Pyrimidine compounds and their use in medicine

Abstract

The application belongs to the technical field of medicines, and relates to a pyrimidine compound and application thereof in medicines, in particular, application of the pyrimidine compound in preparation of medicines for treating and / or preventing diseases or symptoms caused by a novel coronavirus (SARS-CoV-2). Specifically, the application relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in preparation of medicines for preventing and / or treating diseases or symptoms caused by a coronavirus, in particular, application of the compound and the pharmaceutical composition in preparation of medicines for treating and / or preventing diseases or symptoms caused by SARS-CoV-2, wherein each variable in the formula (I) is as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the use of a pyrimidine compound as a medicament for treating and / or preventing coronavirus infection, particularly its use in the preparation of a medicament for treating and / or preventing diseases or symptoms caused by the novel coronavirus (SARS-CoV-2). This invention also relates to the use of pharmaceutical compositions of these pyrimidine compounds with other antiviral drugs in the preparation of a medicament for treating and / or preventing diseases or symptoms caused by coronaviruses such as SARS-CoV-2. Background Technology

[0002] Coronaviruses (CoVs) belong to the order Nematovirales, family Coronaviridae, and subfamily Orthocoronaviruses; this subfamily includes four genera: α, β, γ, and δ. Previously, only six CoVs could infect humans and cause respiratory illness: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 only induce mild upper respiratory tract illness, and in very rare cases, cause severe infection in infants, young adults, and the elderly; SARS-CoV and MERS-CoV can infect the lower respiratory tract and cause severe respiratory syndrome in humans.

[0003] The novel coronavirus is the seventh coronavirus discovered to infect humans and cause disease. It belongs to the beta-coronavirus family and is highly contagious. It can also infect the lower respiratory tract and cause pneumonia. The WHO has named it Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 genome is a single-stranded positive-sense RNA with a genome size of 29,903 nt, containing a 5′ cap structure and a 3′ polyadenylated tail (A new coronavirus associated with human respiratory disease in China[J].Nature, 2020, 579(7798): 265-269). Under an electron microscope, the virus is mostly spherical, with some exhibiting pleomorphism, and a diameter of 60–140 nm. The virus particles have distinct spikes, approximately 9–12 nm in diameter, giving the virus a corona-like appearance.

[0004] The clinical manifestations of novel coronavirus infection are mainly fever, fatigue, and dry cough. A few patients may also experience nasal congestion, runny nose, muscle pain, and diarrhea. Severe cases often develop respiratory distress after one week, and in severe cases, it can rapidly progress to acute respiratory distress syndrome, septic shock, uncorrectable metabolic poisoning, coagulation dysfunction, and multiple organ failure.

[0005] For the initial clinical treatment of novel coronavirus infection, the hospital adopted a combination of remdesivir and oseltamivir, along with Lianhua Qingwen capsules. Remdesivir, an antiviral drug developed by Gilead Sciences, was originally used to treat diseases such as Ebola hemorrhagic fever and Middle East Respiratory Syndrome (MERS). In October 2020, the FDA granted emergency approval to remdesivir for the treatment of novel coronavirus, making it the first injectable drug approved by the FDA for the treatment of the novel coronavirus. Following remdesivir, the 3CL protease inhibitors Paxlovid (nematinatevir / ritonavir), Molnupiravir (monupiravir), and Baricitinib (baricitinib) were subsequently approved. Baricitinib is used alone to treat severely ill COVID-19 patients in adults or children aged 2 years and older. Paxlovid (nematinatevir / ritonavir) and Molnupiravir (monupiravir) are both used for mild to moderate COVID-19 patients at risk of developing severe illness. For the treatment of mild to moderate outpatients without underlying diseases and moderate to severe inpatients, there are currently not many drug options available. Ensitrelvir (S-217622) is a 3CL protease inhibitor (3CLpro), which can be used alone and has good safety and convenience. It has already submitted a marketing application in Japan.

[0006] Therefore, there remains an urgent need to develop new, safe, and effective drugs for the treatment and / or prevention of SARS-CoV-2. Summary of the Invention

[0007] The present invention unexpectedly discovered that the pyrimidine compounds of the present invention are a class of 3CL protease inhibitors, which have good inhibitory activity against coronaviruses, especially SARS-CoV-2. Furthermore, they have advantages such as good pharmacokinetic properties, good solubility, good stability, minimal induction of hepatic drug-metabolizing enzymes, and low toxicity. They have great potential for application in drugs for the treatment and / or prevention of diseases or symptoms caused by coronaviruses, especially SARS-CoV-2.

[0008] On one hand, the present invention relates to a compound, which is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0009]

[0010] Among them, each ring A, R 1 R 1 R 3 R a R b R c and Rd It has the meaning as described in this invention.

[0011] In some embodiments, R 1 It is a monocyclic heteroaryl group composed of 5-6 atoms, a heterocyclic group composed of 3-6 atoms, or a bicyclic heteroaryl group composed of 9-10 ring atoms, wherein the 5-6 atom heteroaryl group, the 3-6 atom heterocyclic group, and the 9-10 ring atom bicyclic heteroaryl group are each independently unsubstituted or converted by 1, 2, or 3 R atoms. w1 Replaced, of which each R w1 It has the meaning as described in this invention.

[0012] In some embodiments, R 2 For deuterium, F, Cl, Br, I, OH, CN, NO2, C 3-6 Cycloalkyl NH-, pyrrole, piperidinyl, piperazine, C 2-6 alkenyl, C 2-6 alkynyl or C 1-4 Alkyl group.

[0013] In some embodiments, R 3 It is phenyl, naphthyl, C 3-6 Cycloalkyl, heteroaryl group consisting of 5-6 atoms, or heterocyclic group consisting of 3-6 atoms; wherein the phenyl, naphthyl, C 3-6 Cycloalkyl groups, heteroaryl groups consisting of 5-6 atoms, and heterocyclic groups consisting of 3-6 atoms are each independently unsubstituted or surrounded by 1, 2, or 3 R groups. w2 Replaced, of which each R w2 It has the meaning as described in this invention.

[0014] In some embodiments, ring A is a monocyclic heteroaryl, phenyl, or C-ring consisting of 5-6 atoms. 3-6 Cycloalkyl, heterocyclic groups consisting of 3-10 ring atoms, or bicyclic heteroaryl groups consisting of 9-10 ring atoms, wherein the 5-6 atoms of the monocyclic heteroaryl, phenyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, and bicyclic heteroaryl groups consisting of 9-10 ring atoms are each independently unsubstituted or converted by 1, 2, or 3 R groups. w3 Replaced, of which each R w3 It has the meaning as described in this invention.

[0015] In some embodiments, each R a R b R c and R d Independently, H, deuterium, F, Cl, Br, CH3CO-, CH3CH2CO-, C 1-4 Alkyl, deuterium-substituted C1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the CH3CO-, CH3CH2CO-, C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl and C 1-4 Each haloalkyl group is independently unsubstituted or substituted by one, two or three independent substituents selected from deuterium, F, Cl, Br, hydroxyl, methyl, ethyl and propyl.

[0016] In some embodiments, each R w3 Independently, it can be deuterium, F, Cl, Br, OH, =O, CN, or -NR. e R f C 1-6 Alkyl, C 1-6 alkoxy- and deuterium-substituted C 1-6 Alkyl, C 1-6 Haloalkyl, -S(=O)2-R 4 -C 1-4 Alkylene-R 5 Heterocyclic groups composed of 3-6 atoms, C 1-6 Alkylamino or C 3-6 cycloalkyl groups, wherein the C 1-6 Alkyl, C 1-6 alkoxy- and deuterium-substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-4 Alkylene-R 5 -C 1-4 Alkylene, heterocyclic groups consisting of 3-6 atoms, C 1-6 Alkylamino and C 3-6 The cycloalkyl groups are either independently unsubstituted or substituted by one, two, or three independent substituents selected from deuterium, F, Cl, Br, methyl, and ethyl.

[0017] In some embodiments, each R e and R f Independently, H, deuterium, -C (=O)C 1-4 Alkyl, C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl or C 1-4 Haloalkyl, wherein the -C(=O)C 1-4 Alkyl, C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl and C 1-4 Each haloalkyl group is independently unsubstituted or substituted by one, two or three independent substituents selected from deuterium, F, Cl, Br, hydroxyl, methyl, ethyl and propyl.

[0018] In some embodiments, R 4 The methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are each independently unsubstituted or substituted by one, two, or three independently selected substituents from deuterium, F, Cl, Br, methyl, and ethyl.

[0019] In some embodiments, R 5 For H, deuterium, HOOC-, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy group, -C(=O)OC 1-4 Alkyl, amino, heterocyclic group consisting of 3-6 atoms or monocyclic heteroaryl group consisting of 5-6 atoms, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy group, -C(=O)OC 1-4 Alkyl, amino, heterocyclic groups of 3-6 atoms, and monocyclic heteroaryl groups of 5-6 atoms are each independently unsubstituted or replaced by 1, 2, or 3 independently selected from deuterium, F, Cl, Br, amino, hydroxyl, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 Alkyl groups are substituted.

[0020] In some embodiments, each R w1 and R w2 Independently, it can be deuterium, F, Cl, Br, OH, =O, CN, or C. 3-9 Alkylsilyl, C 1-4 Alkyl, C 1-4 alkoxy- and deuterium-substituted C 1-4 Alkyl or C 1-4 Haloalkyl, wherein the C 3-9 Alkylsilyl, C 1-4 Alkyl, C 1-4 alkoxy- and deuterium-substituted C 1-4 Alkyl and C 1-4 The haloalkyl groups are either independently unsubstituted or substituted by one, two, or three independent substituents selected from deuterium, F, Cl, Br, methyl, and ethyl.

[0021] In some embodiments, R 1The compounds are furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiophene, pyridinyl, 1,3,5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, azacyclobutyl, oxacyclobutyl, thiocyclobutyl, oxacyclopropyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, benzopyrazolyl, benzo[a]pyrrolyl, benzo[a]imidazolyl, benzo[a]furanyl, benzo[a]thiazolyl, benzo[a]oxazolyl, benzo[a]isooxazolyl, benzo[a]thiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the furanyl, pyrazolyl... The following groups are listed: pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiophene, pyridinyl, 1,3,5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridine, oxacyclobutyl, oxacyclobutyl, thiocyclobutyl, oxacyclopropyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, benzopyrazolyl, benzopyrrolyl, benzoimidazolyl, benzofuranyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl, each independently unsubstituted or substituted by 1, 2, or 3 R groups. w1 Replaced, of which each R w1 It has the meaning as described in this invention.

[0022] In some embodiments, R 2 It can be deuterium, F, Cl, Br, I, OH, CN, NO2, cyclopropylNH-, cyclopentylNH-, pyrrole, piperidinyl, piperazine, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, or 2-butoxy.

[0023] In some embodiments, each R a R b R c and R dIndependently, it is H, deuterium, F, Cl, Br, CH3CO-, CH3CH2CO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CD3, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3, wherein CH3CO-, CH 3CH2CO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3 are each independently unsubstituted or substituted by 1, 2 or 3 independently selected substituents from deuterium, F, Cl, Br, hydroxyl, methyl, ethyl and propyl.

[0024] In some embodiments, R 3 The compounds are phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiophene, pyridinyl, 1,3,5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, azacyclobutyl, oxazolidinyl, thiocyclobutyl, oxazolidinyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, or piperazinyl; wherein the phenyl or naphthyl group is... Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiophene, pyridinyl, 1,3,5-triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, azacyclobutyl, oxacyclobutyl, thiocyclobutyl, oxacyclopropyl, pyrrolylalkyl, pyrazolylalkyl, imidazolealkyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, and piperazinyl are each independently unsubstituted or substituted by 1, 2, or 3 R groups. w2 Replaced, of which each R w2 It has the meaning as described in this invention.

[0025] In some embodiments, each R w3 Independently, it can be deuterium, F, Cl, Br, OH, =O, CN, or -NR. e R f C 1-4 Alkyl, C 1-4 alkoxy- and deuterium-substituted C 1-4 Alkyl, C 1-4 Haloalkyl, -S(=O)2-R 4 -C 1-3 Alkylene-R 5 Heterocyclic groups composed of 3-6 atoms, C 1-4 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the C 1-4 Alkyl, C 1-4 alkoxy- and deuterium-substituted C 1-4 Alkyl, C 1-4 Halogenated alkyl, -C 1-3 Alkylene-R 5 -C 1-3 Alkylene, heterocyclic groups consisting of 3-6 atoms, C 1-4 The alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are each independently unsubstituted or substituted by one, two, or three independent substituents selected from deuterium, F, Cl, Br, methyl, and ethyl.

[0026] In some embodiments, each R w3 Independently, it can be deuterium, F, Cl, Br, OH, =O, CN, or -NR. e R f Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-butylmethylene, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, -CD3, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -S(=O)2-R 4 -CH2-R 5 -CH2CH2-R 5 -CH2CH2CH2-R 5Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, oxacyclopropyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazine, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-butylmethylene, methoxy, ethoxy, 1-propyl Oxygen group, 2-propoxy group, 1-butoxy group, 2-methyl-l-propoxy group, 2-butoxy group, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2-R 5 -CH2- and -CH2CH2-R 5 -CH2CH2- and -CH2CH2CH2-R 5 The -CH2CH2CH2-, azacyclobutyl, oxacyclobutyl, thiocyclobutyl, oxacyclopropyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazine, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are each independently unsubstituted or substituted by one, two, or three independently selected substituents from deuterium, F, Cl, Br, methyl, and ethyl.

[0027] In some embodiments, each R e and R fIndependently, it is H, deuterium, CH3CO-, CH3CH2CO-, CH3(CH2)2CO-, (CH3)2CH2CO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CD3, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3, wherein CH3CO-, CH3CH2 CO-, CH3(CH2)2CO-, (CH3)2CH2CO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3 are each independently unsubstituted or substituted by 1, 2 or 3 independently selected substituents from deuterium, F, Cl, Br, hydroxyl, methyl, ethyl and propyl.

[0028] In some embodiments, R 5H, deuterium, HOOC-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1- Butoxy, 2-methyl-1-propoxy, 2-butoxy, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, amino, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, oxacyclic propyl, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein the methyl, ethyl, n-propyl, iso... Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, -C(=O) O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, amino, aziridine, oxaziridine, thioaziridine, oxaziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or selected independently by 1, 2, or 3 from deuterium, F, Cl, Br, amino, hydroxymethyl, and hydroxyethyl.The substituents include hydroxyl n-propyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methyl, ethyl, n-propyl, and isopropyl.

[0029] In some embodiments, each R w1 and R w2 Independently, it is deuterium, F, Cl, Br, OH, =O, CN, trimethylsilyl, triethylsilyl, tri-n-propylsilyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, -CD3, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3, wherein the trimethylsilyl... The following groups are methylsilyl, triethylsilyl, tri-n-propylsilyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3, each independently unsubstituted or substituted by one, two, or three independently selected substituents from deuterium, F, Cl, Br, methyl, and ethyl.

[0030] In some embodiments, ring A is furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, oxaziridine, pyrrolylalkyl, pyrazolylalkyl, imidazolealkyl, tetrahydrofuran. The following groups are listed: tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazine, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl, 3,4-dihydroquinazoline, benzopyrazolyl, benzopyrroleyl, benzoimidazolyl, benzofuranyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzothiophene, indole, purinyl, quinolinyl, or isoquinolinyl, wherein... Furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thiocyclobutyl, oxacyclopropyl, pyrrolylalkyl, pyrazolylalkyl, imidazolealkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridine 2-yl, tetrahydrothiaranyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazineyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl, 3,4-dihydroquinazoline, benzopyrazolyl, benzopyrroleyl, benzoimidazolyl, benzofuranyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, or 3 R groups. w3 Replaced, of which each R w3 It has the meaning as described in this invention.

[0031] In some embodiments, ring A has the following substructure:

[0032]

[0033] Among them, each R in formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) and (I-10) w3 Having the meaning as described in this invention, each R in formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), and (I-10) 6Independently, it is H, deuterium, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, -CD3, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3, wherein the methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, CHD2, -CH2CD3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3 are each independently unsubstituted or substituted by 1, 2 or 3 independently selected substituents from deuterium, F, Cl, Br, methyl and ethyl.

[0034] On the other hand, the compounds of the present invention include any one of the following compounds or their stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof:

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] On the other hand, the present invention also relates to a pharmaceutical composition comprising the compounds described herein.

[0042] In some embodiments, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable excipients.

[0043] In some embodiments, the pharmaceutical composition of the present invention further comprises other antiviral drugs.

[0044] In some embodiments, other antiviral drugs described in this invention are remdesivir, favipiravir, nematvir, ribavirin, monoupivir, baricitinib, monoupivir, proxalutamide, azvudine, carmostat, naprostine, ritonavir, lopinavir, nitrozonide, chloroquine, hydroxychloroquine, darunavir, arbidol, resveratrol, interferon α, interferon β, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, Jinhua Qinggan granules, Shufeng Jiedu capsules, Lianhua Qingwen capsules, or any combination thereof.

[0045] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of medicaments for the prevention, treatment, or relief of disease in patients caused by coronavirus infection.

[0046] In some embodiments, the coronaviruses described in this invention are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

[0047] In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) in the preparation of a medicament for the prevention, treatment, or relief of disease or symptoms in patients infected with HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2. On the other hand, the present invention relates to a method for the prevention, treatment, or relief of disease or symptoms in patients caused by coronavirus infection, the method comprising administering to a patient a pharmaceutically acceptable and effective dose of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) of the present invention.

[0048] In some embodiments, the present invention relates to a method for preventing, treating or alleviating disease or symptoms in patients caused by infection with HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) of the present invention.

[0049] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds used in the pharmaceutical applications of this invention are within the scope of this invention.

[0050] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the other components of the formulation and the mammal intended for treatment.

[0051] The salts of the compounds of the present invention also include salts used for the preparation or purification of intermediates of the compound of formula (I) or for the isolation of enantiomers of the compound of formula (I), but are not necessarily pharmaceutically acceptable salts.

[0052] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Alternatively, 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 acid and galacturonic acid; α-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, etc., or combinations thereof, can be used.

[0053] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N2, etc. + (R 14 Salts of 4 and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary, and tertiary ammonia, N... + (R 14 )4 salts, such as R 14 It is H, C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl groups, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium salts, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C. 1-8 Sulfonates and aromatic sulfonates.

[0054] Definitions and general terms

[0055] This invention will list in detail the relevant literature for the specific details provided, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usages of terms, described techniques, or the scope controlled as described in this application.

[0056] This invention will apply the following definitions unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75. th Ed., 1994, defines it. Additionally, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all content incorporates references.

[0057] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0058] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0059] As used in this invention, the term "alkyl" includes a monovalent hydrocarbon group consisting of a saturated straight-chain or branched chain of 1-20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments have an alkyl group containing 1-12 carbon atoms, others have an alkyl group containing 1-10 carbon atoms, still others have an alkyl group containing 1-8 carbon atoms, still others have an alkyl group containing 1-6 carbon atoms, still others have an alkyl group containing 1-4 carbon atoms, and still others have an alkyl group containing 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH 2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)) 2) 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)C H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0060] The term "alkylene" refers to a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group contains 1-3 carbon atoms; and in still other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), etc.

[0061] The terms “hydroxyalkyl” and “hydroxyalkoxy” refer to alkyl or alkoxy groups, which, as the case may be, are replaced by one or more hydroxyl groups. “Hydroxyalkyl” and “hydroxyalkyl” can be used interchangeably. Examples of such interchangeability include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH,-CHOHCH3), hydroxypropyl (-CH2CH2CH2OH,-CH2CHOHCH3,-CHOHCH2CH3), hydroxymethoxy (-OCH2OH), etc.

[0062] The terms “haloalkyl,” “haloalkenyl,” or “haloalkoxy” indicate that an alkyl, alkenyl, or alkoxy group is replaced by one or more halogen atoms. Examples of such substitutions include, but are not limited to, difluoroethyl (-CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (-CH2CF3,-CF2CH2F,-CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), etc.

[0063] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in still other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0064] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0065] The term "alkynyl" refers to a monovalent hydrocarbon group consisting of a straight or branched chain of 2-12 carbon atoms, wherein at least one C-C bond is an sp triple bond. The alkynyl group may be independently and optionally substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 2-12 carbon atoms; in other embodiments, the alkyl group contains 2-8 carbon atoms; in still other embodiments, the alkyl group contains 2-6 carbon atoms; and in yet another embodiment, the alkyl group contains 2-4 carbon atoms. Specific examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), propynyl (-C≡C-CH3), ethynylbutyryl (-CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3 and -CH(CH3)C≡CH), and ethynylpentyl (-CH2CH2CH2C≡CH, -CH2CH2C≡CCH3, -CH2C≡CCH2CH3, -C≡CCH2CH2CH3, -CH2CH(CH3)C≡CH, -CH(CH3)CH2C≡CH), -C(CH3)2C≡CH, -CH(CH3)C≡CCH3, -C≡CCH(CH3)CH3 and -C≡CCH(CH3)2), etc.

[0066] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3 to 12 carbon atoms; in another embodiment, it comprises 3 to 8 carbon atoms; in yet another embodiment, it comprises 3 to 7 carbon atoms; and in still other embodiments, it comprises 3 to 6 carbon atoms. Examples of cycloalkyl groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0067] The term "composed of M-M1 atoms" indicates that the cyclic group is composed of M-M1 ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "monocyclic heteroaryl composed of 5-6 atoms" means that it comprises a monocyclic heteroaryl group composed of 5 or 6 atoms.

[0068] The term "composed of n atoms," where n is an integer, typically describes the number of ring atoms in a molecule, where the number of ring atoms in the molecule is n. For example, piperidinyl is a heterocyclic group composed of 6 ring atoms.

[0069] The term "heterocyclic group" refers to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms. The heterocyclic group may optionally be substituted by one or more substituents described in this invention. Unless otherwise stated, the heterocyclic group may be carbocyclic or nitrogen-based, and the -CH2- group may optionally be replaced by -C(=O)- or -C(=S)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic group is a heterocyclic group consisting of 3-12 ring atoms; in some embodiments, it is a heterocyclic group consisting of 5-10 ring atoms; in some embodiments, it is a heterocyclic group consisting of 3-6 ring atoms; in some embodiments, it is a heterocyclic group consisting of 4-6 ring atoms; and in some embodiments, it is a heterocyclic group consisting of 5-6 ring atoms. In some embodiments, the heterocyclic group is a four-atom heterocyclic group, referring to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing four ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. In other embodiments, the heterocyclic group is a five-atom heterocyclic group, referring to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing five ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. In other embodiments, the heterocyclic group is a six-atom heterocyclic group, referring to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing six ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic group. Examples of heterocycles include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, piperazinyl, homopiperazinyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, homopiperidinyl, glycidyl, azirroheptyl, oxacycloheptyl, thiohexacycloheptyl, oxazorphinyl, diazazorphinyl, thioazorphinyl, 2-pyrrolinyl, 3- Pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothienyl, pyrazolylimidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, and N-pyridylurea.Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, wherein examples of carbon atoms on the ring being substituted by oxy (=O) include, but are not limited to, pyrimidinidone, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-keto, etc., wherein examples of carbon atoms on the ring being substituted by the =S group include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thioketone, 1,3,4-oxadiazole-2(3H)-thioketone, etc.

[0070] The term “heteroatom” refers to one or more O, S, N, P, and Si, including N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NR (like NR in N-substituted pyrrolidinyl).

[0071] The term "halogen" or "halogen atom" refers to F, Cl, Br, or I.

[0072] The term "unsaturated" as used in this invention means that the portion contains one or more degrees of unsaturation.

[0073] The term "alkoxy" as used in this invention refers to an alkyl group, as defined in this invention, which is attached to the main carbon chain via an oxygen atom ("alkoxy group").

[0074] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment points to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be optionally and independently substituted by one or more substituents described in this invention.

[0075] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, 9-10, 9, or 5-6 ring atoms, wherein at least one ring is an aromatic ring, and at least one aromatic ring contains one or more heteroatoms, wherein each ring system comprises a ring of 5-7 atoms and has one or more connection points attached to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocycle," "heteroaromatic ring," or "heteroaromatic compound." In some embodiments, a heteroaryl is a heteroaryl comprising 5-12 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, a heteroaryl is a heteroaryl comprising 5-10 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 9-10 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 9 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, the heteroaryl group is a monocyclic heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Furthermore, the heteroaryl group can be substituted or unsubstituted, and the aryl group can be optionally substituted independently by one or more substituents described in this invention.

[0076] Examples of heterocyclic aromatic rings include, but are not limited to, the following monocyclic rings: 1,2,4-oxadiazole-5(4H)-thionyl, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1,3,4-oxadiazole-2(3H)-thionyl, 1H-1,2,4-triazole-5(4H)-keto, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4 -Imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (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-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, diazolyl, thiadiazolyl Triazine group, etc.; also includes the following bicyclic groups, but is by no means limited to these: benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophene, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), benzopyrazolyl, benzopyrroleyl, benzooxazolyl, benzooxazolyl, isoxazolyl, etc.

[0077] The terms "alkylamino" and "alkanoamino" are used interchangeably, including "N-alkanoamino" and "N,N-dialkylamino," indicating that the hydrogen atom in the amino group is independently replaced by one or two alkyl groups. In some embodiments, the alkanoamino group has one or two C24 groups. 1-12 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-6 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-4 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In some other embodiments, the alkylamino group has one or two carbon atoms. 1-3An alkyl group is attached to a nitrogen atom to form a lower-order alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-ethylpropyl-2-amino, etc.

[0078] The terms "alkylsilyl" and "alkylsilyl" indicate that the hydrogen atoms in the silyl (-SiH3) group are independently replaced by one, two, or three alkyl groups. In some embodiments, the alkylsilyl group has one, two, or three carbon atoms. 1-12 The alkyl group is attached to a silicon atom to form a lower-order alkylsilyl group. In other embodiments, the alkylsilyl group has one, two, or three carbon atoms. 1-9 The alkyl group is attached to a silicon atom to form a lower-order alkylsilyl group. In other embodiments, the alkylsilyl group has one, two, or three carbon atoms. 1-6 The alkyl group is attached to a silicon atom to form a lower-order alkylsilyl group. In other embodiments, the alkylsilyl group has one, two, or three carbon atoms. 1-4 The alkyl group is attached to a silicon atom to form a lower-order alkylsilyl group. In some other embodiments, the alkylsilyl group has one, two, or three carbon atoms. 1-3 An alkyl group is formed by attaching an alkyl group to a silicon atom to form a lower-order alkylsilyl group. Suitable alkylsilyl groups can be monoalkylsilyl, dialkylsilyl, or trialkylsilyl. Examples of alkylsilyl groups include, but are not limited to, trimethylsilyl (-Si(CH3)3), triethylsilyl (-Si(CH2CH3)3) / tri-n-propylsilyl (-Si(CH2CH2CH3)3), etc.

[0079] The terms "alkoxyalkyl" or "alkoxyalkylene" indicate that an alkyl group may be replaced by one or more identical or different alkoxy groups, wherein the alkoxy and alkyl groups have the meanings as described in this invention. Examples of such groups include, but are not limited to, cyclohexylmethyl, cyclopropylethyl, etc.

[0080] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases “each and each is independently”, “each and each is independently”, and “each and each is independently” used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0081] The term "room temperature" refers to 10°C to 40°C. In some implementations, "room temperature" refers to 10°C to 30°C. In other implementations, "room temperature" refers to 20°C to 30°C.

[0082] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0083] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (Ia) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0084] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0085] "Metabolic products" refer to the products obtained in vivo through the metabolic processes of a specific compound or its salt. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized experimentally as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0086] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: 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. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is rotated. (-) or l indicates the compound is levorotatory, while (+) or d indicates it is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0087] The terms "tautomer" or "tautomer form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Another example is the compound represented by formula (I) in this invention. and as well as They are tautomers, in which each ring A, R 1 R 2 R 3 R a R b R c and R d This has the meaning as described in this invention. Valence (combination valence) tautomerism includes interconversions involving recombination of bonding electrons. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0088] One or more hydrogen atoms, carbon atoms, or other atoms in the compounds of formula (I), (Ia), or (Ib) of this invention may be substituted with isotopes of hydrogen atoms, carbon atoms, or other atoms. The compounds of formula (I), (Ia), or (Ib) include all radiolabeled forms of the compounds of formula (I), (Ia), or (Ib). Such "radiolabeling," "radiolabeling," etc., of the compounds of formula (I), (Ia), or (Ib) are included in this invention and can be used in pharmacokinetic studies and in binding assays and / or as diagnostic tools. Examples of isotopes that can be incorporated into the compounds of formula (I), (Ia), or (Ib) of this invention include... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl, consisting of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms. The radiolabeled compounds of this invention can be prepared using methods known in the art.

[0089] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0090] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0091] Pharmaceutical compositions, formulations, administration, and uses of the compounds and pharmaceutical compositions of the present invention.

[0092] The pharmaceutical compositions of this invention are characterized by compounds of formula (I), (Ia), or (Ib), compounds listed in this invention, or compounds of the examples, and pharmaceutically acceptable excipients. The pharmaceutical compositions of this invention are effective in inhibiting coronaviruses and are suitable for the treatment of coronavirus infections, particularly for diseases or symptoms caused by HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

[0093] The compounds described in this invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to this invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of this invention, their metabolites, or their residues.

[0094] As described in this invention, the pharmaceutical compositions of this invention comprise any of the compounds of formula (I), (Ia), or (Ib) of this invention, further comprising pharmaceutically acceptable excipients, such as those used in this invention, including 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, etc., suitable for a particular target dosage form. As described in the following literature: 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, 1988-1999, Marcel Dekker, New York, the contents of which, when synthesized, demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0095] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides 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; polyacrylates; waxes; 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 carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients 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; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0096] The pharmaceutical composition provided by this invention also contains other antiviral drugs.

[0097] The other antiviral drugs mentioned are remdesivir, favipiravir, ribavirin, carmostat, naphalostat, ritonavir, lopinavir, nitrozonide, chloroquine, hydroxychloroquine, darunavir, arbidol, resveratrol, interferon α, interferon β, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, Jinhua Qinggan granules, Shufeng Jiedu capsules, Lianhua Qingwen capsules, etc., or any combination thereof.

[0098] The compounds or pharmaceutical compositions of the present invention can be administered in any of the following ways: oral administration, inhalation, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, or intracranial injection or infusion, or administration via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0099] The compounds of this invention, or pharmaceutically acceptable compositions, can be administered in unit doses. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders for injection, inclusion complexes, implants, patches, and liniments.

[0100] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0101] Oral liquids can be formulated as hydrated oil suspensions, solutions, emulsions, syrups, or elixirs, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous excipients (which may contain edible oils such as almond oil), fats such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0102] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0103] For external administration, liquid dosage forms are typically made from a compound and a sterilized excipient. Water is the preferred excipient. Depending on the excipient and drug concentration, the compound can be either dissolved in the excipient or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0104] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more excipients. Excipients that may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Excipients that may be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0105] Generally, it has been proven advantageous, in both human and veterinary medicine, that the total dosage of the active compound of the present invention is about 0.0005-500 mg per 24 hours, preferably 0.5-100 mg / kg body weight, administered in multiple single doses if appropriate, to achieve the desired effect. The amount of active compound in a single dose is preferably about 1-80 mg, more preferably 1-50 mg / kg body weight, but may not follow the above dosages, depending on the type and weight of the patient, the nature and severity of the disease, the type of formulation and the route of administration, and the dosing cycle or time interval.

[0106] Drugs for coronavirus infection can be administered separately from compositions containing compounds of the present invention as part of a multiple-dosing regimen. Alternatively, those drugs can be part of a single-dose formulation, mixed with compounds of the present invention to form a single composition. If administration is part of a multiple-dosing regimen, the two active agents can be delivered simultaneously and continuously or over a period of time to achieve the target agent activity.

[0107] The amount of compounds and compositions that can be combined with excipients to produce single-dose formulations (those comprising a single composition as described in this invention) varies depending on the indication and specific dosing regimen. Normally, the amount of the compositions of this invention will not exceed the amount in a normal dosing where the composition contains the sole active agent. On the other hand, the amounts of the compositions disclosed herein range from approximately 50% to 100% of the normal amounts in existing compositions, containing the agent as the sole active therapeutic agent. In those compositions, the composition will act synergistically with the compounds of this invention.

[0108] General synthetic method of the compound described in this invention

[0109] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I), (Ia), or (Ib). The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0110] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise stated. 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 stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0111] Silica gel columns were used, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0112] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0113] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0114] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table 1.

[0115] Table 1: Gradient elution conditions

[0116] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B (H2O,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

[0117] Compound purity was evaluated using an Agilent 1100 series high-performance liquid chromatography (HPLC) system with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column (2.1 × 30 mm, 4 μm), a flow rate of 0.6 mL / min for 10 min, and a concentration of 5-95% (0.1% formic acid acetonitrile solution) or (0.1% formic acid aqueous solution) at a column temperature of 40 °C.

[0118] The following abbreviations are used throughout this invention:

[0119]

[0120]

[0121] Method for synthesizing the compound described in this invention

[0122] The following synthetic scheme outlines the general experimental steps for preparing the compounds disclosed in this invention. Those skilled in the art can modify the method or adjust the raw materials as needed to obtain the compounds described in this invention. Wherein, each ring A, R... 1 R 3 R a R b R c and R d It has the meaning as described in this invention. Unless otherwise specified, the compounds described in this invention can be prepared by the methods described in the following synthetic schemes.

[0123] Synthesis Scheme 1

[0124]

[0125] The compound shown in formula (a-8) can be prepared by the method described in synthetic scheme 1, wherein each of X1, X2, X3, and X4 is independently F, Cl, Br, or I. First, compound (a-1) undergoes a nucleophilic substitution reaction with compound (a-2) under basic conditions (e.g., DIPEA) to generate compound (a-3); then, compound (a-3) undergoes a nucleophilic substitution reaction with compound (a-4) under basic conditions (e.g., K2CO3) to generate compound (a-5); next, compound (a-5) and compound (a-6) undergo a coupling reaction under appropriate conditions to give compound (a-7); finally, compound (a-7) undergoes a halogenation reaction under appropriate conditions to give compound (a-8). Detailed Implementation

[0126] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0127] Preparation Examples

[0128] In the following preparation examples, the inventors have described in detail the preparation process of the compounds of the present invention using some of the compounds of the present invention as examples.

[0129] Example 1: Synthesis of Compound 1

[0130]

[0131] Step 1: Synthesis of compound C-1

[0132] Compound A-1 (2.00 g, 13.65 mmol) and DMF (20 mL) were added to a 250 mL single-necked flask and stirred until dissolved. Then, DIEA (3.53 g, 27.3 mmol) and compound B-1 (3.07 g, 13.65 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water (10 mL), filtered, and the filter cake was washed with EA (100 mL) to give 1.50 g of the title compound as a white solid, yield 37.8%. MS (ESI, pos.ion) m / z: 291.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.73 (s, 1H), 7.60–7.51 (m, 1H), 7.50–7.42 (m, 1H), 6.02 (d, J = 2.0Hz, 1H), 5.13 (s, 2H).

[0133] Step 2: Synthesis of compound E-1

[0134] Compound C-1 (484 mg, 1.67 mmol) and DMF (20 mL) were added to a 250 mL round-bottom flask, followed by compound D-1 (400 mg, 2.38 mmol) and potassium carbonate (987 mg, 7.14 mmol). The mixture was stirred overnight at room temperature. The reaction solution was poured into ice water (50 mL) and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was separated by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 40 mg of the title compound as a white solid, yield 4.4%. MS (ESI, pos.ion) m / z: 386.2 [M+H] + .

[0135] Step 3: Synthesis of compound G-1

[0136] Compound E-1 (110 mg, 0.29 mmol) and compound F-1 (79 mg, 0.43 mmol) were added to a 50 mL single-necked flask, followed by toluene (10 mL), BINAP (36 mg, 0.058 mmol), cesium carbonate (140 mg, 0.43 mmol), and palladium acetate (13 mg, 0.058 mmol). The mixture was reacted overnight at 90 °C under nitrogen protection. The solvent was evaporated, and the residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 39.8 mg of the title compound as a white solid, yield 26.4%. MS (ESI, pos.ion) m / z: 531.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.86 (s, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.6 2–7.58(m,1H),7.28–7.24(m,1H),5.32(s,2H),4.95(s,2H),4.18(s,3H),4.15(s,1H),3.77(s,3H).

[0137] Step 4: Synthesis of Compound 1

[0138] Compound G-1 (100 mg, 0.19 mmol) and DMF (10 mL) were added to a 250 mL single-necked flask, followed by NCS (25.4 mg, 0.19 mmol). The mixture was stirred at room temperature for 2 h. The reaction solution was then poured into ice water (10 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 70 mg of the title compound as a white solid, in 65.7% yield. MS (ESI, pos.ion) m / z: 565.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.37 (d, J = 3.6Hz, 2H), 8.20 (s, 1H), 7.69 (s, 1H), 7. 30–7.22(m,2H),7.17(s,1H),5.12(s,2H),5.09(s,2H),4.12(s,3H),3.81(s,3H).

[0139] Example 2: Synthesis of Compound 2

[0140]

[0141] Compound G-1 (70 mg, 0.13 mmol) and DMF (10 mL) were added to a 250 mL single-necked flask, followed by NBS (23 mg, 0.13 mmol). The mixture was stirred at room temperature for 2 h. The reaction solution was then poured into ice water (10 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 39.5 mg of the title compound as a white solid, in 49.1% yield. MS (ESI, pos.ion) m / z: 609.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.38 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.69 (s ,1H),7.32–7.21(m,2H),7.05(s,1H),5.12(s,4H),4.12(s,3H),3.82(s,3H).

[0142] Example 3: Synthesis of Compound 3

[0143]

[0144] Compound G-1 (160 mg, 0.30 mmol) and DMF (10 mL) were added to the reaction flask, along with fluorine reagent 3-1 (80.0 mg, 0.22 mmol). The mixture was stirred at room temperature for 4 h. The reaction solution was poured into ice water (10 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 61.1 mg of the title compound as a white solid, yield 36.9%. MS (ESI, pos.ion) m / z: 549.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.58 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.73 (s, 1H), 7.4 8–7.39(m,2H),7.34–7.29(m,1H),5.19(s,2H),5.05(s,2H),4.14(s,3H),3.81(s,3H).

[0145] Example 4: Synthesis of Compound 4

[0146]

[0147] Step 1: Synthesis of Compound 4-3

[0148] Compound 4-1 (1.00 g, 5.06 mmol), cesium carbonate (3.30 g, 10.12 mmol), and DMF (10 mL) were added sequentially to a reaction flask, followed by compound 4-2 (2.00 g, 10.12 mmol). The reaction was carried out under nitrogen protection at 80 °C for 16 h. The mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The aqueous phase was washed with ethyl acetate (50 mL), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA(V / V) = 6 / 1) to give 0.48 g of the title compound as a yellow solid, yield 35.4%. MS (ESI, pos.ion) m / z: 268.1 [M+H] + .

[0149] Step 2: Synthesis of compound 4-4

[0150] Compound 4-3 (0.50 g, 2.53 mmol), iron powder (0.40 g, 7.16 mmol), ammonium chloride (0.77 g, 14.32 mmol), ethanol (30 mL), and water (10 mL) were added sequentially to a reaction flask. The reaction was carried out at 80 °C for 3 h under nitrogen protection. The reaction solution was concentrated, and methanol (50 mL) was added to dissolve the residue. The mixture was then filtered through a diatomaceous earth filter. The filter cake was washed with methanol (50 mL), the filtrate was concentrated, and dichloromethane (50 mL) was added to sonicate and dissolve the residue. The mixture was filtered, and the filtrate was concentrated to give 0.31 g of the title compound as a yellowish-brown solid, with a yield of 72.7%. MS (ESI, pos.ion) m / z: 238.4 [M+H] + .

[0151] Step 3: Synthesis of compounds 4-5

[0152] Using compounds 4-4 and E-1 as starting materials, and following the synthetic method for compound G-1 (i.e., step 3 in Example 1), 97 mg of the title compound as a white solid was obtained, with a yield of 60.5%. MS (ESI, pos.ion) m / z: 587.5 [M+H] + ; 1H NMR (400MHz, CD3OD): δ (ppm) 8.32 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.40–7.31 (m, 1H) ,7.30–7.19(m,1H),5.39(s,2H),5.17(s,2H),4.88(s,1H),4.29(s,2H),3.88(s,3H),1.02(s,9H).

[0153] Step 4: Synthesis of Compound 4

[0154] Using compounds 4-5 as starting materials, and following the synthetic method described in step 4 of compound 1, 10 mg of the title compound was obtained as a white solid, in a yield of 16.6%. MS (ESI, pos.ion) m / z: 621.1 [M+H] + .

[0155] Example 5: Synthesis of Compound 5

[0156]

[0157] Using compounds 4-5 as starting materials and following the synthetic method for compound 2, 20 mg of the title compound was obtained as a white solid, in a yield of 27.5%. MS (ESI, pos.ion) m / z: 665.5 [M+H] + .

[0158] Example 6: Synthesis of Compound 6

[0159]

[0160] Compound 2 (20 mg, 0.033 mmol), THF (2 mL), and cyclopropylamine (4 mg, 0.070 mmol) were added to the reaction flask and stirred at room temperature for about 1 h. The pH was then adjusted to 7 with 1 M hydrochloric acid, the solvent was concentrated, and the residue was purified by thin-layer chromatography (DCM / MeOH (V / V) = 30 / 1) to give 6 mg of the title compound as a light brown solid, yield 31.2%. MS (ESI, pos.ion) m / z: 586.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.37 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.31 (s, 1H), 7.20 (s, 2H), 6.83 (s, 1H), 5.37–5.2 7(m,1H),5.13(s,2H),4.91(s,2H),4.19–4.13(m,1H),4.09(s,3H),3.81(s,3H),1.38–1.31(m,2H),0.90–0.79(m,2H).

[0161] Example 7: Synthesis of Compound 7

[0162]

[0163] Step 1: Synthesis of Compound 7-2

[0164] Compound 4-1 (3.00 g, 15.18 mmol), sodium carbonate (3.22 g, 30.36 mmol), potassium iodide (2.52 g, 15.18 mmol), and DMF (80 mL) were added sequentially to a reaction flask, followed by compound 7-1 (2.54 g, 15.18 mmol). The reaction mixture was reacted at room temperature for 24 h under nitrogen protection. 150 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA(V / V) = 4 / 1) to give 0.75 g of the title compound as a pale yellow solid, yield 17.4%. MS (ESI, pos.ion) m / z: 284.1 [M+H] + .

[0165] Step 2: Synthesis of Compound 7-3

[0166] Compound 7-2 (0.74 g, 2.61 mmol), iron powder (0.58 g, 10.47 mmol), ammonium chloride (1.12 g, 20.88 mmol), ethanol (40 mL), and water (10 mL) were added sequentially to a reaction flask. The reaction was carried out at 80 °C for 3 h under nitrogen protection. The reaction solution was concentrated, and the residue was dissolved in methanol (100 mL). The mixture was filtered through a diatomaceous earth filter. The filter cake was washed with methanol (100 mL), and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA(V / V) = 2 / 1) to obtain 0.52 g of the title compound as a yellowish-brown solid, with a yield of 78.6%. MS (ESI, pos.ion) m / z: 254.1 [M+H] + .

[0167] Step 3: Synthesis of Compound 7-4

[0168] Using compound 7-3 as a starting material, and following the synthetic method of compound G-1 (step 3 in Example 1), 177 mg of the title compound as a pale yellow solid was obtained, with a yield of 56.6%. MS (ESI, pos.ion) m / z: 603.5 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ (ppm) 8.03 (s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.45 (dd, J = 17.4, 8.2Hz, 1H), 7.14–6.93 (m, 1 H),6.07(s,1H),5.36(s,2H),5.31(s,2H),5.06(s,1H),4.73(t,J=6.3Hz,2H),3.89(s,3H),3.71(s,3H),3.08(t,J=6.3Hz,2H).

[0169] Step 4: Synthesis of Compound 7

[0170] Using compounds 7-4 as starting materials and following the synthetic method for compound 2, 121 mg of the title compound was obtained as a white solid, in yield 53.5%. MS (ESI, pos.ion) m / z: 681.4 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ (ppm) 8.15 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.13 (s, 1H), 7.01 (dd, J = 17.9, 8.3Hz, 1H), 6. 66–6.51(m,1H),5.33(s,2H),5.00(s,2H),4.66(t,J=6.5Hz,2H),3.91(s,3H),3.69(s,3H),3.03(t,J=6.5Hz,2H).

[0171] Example 8: Synthesis of Compound 8

[0172]

[0173] Using compounds 4-1 and 8-1 as starting materials, and following the synthetic method for compound 7, the title compound was obtained as a white solid, 60 mg, in yield 53.1%. MS (ESI, pos.ion) m / z: 687.4 [M+H] + ; 1H NMR (400MHz, CD3OD): δ (ppm) 8.75 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.36 (t, J = 5.0Hz, 1H) ,7.18(s,1H),7.05(dd,J=18.1,8.1Hz,1H),6.67–6.57(m,1H),5.79(s,2H),5.33(s,2H),5.02(s,2H),3.90(s,3H).

[0174] Example 9: Synthesis of Compound 9

[0175]

[0176] Using compounds 4-1 and 9-1 as starting materials, and following the synthetic method for compound 7, the title compound was obtained as a white solid, 40 mg, in yield 64.6%. MS (ESI, pos.ion) m / z: 663.1 [M+H] + ; 1 H NMR(400MHz, CD3OD / CDCl3)δ8.25(s,1H),7.96(s,1H),7.64(s,1H),7.19(s,1H),7.02–6.93(m,1H),6.61–6.50(m,1H),5.33(s ,2H),5.01(s,2H),4.95–4.86(m,1H),3.92(s,3H),2.37–2.25(m,2H),2.16–2.06(m,2H),2.01–1.92(m,2H),1.86–1.74(m,2H).

[0177] Example 10: Synthesis of Compound 10

[0178]

[0179] Using compounds 4-1 and 10-1 as starting materials, and following the synthetic method for compound 7, the title compound was obtained as a white solid, 30 mg, in yield 46.4%. MS (ESI, pos.ion) m / z: 667.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.27(s,1H),8.15(s,1H),7.73(s,1H),7.38–7 .23(m,2H),7.10(s,1H),5.39(s,2H),5.22–5.06(m,4H),3.82(s,3H),3.71(s,3H).

[0180] Example 11: Synthesis of Compound 11

[0181]

[0182] Pd₂(dba)₃ (3 mg, 0.0033 mmol), Xantphos (2 mg, 0.0035 mmol), 1,4-dioxane (2 mL), and piperidine (6 mg, 0.070 mmol) were added to a reaction flask. Under nitrogen protection, compound 2 (20 mg, 0.033 mmol) was added, and the reaction mixture was stirred at room temperature for 14.5 h. The solvent was concentrated, and the residue was purified by thin-layer chromatography (DCM / MeOH (V / V) = 30 / 1) to give the title compound as a light brown solid (7 mg, 34.8%). MS (ESI, pos.ion) m / z: 614.5 [M+H] + ; 1 H NMR(400MHz, DMSO-d6): δ(ppm)8.34(s,1H),8.19(s,1H),7.82(s,1H),7.74–7.64(m,2H),7.34–7.25(m,1 H),7.24–7.21(m,1H),4.95–5.10(s,4H),4.12(s,3H),3.80(s,3H),3.55–3.34(m,4H),1.20–0.95(m,6H).

[0183] Example 12: Synthesis of Compound 12

[0184]

[0185] Compound 2 (50 mg, 0.082 mmol), DMF (3 mL), and NaNO2 (28 mg, 0.41 mmol) in water (1 mL) were added to the reaction flask, and the reaction was allowed to proceed for 6 hours. The mixture was diluted with EA (20 mL) and water (10 mL), and the organic phase was washed with water (10 mL × 2). The solution was then concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (DCM / MeOH (V / V) = 25 / 1) to give 6 mg of the title compound as a yellow solid, in 25.4% yield. MS (ESI, pos.ion) m / z: 576.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.60 (s, 1H), 8.46–8.28 (m, 2H), 7.80–7.61 (m ,2H),7.55–7.43(m,2H),5.31(s,2H),5.01(s,2H),4.13(s,3H),3.80(s,3H).

[0186] Example 13: Synthesis of Compound 13

[0187]

[0188] Compound G-1 (220 mg, 0.41 mmol), DMF (10 mL), potassium carbonate (74 mg, 0.53 mmol), and methyl iodide (47 mg, 0.33 mmol) were added to the reaction flask and stirred at room temperature for 2 h. The reaction mixture was poured into ice water (10 mL) and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 65 mg of the title compound as a yellow solid, yield 28.8%. MS (ESI, pos.ion) m / z: 545.5 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 8.07 (s, 1H), 7.70 (d, J = 1.8Hz, 2H), 7.22–7. 17(m,2H),6.75(s,1H),5.07–4.98(m4H),4.09(s,3H),3.82(s,3H),1.69(s,3H).

[0189] Example 14: Synthesis of Compound 14

[0190]

[0191] Using compounds 4-1 and 14-1 as starting materials, and following the synthetic method for compound 7, 16 mg of the title compound was obtained as a white solid, in 70.4% yield. MS (ESI, pos.ion) m / z: 659.4 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ (ppm) 8.24 (s, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.05 (dd, J = 18.2, 8.3Hz, 1H), 6.69–6.54 ( m,1H),6.37(s,1H),6.24(t,J=4.0Hz,1H),6.09(d,J=4.0Hz,1H),5.33(s,2H),5.04(s,2H),4.85–4.75(m,2H),3.92(s,3H).

[0192] Example 15: Synthesis of Compound 15

[0193]

[0194] Using compounds 4-1 and 15-1 as starting materials, and following the synthetic method for compound 7, 26 mg of the title compound was obtained as a white solid, in a yield of 46.1%. MS (ESI, pos.ion) m / z: 691.5 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ (ppm) 7.99 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.15 (s, 1H), 7.03 (dd, J = 17.8, 8.5Hz, 1H) ,6.60(td,J=9.8,6.6Hz,1H),5.33(s,2H),5.03(s,2H),4.64(t,J=7.2Hz,2H),3.92(s,3H),2.96–2.78(m,2H).

[0195] Example 16: Synthesis of Compound 16

[0196]

[0197] Using compound 9 as the starting material and following the synthetic method of compound 2, 20 mg of the title compound as a pale yellow solid was obtained in a yield of 40.9%. MS (ESI, pos.ion) m / z: 741.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.82(s,1H),7.67(s,1H),7.13–7.03(m,1H),6.41–6.33(m,1H),6.31(s,1H),5.39(d,J=9.1Hz,2 H),5.06–4.98(m,1H),4.94–4.86(m,2H),3.89(s,3H),2.37–2.31(m,2H),2.20–2.13(m,2H),2.02–1.98(m,2H),1.83–1.79(m,2H).

[0198] Example 17: Synthesis of Compound 17

[0199]

[0200] Step 1: Synthesis of Compound 17-2

[0201] Compound 4-1 (1.25 g, 6.33 mmol), 4,4-difluorocyclohexane-1-ol (0.95 g, 6.96 mmol), diisopropyl azodicarbonate (1.92 g, 9.50 mmol), triphenylphosphine (2.49 g, 9.50 mmol), and tetrahydrofuran (40 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA(V / V) = 3 / 1) to give 1.3 g of the title compound as a yellow liquid, yield: 65.1%. MS (ESI, pos.ion) m / z: 316.3 [M+H] + .

[0202] Step 2: Synthesis of Compound 17

[0203] Using compound 17-2 as the starting material, and following steps 2 to 4 of compound 7, 11 mg of the title compound as a light brown solid was obtained in 36.5% yield. MS (ESI, pos.ion) m / z: 713.5 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ7.99(s,1H),7.81(s,1H),7.79(s,1H),7.15–7.05(m,1H),6.99(s,1H),6.65–6.56(m,1H) ,6.12(s,1H),5.41(s,2H),5.00(s,2H),4.55–4.49(m,1H),3.91(s,3H),2.36–2.29(m,5H),2.10–1.93(m,3H).

[0204] Example 18: Synthesis of Compound 18

[0205]

[0206] Compound 8-4 was prepared from compounds 4-1 and 8-1 using the synthetic method described in steps 1-3 of Example 7. MS (ESI, pos.ion) m / z: 609.6 [M+H] + ; 1¹H NMR (400MHz, CDCl₃): δ (ppm) 8.75 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.44 (dd, J = 17.3, 8.4Hz, 1H), 7.27 (t, 1H), 7.05–6.95 (m, 1H), 6.16 (s, 1H), 5.86 (s, 2H), 5.35 (s, 2H), 5.30 (s, 2H), 5.09 (s, 1H), 3.88 (s, 3H)). Following the synthetic method of compound 2, 16 mg of the title compound as a yellow solid was obtained, with a yield of 25.4%. MS (ESI, pos.ion) m / z: 765.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ (ppm) 8.37 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.31 (s, 1H), 7.19 (s,2H),6.83(s,1H),5.32(s,1H),5.13(s,2H),4.90(s,2H),4.09(s,2H),3.81(s,3H).

[0207] Example 19: Synthesis of Compound 19

[0208]

[0209] Step 1: Synthesis of Compound 19-3

[0210] 4-Chloro-2-fluoro-5-nitrobenzaldehyde (0.50 g, 2.46 mmol) and ethylene glycol dimethyl ether (20 mL) were added to a reaction flask. The reaction system was purged with nitrogen three times. Cyclopropyl-hydrazine hydrochloride (0.53 g, 4.92 mmol) and TEA (0.50 g, 4.92 mmol) were added under ice bath conditions, and the reaction was carried out at room temperature for 22 h. The mixture was diluted with dichloromethane (100 mL) and water (100 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA(V / V) = 4 / 1) to give 80 mg of the title compound as a yellow solid, yield: 13.7%. MS (ESI, pos.ion) m / z: 238.1 [M+H] + .

[0211] Step 2: Synthesis of Compound 19

[0212] Using compound 19-3 as a starting material, and following the synthetic method described in steps 2 to 4 of Example 7, 6 mg of the title compound as a white solid was obtained, with a yield of 20.6%. MS (ESI, pos.ion) m / z: 635.4 [M+H] + ; 1 H NMR(400MHz, DMSO-d6): δ(ppm)8.37(s,1H),8.29(s,1H),8.14(s,1H),7.66(s,1H),7.29–7.17(m,2 H),7.02(s,1H),5.11(s,4H),4.14–4.07(m,1H),3.82(s,3H),1.26–1.21(m,2H),1.14–1.08(m,2H).

[0213] Example 20: Synthesis of Compound 20

[0214]

[0215] Using compounds 4-1 and 20-1 as starting materials, and following the synthetic method for compound 7, 20 mg of the title compound was obtained as a white solid, in 19.5% yield. MS (ESI, pos.ion) m / z: 690.1 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ (ppm) 8.01 (s, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.10 (dd, J = 17.6, 8.4Hz, 1H), 6.98 (s,1H),6.64(dd,J=16.2,9.6Hz,1H),6.11(s,1H),5.64(s,2H),5.37(s,2H),4.96(s,2H),3.92(s,3H),3.88(s,3H).

[0216] Example 21: Synthesis of Compound 21

[0217]

[0218] Compound 14 (120.0 mg, 0.18 mmol), THF (10 mL), and cyclopentanamine (23.0 mg, 0.27 mmol) were added to the reaction flask and stirred overnight at room temperature. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give 8.5 mg of the title compound as a yellow solid, yield 7.0%. MS (ESI, pos.ion) m / z: 664.2 [M+H] + ; 1H NMR (400MHz, CDCl3): δ (ppm) 7.98 (s, 1H), 7.83 (d, J = 8.5Hz, 2H), 7.18–7.10 (m, 1H), 6.91 (s, 1H), 6.76–6.57 (m, 2H), 6.24 (t, J = 4. 2Hz,1H),5.46(s,1H),5.37(d,J=3.4Hz,3H),4.97(s,2H),4.73–4.68(m,2H),3.89(s,4H),3.41–3.35(m,1H),1.68–1.58(m,6H).

[0219] Biological tests

[0220] In vitro biochemical reactions were used to evaluate the inhibitory activity of the compounds of this invention on Mpro / 3CLpro protease.

[0221] Compound activity was determined using a modified Beyotime's "Novel Coronavirus Mpro / 3CLpro Inhibitor Screening Kit". The fluorescence resonance energy transfer (FRET) method was employed, with the following detection principle: Edans is the fluorescent donor, and Dabcyl is the fluorescent acceptor or quencher. The absorption spectra of these two fluorophores overlap to some extent. When the distance between these two fluorophores is appropriate, fluorescence energy is transferred from the donor to the acceptor, causing the fluorescence intensity of the donor molecule to decrease. Edans and Dabcyl are attached to both ends of the natural substrate of the SARS-CoV-2 Mpro / 3CLpro protease, i.e., Dabcyl-KTSAVLQSGFRKME-Edans. When the SARS-COV-2Mpro / 3CLpro protease does not cleave the substrate, the two groups are close enough to undergo fluorescence resonance energy transfer, meaning Dabcyl quenches Edans fluorescence, resulting in undetectable fluorescence. However, when the substrate is cleaved by the SARS-COV-2Mpro / 3CLpro protease, the peptide ends separate, the two groups separate, and Edans fluorescence is no longer quenched by Dabcyl, allowing for detection. This fluorescence detection method provides highly sensitive detection of the SARS-COV-2Mpro / 3CLpro protease activity. Adding a SARS-COV-2Mpro / 3CLpro inhibitor to the reaction system suppresses fluorescence generation; the fluorescence intensity is inversely proportional to the inhibitory effect, allowing for the detection of the inhibitory effect of the SARS-COV-2Mpro / 3CLpro protease inhibitor. Edans has a maximum excitation wavelength of 340 nm and a maximum emission wavelength of 490 nm.

[0222] Compound preparation: Dissolve the compound in DMSO to prepare a 20 mM stock solution, further dilute with DMSO to prepare a 200 μM working solution, and then perform a 4-fold dilution to obtain 8 concentration points.

[0223] Enzyme activity assay: Compound activity was determined using the modified Beyotime "Novel Coronavirus Mpro / 3CLpro Inhibitor Screening Kit". Before use, the Assay Buffer and Substrate in the kit were thawed and equilibrated to room temperature, and the SARS-COV-2Mpro / 3CLpro protease was placed on ice. 92.75 μL of Assay Buffer and 0.25 μL of SARS-COV-2Mpro / 3CLpro protease were added to each well. The total amount of Assay Buffer and SARS-COV-2Mpro / 3CLpro protease required was calculated based on the number of samples (including relevant controls). After thorough mixing, 93 μL of Assay Buffer was added to each well of a 96-well plate. For the blank control, 93 μL of Assay Buffer was added to each well, without enzyme. For the 100% enzyme activity control, 92.75 μL of Assay Buffer and 0.25 μL of SARS-COV-2Mpro / 3CLpro protease were added to each well. Then, 5 μL of serially diluted compound was added to each well, with two replicates for each concentration. The highest final concentration was 10 μM (20-fold dilution). Shionogi 3Clpro inhibitor S-217622 was used as a positive control, also at a maximum concentration of 10 μM. 5 μL of DMSO was added to each well for the blank control and 100% enzyme activity control. The 96-well plate was incubated at 37°C for 10 minutes. 2 μL of substrate was quickly added to each well and mixed well. After incubation at 37°C in the dark for 15 minutes, fluorescence was measured using a multifunctional enzyme label. The excitation wavelength was 340 nm, and the emission wavelength was 490 nm. The inhibition percentage for each sample was calculated using the following formula:

[0224] Inhibition rate (%) = (RFU 100% enzyme activity control - RFU sample) / (RFU 100% enzyme activity control - RFU blank control) × 100%

[0225] RFU, Relative Fluorescence Unit.

[0226] The concentration-inhibition rate was processed using Graphpad Prism 7 software, and the IC50 of the compound inhibiting the SARS-CoV-2Mpro / 3CLpro protease was calculated using a four-parameter nonlinear regression model. 50 The experimental results are shown in Table A.

[0227] Table A: Experimental results of in vitro inhibition of SARS-CoV-2Mpro / 3CLpro protease by the compounds of this invention.

[0228] Example No. <![CDATA[IC 50 (nM)]]> 1 16.28 3 205.2 5 23.57 7 30.92 8 36.15 9 41.79 10 23.71 13 >10000 14 24.52 15 33.11 16 14.69 17 13.16 18 14.4 19 32.17 20 51.76

[0229] Conclusion: Experimental results show that the compound of the present invention has good inhibitory activity against SARS-COV-2Mpro / 3CLpro protease.

[0230] 3. Liver microsomal stability experiments of the compounds of the present invention in different species

[0231] Experimental Methods: 30 μL of a mixture of the test compound and liver microsomes was added to each well of a 96-well plate to prepare two parallel samples. After pre-incubation at 37°C for 10 min, 15 μL of NADPH solution (6 mM) was added at each time point. The final concentration of the test compound was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentration of NADPH was 2 mM. Incubation was performed for 0, 15, 30, and 60 min, respectively. After incubation, 150 mL of acetonitrile (containing internal standard) was added to the mixture. The acetonitrile-diluted sample was centrifuged at 4000 rpm for 5 min, and 150 μL of the supernatant was analyzed by LC-MS / MS. The compounds of this invention exhibited good stability in liver microsomes across different species. The results of liver microsome stability experiments for some compounds are shown in Table B.

[0232] Table B: Liver microsomal stability experiments of the compounds of the present invention in different species

[0233]

[0234] Conclusion: The compounds of this invention exhibit good stability in liver microsomes across different species.

[0235] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A compound comprising one of the following compounds or a pharmaceutically acceptable salt thereof: (7)、 (8) 、 (17)、 (18)、 (20)。 2. A pharmaceutical composition comprising the compound of claim 1, optionally further comprising pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 2, further comprising other antiviral drugs, wherein the other antiviral drugs are remdesivir, favipiravir, nematvir, ribavirin, monoupivir, baricitinib, monoupivir, proxalutamide, azvudine, carmostat, naprostine, ritonavir, lopinavir, nitrozonide, chloroquine, hydroxychloroquine, darunavir, arbidol, resveratrol, interferon α, interferon β, chlorpromazine, imatinib, oseltamivir, loperamide, darunavir, nelfinavir, Jinhua Qinggan granules, Shufeng Jiedu capsules, Lianhua Qingwen capsules, or any combination thereof.

4. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention, treatment, or relief of a patient’s illness caused by coronavirus infection, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

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