CN114948962A

CN114948962A - Application of dihydropyrimidine compound in preparation of anti-coronavirus drugs

Info

Publication number: CN114948962A
Application number: CN202210175201.XA
Authority: CN
Inventors: 任青云; 刘辛昌; 刘名; 张英俊
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2021-02-26
Filing date: 2022-02-25
Publication date: 2022-08-30

Abstract

The invention relates to an application of dihydropyrimidine compounds in preparing medicaments for treating and/or preventing coronavirus infection, in particular to an application in preparing medicaments for treating and/or preventing diseases or symptoms caused by novel coronavirus (SARS-CoV-2). In particular to the application of a compound shown in a general formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I) and the application of a pharmaceutical composition containing the compound in preparing medicaments for preventing and/or treating diseases or symptoms caused by coronavirus, in particular the application in preparing medicaments for treating and/or preventing diseases or symptoms caused by SARS-CoV-2, wherein all variables in the formula (I) are shown in the specificationAnd (4) defining.

Description

Application of dihydropyrimidine compound in preparation of anti-coronavirus drugs

Technical Field

The invention belongs to the technical field of medicaments, and relates to application of dihydropyrimidine compounds as medicaments for treating and/or preventing coronavirus infection, in particular to application of dihydropyrimidine compounds in preparing medicaments for treating and/or preventing diseases or symptoms caused by novel coronavirus (SARS-CoV-2). The invention also relates to the use of the pharmaceutical composition of these dihydropyrimidine compounds and other antiviral drugs in the preparation of drugs for treating and/or preventing diseases or symptoms caused by coronaviruses such as SARS-CoV-2.

Background

Coronaviruses (CoVs) belong to the order Neurovirales, family Coronaviridae, subfamily orthocoronaviruses; this subfamily includes four genera: α, β, γ, and δ. Before 2019, only 6 covs can infect humans and cause respiratory diseases: of these, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 induce only mild upper respiratory diseases and, in rare cases, cause severe infections in infants, young and elderly; SARS-CoV and MERS-CoV can infect the lower respiratory tract and cause severe respiratory syndrome in humans.

The novel coronavirus is the 7 th coronavirus which is discovered at present and can infect humans and cause diseases, belongs to beta coronavirus, is high in infectivity, can infect lower respiratory tract and cause pneumonia, and is named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 is single-stranded positive-strand RNA, its genome size is 29903nt, and contains 5 'end cap structure and 3' end polyadenylic tail (A new polynucleotide associated with human respiratory disease in China [ J ] Nature, 2020, 579 (7798): 265) -269), and under the electron microscope the virus is mostly spherical, and some are polymorphic, and its diameter is 60-140 nm. The virus particles have obvious spinous processes, about 9-12 nm, which make the virus corona-like.

The clinical manifestations of the new type of coronary virus pneumonia are mainly fever, hypodynamia and dry cough. A few patients have nasal obstruction, watery nasal discharge, myalgia, diarrhea and other symptoms. In severe cases, dyspnea occurs after one week, and severe cases rapidly progress to acute respiratory distress syndrome, septic shock, difficult-to-correct metabolic poisoning, blood coagulation dysfunction, multiple organ failure, and the like.

By 2 months and 15 days 2022, more than 4.1 million patients have been diagnosed globally, more than 582 ten million patients have died globally, and the global diagnosis and died number still continuously rise, so that the severity and positive prevention and control of epidemic disease hazards must be paid high attention. After outbreak, the clinical treatment scheme adopted initially in hospitals was the combination of baefletin and lotus antipyretic, abidol, lopinavir, ritonavir, chloroquine phosphate, faviravir and the like, and the curative effects of these drugs were proved to be unknown by use. The FDA has urgently approved reidcvir for new coronavirus treatment in 10 months of 2020, making it the first approved by the bureau of the americans for treating new coronavirus drugs, but its effectiveness and safety are still controversial. Mornupiravir (Molnopiravir) is a highly effective orally administrable ribonucleoside analog that is active against the most common SARS-CoV-2 variant and inhibits viral replication, but it reduces the risk of hospitalization by only 30% and may mutate human DNA, especially in rapidly proliferating cells such as blood cells or sperm, thus presenting a safety issue; the oral drug Paxlovid can obviously reduce the mortality and hospitalization rate of new coronary patients, but the drug needs to be used in combination with ritonavir, and the dosage is large. Therefore, there is an urgent need for a new drug that can be effectively used for the treatment and/or prevention of SARS-CoV-2.

Chinese applications CN 111848627 and PCT applications WO2015132276, WO2008154817, WO 2014029193, WO2015074546, WO2019001396, WO2019076310, WO2015132276, WO2017064156, WO2015180631, WO2015078392 and the like disclose that dihydropyrimidine compounds have good inhibitory activity on HBV, however, to date, the use of the dihydropyrimidine compounds in the treatment of coronavirus infection has not been disclosed.

Summary of the invention

The dihydropyrimidine compound has better inhibitory activity on coronavirus, particularly SARS-CoV-2, better pharmacokinetic property, good solubility, good stability, basically no induction effect on liver drug enzyme, small toxicity and the like, and has good application prospect in the aspect of preparing medicaments for treating and/or preventing diseases or symptoms caused by coronavirus, particularly SARS-CoV-2.

In one aspect, the invention relates to an application of dihydropyrimidine compounds in preparing medicines for preventing and/or treating diseases or symptoms caused by coronavirus, wherein the compounds are compounds shown in formula (I) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds shown in formula (I),

wherein each R is ¹ Independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-trifluoromethylphenyl, 3, 5-bis (trifluoromethyl) phenyl, or trifluoromethyl;

R ² is C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 cycloalkyl-C _1-6 Alkylene or heterocyclyl-C consisting of 5 to 6 ring atoms _1-6 An alkylene group;

R ³ is C _6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said C _6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or 1,2,3,4 or 5 independently selected from deuterium, F, Cl, Br, OH, CN, C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 alkyl-OC (═ O) -, C _1-6 alkyl-OC (═ O) -C _1-6 Alkylene, HOOC-C _1-6 Alkylene radical, C _1-6 alkoxy-C _1-6 Alkylene and C _1-6 alkyl-S (═ O) ₂ -is substituted with a substituent of;

R ^1a is composed of

Wherein R is ⁴ Is C _1-6 Alkyl radical, C _3-7 Cycloalkyl, heterocyclic radical consisting of 5-6 ring atoms, C _6-10 Aryl, heteroaryl of 5 to 6 ring atoms or-R ⁵ -L-R ⁶ Wherein said C _1-6 Alkyl radical, C _3-7 Cycloalkyl, heterocyclic radical consisting of 5-6 ring atoms, C _6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w1 Substituted;

each R ⁵ And R ⁶ Independently a heterocyclic group consisting of 5 to 6 ring atoms, C _3-6 Cycloalkyl radical, C _2-6 Alkynyl, heteroaryl consisting of 5-6 ring atoms, phenyl or naphthyl, wherein the heterocyclyl consisting of 5-6 ring atoms, C _3-6 Cycloalkyl radical, C _2-6 Alkynyl, heteroaryl of 5 to 6 ring atoms, phenyl and naphthyl are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w2 Substituted;

l is a single bond, C _1-4 Alkylene, -O-, -S (═ O) _t -, -C (═ O) -, -NH-or-O-C _1-4 Alkylene-;

each R ⁷ And R ⁸ Independently hydrogen, deuterium, F, Cl, Br, OH, R ^7a -C(＝O)-、HOOC-C _1-6 Alkylene-, C _1-6 Alkyl or HO-C _1-6 Alkylene-, wherein said HOOC-C _1-6 C in alkylene- _1-6 Alkylene radical, C _1-6 Alkyl and HO-C _1-6 C in alkylene-radical _1-6 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w3 Substituted;

each R ^7a Independently is OH, amino, C _1-6 Alkoxy radical, C _1-6 Alkyl or C _1-6 An alkylamino group;

R ^1b is hydrogen;

or R ^1a And R ^1b Together with the atoms to which they are attached form a group

Wherein R is ^9a Hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl;

R ⁹ is amino, C _1-6 Alkyl radical, C _1-6 Alkylamino radical, C _3-6 Cycloalkyl radical, C _6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said amino, C _1-6 Alkyl radical, C _1-6 Alkylamino radical, C _3-6 Cycloalkyl radical, C _6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w4 Substituted;

each R ^w1 、R ^w2 、R ^w3 And R ^w4 Independently deuterium, F, Cl, Br, OH, CN, HOOC-, NH ₂ C(＝O)-、HOOC-C _1-6 Alkylene-, amino, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-7 Cycloalkyl or hydroxy C _1-6 An alkyl group;

f is 0, 1,2,3,4 or 5;

t is 0, 1 or 2.

In some embodiments, the compounds of the present invention are compounds having formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (II), or prodrug thereof,

wherein each R is ^1c And R ^1d Independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-trifluoromethylphenyl, 3, 5-bis (trifluoromethyl) phenyl or trifluoromethyl.

In some embodiments, R is described herein ² Is methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, C _3-6 cycloalkyl-C _1-3 Alkylene or hetero 5-6 ring atomsCyclic radical-C _1-3 An alkylene group;

R ³ is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or 1,2,3,4 or 5 substituents independently selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, hydroxyC, C, Cl, Br, OH, CN _1-4 Alkyl radical, C _1-4 alkyl-OC (═ O) -, C _1-4 alkyl-OC (═ O) -C _1-3 Alkylene-, HOOC-C _1-4 Alkylene-, C _1-4 alkoxy-C _1-3 Alkylene-and C _1-4 alkyl-S (═ O) ₂ -is substituted with a substituent of (a).

In some embodiments, L of the present invention is a single bond, methylene, ethylene, propylene, -O-, -S (═ O) _t -、-C(＝O)-、-NH-、-OCH ₂ -or-OCH ₂ CH ₂ -；

Each R ⁵ And R ⁶ Independently is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propargyl, propynyl, alkynylbutyl, alkynylpentyl, pyridinyl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl or naphthyl, wherein said pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, cyclopentyl, Propargyl, propynyl, propargyl, pyridyl, 1,3, 5-triazinyl, propargyl, pyridyl, and the like,Pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl and naphthyl are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w2 And (4) substitution.

In some embodiments, R is described herein ⁴ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or-R. ⁵ -L-R ⁶ Wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted by 1, 5, 2-pentyl, 3-methyl-2-butyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyridazinyl and pyrimidinyl, 2. 3,4 or 5R ^w1 Substituted;

each R ⁷ And R ⁸ Independently hydrogen, deuterium, F, Cl, Br, OH, R ^7a -C(＝O)-、HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -、HO-(CH ₂ ) ₂ -or HO- (CH) ₂ ) ₃ -, wherein said HOOC-CH ₂ -CH of (A-O-) ₂ -、HOOC-(CH ₂ ) ₂ In- (CH) ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ In- (CH) ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -CH of (A-O-) ₂ -、HO-(CH ₂ ) ₂ In- (CH) ₂ ) ₂ And HO- (CH) ₂ ) ₃ In- (CH) ₂ ) ₃ Each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w3 Substituted;

each R ^7a Independently is OH, amino, C _1-4 Alkoxy radical, C _1-4 Alkyl, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino or N-ethylpropyl-2-amino.

In some embodiments, R is described herein ⁹ Is amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylamino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylamino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3,4 or 5R ^w4 And (4) substituting.

In some embodiments, each R described herein ^w1 、R ^w2 、R ^w3 And R ^w4 Independently deuterium, F, Cl, Br, OH, CN, HOOC-, NH ₂ C(＝O)-、HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ CH ₂ -, amino, C _1-4 Haloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, C _1-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, HO-CH ₂ -、HO-(CH ₂ ) ₂ -or HO- (CH) ₂ ) ₃ -。

In another aspect, the present invention also relates to a use of a pharmaceutical composition for the preparation of a medicament for preventing and/or treating a disease or symptom caused by coronavirus, the pharmaceutical composition comprising a compound represented by formula (I) or formula (II) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound represented by formula (I) or formula (II) according to the present invention.

In some embodiments, the pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical compositions of the present invention further comprise other antiviral drugs.

In some embodiments, the additional antiviral agent described herein is resixilvir, faviravir, ribavirin, camostat, nafamostat, ritonavir, lopinavir, nitazoxanide, chloroquine, hydroxychloroquine, darunavir, abidol, resveratrol, interferon alpha, interferon beta, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, jinhua qinggan granules, wind dispelling and detoxifying capsules, copaihuaqingwen capsules, or any combination thereof.

In some embodiments, the coronavirus of the invention is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

Another aspect of the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) for the manufacture of a medicament for preventing, treating or alleviating a disease or condition caused by a coronavirus in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

In some embodiments, the invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) in the manufacture of a medicament for preventing, treating, or ameliorating a disease or condition caused by HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

In another aspect, the present invention relates to a method for preventing, treating or ameliorating a disease or condition caused by a coronavirus in a patient, said method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

In some embodiments, the invention relates to a method of preventing, treating, or ameliorating a disease or condition caused by HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2 in a patient, the method comprising administering to the patient an effective pharmaceutically acceptable dose of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects are more fully described below.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be distinguished or contradicted by context, including but in no way limited to, definitions of terms, usage of terms, techniques described, or scope as controlled by the present application.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75, ^th ed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley Chemistry&Sons, New York, 2007, all of which are hereby incorporated by reference.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C _1-6 Alkyl "in particular denotes independently disclosed methyl, ethyl, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ An alkyl group.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, in other embodiments, the alkyl group contains 1 to 10 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Still further examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et-CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methylpropyl or isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) T-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ )、3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like.

The term "alkylene" denotes a saturated divalent or polyvalent hydrocarbyl radical derived from a saturated straight or branched chain hydrocarbyl radical by the removal of two or more hydrogen atoms. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains from 1 to 4 carbon atoms; in still other embodiments, the alkylene group contains 1 to 3 carbon atoms; in still other embodiments, the alkylene groups contain 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -, ethylene (-CH) ₂ CH ₂ -, isopropylidene (-CH (CH) ₃ )CH ₂ -) and the like.

The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups, where "hydroxyalkyl" and "hydroxyalkyl" may be used interchangeably, and examples include, but are not limited to, hydroxymethyl (-CH) ₂ OH), hydroxyethyl (-CH) ₂ CH ₂ OH,-CHOHCH ₃ ) Hydroxypropyl (-CH), hydroxypropyl (-CH) ₂ CH ₂ CH ₂ OH,-CH ₂ CHOHCH ₃ ,-CHOHCH ₂ CH ₃ ) Hydroxy methoxy (-OCH) ₂ OH), and the like.

The term "haloalkyl" or "haloalkoxy" denotes an alkyl groupOr alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, difluoroethyl (-CH) ₂ CHF ₂ ,-CF ₂ CH ₃ ,-CHFCH ₂ F) Trifluoroethyl (-CH) ₂ CF ₃ ,-CF ₂ CH ₂ F,-CFHCHF ₂ ) Trifluoromethyl (-CF) ₃ ) Trifluoro-methoxy (-OCF) ₃ ) And the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 8 carbon atoms; in other embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) 1-pentyloxy (n-pentyloxy, -OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyloxy (-OCH (CH)) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyloxy (-OCH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxy (-OC (CH)) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butoxy (-OCH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-l-butoxy (Butoxy)Radical (-OCH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-l-butoxy (-OCH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) And so on.

The term "alkynyl" refers to a monovalent hydrocarbon group of 2 to 12 carbon atoms, straight or branched, wherein at least one C-C is an sp triple bond, wherein the alkynyl group may independently be optionally substituted with one or more substituents described herein, wherein in some embodiments the alkynyl group contains 2 to 12 carbon atoms, in other embodiments the alkynyl group contains 2 to 8 carbon atoms, in other embodiments the alkynyl group contains 2 to 6 carbon atoms, and in yet other embodiments the alkynyl group contains 2 to 4 carbon atoms. Specific examples include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) ₂ C ≡ CH), propynyl (-C ≡ C-CH) ₃ ) Acetylenic butyl (-CH) ₂ CH ₂ C≡CH、-CH ₂ C≡CCH ₃ 、-C≡CCH ₂ CH ₃ and-CH (CH) ₃ ) C ≡ CH) and alkynylpentyl (-CH) ₂ CH ₂ CH ₂ C≡CH、-CH ₂ CH ₂ C≡CCH ₃ 、-CH ₂ C≡CCH ₂ CH ₃ 、-C≡CCH ₂ CH ₂ CH ₃ 、-CH ₂ CH(CH ₃ )C≡CH、-CH(CH ₃ )CH ₂ C≡CH)、-C(CH ₃ ) ₂ C≡CH、-CH(CH ₃ )C≡CCH ₃ 、-C≡CCH(CH ₃ )CH ₃ and-C ≡ CCH (CH) ₃ ) ₂ ) And so on.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 7 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "M-M ₁ "consisting of atoms" means that the cyclic group consists of M-M ₁ Group of ring atomsThe ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P. For example, "heteroaryl of 5 to 10 atoms" means that it includes heteroaryl of 5, 6, 7, 8, 9 or 10 atoms.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocyclic group consisting of 6 ring atoms.

The term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atoms. Wherein said heterocyclyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH ₂ -a group may optionally be replaced by-C (═ O) -or-C (═ S) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atoms of the ring may optionally be oxidized to the N-oxide. In some embodiments, heterocyclyl is a heterocyclyl consisting of 3-12 atoms; in some embodiments, heterocyclyl is a heterocyclyl consisting of 5 to 10 ring atoms; in some embodiments, heterocyclyl is a heterocyclic group consisting of 4-6 ring atoms; in some embodiments, heterocyclyl is a heterocyclyl consisting of 5-6 ring atoms. In other embodiments, heterocyclyl is a 4-atom heterocyclyl and refers to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic, monocyclic ring comprising 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. In other embodiments, heterocyclyl is a 5-atom heterocyclyl and refers to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring comprising 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. In other embodiments, heterocyclyl is a 6-atom heterocyclyl and refers to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring comprising 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. "Heterocyclyl" likewise includes heterocyclic groups and saturated or partially unsaturated heterocyclic groupsUnsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thienylalkyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepinyl, oxepinyl, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienyl, dihydrothienyl, pyrazolidinimidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, dihydrofuranyl, tetrahydrothiofuranyl, piperazinyl, homopiperazinyl, azetidinyl, oxazepinyl, and the like, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolylquinozinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1, 1-dioxothiomorpholinyl, examples in which a carbon atom on a ring is substituted with oxo (═ O) include, but are not limited to, pyrimidinedione, 1,2, 4-thiadiazol-5 (4H) -one, 1,2, 4-oxadiazol-5 (4H) -one, 1H-1,2, 4-triazol-5 (4H) -one, and the like, and examples in which a carbon atom on a ring is substituted with group ═ S include, but are not limited to, 1,2, 4-oxadiazol-5 (4H) -thioone, 1,3, 4-oxadiazol-2 (3H) -thioone, and the like.

The term "heteroatom" means one or more of O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" or "halogen atom" refers to F, Cl, Br or I.

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

The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the rest of the molecule through an oxygen atom.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 9 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 12 atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 5-10 atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is 9-10 atom composed of 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 9 atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 5-6 atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. And the heteroaryl group can be substituted or unsubstituted, and the aryl group can independently be optionally substituted with one or more substituents described herein.

Examples of heteroaromatic rings include, but are not limited to, the following monocyclic rings: 1,2, 4-oxadiazol-5 (4H) -thioketo group, 1,2, 4-thiadiazol-5 (4H) -keto group, 1,2, 4-oxadiazol-5 (4H) -keto group, 1,3, 4-oxadiazol-2 (3H) -thioketo group, 1H-1,2, 4-triazol-5 (4H) -keto group, 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, and the like, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyranyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, Diazolyl, thiadiazolyl, triazinyl, and the like; the following bicyclic rings are also included, but are in no way limited to these: benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), and the like.

The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the hydrogen atoms in the amino groups are each independently substituted with one or two alkyl groups. Wherein, in some embodiments, the alkylamino group is one or two C ₁ -C ₁₂ The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C ₁ -C ₆ The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C ₁ -C ₄ The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In still other embodiments, the alkylamino group is one or two C ₁ -C ₃ Lower alkylamino radicals formed by alkyl radicals attached to nitrogen atoms. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, and the like.

The terms "cycloalkylalkyl", "cycloalkylalkylene" indicate that the alkyl group may be substituted by one or more identical or different cycloalkyl groups, wherein cycloalkyl and alkyl groups have the meaning as described herein. Examples include, but are not limited to, cyclohexylmethyl, cyclopropylethyl, and the like.

The term "alkoxyalkyl" or "alkoxyalkylene" means that the alkyl group may be substituted by one or more of the same or different alkoxy groups, wherein the alkoxy and alkyl groups have the meaning as described herein. Examples include, but are not limited to, cyclohexylmethyl (or cyclohexylmethylene), cyclopropylethyl (or cyclopropylethylene), and the like.

As described herein, the ring system formed by a substituent that is attached to the central ring through a bond (as shown in formula a) represents that the substituent may be substituted at any substitutable position on the ring, and may be an enantiomer-containing substitution, as shown in formulae b, c, d, e, f, g, and h.

In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently," and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other. For example, of the formula p, a plurality of R ¹ Are not affected by each other.

As described in the present invention, there are two linking sites in the system that are linked to the rest of the molecule, for example, as shown by formula q, which means that either the E or E' end is linked to the rest of the molecule, i.e., the linking modes at the two ends can be interchanged under the condition of reasonable molecular structure.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational isomers) such as the R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and conformational isomers of (Z), (E). accordingly, a single stereochemical isomer of a compound of the invention or an enantiomer, diastereomer, or mixture of geometric isomers (or conformational isomers) thereof is within the scope of the invention.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) or (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.symposium Series, Edward B.Roche, ed., Bioreproducible Cariers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。

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

"metabolite" refers to the product of a particular compound or salt thereof that is metabolized in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50: 50 is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, diglucosides, and mixtures thereofExamples of suitable organic solvents include, but are not limited to, sugar salts, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

Detailed description of the use of the compounds of the invention

In the application of the medicine, the compound related to the invention and the pharmaceutically acceptable composition thereof can effectively inhibit the disease or symptom infection caused by SARS-CoV-2.

In one aspect, the invention relates to an application of a dihydropyrimidine compound or a pharmaceutical composition containing the same in preparing medicines for preventing and/or treating diseases or symptoms caused by coronavirus, wherein the compound is a compound shown as a formula (I), a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound shown as the formula (I),

R ^1a is composed of

Wherein R is ⁴ Is C _1-6 Alkyl radical, C _3-7 Cycloalkyl, heterocyclic radical consisting of 5-6 ring atoms, C _6-10 Aryl, heteroaryl of 5 to 6 ring atoms or-R ⁵ -L-R ⁶ Wherein said C _1-6 Alkyl radical, C _3-7 Cycloalkyl, heterocyclic radical consisting of 5-6 ring atoms, C _6-10 Heteroaryl groups consisting of aryl and 5-6 ring atomsEach independently of the others being unsubstituted or substituted by 1,2,3,4 or 5R ^w1 Substituted;

each R ⁷ And R ⁸ Independently hydrogen, deuterium, F, Cl, Br, OH, R ^7a -C(＝O)-、HOOC-C _1-6 Alkylene-, C _1-6 Alkyl or HO-C _1-6 Alkylene-, wherein said HOOC-C _1-6 C in alkylene-radical _1-6 Alkylene radical, C _1-6 Alkyl and HO-C _1-6 C in alkylene- _1-6 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w3 Substituted;

R ^1b is hydrogen;

Wherein R is ^9a Hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl;

f is 0, 1,2,3,4 or 5;

t is 0, 1 or 2.

In some embodiments, R is described herein ² Is methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, C _3-6 cycloalkyl-C _1-3 Alkylene or heterocyclyl-C consisting of 5 to 6 ring atoms _1-3 An alkylene group.

In some embodiments, R is described herein ³ Is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolylEach of the radicals, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently unsubstituted or 1,2,3,4 or 5 independently selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, hydroxy C _1-4 Alkyl radical, C _1-4 alkyl-OC (═ O) -, C _1-4 alkyl-OC (═ O) -C _1-3 Alkylene-, HOOC-C _1-4 Alkylene-, C _1-4 alkoxy-C _1-3 Alkylene-and C _1-4 alkyl-S (═ O) ₂ -is substituted by a substituent of (a).

In some embodiments, L of the present invention is a single bond, methylene, ethylene, propylene, -O-, -S (═ O) _t -、-C(＝O)-、-NH-、-OCH ₂ -or-OCH ₂ CH ₂ -, where t has the meaning stated in the invention.

In some embodiments, each R described herein ⁵ And R ⁶ Independently is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propargyl, propynyl, alkynylbutyl, alkynylpentyl, pyridinyl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl or naphthyl, wherein said pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, cyclopentyl, Propargyl, propynyl, alkynbutyl, alkynylpentyl, pyridyl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl and naphthyl are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w2 Wherein each R is ^w2 Have the meaning as described in the present invention.

In some embodiments, R is described herein ⁴ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or-R. ⁵ -L-R ⁶ Wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted by 1, 5, 2-pentyl, 3-methyl-2-butyl, 3-methyl-2-pentyl, 3-pentyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridazinyl and pyrimidinyl, 2. 3,4 or 5R ^w1 Wherein each R is ^w1 Have the meaning as described in the present invention.

Each R ⁷ And R ⁸ Independently hydrogen, deuterium, F, Cl, Br, OH, R ^7a -C(＝O)-、HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -、HO-(CH ₂ ) ₂ -or HO- (CH) ₂ ) ₃ -, wherein said HOOC-CH ₂ in-CH ₂ -、HOOC-(CH ₂ ) ₂ In (C) - (CH) ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ In- (CH) ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -CH of (A-O-) ₂ -、HO-(CH ₂ ) ₂ In- (CH) ₂ ) ₂ And HO- (CH) ₂ ) ₃ In- (CH) ₂ ) ₃ Each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w3 Is substituted wherein each R is ^w3 Have the meaning described in the invention

In some embodiments, R is described herein ⁹ Is amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylamino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylamino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3,4 or 5R ^w4 Wherein each R is ^w4 Have the meaning as described in the present invention.

In some embodiments, the invention relates to the use of dihydropyrimidine compounds or pharmaceutical compositions containing the same in the preparation of medicaments for preventing and/or treating diseases or symptoms caused by coronavirus, wherein the compounds are one of the following compounds or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

in some embodiments, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable excipient or combination of excipients.

In some embodiments, the coronavirus-mediated disease or condition described herein is a disease or condition mediated by HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

Another aspect of the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) for the manufacture of a medicament for preventing, treating or ameliorating a disease or condition caused by a coronavirus in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

Another aspect of the present invention relates to a method for preventing, treating or ameliorating a disease or condition caused by a coronavirus in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective amount of a compound of formula (I) or formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II) as described herein.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds used in the pharmaceutical use of the present invention are within the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or (II) or isolated enantiomers of the compounds of formula (I) or (II).

If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids, such as glucuronic and galacturonic acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like, or combinations thereof.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary)Ammonia), alkali metal hydroxides, ammonium, N ⁺ (R ¹⁴ ) ₄ Salts and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, N ⁺ (R ¹⁴ ) ₄ Salts, e.g. R ¹⁴ Is H, C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl, etc., and cyclic amines such as piperidine, morpholine, piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

Pharmaceutical compositions for the uses of the invention

The pharmaceutical composition provided by the invention is characterized by comprising a compound shown as a formula (I) or (II), a compound listed in the invention or an embodiment compound and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition can effectively inhibit coronavirus, is suitable for treating coronavirus infection, and is especially suitable for diseases or symptoms caused by HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I) or (II) of the present invention, and further comprises pharmaceutically acceptable excipients, such as any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as used herein, suitable for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Substances that may serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.

The pharmaceutical composition provided by the invention also comprises other antiviral drugs.

The other antiviral drugs are Ridexilvir, Favipiravir, ribavirin, camostat, Namomostat, ritonavir, lopinavir, Nitrazolide, chloroquine, hydroxychloroquine, Darunavir, Abidol, resveratrol, interferon alpha, interferon beta, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, Jinhua qinggan granules, Shufeng Jiedu capsules, Lianhua qingwen capsules, and the like, or any combination thereof.

Administration of the Compounds or pharmaceutical compositions of the invention

The compounds or pharmaceutical compositions of the present invention may be administered in any of the following ways: oral administration, inhalation spray, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of a reservoir of external value. Preferred modes of administration are oral, intramuscular, intraperitoneal or intravenous.

The compounds of the present invention or compositions containing them which are pharmaceutically acceptable may be administered in unit dosage form. The dosage form for administration may be a liquid dosage form or other dosage forms. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.

Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.

Oral liquids may be in the form of suspensions of hydrated oils, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats and oils, emulsifying agents, such as lecithin, sorbitan monooleate, acacia; or non-aqueous vehicles (which may include edible oils), such as almond oil, fats and oils such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired.

Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, the liquid dosage form is usually prepared from the compound and a sterile excipient. The adjuvant is preferably water. According to different selected adjuvants and drug concentrations, the compound can be dissolved in adjuvants or made into suspension solution, and can be dissolved in water for injection, filtered, sterilized and filled into sealed bottle or ampoule.

When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in ointment formulations including, but not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams adjuvants that may be used include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In general, it has proven advantageous, both in human medicine and in veterinary medicine, to administer the active compounds according to the invention in a total amount of from about 0.0005 to 500mg, preferably from 0.5 to 100mg, per kg of body weight per 24 hours, if appropriate in divided single doses, in order to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1 to 80mg, more preferably 1 to 50mg per kg body weight, but may be varied from the above-mentioned dose, i.e., depending on the kind and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, and the period or interval of administration.

The medicament for coronavirus infection may be administered separately from a composition comprising a compound of the invention as part of a multiple dosing regimen. Alternatively, those drugs may be part of a single dosage form, mixed together with the compounds of the present invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other simultaneously, sequentially or over a period of time, to achieve the desired agent activity.

The amount of compound and composition that can be combined with an adjuvant material to produce a single dosage form (those containing a composition like that described herein) will vary depending on the indication and the particular mode of administration. Normally, the amount of the composition of the invention will not exceed the amount of the composition normally administered containing as the only active agent. In another aspect, the amount of the presently disclosed compositions ranges from about 50% to 100% of the normal amount of the presently disclosed compositions, including the agent as the sole active therapeutic agent. In those compositions encompassed, the composition will act synergistically with the compounds of the present invention.

General Synthesis of the Compounds of the invention

In general, the compounds of the invention can be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

The examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (. degree. C.). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The column used silica gel column, silica gel (200-300 mesh) purchased from Qingdao oceanic plant. Nuclear magnetic resonance spectroscopy with CDC1 ₃ 、DMSO-d ₆ 、CD ₃ OD or acetone-d ₆ As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets), dt (doublet of triplets, double triplet), br. Coupling constant J, in Hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

table 1: gradient elution conditions

Time (min)	A(CH ₃ CN，0.1％HCOOH)	B(H ₂ O，0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

Synthesis method of compound of the invention

The following synthetic schemes set forth general experimental procedures for preparing the compounds disclosed herein, including modifications of the procedures or adjustments of starting materials that may be appropriate to those skilled in the art in view of the circumstances in which they are practiced. Wherein each R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ⁹ 、X ¹ And f has a structure as described in the inventionThe meaning of (a). Unless otherwise indicated, the compounds of the present invention may be prepared by the methods described in the following synthetic schemes.

Synthesis scheme 1

Compound (2a) can be prepared by the method described in synthesis scheme 1, and compound (1a) (prepared by reference to synthesis scheme 1 and/or the specific examples thereof in WO 2015074546) is reacted with compound (a) or a salt thereof in a suitable solvent (e.g., ethanol, etc.) under basic conditions (e.g., potassium carbonate, etc.) to give compound (2 a).

Synthesis scheme 2

Compound (2b) can be prepared by the method described in synthetic scheme 2, and compound (1a) is reacted with compound (b) or a salt thereof under basic conditions (e.g., potassium carbonate, etc.) and in a suitable solvent (e.g., ethanol, etc.) to give compound (2 b).

Synthesis scheme 3

Compound (3c) can be produced by the method described in FIG. 3, and compound (c) (obtained by the method of producing compound 36-6 or compound 171-1 in WO 2015180631) or a salt thereof is reacted with compound (2c) under basic conditions (e.g., triethylamine, etc.) in a suitable solvent (e.g., dichloromethane, etc.) to give compound (3 c).

Some of the compounds of the present invention and the specific preparation method are shown in the following table 2:

table 2:

example A: the compounds of the invention inhibit the novel coronavirus (SARS-CoV-2) at the cellular level

Purpose of experiment

The inhibition effect of the compound on the novel coronavirus at a cellular level is detected by using a qRT-PCR method.

Experimental methods

Antiviral activity assays were performed on a Vero-E6 cell model, setting two concentration gradients (2. mu.M, 20. mu.M) for each compound, 2 replicate wells per concentration, one experiment.

24-well cell culture plates were seeded with 8X 104 Vero-E6 cells per well at 37 ℃ in 5% CO ₂ Culturing under the culture condition until the confluence degree reaches 70-80 percent; diluting the compound to be tested by 2% FBS-containing DMEM medium in multiple proportion, discarding the medium in the hole of 24-well cell culture plate, adding 1mL of DMEM medium containing COVID-19 virus solution (with MOI of 0.005) and the compound to be tested at corresponding concentration into each well, setting the control group (virus group without drug and normal cell group), and performing dilution at 37 deg.C and 5% CO ₂ Culturing in an incubator, and collecting supernatant virus liquid 24h after infection; RNA quantification of the collected viruses was performed using real-time RT-PCR (qRT-PCR): the collected supernatant virus solutions were collected at 200. mu.L each according to the QIAamp viral RNA mini kit instructionsRNA extraction was performed. qRT-PCR detection (Taqman probe method) was performed using a novel coronavirus nucleic acid detection (fluorescent quantitative PCR) kit. The drug inhibition rate was calculated at each concentration. Inhibition (%) [1- (number of copies of Experimental group viral RNA/number of copies of drug-free viral RNA ]]×100％。

The results of the experiment are shown in table a below.

Table a: the compounds of the invention inhibit the novel coronaviruses at the cellular level

And (4) conclusion: experimental data show that the compound has a better inhibiting effect on the novel coronavirus at a cellular level.

Example B: the compounds of the invention are active at the cellular level against half the Effective Concentration (EC) of SARS-CoV-2 virus ₅₀ )

Purpose of the experiment:

the test adopts nucleic acid quantitative method, and calculates the inhibition rate of compounds with different concentrations on SARS-CoV-2 virus by detecting RNA copy number of SARS-CoV-2 virus under the action of compounds with different concentrations, thereby preliminarily clarifying half Effective Concentration (EC) ₅₀ )。

The experimental method comprises the following steps:

antiviral activity assays were performed on a model of Vero-E6 cells, with five or eight concentration gradients (see Table B for details of concentration settings) per compound, 2 duplicate wells per concentration.

Seeding of 24 well cell culture plates with 8X 10 cells per well ⁴ Vero-E6 cells, 5% CO at 37 ℃ ₂ Culturing under culture condition, diluting the compound to be tested by multiple times with DMEM medium containing 2% FBS when the confluence reaches 70% -80%, discarding the culture medium in the wells, adding 1mL of DMEM medium containing SARS-CoV-2 virus solution (MOI 0.005 according to the multiplicity of infection) and the compound to be tested at corresponding concentration into each well, setting the control group (virus group without compound and normal cell group), and culturing at 37 deg.C and 5% CO ₂ IncubatorCulturing, and collecting supernatant virus liquid 24h after infection; RNA quantification of the collected viruses was performed using real-time RT-PCR (qRT-PCR): the collected supernatant virus solutions were each collected in 200. mu.L, and RNA extraction was performed according to the QIAamp viral RNA mini kit instructions. qRT-PCR detection (Taqman probe method) was performed using a novel coronavirus nucleic acid detection (fluorescent quantitative PCR) kit.

The rate of inhibition of the virus by the compound at each concentration was calculated. Inhibition (%) [1- (test group viral RNA copy number/compound-free group viral RNA copy number)]X 100%. While half Effective Concentration (EC) of the compound against SARS-CoV-2 virus was calculated using GraphPad PrisM6.0 software analysis ₅₀ )。

The results of the experiment are shown in table B below.

Table B: the compounds of the invention are present at a cell level at a concentration (EC) that is half as effective against the novel coronavirus ₅₀ )

Test Compound numbering	Test concentration	EC ₅₀
			Compound 1	30/15/7.5/3.75/1.875/0.9375/0.46875/0.234375μM	5.95μM
Compound 2	30/15/7.5/3.75/1.875μM	7.63μM

And (4) conclusion: experimental data show that the compound has better inhibitory activity to the novel coronavirus at a cellular level.

Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. The application of dihydropyrimidine compounds in the preparation of drugs for preventing and/or treating diseases or symptoms caused by coronavirus, wherein the compounds are compounds shown in formula (I) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds shown in formula (I),

R ³ is C _6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said C _6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or 1,2,3,4 or 5 are independently selected from deuterium, F, Cl, Br, OH, CN, C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 alkyl-OC (═ O) -, C _1-6 alkyl-OC (═ O) -C _1-6 Alkylene, HOOC-C _1-6 Alkylene radical, C _1-6 alkoxy-C _1-6 Alkylene and C _1-6 alkyl-S (═ O) ₂ -is substituted with a substituent;

R ^1a is composed of

each R ⁵ And R ⁶ Independently a heterocyclic group consisting of 5 to 6 ring atoms, C _3-6 Cycloalkyl radical, C _2-6 Alkynyl, heteroaryl consisting of 5-6 ring atoms, phenyl or naphthyl, wherein the heterocyclyl consisting of 5-6 ring atoms, C _3-6 Cycloalkyl, C _2-6 Alkynyl, 5-6 ring atoms constituting heteroaryl, phenyl and naphthyl are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w2 Substituted;

each R ^7a Independently of one another OH, amino, C _1-6 Alkoxy radical, C _1-6 Alkyl or C _1-6 An alkylamino group;

R ^1b is hydrogen;

Wherein R is ^9a Hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl;

f is 0, 1,2,3,4 or 5;

t is 0, 1 or 2.

2. The use according to claim 1, wherein the compound is a compound having formula (II) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound having formula (II),

wherein each R is ^1c And R ^1d Independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro4-trifluoromethylphenyl, 3, 5-bis (trifluoromethyl) phenyl or trifluoromethyl.

3. Use according to claim 1 or 2, wherein R ² Is methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, C _3-6 cycloalkyl-C _1-3 Alkylene or heterocyclyl-C consisting of 5 to 6 ring atoms _1-3 An alkylene group;

R ³ is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or 1,2,3,4 or 5 are independently selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, hydroxyC, C, Z _1-4 Alkyl radical, C _1-4 alkyl-OC (═ O) -, C _1-4 alkyl-OC (═ O) -C _1-3 Alkylene-, HOOC-C _1-4 Alkylene-, C _1-4 alkoxy-C _1-3 Alkylene-and C _1-4 alkyl-S (═ O) ₂ -is substituted with a substituent of (a).

4. Use according to claim 1 or 2, wherein L is a single bond, methylene, ethylene, propylene, -O-, -S (═ O) _t -、-C(＝O)-、-NH-、-OCH ₂ -or-OCH ₂ CH ₂ -；

Each R ⁵ And R ⁶ Independently pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propargyl, propynyl, propargyl, pyridyl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furyl, pyrrolyl, pyrazolyl, and the like,Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl or naphthyl, wherein said pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propargyl, propynyl, propargyl, pyridyl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thienyl, phenyl and naphthyl are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^w2 And (4) substituting.

5. Use according to claim 1 or 2, wherein R ⁴ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or-R. ⁵ -L-R ⁶ Wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, and the likeOxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^w1 Substituted;

each R ⁷ And R ⁸ Independently hydrogen, deuterium, F, Cl, Br, OH, R ^7a -C(＝O)-、HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -、HO-(CH ₂ ) ₂ -or HO- (CH) ₂ ) ₃ -, wherein said HOOC-CH ₂ -CH of (A-O-) ₂ -、HOOC-(CH ₂ ) ₂ In- (CH) ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ In- (CH) ₂ ) ₃ -, methyl, ethyl, n-propyl, isopropyl, HO-CH ₂ -CH of (A-O-) ₂ -、HO-(CH ₂ ) ₂ In (C) - (CH) ₂ ) ₂ And HO- (CH) ₂ ) ₃ In- (CH) ₂ ) ₃ Each independently unsubstituted or substituted by 1,2,3,4 or 5R ^w3 Substituted;

6. Use according to claim 1 or 2, wherein R ⁹ Is amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylamino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, N-methylamino, N-ethylaminoAmino, N-N-propylamino, N-isopropylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently of the others being unsubstituted or substituted by 1,2,3,4 or 5R ^w4 And (4) substitution.

7. Use according to claim 1 or 2, wherein each R is ^w1 、R ^w2 、R ^w3 And R ^w4 Independently deuterium, F, Cl, Br, OH, CN, HOOC-, NH ₂ C(＝O)-、HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ CH ₂ -, amino, C _1-4 Haloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, C _1-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, HO-CH ₂ -、HO-(CH ₂ ) ₂ -or HO- (CH) ₂ ) ₃ -。

8. The use according to claim 1 or 2, wherein the compound is a compound of one of the following or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

9. the use according to any one of claims 1 to 8, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2.

10. Use of a pharmaceutical composition comprising a dihydropyrimidine compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of such a compound, or a prodrug thereof, for the preparation of a medicament for the prevention and/or treatment of diseases or conditions caused by coronaviruses.

11. The use according to claim 10, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

12. The use of claim 10 or 11, said pharmaceutical composition further comprising an additional antiviral agent selected from the group consisting of resixilvir, faviravir, ribavirin, camostat, nafamostat, ritonavir, lopinavir, nitazoxanide, chloroquine, hydroxychloroquine, darunavir, abidol, resveratrol, interferon alpha, interferon beta, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, jinhua qinggan granules, a capsule for dispelling wind and removing toxicity, a capsule for treating lianhua qingwen, and any combination thereof.

13. The use according to any one of claims 10 to 12, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2.