed at 80 ℃, the resulting mixture was concentrated under reduced pressure, diluted with 100 ml of a saturated sodium bicarbonate solution, and extracted three times with 100 ml of ethyl acetate. The organic phase was washed twice with 40 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 1b (10.3g, 98% yield).

¹H NMR:(400MHz,CDCl₃)δ＝7.76-7.67(m,1H),7.04(q,J＝8.8Hz,1H),4.36 (q,J＝6.8Hz,2H),2.55(d,J＝2.8Hz,3H),1.40(t,J＝7.2Hz,3H).

Second step of

3, 4-difluoro-6-hydroxy-2-methylbenzoic acid ethyl ester 1c

Compound 1c (5.3g,26.47mmol) was dissolved in a mixed solution of 30 ml of trifluoroacetic acid and 30 ml of trifluoroacetic anhydride, followed by the addition of potassium persulfate (17.9g,66.19mmol) and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (1.6g,2.65mmol) in that order. After the reaction was carried out at 100 ℃ to substantially complete under nitrogen, the crude product was concentrated under reduced pressure, diluted with 300 ml of ethyl acetate and 200 ml of water and filtered through celite. The filter cake was washed twice with 50 ml of ethyl acetate. The filtrate was extracted twice with 100 ml ethyl acetate, the combined organic phases were washed twice with 100 ml water, twice with 100 ml brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography purification (elution phase of ethyl acetate and petroleum ether) afforded the title compound 1c (3.58g, 63% yield).

¹H NMR:(400MHz,CDCl₃)δ＝11.44(d,J＝1.2Hz,1H),6.65(dd,J＝6.8,10.8 Hz,1H),4.45(q,J＝7.2Hz,2H),2.50(d,J＝2.8Hz,3H),1.45(t,J＝7.2Hz,3H).

The third step

3, 4-difluoro-6-methoxy-2-methylbenzoic acid ethyl ester 1d

Compound 1c (3.58g,16.56mmol) was dissolved in 30 ml of N, N-dimethylformamide, and sodium hydride (60% dispersed in liquid paraffin) (0.80g,19.87mmol) was added at 0 ℃ and stirred at this temperature for 30 minutes. Methyl iodide (1.34mL,21.53mmol) was added to the reaction, and after the reaction was continued at 0 ℃ to be substantially complete, the reaction solution was poured into 60 mL of saturated ammonium chloride solution, followed by extraction three times with 30 mL of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, twice with 20 ml of brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave a crude product, which was purified by column chromatography (elution phases ethyl acetate and petroleum ether) to give the title compound 1d (3.6g, 94% yield).

¹H NMR:(400MHz,CDCl₃)δ＝6.60(dd,J＝6.4,12.0Hz,1H),4.39(q,J＝7.2 Hz,2H),3.79(s,3H),2.25(d,J＝2.4Hz,3H),1.38(t,J＝7.2Hz,3H).

The fourth step

2- (bromomethyl) -3, 4-difluoro-6-methoxybenzoic acid ethyl ester 1e

Compound 1d (3.6g,15.64mmol) was dissolved in 30 mL of acetonitrile, and N-bromosuccinimide (4.17g,23.46mmol) and azobisisobutyronitrile (0.61g,3.13mmol) were added in that order. After the reaction was substantially completed at 80 ℃, acetonitrile was removed by concentration under reduced pressure, and 60 ml of water was added for dilution. The mixture was extracted three times with 30 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water and twice with 20 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography purification (elution phase ethyl acetate and petroleum ether) afforded the title compound 1e (3.8g, 79% yield).

¹H NMR:(400MHz,CDCl₃)δ＝6.75(dd,J＝6.0,11.2Hz,1H),4.54(d,J＝1.6 Hz,2H),4.45(q,J＝7.2Hz,2H),3.82(s,3H),1.42(t,J＝7.2Hz,3H).

The fifth step

3, 4-difluoro-6-methoxy-2- [ (phenylsulfanyl) methyl ] benzoic acid ethyl ester 1f

Compound 1e (3.8g,12.29mmol) was dissolved in 150 mL of acetone, followed by the addition of sodium thiophenolate (1.95g,14.75 mmol). After the reaction was substantially complete at 30 ℃, the celite was filtered and the filter cake was washed twice with 30 ml of acetone. Concentration under reduced pressure gave a crude product which was purified by column chromatography (elution phase of ethyl acetate and petroleum ether) to give the title compound 1f (3.7g, 89% yield).

¹H NMR：(400MHz,CDCl₃)δ＝7.41-7.32(m,2H),7.30-7.27(m,1H),7.27-7.20 (m,2H),6.65(dd,J＝6.0,11.6Hz,1H),4.36(q,J＝7.2Hz,2H),4.21(d,J＝1.6Hz, 2H),3.80(s,3H),1.36(t,J＝7.2Hz,3H).

The sixth step

3, 4-difluoro-6-methoxy-2- ((phenylthio) methyl) benzoic acid 1g

After compound 1f (6g,17.73mmol) was dissolved in 60 ml of ethanol and 30 ml of water and sodium hydroxide (3.55g,88.66mmol) was added thereto to react at 80 ℃ until completion, the reaction solution was concentrated under reduced pressure to remove ethanol, and then diluted with 40 ml of water. And adjusting the pH of the mixed solution to 3-4 by using 2 mol/L hydrochloric acid solution. Extracted three times with 50 ml ethyl acetate, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the title compound 1g (6g, crude) which was used in the next step without purification.

¹H NMR:(400MHz,CDCl₃)δ＝7.36-7.28(m,2H),7.19-7.15(m,2H),6.64(dd,J ＝6.0,11.2Hz,1H),4.31(d,J＝1.6Hz,2H),3.80(s,3H).

Seventh step

12, 13-difluoro-15-methoxy-9-thiatricyclo [9.4.0.0^ {3,8} ] pentadecan-1 (11),3(8),4,6,12, 14-hexaen-2-one 1h

1g (5g,16.11mmol) of the compound was dissolved in 50 ml of polyphosphoric acid and reacted at 120 ℃ for 1 hour. The temperature of the reaction solution was lowered to 0 ℃, then 150 ml of ice water was added, and the reaction solution was filtered after stirring until substantially complete reaction. The filter cake was washed twice with 15 ml of water to give the title compound 1h (4.48g, crude) which was used in the next step without further purification.

MS(ESI)m/z 293.0[M+H]⁺

¹H NMR:(400MHz,CDCl₃)δ＝7.88(dd,J＝1.6,8.4Hz,1H),7.33-7.26(m,1H), 7.19-7.14(m,2H),6.60(dd,J＝6.0,11.6Hz,1H),4.01(s,2H),3.69(s,3H).

Eighth step

12, 13-difluoro-15-hydroxy-9-thiatricyclo [9.4.0.0^ {3,8} ] pentadecan-1 (11),3(8),4,6,12, 14-hexaen-2-one 1i

Compound 1h (4.48g,15.33mmol) was added to 60 mL of dichloromethane and boron tribromide (2.95mL,30.65mmol) diluted in 30 mL of dichloromethane was added slowly dropwise at 0 ℃. After the reaction was substantially complete at 0 ℃ under nitrogen, the reaction was quenched with 60 ml of saturated sodium bicarbonate solution. Extracted three times with 40 ml of dichloromethane. The combined organic phases were washed twice with 40 ml of water, twice with 40 ml of brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the title compound 1i (3.45g, crude) which was used in the next step without further purification.

MS(ESI)m/z 279.0[M+H]⁺

¹H NMR:(400MHz,CDCl₃)δ＝12.80(d,J＝1.2Hz,1H),8.23(dd,J＝1.6,8.0 Hz,1H),7.54-7.34(m,3H),6.77(dd,J＝7.2,11.2Hz,1H),4.14(d,J＝0.8Hz,2H).

The ninth step

12, 13-difluoro-15- (prop-2-en-1-oxy) -9-thiatricyclo [9.4.0.0^ 3,8} pentadecan-1 (11),3(8),4,6,12, 14-hexaen-2-one 1k

After compound 1i (3.45g, crude) was dissolved in 60 mL of acetonitrile and potassium carbonate (5.14g,37.19 mmol) and allyl bromide ((1.62mL,18.60mmol) were added the reaction was reacted to substantial completion at 50 ℃, filtered through celite, the filter cake was washed twice with 20 mL ethyl acetate and concentrated under reduced pressure to give the title compound 1k (4.2 g, crude) which was used in the next step without further purification.

¹H NMR:(400MHz,CDCl₃)δ＝8.02-7.85(m,1H),7.43-7.36(m,1H),7.28-7.24 (m,1H),6.69(dd,J＝6.0,11.6Hz,1H),6.02-5.88(m,1H),5.48-5.20(m,2H), 4.55-4.43(m,2H),4.11(s,2H).

The tenth step

12, 13-difluoro-15- (prop-2-en-1-oxy) -9-thiatricyclo [9.4.0.0^ 3,8} pentadecan-1 (11),3(8),4,6,12, 14-hexaen-2-ol 1l

Compound 1k (4g, crude) was dissolved in 80 mL tetrahydrofuran and lithium aluminum hydride (0.48g,12.57mmol) was added at 0 ℃ under nitrogen. After the reaction was substantially completed at 0 ℃, 2ml of water, 2ml of 15% sodium hydroxide solution and 6ml of water were sequentially added to the reaction system. After filtration through celite, the filter cake was washed twice with 50 ml of ethyl acetate. The filtrate was washed with 50 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (elution phases of ethyl acetate and petroleum ether) to give the title compound 1l (1.76 g, total yield 33% over 5 consecutive steps).

¹H NMR:(400MHz,CDCl₃)δ＝7.38(d,J＝7.2Hz,1H),7.20-7.13(m,2H), 7.13-7.07(m,1H),6.63(dd,J＝6.4,11.6Hz,1H),6.43(br s,1H),6.10-5.96(m,1H), 5.50-5.39(m,1H),5.38-5.30(m,1H),5.20(dd,J＝1.6,14.0Hz,1H),4.49(br d,J＝ 5.2Hz,2H),4.05(d,J＝14.4Hz,1H),3.13(br s,1H).

The eleventh step

3, 4-Dicarbonylhexanedicarboxylic acid diethyl ester 1n

60% sodium hydride (4.0g,99.57mmol) dispersed in oil was suspended in 100 mL tetrahydrofuran and ethanol (5.8mL,99.46mmol) was added slowly at room temperature. After the reaction was carried out at 80 ℃ for 30 minutes, 1m (13.6mL,99.57mmol) of diethyl oxalate and 9.7mL,99.57mmol of ethyl acetate were added to the reaction mixture in this order. After the reaction was continued at 80 ℃ for 30 minutes, 60% sodium hydride (4.0g,99.57mmol) dispersed in oil and ethyl acetate (9.7mL,99.57mmol) were added to the reaction mixture. After the reaction was continued at 80 ℃ until completion, the reaction was concentrated under reduced pressure, and after the concentration was completed, the reaction mixture was diluted with 200 ml of a 15% ice hydrochloric acid solution, and filtered to obtain a solid, which was then slurried with ethanol, and filtered to obtain the title compound 1n (8g, yield 35%).

MS(ESI)m/z 231.3[M+H]⁺

The twelfth step

5-hydroxy-4-carbonyl-1, 4-dihydropyridazine-3, 6-dicarboxylic acid diethyl ester 1o

The compound 1n (7.9g,34.32mmol) is dissolved in 190 mL of acetonitrile, the temperature of the reaction system is reduced to 0-5 ℃ through an ice water bath, and then triethylamine (14.3mL,102.95mmol) and 4-acetamidophenylsulfonyl azide (9.1g,37.75mmol) are sequentially added. After the reaction was substantially completed at room temperature, it was concentrated under reduced pressure to give a crude product, which was then diluted with 200 ml of dichloromethane, stirred for 10 minutes and filtered, the filtrate was washed twice with 200 ml of 1mol/l hydrochloric acid solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a solid, slurried with 50 ml of ethyl acetate, and filtered to give the title compound 1o (4g, yield 45%).

MS(ESI)m/z 257.3[M+H]⁺

Thirteenth step

1-amino-5-hydroxy-4-carbonyl-1, 4-dihydropyridazine-3, 6-dicarboxylic acid diethyl ester 1p

Compound 1o (4g,15.61mmol) was dissolved in 40 ml of N, N-dimethylformamide, and potassium carbonate (6.5g,46.84mmol) was added thereto at room temperature, followed by stirring for 5 minutes, to which was added 2, 4-dinitrophenylhydroxylamine (3.7g, 18.73 mmol). After the reaction was substantially completed at room temperature, the reaction solution was diluted with 80 ml of dichloromethane, 200 ml of 1mol/L hydrochloric acid solution was added, extraction was performed twice with 200 ml of dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to obtain a solid, slurried with 50 ml of ethyl acetate, and filtered to obtain the title compound 1p (2.8g, 66% yield).

MS(ESI)m/z 272.3[M+H]⁺

Fourteenth step

1-amino-5- (benzyloxy) -4-carbonyl-1, 4-dihydropyridazine-3, 6-dicarboxylic acid diethyl ester 1q

Compound 1p (2.7g,9.95mmol) was dissolved in 54 mL tetrahydrofuran and triphenylphosphine (1.3g,12.94mmol), benzyl alcohol (1.34mL,12.94mmol) and diisopropyl azodicarboxylate (2.56mL,12.94mmol) were added sequentially under ice water bath and nitrogen blanket. After the reaction was substantially completed at room temperature, the crude product was concentrated under reduced pressure and purified by column chromatography (elution phases of ethyl acetate and n-hexane) to obtain the title compound 1q (2.2g, yield 61%).

MS(ESI)m/z 362.4[M+H]⁺

The fifteenth step

1-amino-5- (benzyloxy) -6- (carbethoxy < ethoxycarbonyl >) -4-carbonyl-1, 4-dihydropyridazine-3-carboxylic acid 1r

Compound 1q (1g,2.77mmol) was dissolved in 25 ml of tetrahydrofuran and 25 ml of ethanol, and 5ml of 1mol/l sodium hydroxide solution was slowly dropped under ice water bath. After the reaction solution was almost completed in an ice water bath, 5ml of 1mol/l hydrochloric acid solution was added for neutralization, followed by concentration under reduced pressure to remove the solvent, dilution with 20 ml of water and extraction with 30 ml of dichloromethane twice. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1r (922mg, 87% yield).

MS(ESI)m/z 334.4[M+H]⁺

Sixteenth step

6- (Allylcarbamoyl) -1-amino-5- (benzyloxy) -4-carbonyl-1, 4-dihydropyridazine-3-carboxylic acid 1t

Compound 1r (800mg,2.40mmol) was dissolved in 3ml of 1, 8-diazabicyclo [5.4.0] undec-7-ene, 3ml of 60% aqueous allylamine hydrochloride was added, the reaction was allowed to proceed to completion at 80 ℃, and after completion of the reaction, 20 ml of 1mol/l hydrochloric acid solution was added at room temperature for dilution, followed by extraction with dichloromethane, drying with anhydrous sodium sulfate, and concentration under reduced pressure to give the title compound 1t (800mg, 97% yield).

MS(ESI)m/z 345.4[M+H]⁺

Seventeenth step

3-allyl-5- (benzyloxy) -4, 6-dicarbonyl-2, 3,4, 6-tetrahydro-1H-pyridoxazinyl [6,1-f ] [1,2,4] triazine

-7-carboxylic acid 1u

Compound 1t (800mg,2.33mmol) was dissolved in 10 ml of N, N-dimethylformamide, and paraformaldehyde (140mg,4.65mmol) and 2ml of acetic acid were added. After the reaction was substantially completed at 120 ℃,20 ml of water was added for dilution, and extraction was performed twice with 30 ml of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained crude product was dissolved in 10 ml of methanol, potassium carbonate (642mg,4.65mmol) was added thereto, and after stirring for reaction, the reaction was substantially completed, concentrated, diluted with 20 ml of 1mol hydrochloric acid solution, extracted twice with 30 ml of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained product was purified by C18 reverse phase column to obtain the title compound 1u (200mg, 24% yield).

MS(ESI)m/z 357.3[M+H]⁺

Eighteenth step

3-allyl-1- (10- (allyloxy) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -5- (benzyloxy) -4, 6-dicarbonyl-2, 3,4, 6-tetrahydro-1H-pyridoxaz [6,1-f ] [1,2,4] triazine-7-carboxylic acid 1v

Compound 1u (200mg,0.56mmol) was added to 2ml of a 50% solution of 1-propylphosphoric cyclic anhydride in ethyl acetate, and 10- (allyloxy) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-ol (216 mg,0.67mmol) was added. After the reaction was heated to 110 ℃ by microwave until it was substantially complete, the crude product was concentrated under reduced pressure and then purified by C18 reverse phase column to give the title compound 1v (200mg, 54% yield).

MS(ESI)m/z 659.4[M+H]⁺

Nineteenth step

3-allyl-1- (10- (allyloxy) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -7-amino-5- (benzyloxy) -2, 3-dihydro-1H-pyridoxazo [6,1-f ] [1,2,4] triazine-4, 6-dione 1w

Compound 1v (200mg,0.30mmol) was dissolved in 4mL of N, N-dimethylformamide, and triethylammine (0.21mL,1.51mmol) and diphenylphosphorylazide (249mg,0.91mmol) were added. The reaction was carried out at room temperature for 1 hour. Heating the reaction to 80 ℃ for 20 minutes, cooling the temperature to 0 ℃, adding 1.6 ml of 1mol/L sodium hydroxide solution, stirring the reaction solution at 0 ℃ until the reaction is almost complete, adding 10 ml of water for dilution, and neutralizing with 1mol/L hydrochloric acid solution. The reaction solution was extracted 2 times with 20 ml of ethyl acetate, and the organic phase was washed with 10 ml of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by C18 reverse phase column to give the title compound 1w (120mg, 63% yield).

MS(ESI)m/z 630.4[M+H]⁺

Twentieth step

3-allyl-1- (10- (allyloxy) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -5- (benzyloxy) -2, 3-dihydro-1H-pyridoxazo [6,1-f ] [1,2,4] triazine-4, 6-dione 1x

Compound 1w (120mg,0.19mmol) is dissolved in 3ml of tetrahydrofuran and 3ml of 50% hypophosphorous acid solution are added. The reaction was cooled to 0 ℃, sodium nitrite (26mg,0.38mmol) was added, the reaction was allowed to react to substantial completion at this temperature, after completion of the reaction 10 ml of water was added to the reaction, which was then extracted twice with 10 ml of ethyl acetate, washed with 10 ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1x (60mg, 51% yield).

MS(ESI)m/z 615.5[M+H]⁺

The twentieth step

(E) -12- (benzyloxy) -24, 25-difluoro-2, 6,9,17 a-tetrahydro-3, 4- (cyclopropa [1] en [1] yl [3] ylidene) -10, 17-methylenebenzo [6,7] thiepino [4,5-c ] pyridizidine diaza [1,6-f ] [1] oxa [5,6,9] triazacyclotridecyne-11, 13-dione 1y

(Z) -4- (benzyloxy) -23, 24-difluoro-7, 10,14,19 b-tetrahydro-13, 12- (cyclopropa [1] en [1] yl [3] ylidene) -6, 20-methylenebenzo [6,7] thiepino [4,5-c ] pyridinylazao [1,6-f ] [1] oxa [5,6,9] triazacyclotridecyne-3, 5-dione 1Z

Compound 1X (60mg,0.10mmol) was dissolved in 5mL of 1, 2-dichloroethane and ruthenium (VI) (12mg,0.02mmol) was added (1, 3-dimethylimidazolidin-2-ylidene) (2-isopropoxybenzylidene) ruthenium chloride. After the reaction was carried out at 80 ℃ to completion under argon atmosphere, the crude product was concentrated under reduced pressure and subjected to reverse phase purification with C18 to obtain the title compound 1y (10mg, yield 17%) and the title compound 1z (22mg, yield 38%), respectively.

1y MS (ESI) M/z 587.4[ M + H ]]⁺Retention time: 2.03 min.

1z MS (ESI) M/z 587.4[ M + H ]]⁺Retention time: 2.08 min.

The chromatographic method comprises the following steps:

a chromatographic column: waters Acquity UPLC BEH C181.7 μm 2.1x50 mm;

column temperature: 40 ℃;

flow rate: 0.6ml/min

The mobile phase is A, water (containing 0.05 percent of trifluoroacetic acid) B, acetonitrile (containing 0.05 percent of trifluoroacetic acid) and is eluted in a gradient way.

The twenty second step

(E) -24, 25-difluoro-12-hydroxy-2, 6,9,17 a-tetrahydro-3, 4- (cyclopropa [1] en [1] yl [3] ylidene) -10, 17-methylenebenzo [6,7] thiepino [4,5-c ] pyridizidine diaza [1,6-f ] [1] oxa [5,6,9] triazacyclotridecyne-11, 13-dione 1

Compound 1y (10mg,0.017mmol) was dissolved in 4ml of acetonitrile and magnesium dibromide (6mg, 0.034mmol) was added. The reaction was allowed to react at 50 ℃ to substantial completion, concentrated, and subjected to reverse phase purification with C18 to give the title compound 1(3.5mg, 41% yield).

MS(ESI)m/z 497.4[M+H]+

¹H NMR(400MHz,DMSO-d6)δ＝7.56(dd,J＝7.2,11.6Hz,1H),7.14(s,1H), 7.11-7.04(m,1H),6.98(d,J＝8.0Hz,1H),6.89-6.82(m,1H),6.75(d,J＝7.2Hz,1H), 6.34-6.17(m,2H),6.13(br d,J＝14.4Hz,1H),5.54(s,1H),5.13(d,J＝14.4Hz,1H), 4.81-4.73(m,1H),4.73-4.59(m,2H),4.33(d,J＝14.4Hz,1H),4.00(br d,J＝14.0 Hz,1H),3.18(br dd,J＝8.4,13.2Hz,1H).

Example 2

(Z) -23, 24-difluoro-4-hydroxy-7, 10,14,19 b-tetrahydro-13, 12- (cyclopropa [1] en [1] yl [3] ylidene) -6, 20-methanobenzo [6,7] thiepino [4,5-c ] pyridinylazao [1,6-f ] [1] oxa [5,6,9] triazacyclotridecyne-3, 5-dione 2

Compound 1z (22mg,0.038mmol) was dissolved in 4ml of acetonitrile and magnesium dibromide (14mg, 0.079mmol) was added. The reaction was allowed to react at 50 ℃ to substantial completion, concentrated, and subjected to reverse phase purification with C18 to give the title compound 2(7mg, 37% yield).

MS(ESI)m/z 497.4[M+H]+

¹H NMR(400MHz,DMSO_d6)δ＝7.50(br dd,J＝6.8,11.8Hz,1H),7.17-7.02 (m,3H),6.84(br t,J＝7.3Hz,1H),6.53(br d,J＝7.7Hz,1H),6.43-6.25(m,2H),6.05 (s,1H),5.82(br d,J＝14.1Hz,1H),5.08(br d,J＝13.7Hz,1H),4.95-4.83(m,1H), 4.69-4.55(m,1H),4.42(br d,J＝13.8Hz,1H),4.21(br dd,J＝7.1,13.2Hz,1H),4.06- 3.88(m,2H).

Biological evaluation

The following further description explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

In vitro anti-influenza virus activity assay for compounds

1. Purpose of experiment

And (3) detecting the in-vitro anti-influenza virus activity of the compound by using a cytopathic effect experiment, and simultaneously detecting the toxicity of the compound to MDCK cells.

2. Experimental Material

2.1. Compound (I)

Test compounds were prepared as stock solutions in 100% DMSO, tested at 8 concentration points, 3-fold gradient diluted, double-well.

2.2. Cells

Canine kidney cells MDCK were purchased from ATCC, cat # CCL-34. Cells were cultured in EMEM (Sigma) medium supplemented with 10% fetal bovine serum (Hyclone), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acids (Gibco). The culture solution of OptiPRO SFM (Gibco) supplemented with 1% of double antibody, 1% of L-glutamine and 1% of non-essential amino acid was used as the experimental culture solution. The experimental culture medium to which pancreatin (Invitrogen) was added was a virus infection culture medium.

2.3. Virus

Influenza A/WSN/33(H1N1) strain was purchased from Virapur under accession number F1003A.

3. Experimental procedure

MDCK cells were seeded into 384-well test plates at a density of 2,000 cells per well and cultured overnight in a 5% CO2, 37 ℃ incubator. The next day, compounds (8 concentration points, duplicate wells) and virus were added to 384-well cell culture plates. The final concentrations of DMSO and pancreatin in the culture were 0.5% and 2.5. mu.g/ml, respectively. Cells were cultured in 5% CO2 at 37 ℃ for 5 days until cytopathic effects reached 80-95% in compound-free virus control wells. Cell viability was measured using the Cell counting kit 8 kit (Shanghai Liji). The cytotoxicity test is the same as the antiviral test condition, but without virus infection. The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) of the compound against the virus-induced cytopathic effect and the survival rate (%) of MDCK cells at different concentrations, respectively. The calculation formula is as follows:

inhibition (%) ═ test well readings-mean of virus controls)/(mean of cell controls-mean of virus controls) × 100

Cell viability (%) — x 100 (test well reading-broth control average)/(cell control average-broth control average)

Inhibition and cell viability of the compounds were analyzed by non-linear fit using GraphPad Prism software to calculate half maximal effective (EC50) and half maximal cytotoxic (CC50) concentrations of the compounds.

Mode (2): log (inhibitor) vs. response- -Variable slope

Formula, Y ═ Bottom + (Top-Bottom)/(1+10^ ((Logicc 50-X) } HillSlope))

In vitro anti-influenza virus activity and cytotoxicity of the compounds of the disclosure IC determined by the above protocol₅₀The values are shown in Table 1.

TABLE 1

Claims (10)

1. A compound of the formula I, wherein,

or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron thereof,

wherein the content of the first and second substances,

R¹is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene or 3-to 7-membered heterocycloalkylene, C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene or 3-to 7-membered heterocycloalkylene optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl;

R²is selected from C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene N-with said C_1-6Alkylene radical, C_1-6Alkylene O-C_1-6Alkylene N-, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkenylene O-or C_2-6Alkenylene N-is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitrile, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl substituted C_3-7Cycloalkyl radical, C_1-6Alkyl substituted 3 to 7 membered heterocycloalkyl;

R³is selected from-O-, C_1-6Alkylene or NH, said C_1-6Alkylene being optionally substituted by oneOr more are independently selected from halogen, deuterium, oxo, nitrile, nitro or C_1-6Alkyl substituted;

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen, hydroxy, deuterium, oxo, nitrile, nitro or C_1-6Alkyl substituted;

X¹to X⁹Each independently selected from N or C, and X¹To X⁹Is selected from C, said C is optionally substituted by one or more substituents independently selected from halogen, deuterium, hydroxy, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂Said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, -S (C)_1-6Alkyl), -SO (C)_1-6Alkyl), -SO₂(C_1-6Alkyl) or-SO₂N(C_1-6Alkyl radical)₂Optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, oxo, nitro or cyano; the dotted lines are each an optional bond; r⁴Is absent or selected from-CH₂CH₂-、-OCH₂-、-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-CH₂CH₂-、-OCH₂-、-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitrile, nitro, alkyl optionally substituted with a, alkoxy optionally substituted with a, cycloalkyl optionally substituted with a, heterocycloalkyl optionally substituted with a;

R⁵selected from hydrogen OR-C (O) R ', - (C) O (CO) OR ', - (C) O (CO) NHR ', - (C) O (CO) C (R ') NH (R ' "), R ' and R '" are independently selected from hydrogen OR C (O) R ', - (C) O (CO) NH (R ' "), R ' and R '" are independently selected from hydrogen OR C_1-20An alkyl group;

R⁶or R⁷Each independently selected from hydrogen, deuterium, C_1-6Alkyl or C_3-7Cycloalkyl radical, said C_1-6Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷Together with their adjacent carbon atoms form C_3-7Cycloalkyl or C_4-7A heterocycloalkyl group;

a is selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

2. The compound of claim 1, wherein R¹Is selected from C_1-4Alkylene radical, C_1-4alkylene-O-, C_1-4alkylene-N-, C_3-6Cycloalkylene or 3-to 6-membered heterocycloalkylene, C_1-4Alkylene radical, C_1-4alkylene-O-, C_1-4alkylene-N-, C_3-6Cycloalkylene or 3-to 6-membered heterocycloalkylene optionally substituted with one or more groups selected from halogen, deuterium, oxo, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7Cycloalkyl groups are substituted.

3. The compound of claim 1 or 2, wherein,

R²is selected from C_1-6Alkylene radical, C_3-6Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6alkenylene-O-or C_2-6alkenylene-N-, said C_1-6Alkylene radical, C_3-6Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6alkenylene-O-or C_2-6alkenylene-N-optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted;

R³selected from O, C_1-6Alkylene radical of the formula C_1-6Alkylene is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo or C_1-4Alkyl substituted;

or, R²And R³Together form C_2-8Alkenylene radical, said C_2-8Alkenylene is optionally substituted by one or more groups selected from halogen, deuterium, oxo or C_1-4Alkyl groups are substituted.

4. The compound according to any one of claims 1 to 3, wherein,

X¹to X⁹Each independently selected from N or C, and X¹To X⁹Is selected from C, said C being optionally substituted by one or more groups independently selected from halogen, deuterium, hydroxy, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy, C optionally substituted by halogen_3-7Cycloalkyl, -SCF₃、-SCH₃、-SCH₃、-SO₂CH₃or-SO₂CF₃And (4) substituting.

5. The compound of any one of claims 1-4,

the dotted lines are each an optional bond; r⁴Is absent or selected from-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl radical, said-SCH₂-、-S(O)CH₂-、-S(O)₂CH₂-or C_3-7Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, deuterium, oxo, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by halogen_1-4Alkoxy groups.

6. The compound of any one of claims 1-5, wherein R¹Is selected from-CH₂-、-CH₂CH₂-、-CH(CH₃)-、-CH(CH₂CH₃)-、

Optionally substituted by one or more groups selected from halogen, deuterium, oxo, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7Cycloalkyl groups are substituted.

7. The compound of any one of claims 1-6, wherein R⁶Or R⁷Each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted by one or more groups selected from halogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy substituted; or R⁶Or R⁷Together with adjacent carbon atoms thereof form

8. The compound of claim 1, selected from:

or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron thereof.

9. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer, deuteron, and pharmaceutically acceptable excipient thereof.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prophylaxis or treatment of a patient with a viral infection, preferably an influenza a virus infection, an influenza b virus infection or a combination thereof.