Compound ATV014 or a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof

Abstract

Compounds ATV014 or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof. Compound ATV014 has the following structural formula:

Description

[0001] This application is a divisional application of the application filed on September 15, 2021, with application number 202111083730.9 and invention title "A nucleoside compound for treating viral infections and its use therein". Technical Field

[0002] This invention belongs to the field of drug synthesis, and relates to the fields of pharmaceutical technology and viral infection disease technology. Specifically, it relates to a nucleoside derivative, its prodrug, and / or its pharmaceutically acceptable salt, as well as compositions and uses thereof. Background Technology

[0003] SARS-CoV-2 is an enveloped, single-stranded RNA virus belonging to the β-coronavirus genus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes non-structural proteins: 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase (RdRp); and structural proteins such as the spike glycoprotein and accessory proteins. The spike glycoprotein on the surface of SARS-CoV-2 binds to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells, thereby infecting human respiratory epithelial cells. After entering the host cell, the virus disintegrates, releasing the nucleocapsid and viral RNA into the cytoplasm. The 5′ open reading frame (ORF1a / b) of the viral RNA encodes polyproteins (pp1a and pp1ab), which play important roles in the processing and maturation of enzymes required for viral replication. pp1a and pp1ab can be cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins, including RNA-dependent RNA polymerase and helicase, which play a crucial role in the transcription and replication of SARS-CoV-2. Currently, the surface spike glycoprotein of the coronavirus receptor, and the important proteins involved in replication and transcription, 3CLpro, PLpro, and RdRp, are four highly attractive targets for antiviral drug development.

[0004] Several variants of the novel coronavirus SARS-CoV-2 have recently attracted widespread attention. Among them, the Delta variant, also known as B.1.617.2, has been listed as a "variant of concern" by the World Health Organization (WHO). The Delta variant is more infectious and pathogenic, with a viral load 1260 times higher than the original virus, and may cause more severe illness. Despite more than 2.76 billion doses of vaccine being administered globally, the effectiveness of vaccines against rapidly mutating SARS-CoV-2, especially the Delta variant, remains a concern.

[0005] Regarding the development of COVID-19 vaccines, on December 2nd, the UK became the first country to approve emergency use authorization for the Pfizer and BioNTech COVID-19 vaccines. However, the general efficacy of these vaccines is still unknown, and the strict cryogenic storage requirements pose significant inconvenience for their widespread use.

[0006] Regarding COVID-19 drug development, Remdesivir is currently the only FDA-approved drug for COVID-19 in the United States. Remdesivir is an adenosine analogue, methylparaben, initially developed by Gilead Sciences as an anti-Ebola virus drug. As an RdRp inhibitor, Remdesivir has shown anti-COVID-19 activity at the cellular level, but clinical trials have shown that it has not significantly reduced mortality in humans. Furthermore, because the clinically used dosage is already close to the safe level, some significant side effects have become a concern.

[0007] Based on the applicant's previous research on remdesivir and its precursor compound GS-441524 (Li, et al., J. Med. Chem. 2020), it was found that GS-441524 produced superior antiviral activity to remdesivir in in vivo activity tests in mice. Although compound GS-441524 has a similar mechanism of action to remdesivir, it showed better safety. Therefore, the applicant has applied for a patent describing the use of compound GS-441524 in the prevention, mitigation, and / or treatment of SARS-CoV-2 (application number or patent number 202011000517.2).

[0008] Subsequent pharmacokinetic analysis of GS-441524 revealed its very low oral bioavailability, limiting its use to injection. Therefore, research into orally bioavailable, low-toxicity nucleoside derivatives or prodrugs of GS-441524 is of great significance. Summary of the Invention Invention Overview

[0010] The object of this invention is to provide nucleoside derivatives having the structure of Formula I or pharmaceutically acceptable salts thereof. The compounds of Formula I or pharmaceutically acceptable salts thereof can effectively inhibit the replication and / or reproduction of coronaviruses in cells, especially inhibiting the replication and / or reproduction of SARS-CoV-2 and MHV-A59 viruses in cells, exhibiting high activity, low toxicity, and high bioavailability.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising a nucleoside derivative having the structure of Formula I, a prodrug, and / or a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention is to provide the use of nucleoside derivatives, prodrugs and / or pharmaceutically acceptable salts having the structure of Formula I. Invention Details

[0014] To achieve one of the above objectives, the present invention adopts the following technical solution:

[0015] In a first aspect, the present invention provides a nucleoside derivative, its prodrug, and / or a pharmaceutically acceptable salt thereof.

[0016] The compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0017]

[0018] in:

[0019] R 1 Selected from H, D, fluorine, or chlorine atoms;

[0020] R 2 R 3 R 4 R 5 Each is independently selected from H, D, halogen atoms, and R. 6 R 7 OH, -OR 6 -OR 7 -NH2, -NHR 6 -NHR 7 -NR 7 R 8 , SH, -SR 7 -SSR 7 、SeR 7 L-type amino acid esters or D-type amino acid esters;

[0021] R 6 Independently selected from -C(=O)R 7 -C(=O)OR 7 -C(=O)NHR 7 -C(=O)NR 7 R8 -CH2OC(=O)OR 7 -CH2OC(=O)NHR 7 -CH2OC(=O)NR 7 R 8 -C(=O)SR 7 -C(=S)R 7 -S(=O)R 7 or -S(=O)2R 7 ;

[0022] R 7 and R 8 Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Cycloalkenyl, substituted or unsubstituted C3-C 10 Cycloalkynyl, substituted or unsubstituted C2-C 10 alkenyl, substituted or unsubstituted C2-C 10 Alkyne, substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C3-C 20 Heterocyclic groups, substituted or unsubstituted C6-C 20 Aryl alkyl groups, or deuterated derivatives of any one of them;

[0023] R 9 Choose from H or F.

[0024] The substituted or unsubstituted C1-C 10 The alkyl group can be selected from substituted or unsubstituted C1-C5 alkyl groups, substituted or unsubstituted C2-C4 alkyl groups, and substituted or unsubstituted C2-C3 alkyl groups.

[0025] The substituted or unsubstituted C3-C 10 Cycloalkyl groups can be selected from substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted C4-C6 cycloalkyl groups. 10 Cycloalkyl, substituted or unsubstituted C4-C8 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkyl, substituted or unsubstituted C5-C6 cycloalkyl.

[0026] The substituted or unsubstituted C3-C 10 The cycloalkenyl group can be selected from substituted or unsubstituted C3-C. 10 Cycloalkenyl, substituted or unsubstituted C4-C 10 Cycloalkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C5-C6 cycloalkenyl.

[0027] The substituted or unsubstituted C3-C 10 The cycloalkynyl group can be selected from substituted or unsubstituted C3-C. 10 Cycloynyl, substituted or unsubstituted C4-C 10 Cycloynyl, substituted or unsubstituted C4-C8 cycloynyl, substituted or unsubstituted C4-C6 cycloynyl, substituted or unsubstituted C5-C6 cycloynyl.

[0028] The substituted or unsubstituted C6-C 20 The aryl group can be selected from substituted or unsubstituted C6-C. 12 aryl, substituted or unsubstituted C6-C 10 Aryl.

[0029] The substituted or unsubstituted C3-C 20 The heterocyclic group can be selected from substituted or unsubstituted C4-C. 10 Heterocyclic groups, substituted or unsubstituted C4-C6 heterocyclic groups, substituted or unsubstituted C4-C5 heterocyclic groups.

[0030] The substituted or unsubstituted C3-C 20 The heteroatom in the heterocyclic group can be a nitrogen atom or an oxygen atom.

[0031] The substituted or unsubstituted C3-C 20 The number of heteroatoms in a heterocyclic group can be one or two.

[0032] The substitution may include substitution by methyl, ethyl, phenyl, indole, pyrrole, amino, halogen atom, mercapto or mercaptomethyl.

[0033] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 2 H, OH or -R 6 .

[0034] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 2 For H.

[0035] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 2 It is OH.

[0036] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 2 -R 6 .

[0037] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 9 It can be H or F.

[0038] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, the R 9 For H.

[0039] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 9 It is F.

[0040] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 3 and R 4 It is OH.

[0041] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 1 It can be H, F, or D.

[0042] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 1 For H.

[0043] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 1 It is F.

[0044] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 1 The answer is D.

[0045] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 5 For -OR 6 L-type amino acid esters or D-type amino acid esters.

[0046] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 5 For -OR 6 .

[0047] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 2 H, OH or -R 6 ;R 9 For H or F; R 3 and R 4 For OH; R 1 For H, F, or D; R 5 For -OR 6 L-type amino acid esters or D-type amino acid esters; R 6 -C(=O)R 7 .

[0048] In some embodiments, the compound represented by Formula I is the compound represented by Formula II:

[0049]

[0050] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 7 It is selected from phenyl, 2-propyl, methyl, ethyl, -CH2CF3, 1-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, octyl, naphthyl, tetrahydro-2H-pyranyl, and 1-methylpiperidinyl.

[0051] In some embodiments, the R in the compound or a pharmaceutically acceptable salt thereof 7 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0052] In some embodiments, the compound represented by Formula I comprises any one of the following structures:

[0053]

[0054]

[0055]

[0056]

[0057] In some preferred embodiments, the compound represented by Formula 1 comprises any one selected from the following structures:

[0058]

[0059] Among them, compounds ATV014 and ATV006, in addition to exhibiting higher inhibitory rates against SARS replicons on HEK293T cells compared to GS-441524 and remdesivir intermediate 5, also showed higher IC50 values. 50In addition to lower concentrations and higher activity, ATV014 and ATV006 exhibit significantly improved oral bioavailability and better oral drugability compared to GS-441524. Furthermore, both compounds ATV014 and ATV006 demonstrate good anti-SARS-CoV and anti-SARS-CoV-2 activity, with their anti-SARS-CoV-2 activity being more than twice that of GS-441524. This indicates that both compounds ATV014 and ATV006 can effectively inhibit the replication and / or proliferation of the virus and its variants within cells. Moreover, the compounds provided in this invention exhibit good inhibitory activity against novel SARS-CoV-2 mutants, such as SARS-CoV-2 mutants B.1, B.1.351, and B.1.617.2, especially ATV014, which shows excellent inhibitory activity with an IC50 as low as below 0.34 μM, nearly eight times more potent than GS-441524.

[0060] In some embodiments, the compound represented by Formula I does not include the following structures:

[0061]

[0062] In some embodiments of the present invention, the compound represented by Formula 1 includes racemic derivatives, enantiomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates of the compound represented by Formula I.

[0063] In a second aspect, the present invention provides a pharmaceutical composition.

[0064] A pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt thereof.

[0065] The pharmaceutical composition may also include a pharmaceutically acceptable carrier or excipient.

[0066] The pharmaceutical composition may be in the form of tablets, pills, creams, emulsions, ointments, suspensions, lyophilized preparations, capsules, sustained-release preparations, granules, powders, injectable preparations, or sprays.

[0067] The pharmaceutical composition may also include traditional Chinese medicine ingredients and / or Western medicine ingredients.

[0068] The pharmaceutical ingredients may include: apilimod, R 82913 (CAS No.: 126347-69-1), DS-6930 (CAS No.: 1242328-82-0), ONO 5334 (CAS No.: 868273-90-9), oseltamivir phosphate, Hanfangchin A, clofazamine, astemizole, recombinant human angiotensin-converting enzyme 2 (rhACE2) or favipiravir and / or their pharmaceutically acceptable salts.

[0069] Thirdly, the present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition described in the second aspect.

[0070] Use of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect in the preparation of a product for the prevention, mitigation or treatment of coronavirus infection, or the replication or propagation of a homologous variant of the coronavirus and the resulting cytopathic effects.

[0071] Use of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect in the prevention, mitigation or treatment of coronavirus infection, or the replication or reproduction of a homologous variant of the coronavirus and the resulting cytopathic effects.

[0072] The infections include fever, cough, sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0073] Use of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect in the preparation of a product for detecting coronavirus or its homologous variants.

[0074] Use of a compound described in the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the second aspect, in the detection of coronaviruses or their homologous variants.

[0075] The coronaviruses may include: MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus, or porcine coronavirus.

[0076] The SARS-CoV-2 mentioned includes mutant or non-mutant strains of SARS-CoV-2.

[0077] The SARS-CoV-2 mutant strains include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351 (Beta), SARS-CoV-2 mutant strain B.1.617.2 (Delta), SARS-CoV-2 mutant strain C.37 (Lamda: a variant strain originating in Peru), SARS-CoV-2 mutant strain P.1 (a variant strain originating in Brazil), SARS-CoV-2 mutant strain B.1.525 (Eta: another variant strain originating in the UK), SARS-CoV-2 mutant strain B.1.427 (Epsilon: a variant strain originating in Northern California), or SARS-CoV-2 mutant strain B.1.429 (Epsilon: a variant strain originating in Northern California).

[0078] The compound or a pharmaceutically acceptable salt thereof may be used in humans or animals.

[0079] The animals may include bovines, equines, sheep, pigs, canines, felines, rodents, primates, birds, and fish.

[0080] Beneficial effects

[0081] Compared with the prior art, the present invention has the following technical effects:

[0082] 1) The compound of Formula 1 or its pharmaceutically acceptable salt thereof can effectively inhibit the replication and / or reproduction of coronaviruses in cells, especially SARS-CoV-2 and its mutant strains, such as SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351 (Beta) and SARS-CoV-2 mutant strain B.1.617.2 (Delta), and MHV-A59 virus, and has high activity, low toxicity and high bioavailability.

[0083] 2) Both compounds ATV014 and ATV006 exhibit good anti-SARS-CoV-2 activity. The anti-SARS-CoV-2 activity of both compounds is more than twice that of GS-441524. In particular, the activity against SARS-CoV-2 delta mutant strains is three to four times that of GS-441524. The IC50 of ATV014 can be as low as below 0.34 μM, indicating that compounds ATV014 and ATV006 can effectively inhibit the replication and / or proliferation of SARS virus in cells.

[0084] 3) Both compounds ATV006 and ATV014 have good pharmacokinetic properties. The bioavailability of ATV006 is as high as 79% (rat) and 30% (cynomolgus monkey); the bioavailability of ATV014 in rats is as high as 49%.

[0085] 4) The compounds of Formula I or their pharmaceutically acceptable salts described in this invention have simple structures, are easy to synthesize, and are conducive to production and distribution.

[0086] 5) The method for preparing the compound of Formula I or its pharmaceutically acceptable salt according to the present invention is simple to operate and conducive to industrial production.

[0087] Terminology Definition

[0088] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings:

[0089] The SARS-CoV-2 mutant strain B.1 is the hCoV-19 / CHN / SYSU-IHV / 2020 strain, and its Accession ID on GISAID is: EPI_ISL_444969.

[0090] "Compounds of this invention" means the compound of Formula I or its pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates. Similarly, the phrase "compound of Formula I" means the compound of that formula and its pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates.

[0091] In this invention, the terms "compound I" and "compound shown in formula I" refer to the same compound.

[0092] “VN” indicates the volume ratio. IC s0 This indicates the half-inhibitory concentration.

[0093] The “H” represents a hydrogen atom, and the “D” represents a deuterium atom. The “halogen atom” represents a fluorine atom (F), a chlorine atom (CI), a bromine atom (Br), an iodine atom (I), an astatine atom (At), or a dichroic atom (Ts).

[0094] In this invention, "room temperature" refers to ambient temperature, ranging from approximately 10°C to approximately 40°C. In some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C; in other embodiments, "room temperature" refers to a temperature ranging from approximately 25°C to approximately 30°C; and in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0095] "Alkyl" is a hydrocarbon containing a positive carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom. For example, alkyl groups can have 1 to 10 carbon atoms (i.e., C1-C1). 10 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl, -CH2CH2CH2CH3). (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (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), 1-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)CH2CH3), 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 and octyl (-(CH2)7CH3).

[0096] "Alkenyl" refers to a group containing at least one unsaturated site, i.e., carbon-carbon sp. 2 Hydrocarbons with double bonds consisting of a positive, secondary, tertiary carbon atom, or a cyclic carbon atom. For example, alkenyl groups can have 2 to 10 carbon atoms (C2-C4). 10 alkenyl), 2 to 12 carbon atoms (C2-C) 12Alkenyl (or 2 to 6 carbon atoms, C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0097] "Alynyl" is a hydrocarbon containing at least one unsaturated carbon atom, namely a carbon-carbon sp triple bond, or a cyclic carbon atom. For example, an alkynyl group can have 2 to 10 carbon atoms (C2-C4). 10 alkynyl group), 2 to 12 carbon atoms (C2-C) 12 Alkyne group (or 2 to 6 carbon atoms, C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynylate (-CH2C=CH), and the like.

[0098] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and similar groups.

[0099] "Arylalkyl" refers to a compound that is bonded to a carbon atom (usually terminal or sp). 3 An aryl alkyl group is an acyclic alkyl group in which one of the hydrogen atoms of a carbon atom is replaced by an aryl group. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl, and the like. An aryl alkyl group may include 7 to 20 carbon atoms; for example, the alkyl moiety may be 1 to 6 carbon atoms, and the aryl moiety may be 6 to 14 carbon atoms.

[0100] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclic, heteroaryl, carbocyclic, etc., such as "substituted C1-C". 10 Alkyl, substituted C6-C 20 "Aryl", "Substituted arylalkyl", "Substituted C1-C" 20 "Heterocyclic" and "substituted carbocyclic" refer to C1-C rings in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents, respectively. 10 Alkyl, C6-C 20 Aryl, arylalkyl, C1-C 20 Heterocyclic, carbocyclic. Unless otherwise stated, when the term “substituted” is used in conjunction with a group having two or more moieties capable of substitution, such as an arylalkyl group, the substituent may be attached to the aryl moieties, alkyl moieties, or both.

[0101] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a drug, i.e., an active ingredient, through spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. A prodrug is therefore a covalently modified analogue or potential form of a therapeutically active compound.

[0102] As used herein, “heterocyclic” or “heterocyclic group” includes, by example but not limited to, those heterocycles described in: Paquette, Leo A.: Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7 and 9: The Chemistry of Heterocyclic Compounds, A Series of Monographs^ (John Wiley & Sons, New York, 1950 to present), particularly Volumes 13, 14, 16, 19 and 28 and J. Am. Chem. Soc. (1960) 82: 5566. In a specific embodiment of the invention, “heterocyclic” includes “carbon ring” as defined herein, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N or S). The term “heterocyclic” or “heterocyclic group” includes saturated rings, partially unsaturated rings and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclic groups include, for example, heterocycles substituted by any substituent including a carbonyl group disclosed herein.

[0103] Examples of heterocycles include, but are not intended to limit, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophene, sulfur-oxidized tetrahydrothiophene, pyrimidinyl, furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl, indole, indoleenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, acrylonitrile (azacyclooctane), triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophene, thiaanthryl, pyranyl, isobenzofuranyl, Chromyl, ketone, phenolic flavinyl, 2H-pyrroleyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indazinyl, isoydinolyl, 3H-indolyl, 1H-indazolyl, purine, 4H-quinazinyl, phthalazinyl, naphthidyl, quinoxalinyl, quinazolinyl, cinnamolineyl, pteridinyl, 4aH-carbazoleyl, carbazoleyl, β-carbolinyl, phenanthridineyl, acridineyl, pyrimidinyl The following are listed: pyridyl, phenanthroline, phenazinyl, phenothiazinyl, furazinyl, phenoxazinyl, isochromyl, chromanyl, imidazoalkyl, imidazoline, pyrazolyl, pyrazolyl, piperazinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, oxazolyl, benzotriazolyl, benzoisooxazolyl, hydroxyindolyl, benzooxazolinyl, indigo acyl, and bis-tetrahydrofuranyl.

[0104] "Heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included on an aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclic group," including pyridinyl, pyrroloyl, oxazolyl, indolyl, isoydinolyl, purinyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, carbazoyl, imidazoyl, thiazoyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc.

[0105] "Prodrug fraction" refers to the unstable functional group that is isolated from an active inhibitory compound during metabolism, systemically or intracellularly, through hydrolysis, enzymatic cleavage, or other processes (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Prodrug fractions can be used to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy.

[0106] The prodrug portion may include an active metabolite or the drug itself.

[0107] Compounds of Formula I or their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. Crystal polymorphism, as used herein, refers to the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can originate from differences in crystal packing (packing polymorphism) or differences in packing between different conformational isomers of the same molecule (conformational polymorphism). Pseudopolymorphism, as used herein, refers to the ability of a compound's hydrates or solvates to exist in different crystal structures. The pseudopolymorphs of this invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformational isomers of the same molecule (conformational pseudopolymorphism). This invention comprises all polymorphs and pseudopolymorphs of compounds of Formulas I-III and their pharmaceutically acceptable salts.

[0108] Compounds of Formula I or their pharmaceutically acceptable salts can also exist as amorphous solids. The amorphous solids used herein are solids in which the positions of atoms do not exhibit long-range order. This definition also applies when the crystal size is 2 nanometers or less. The amorphous forms of the present invention can be established using additives, including solvents. The present invention encompasses all amorphous forms of compounds of Formulas I-III and their pharmaceutically acceptable salts.

[0109] As used herein, the term "treatment" means, unless otherwise stated, reversing or alleviating the condition or ailment to which the term applies, or one or more symptoms of such condition or ailment, inhibiting the progression of said condition or ailment or one or more symptoms thereof, or preventing said condition or ailment or one or more symptoms thereof. As used herein, "treatment" refers to the act of treatment, as defined above.

[0110] The compounds described in this invention also include, by way of their physiologically acceptable salts, examples of which include salts derived from suitable bases, such as alkali metals or alkaline earth metals (e.g., Na). + Li + K + Ca +2 and Mg +2 ), ammonium and NR4 + (where R is as defined herein). Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; (b) salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, ethanesulfonic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene. Sulfonic acids, methanesulfonic acids, p-toluenesulfonic acids, benzenesulfonic acids, naphthalenedisulfonic acids, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthylcarboxylate, dihydroxynaphthylcarboxylate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed with elemental anions, such as chlorine, bromine, and iodine. Physiologically acceptable salts of hydroxyl compounds include salts formed with anions of the compounds such as Na+. + and NR4 + A suitable combination of cations.

[0111] For therapeutic purposes, the salts of the active ingredients of the compounds of this invention are physiologically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts that are not physiologically acceptable acids or bases may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of this invention.

[0112] Compounds of Formula I may have a chiral center, such as a chiral carbon. Compounds of Formula I therefore comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Additionally, compounds of this invention comprise optical isomers enriched or resolved at any or all of the asymmetric chiral atoms. In other words, the chiral center, similar to that described, is provided in the form of chiral isomers or racemic mixtures. Mixtures of racemic and diastereomers, as well as isolated or synthesized individual optical isomers substantially free of their enantiomers or diastereomer conjugates, are all within the scope of this invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers using known techniques, such as isolating salts of diastereomers formed with optically active auxiliaries (e.g., acids or bases) and then converting them back to the optically active substance. In most cases, the desired optical isomer is synthesized from a suitable stereoisomer of the desired starting material through a stereospecific reaction.

[0113] Whenever a compound described herein is designated by more than one identical specified group (e.g., “R” or “R”), 1 When substitution is performed, it should be understood that these groups may be the same or different, that is, each group is selected independently.

[0114] Methods for detecting the activity of anti-COVID-19 virus:

[0115] Another aspect of the present invention relates to a method for detecting the activity against the novel coronavirus, comprising the step of treating a sample suspected of containing the SARS-CoV-2 family using the compound described in the present invention.

[0116] The compounds described in this invention can be used as anti-SARS-CoV-2 compounds, as intermediates for such compounds, or for other uses as described below. The anti-SARS-CoV-2 compounds bind to sites on surfaces or cavities having a geometry unique to SARS-CoV-2. The binding of anti-SARS-CoV-2 compounds can be reversible to varying degrees. Those compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, those substantially irreversibly bound compositions can be used as probes for detecting SARS-CoV-2. Therefore, this invention relates to a method for detecting SARS-CoV-2 in samples suspected of containing SARS-CoV-2, comprising the steps of: treating a sample suspected of containing SARS-CoV-2 with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the field of diagnostics and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds described herein are labeled in a conventional manner using functional groups (e.g., hydroxyl, carboxyl, thiol, or amino groups).

[0117] In the context of this invention, samples suspected of containing SARS-CoV-2 include natural or artificial materials, such as living organisms; tissue or cell cultures; biological samples, such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; food, water, or air samples; and biological product samples, such as cell extracts, particularly recombinant cell extracts for synthesizing desired glycoproteins. Typically, the sample will be suspected of containing an organism that produces SARS-CoV-2, often a pathogenic organism, such as a member of the SARS-CoV-2 family. The sample can be contained in any medium, including water and organic solvent / water mixtures. Samples include living organisms, such as humans, and artificial materials, such as cell cultures.

[0118] The processing steps of this invention include adding the composition of this invention to the sample, or it includes adding a precursor of the composition to the sample. The addition step includes any of the application methods described above.

[0119] If needed, the activity of the SARS-CoV-2 virus after application of the composition can be observed by any method, including direct and indirect methods for detecting its anti-SARS-CoV-2 activity. Quantitative, qualitative, and semi-quantitative methods for detecting SARS-CoV-2 activity have all been conceived. Typically, one of the screening methods described above is applied; however, any other method may also be applied, such as observing the physiological properties of living organisms.

[0120] Screening of compositions with anti-SARS-CoV-2 activity:

[0121] The compounds described in this invention are suitable for treating or preventing SARS-CoV-2 infection in animals or humans. However, cell-based assays should be the primary screening tool in the process of screening compounds that can inhibit human SARS-CoV-2.

[0122] The compositions of the present invention are screened for compounds exhibiting antiviral activity against SARS-CoV-2 using any conventional techniques for evaluating antiviral activity. In the context of the present invention, typically, compositions exhibiting antiviral activity are first screened, followed by screening for in vivo activity of compositions demonstrating antiviral activity. [The last sentence appears to be incomplete and possibly refers to a specific type of compound.] -6 M is preferably less than about 1×10 -7 Compositions for the in vitro Ki (inhibition constant) of M are preferably used in vivo. Useful in vitro screening methods have been described in detail in the literature and will not be repeated here. However, the examples describe suitable in vitro assays.

[0123] pharmaceutical preparations

[0124] The compounds described in this invention are formulated using conventional carriers and excipients, which will be selected according to conventional practice. Although the active ingredients can be administered alone, they are preferably formulated into pharmaceutical preparations. The preparations of this invention, whether for animal or human use, comprise at least one active ingredient as defined above and one or more acceptable carriers therefor, and optionally include other therapeutic components, particularly those disclosed herein. The carrier must be "acceptable," meaning it is compatible with other components in the preparation and physiologically harmless to its recipient.

[0125] Formulations include those suitable for the routes of administration described above. Formulations can be conveniently formulated into unit dosage forms and can be prepared using any method well-known in the pharmaceutical industry. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA.). Such methods involve the step of mixing the active ingredient with a carrier constituting one or more auxiliary components. Generally, formulations are prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if necessary, shaping the product.

[0126] The present invention further provides a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier thereon.

[0127] The veterinary carrier is a substance intended for use in veterinary compositions and can be a solid, liquid, or gaseous substance. Furthermore, it is inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or via any other desired route.

[0128] Application route:

[0129] One or more compounds of the present invention (referred to herein as active ingredients) may be administered via any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, local (including oral and sublingual), and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. The advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0130] Metabolites of the compounds of this invention:

[0131] The in vivo metabolites of the compounds described herein also fall within the scope of this invention to the extent that such products are novel and non-obvious relative to the prior art. These products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, this invention includes novel and non-obvious compounds produced by a method comprising exposing the compound of this invention to a mammal for a sufficient period of time to produce its metabolites. Such products are typically identified as follows: preparation of radiolabeled (e.g., 14 C or 3 The compounds of the present invention (H) are administered parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and their metabolites are isolated from urine, blood, or other biological samples. These products are readily isolated because they are labeled (other methods use antibodies that bind to epitopes remaining in the metabolites). The structure of the metabolites is determined in a conventional manner, such as by MS or NMR analysis. Generally, the analysis of the metabolites is performed using methods known to those skilled in the art for routine drug metabolism studies. The metabolites, provided they are not otherwise found in vivo, even if they themselves do not possess SARS-CoV-2 polymerase inhibitory activity, can be used for diagnostic assays of therapeutic administration of the compounds of the present invention.

[0132] Formulations and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract, wherein less than about 50 molar percentage of the protected group is deprotected in an intestinal or gastric juice substitute after incubation at 37°C for 1 hour. The fact that compounds are stable in the gastrointestinal tract does not necessarily mean they will not hydrolyze in vivo. The prodrugs of this invention are typically stable in the digestive system, but they are generally hydrolyzed substantially to the parent drug in the digestive lumen, liver, or other metabolic organs, or intracellularly.

[0133] It should also be noted that the specific dosage and method of administration for the compounds having Formula I, their prodrugs, and / or their pharmaceutically acceptable salts for different patients are determined by a number of factors, including the patient's age, weight, sex, natural health condition, nutritional status, the potency of the drug, the timing of administration, the rate of metabolism, the severity of the condition, and the subjective judgment of the treating physician. The effective dosage of the active ingredient depends at least on the nature of the condition to be treated, its toxicity (whether the compound is used prophylactically or against an active viral infection), the method of delivery, and the pharmaceutical formulation, and will be determined through clinicians using routine dose escalation studies. Doses can be expected to be from about 0.0001 to about 100 mg / kg body weight per day; typically, from about 0.01 to about 10 mg / kg body weight per day; more typically, from about 0.01 to about 5 mg / kg body weight per day; and most typically, from about 0.05 to about 0.5 mg / kg body weight per day. For example, for an adult weighing about 70 kg, the candidate daily dose will be in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can be administered in single or multiple doses.

[0134] All of the above-mentioned dosage forms of drugs can be prepared according to conventional methods in the pharmaceutical field.

[0135] In this invention, the abbreviations of some compounds represent the following compound structures:

[0136]

[0137]

[0138] Certain abbreviations and acronyms were used in describing the experimental details. While most of them are understandable to those skilled in the art, the table below contains a list of these abbreviations and acronyms.

[0139] abbreviation meaning ACN Acetonitrile DCC Dicyclohexylcarbodiimide DCM dichloromethane DMAP 4-Dimethylaminopyridine EA Ethyl acetate EDMA N,N-Dimethylethylamine MeOH methanol PE petroleum ether rt room temperature TEA Triethylamine THF Tetrahydrofuran TLC Thin-layer chromatography Attached Figure Description

[0140] Figure 1 This example illustrates the inhibitory effects of compounds GS-441524, ATV003, ATV004, ATV019, ATV006, and ATV020 on SARS-CoV-2 replicons in HEK293T cells. The horizontal axis represents drug concentration in μM, and the vertical axis represents inhibition rate in %.

[0141] Figure 2This example illustrates the inhibitory effects of compounds RDV, GS-441524, ATV006, ATV009, ATV010, ATV011, ATV013, ATV014, ATV017, and ATV018 in Vero-E6 cells against SARS-CoV-2 mutant strains B.1, B.1.351, and B.1.617.2. The horizontal axis represents drug concentration in μM, and the vertical axis represents inhibition rate in %.

[0142] Figure 3 The following are pharmacokinetic curves of ATV006 and ATV014 in rats and ATV006 in cynomolgus monkeys in Examples 37 and 38. The horizontal axis represents time in hours, and the vertical axis represents the drug concentration in plasma in μg / L. Figure A is the pharmacokinetic curve of ATV006 in rats in Example 33; Figure B is the pharmacokinetic curve of ATV006 in cynomolgus monkeys in Example 34.

[0143] Figure 4 The in vivo efficacy results of ATV006 against mouse coronavirus (MHV-A59) in Example 39 are shown. Figure A shows the changes in mouse body weight in each treatment group after viral infection, with the horizontal axis representing time (in days) and the vertical axis representing mouse body weight (in grams). Figure B shows the survival curves of each group of mice, with the horizontal axis representing time (in days) and the vertical axis representing survival rate (in %). Figure C shows the viral titer in mouse liver 72 hours after viral infection, determined by quantitative real-time PCR, with the horizontal axis representing different drugs and the vertical axis representing the logarithmic function of viral load.

[0144] Figure 5 Example 40 illustrates the efficacy of ATV006 against SARS-CoV-2 in mice. Figure A shows the dosing time and body weight measurement plan. Figure B shows the gene copy number on the vertical axis and the different experimental groups on the horizontal axis, including the control group, the 500mg dosing group, and the 250mg dosing group. Figure C shows the mRNA level on the vertical axis and the different experimental groups on the horizontal axis, including the control group, the 500mg dosing group, and the 250mg dosing group.

[0145] Figure 6 This example 40 illustrates the efficacy of ATV006 against a variant strain (B.1.617.2) of SARS-CoV-2 in mice. Figure A shows the dosing time and body weight measurement plan. Figure B shows the gene copy number on the vertical axis and the different experimental groups (including the control group and the 250mg dosing group) on the horizontal axis. Figure C shows the mRNA level on the vertical axis and the different experimental groups (including the control group and the 250mg dosing group) on the horizontal axis. Detailed Implementation

[0146] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0147] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0148] In this invention, μM represents micromoles per liter; mmol represents millimoles; and equiv represents equivalents.

[0149] Example 1: Synthesis of (2R,3R,4R,5R)-2-cyano-2-(4-isobutyramide pyrrole[2,1-f][1,2,4]triazine-7-yl)-5-(isobutyl carboxylate)tetrahydrofuran 3,4-bis(isobutyl carboxylate) (compound ATV001)

[0150]

[0151] 594 mg (2 mmol) of compound GS-441524, 50 mg (0.4 mmol, 0.2 equiv) of 4-dimethylaminopyridine, 804 mg (1.2 mL, 11 mmol, 5.5 equiv) of EDMA (N,N-dimethylethylamine), and 1.58 g (1.66 mL, 10 mmol) of isobutyric anhydride were mixed. The resulting mixture was then mixed with 10 mL of acetonitrile and stirred at 40 °C for 1 hour. The organic solvent was removed by rotary evaporation, yielding a crude residue. The crude residue was eluted by silica gel chromatography (eluting agent: methanol / dichloromethane (VN) = 5 / 95) to obtain 624 mg of compound ATV001 (colorless viscous liquid, yield 61%). The obtained compound ATV001 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0152] Hydrogen spectrum: 1 H NMR (400MHz, CDCl3) δ9.33 (s, 1H), 8.21 (s, 1H), 7.34 (d, J = 4.9Hz, 1H), 7.06 (d, J = 4.9Hz, 1H), 6.23 (d, J = 5.8Hz, 1H), 5.51 (dd, J = 5.8, 4.3Hz, 1H), 4.6 7 (q, J=4.0Hz, 1H), 4.41 (qd, J=12.3, 3.9Hz, 2H), 3.19 (dt, J=13.4, 6.7Hz, 1H), 2.74-2.62(m, 2H), 2.56(dq, J=14.0, 7.0Hz, 1H), 1.35-1.10(m, 24H).

[0153] Carbon spectrum: 13C NMR (101MHz, CDCl3) δ177.46, 176.45, 175.76, 174.98, 151.38, 145.87, 123.21, 118.26, 114.91, 113.27, 106.29, 81. 60, 76.86, 71.97, 70.54, 62.56, 36.01, 33.85, 33.84, 33.74, 19.13, 19.11, 18.91, 18.85, 18.81, 18.70, 18.67, 18.54.

[0154] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV001 was 3.319 min.

[0155] Example 2: Synthesis of (2R,3R,4R,5R)2-(4-acetamidopyrrole[2,1-f][1,2,4]triazine-7-yl)-5-(acetylhydroxymethyl ester)-2-cyanotetrahydrofuran-3,4-diacetate (compound ATV002)

[0156]

[0157] 594 mg (2 mmol) of compound GS-441524, 50 mg (0.4 mmol, 0.2 equiv) of 4-dimethylaminopyridine, 804 mg (1.2 mL, 11 mmol, 5.5 equiv) of EDMA (N,N-dimethylethylamine), and 1.02 g (1 mL, 10.6 mmol) of acetic anhydride were mixed. The resulting mixture was then mixed with 10 mL of acetonitrile and stirred at 40 °C for 30 minutes. The organic solvent was removed by rotary evaporation, yielding a crude residue. The crude residue was eluted by silica gel chromatography (eluting solvent: methanol / dichloromethane (VN) = 5 / 95) to give 518 mg of compound ATV002 (white solid, yield 56%). The obtained compound ATV002 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0158] Hydrogen spectrum: 1H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 8.23 ​​(s, 1H), 7.21 (d, J = 4.8Hz, 1H), 7.11 (d, J = 4.8Hz, 1H), 6.25 (d, J = 5.9Hz, 1H), 5.56-5.41 (m, 1H), 4. 65 (dd, J=8.5, 4.7Hz, 1H), 4.47 (dd, J=12.3, 3.6Hz, 1H), 4.34 (dd, J=12.3, 4.9Hz, 1H), 2.63 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H).

[0159] Carbon spectrum: 13 C NMR (101MHz, CDCl3) δ172.03, 170.43, 169.84, 169.03, 151.01, 146.16, 122.96, 117.82, 114.85, 114.01, 103.74, 81.00, 77.21, 71.79, 70.60, 62.58, 26.12, 20.76, 20.53, 20.51.

[0160] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV002 was 2.162 min.

[0161] Example 3: Synthesis of (2R,3R,4R,5R)-5-(acetylhydroxymethyl ester)-2-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-2-cyanotetrahydrofuran-3,4-diacetate (compound ATV003)

[0162]

[0163] 594 mg (2 mmol) of compound GS-441524, 50 mg (0.4 mmol, 0.2 equiv) of 4-dimethylaminopyridine, 804 mg (1.2 mL, 11 mmol, 5.5 equiv) of EDMA (N,N-dimethylethylamine), and 1.02 g (1 mL, 10.6 mmol) of acetic anhydride were mixed. The resulting mixture was then mixed with 10 mL of acetonitrile and stirred at 40 °C for 30 minutes. The organic solvent was removed by rotary evaporation, yielding a crude residue. The crude residue was eluted by silica gel chromatography (eluting solvent: methanol / dichloromethane (VN) = 5 / 95) to give 384 mg of compound ATV003 (white solid, yield 46%). The obtained compound ATV003 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0164] Hydrogen spectrum: 1 H NMR (400MHz, CDCl3) δ7.94 (s, 1H), 6.92 (d, J = 4.6Hz, 1H), 6.61 (d, J = 4.7Hz, 1H), 6.30 (d, J = 5.9Hz, 3H), 5.61-5.43 (m, 1H), 4. 63 (dd, J=8.7, 4.9Hz, 1H), 4.49 (dd, J=12.2, 3.7Hz, 1H), 4.34 (dd, J=12.2, 5.1Hz, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 2.08 (s, 3H).

[0165] Carbon spectrum: 13 C NMR (101MHz, CDCl3) δ170.55, 169.91, 169.16, 155.54, 147.39, 121.63, 117.2 3, 115.28, 112.61, 100.23, 80.85, 77.48, 71.90, 70.67, 62.67, 20.77, 20.55.

[0166] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV003 was 2.157 min.

[0167] Example 4: Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-2-cyano-5-(isobutyl carboxylate)tetrahydrofuran-3,4-bis(isobutyl carboxylate) (compound ATV004)

[0168]

[0169] 594 mg (2 mmol) of compound GS-441524, 50 mg (0.4 mmol, 0.2 equiv) of 4-dimethylaminopyridine, 804 mg (1.2 mL, 11 mmol, 5.5 equiv) of EDMA (N,N-dimethylethylamine), and 1.58 g (1.66 mL, 10 mmol) of isobutyric anhydride were mixed. The resulting mixture was then mixed with 10 mL of acetonitrile and stirred at 40 °C for 1 hour. The organic solvent was removed by rotary evaporation, yielding a crude residue. The crude residue was eluted by silica gel chromatography (eluting agent: methanol / dichloromethane (VN) = 5 / 95) to obtain 410 mg of compound ATV004 (colorless viscous liquid, yield 35%). The obtained compound ATV004 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0170] Hydrogen spectrum: 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 6.86 (d, J = 4.7Hz, 1H), 6.70 (d, J = 4.7Hz, 1H), 6.28 (d, J = 5.9Hz, 1H), 5.53 (dd , J=5.7, 4.4Hz, 1H), 4.65 (q, J=4.1Hz, 1H), 4.42 (qd, J=12.3, 4.1Hz, 2H), 2.75-2.51 (m, 3H), 1.32-1.10 (m, 18H).

[0171] Carbon spectrum: 13 C NMR (101MHz, CDCl3) δ176.58, 175.85, 175.11, 155.65, 146.56, 122.08, 117.09, 115.34, 112.03, 101.0 9, 81.50, 77.04, 71.99, 70.63, 62.66, 33.85, 33.82, 33.74, 18.96, 18.82, 18.78, 18.69, 18.67, 18.54.

[0172] High performance liquid chromatography: The mobile phase was water / acetonitrile (VN) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV004 was 2.767 min.

[0173] Example 5. Synthesis of (3aR, 4R, 6R, 6aR). 4-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepentyl-4-carboxynitrile (compound 5)

[0174]

[0175] 5.62 g of compound GS-441524 was dissolved in 30 mL of acetone, followed by the addition of 11.50 mL of 2,2-dimethoxypropane and 1.34 mL of 98% sulfuric acid. The mixture was stirred at 45 °C for half an hour, cooled to room temperature, and the organic solvent was removed by rotary evaporation. The mixture was extracted with 100 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution, repeated three times. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and filtered to remove the sodium sulfate. The organic solvent was removed by rotary evaporation, and the mixture was separated by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 2) to give 6.20 g of compound 5 (white solid, 97% yield). The proton NMR spectrum of the obtained compound 5 was analyzed, and the results are as follows:

[0176] Hydrogen spectrum: 1H NMR (400MHz, Chloroform-d) δ7.95 (s, 1H), 7.11 (d, J=4.7Hz, 1H), 6.69 (dd, J=4.8, 2.4Hz, 1H), 5.77 (s, 2H), 5.42 (d, J=6.6Hz, 1H), 5.2 4 (dd, J=6.6, 2.4Hz, 1H), 4.67 (q, J=1.9Hz, 1H), 3.99 (dd, J=12.5, 1.9Hz, 1H), 3.84 (dd, J=12.5, 1.7Hz, 1H), 1.81 (s, 3H), 1.40 (s, 3H).

[0177] Example 6: Synthesis of pentyl(7-((2R,3R,4R,5R)-2-cyano-3,4-di(((pentoxy)carbonyl)oxy)-5-((((pentoxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrole[2,1-f][1,2,4]triazine-4-yl)carbamate (compound 6)

[0178]

[0179] Compound GS-441524 (50 mg, 0.17 mmol) was dissolved in 2.5 mL of dry dichloromethane. The gas was purged with argon, and then pyridine (80.7 mg, 1.02 mmol) was added. The mixture was cooled to 0 °C, and then n-amyl chloroformate (107.5 mg, 0.71 mmol) was added dropwise. The mixture was then allowed to rise naturally to room temperature and stirred for 3 hours. After the reaction of compound GS-441524 was complete, the organic solvent was removed by rotary evaporation. Silica gel column chromatography (eluent: n-hexane / ethyl acetate, (VN) = 10:1) yielded 71.7 mg of compound 6 (colorless liquid, yield 56%). The proton and carbon spectra of compound 6 were analyzed, and the results are as follows:

[0180] Hydrogen spectrum: 1H NMR (400MHz, Chloroform-d) δ9.00 (s, 1H), 8.27 (s, 1H), 7.39 (d, J=4.9Hz, 1H), 7.17 (d , J=5.0Hz, 1H), 6.12 (d, J=5.8Hz, 1H), 5.38 (t, J=5.9Hz, 1H), 4.69 (q, J=4.6Hz, 1H), 4.5 7 (dd, J=12.1, 3.4Hz, 1H), 4.40 (dd, J=12.1, 4.7Hz, 1H), 4.28 (t, J=6.8Hz, 2H), 4.23-4 .07 (m, 6H), 1.85-1.60 (m, 8H), 1.36 (ddp, J=14A, 7.0, 3.5Hz, 16H), 1.02-0.83 (m, 12H).

[0181] Carbon spectrum: 13 C NMR (101MHz, Chloroform-d) δ154.8, 154.0, 153.5, 151.7, 151.5, 146.0, 122.7, 117.7, 114.2, 114.1, 107.0, 79.9, 77.3 (d, J =24.5Hz), 74.6, 72.8, 69.5, 69.2, 68.7, 66.9, 65.1, 28.3, 28.2, 28.1, 28.1, 27.8, 27.7, 27.6, 27.6, 22.2, 13.9 (d, J=4.4Hz).

[0182] Example 7: Synthesis of pentyl (7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrrole[2,1-f][1,2,4]triazine-4-yl)carbamate (compound ATV005)

[0183]

[0184] Compound 6 (58.3 mg, 0.078 mmol) was dissolved in 2 mL of tetrahydrofuran, and lithium hydroxide (18.7 mg, 0.78 mmol) was added, followed by 20 drops of water. The mixture was stirred at room temperature for 6 hours. After the reaction of compound 6 was monitored by thin-layer chromatography to ensure complete reaction, the organic solvent was removed by rotary evaporation. Silica gel column chromatography (eluent: 3-10% methanol in dichloromethane) was then performed to obtain 32.7 mg of ATV005 (white solid, yield 82%). The obtained ATV005 was analyzed by 1H NMR, 1C NMR, and HPLC. The results are as follows:

[0185] Hydrogen spectrum: 1H NMR (400MHz, Methanol-d4) δ8.20 (s, 1H), 7.25 (d, J = 4.7Hz, 1H), 7.15 (d, J = 4.8Hz, 1H), 4.82 (d, J = 7.4Hz, 2H), 4.26 (t, J = 6.6Hz, 3H), 4.15 (t, J=5.5Hz, 1H), 3.87 (dd, J=12.4, 3.1Hz, 1H), 3.74 (dd, J=12.4, 4.4Hz, 1H), 1.82-1.69 (m, 2H), 1.49-1.36 (m, 4H), 0.95 (t, J=6.9Hz, 3H).

[0186] Carbon spectrum: 13 C NMR (101MHz, Methanol-d4) δ153.5, 153.2, 147.3, 127.0, 118.6, 117.6, 114.3, 104.6, 87.2, 81.2, 75.6, 71.8, 67.3, 62.7, 29.6, 29.1, 23.4, 14.3.

[0187] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of ATV005 was 2.173 min.

[0188] Example 8: Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepent-4-yl)methyl isobutyrate (compound 7)

[0189]

[0190] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of isobutyric acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation was performed by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 1.71 g of compound 7 (white solid, yield 94%). The proton and carbon spectra of compound 7 were analyzed, and the results are as follows:

[0191] Hydrogen spectrum: 1H NMR (400MHz, CDCl3, ZQF-RD01-2) δ (ppm): 7.99 (s, 1H), 6.99 (d, J = 4.6Hz, 1H), 6.62 (d, J = 4.6Hz, 1H), 5.72 (br, 2H), 5.49 (d, J = 6.8Hz, 1H), 4.93-4.90 (dd, J=6.8Hz, 4.3Hz, 1H), 4.61-4.58 (q, J=4.4Hz, 1H), 4.44-4.26 (m, 2H), 2.61-2.50 (m, 1H), 1.77 (s, 3H), 1.42 (s, 3H), 1.17-1.14 (q, J=3.8Hz, 6H).

[0192] Carbon spectrum: 13 C NMR (100MHz, CDCl3, ZQF-RD01-2) δ (ppm): 176.7, 155.2, 147.3, 123.5, 117.2, 11 6.7, 115.6, 112.6, 100.0, 83.8, 83.0, 82.0, 81.4, 63.1, 33.8, 26.4, 25.6, 18.9.

[0193] Example 9. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound ATV006).

[0194]

[0195] 1.50 g of compound 7 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation, and the solution was separated by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 3) to give 0.66 g of compound ATV006 (white solid, yield 49%). The obtained compound ATV006 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0196] Hydrogen spectrum: 1 H NMR (400MHz, Methanol-d4) δ7.76 (s, 1H), 6.78 (s, 2H), 4.78 (d, J = 5.3Hz, 1H), 4.40-4.24 (m, 2 H), 4.24-4.11 (m, 1H), 4.10-4.01 (m, 1H), 2.42 (p, J=7.0Hz, 1H), 0.99 (dd, J=7.0, 4.1Hz, 6H).

[0197] Carbon spectrum: 13 C NMR (101MHz, Methanol-d4) δ176.96, 155.82, 146.92, 124.25, 116.54, 116.29, 1 10.75, 101.20, 82.04, 80.00, 74.27, 70.68, 62.93, 33.58, 25.00, 17.95, 17.87.

[0198] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV006 was 2.036 min.

[0199] Example 10. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl acetate (compound ATV007)

[0200]

[0201] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of acetic acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 1.78 g of compound 8 (yield 98%).

[0202] 1.50 g of compound 8 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 3) to obtain 0.68 g of compound ATV007 (white solid, purity 98.7%, yield 51%). The proton and carbon spectra of the obtained compound ATV007 were analyzed, and the results are as follows:

[0203] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.89 (t, J = 5.0Hz, 2H), 4.87 (s, 1H), 4.43-4.41 (dd, J=12Hz, 2.8Hz, 1H), 4.37-4.34(m, 1H), 4.30-4.27(m, 1H), 4.13(t, J=5.7Hz, 1H), 2.03(s, 3H).

[0204] Carbon spectrum: 13 C NMR (150MHz, CD3OD) δ (ppm): 171.0, 155.8, 146.9, 124.2, 116.6, 116.2, 110.7, 101.1, 81.9, 80.2, 74.1, 70.7, 63.1, 19.3.

[0205] Example 11. Synthesis of methyl propionate ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)propionate (compound ATV008)

[0206]

[0207] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of propionic acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 1.74 g of compound 9 (yield 99%).

[0208] 1.50 g of compound 9 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 3) to obtain 0.68 g of compound ATV008 (white solid, purity 98%, yield 48%). The proton and carbon spectra of the obtained compound ATV008 were analyzed, and the results are as follows:

[0209] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.88 (q, J=4.5Hz, 2H), 4.87-4.86 (m, 1H), 4.46-4.43 (dd, J=12Hz, 2.8Hz, 1H), 4.37-4.36 (m, 1H), 4.31-4.28 (m, 1H), 4.15 (t, J=5.8Hz, 1H), 2.38-2.28 (m, 2H), 1.08 (t, J=7.5Hz, 3H).

[0210] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 174.3, 155.8, 146.9, 124.2, 116.5, 116.2, 110.7, 101.1, 82.0, 80.1, 74.2, 70.7, 62.9, 26.7, 7.9.

[0211] Example 12. Synthesis of methyl ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)butyrate (compound ATV009)

[0212]

[0213] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of n-butyric acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 1.78 g of compound 10 (yield 98%).

[0214] 1.50 g of compound 10 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 3) to obtain 0.76 g of compound ATV009 (white solid, purity 97%, yield 56%). The proton and carbon spectra of the obtained compound ATV009 were analyzed, and the results are as follows:

[0215] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.88 (q, J=4.5Hz, 2H), 4.87-4.86 (m, 1H), 4.44-4.42 (dd, J=12Hz, 2.8Hz, 1H ), 4.37-4.35 (m, 1H), 4.31-4.28 (m, 1H), 4.14 (t, J = 5.8Hz, 1H), 2.32-2.23 (m, 2H), 1.62-1.56 (m, 2H), 0.91 (t, J = 7.4Hz, 3H).

[0216] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 174.3, 155.9, 146.9, 124.3, 116.5, 116.2, 110.7, 101.1, 82.0, 80.1, 74.2, 70.7, 62.8, 35.4, 17.9, 12.5.

[0217] Example 13. Synthesis of methyl nonanoate ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)nonanoate (compound ATV010)

[0218]

[0219] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of nonanoic acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 2.07 g of compound 11 (yield 97%).

[0220] 1.50 g of compound 11 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (elution buffer: petroleum ether / ethyl acetate (VN) = 1 / 3) to obtain 0.55 g of compound ATV010 (white solid, purity 98%, yield 40.3%). The proton and carbon spectra of the obtained compound ATV010 were analyzed, and the results are as follows:

[0221] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.88 (q, J=4.5Hz, 2H), 4.87-4.86 (m, 1H), 4.43-4.41 (dd, J=12Hz, 2.8Hz, 1H), 4.37-4. 35 (m, 1H), 4.32-4.29 (m, 1H), 4.14 (t, J=5.8Hz, 1H), 2.38-2.23 (m, 2H), 1.56-1.53 ​​(m, 2H), 1.29-1.27 (m, 10H), 0.87 (t, J=7.0Hz, 3H).

[0222] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 173.7, 155.9, 146.9, 124.3, 116.5, 116.2, 110.7, 101.1, 82.0, 74.2, 70.7, 62.8, 33.5, 31.5, 28.8, 28.7, 24.6, 22.3.

[0223] Example 14. Synthesis of methyl ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-2-ethylbutyrate (compound ATV011)

[0224]

[0225] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of 2-ethylbutyric acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 1.94 g of compound 12 (yield 99%).

[0226] 1.50 g of compound 12 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (eluting buffer: petroleum ether / ethyl acetate (VN) = 1 / 3) to obtain 0.70 g of compound ATV011 (white solid, purity 98.3%, yield 51.3%). The proton and carbon spectra of the obtained compound ATV011 were analyzed, and the results are as follows:

[0227] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.89 (s, 2H), 4.87-4.86 (m, 1H), 4.39-4.43 (dd, J=12Hz, 2.8Hz , 1H), 4.37-4.35 (m, 1H), 4.14 (t, J=5.8Hz, 1H), 2.38-2.22 (m, 1H), 1.60-1.45 (m, 4H), 0.86-0.82 (m, 6H).

[0228] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 176.1, 155.9, 146.9, 124.3, 116.6, 116.2, 110.7, 101.1, 81.9, 79.9, 74.2, 70.7, 62.8, 48.9, 24.7, 24.6.10.7, 10.6.

[0229] Example 15. Synthesis of methyl ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-cyclopropanecarboxylate (compound ATV012)

[0230]

[0231] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.42 mL of cyclopropionic acid and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (elution buffer: petroleum ether / ethyl acetate (VN) = 1 / 1) yielded 1.52 g of compound 13 (yield 99%).

[0232] 1.50 g of compound 13 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 3) to obtain 0.98 g of compound ATV012 (white solid, purity 97%, yield 62%). The proton and carbon spectra of the obtained compound ATV012 were analyzed, and the results are as follows:

[0233] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.89 (t, J = 4.5Hz, 2H), 4.87-4.86 (m, 1H), 4.46-4.44 (dd, J = 12Hz, 2 .8Hz, 1H), 4.36-4.34 (m, 1H), 4.29-4.26 (m, 1H), 4.15 (t, J=5.8Hz, 1H), 1.64-1.60 (m, 1H), 0.92-0.87 (m, 4H).

[0234] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 174.9, 155.9, 146.9, 124.2, 116.6, 116.2, 110.7, 101.1, 80.2, 80.1, 74.2, 70.6, 63.0, 12.1, 7.5, 7.4.

[0235] Example 16. Synthesis of methyl benzoate (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)benzoate (compound ATV013)

[0236]

[0237] Following the methods described in Examples 8 and 9, but replacing isobutyric acid with benzoic acid, 0.21 g of compound ATV013 was synthesized as a white solid, with an overall yield of 34.9% for both steps. The obtained compound ATV013 was subjected to proton and carbon spectral analysis, and the results are as follows:

[0238] Hydrogen spectrum: 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (br, 2H), 7.90 (d, J = 7.4Hz, 2H), 7.86 (s, 1H), 7.68 (t , J=7.4Hz, 1H), 7.52 (t, J=7.7Hz, 2H), 6.87 (d, J=4.5Hz, 1H), 6.81 (d, J=4.5Hz, 1H), 6.36 (d, J=5.9Hz, 1H), 5.46 (d, J=5.9Hz, 1H), 4.79 (t, J=5.3Hz, 1H), 4.61-4.58 (dd, J=12.2Hz ,2.6Hz, 1H), 4.45-4.42 (dd, J=12.3Hz, 4.8Hz, 1H), 4.39-4.37 (m, 1H), 4.14-4.10 (m, 1H).

[0239] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 166.0, 156.1, 148.4, 134.0, 129.8, 129.7, 129.2, 123.9, 117.4, 117.1, 110.8, 101.3, 81.7, 79.7, 74.5, 70.6, 63.9.

[0240] Example 17. Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclohexanecarboxylate (compound ATV014).

[0241]

[0242] Following the methods described in Examples 8 and 9, and replacing isobutyric acid with cyclohexylformic acid, 0.28 g of compound ATV014 was synthesized as a white solid, with an overall yield of 45.8% for both steps. The obtained compound ATV014 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0243] Hydrogen spectrum: 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.86 (br, 1H), 6.92 (d, J = 4.5Hz, 1H), 6.81 (d, J = 4 .5Hz, 1H), 6.33 (d, J=5.9Hz, 1H), 5.38 (d, J=5.9Hz, 1H), 4.70 (t, J=5.3Hz, 1H), 4.32-4.29 (dd , J=12.2Hz, 2.6Hz, 1H), 4.24-4.21(m, 1H), 4.16-4.13(dd, J=12.3Hz, 4.8Hz, 1H), 3.98-3.95( q, J=5.9Hz, 1H), 2.26-2.22(m, 1H), 1.75-1.72(m, 2H), 1.64-1.56(m, 3H), 1.30-1.12(m, 5H).

[0244] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 175.34, 156.06, 148.4, 124.0, 117.4, 117.0, 1 10.7, 101.2, 81.7, 79.4, 74.5, 70.6, 63.0, 42.6, 29.0, 28.9, 25.7, 25.2, 25.1.

[0245] Example 18. Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclopentane carboxylate (compound ATV015)

[0246]

[0247] Following the methods described in Examples 8 and 9, and replacing isobutyric acid with cyclopentylcarboxylic acid, 0.33 g of compound ATV015 was synthesized as a white solid, with an overall yield of 56.1% for both steps. The obtained compound ATV015 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0248] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.87 (q, J=4.6Hz, 2H), 4.85-4.83 (m, 1H), 4.39-4.43 (dd, J=12.1H z, 3.1Hz, 1H), 4.37-4.35 (m, 1H), 4.14 (t, J=5.7Hz, 1H), 2.75-2.70 (m, 1H), 1.87-1.80 (m, 2H), 1.75-1.53 ​​(m, 6H).

[0249] Carbon spectrum: 13 C NMR (150MHz, CD3OD) δ (ppm): 176.5, 155.9, 146.9, 124.3, 116.5, 116.2, 110.7, 101.1, 82.0, 80.0, 74.3, 70.7, 62.8, 43.5, 29.5, 29.4, 25.3.

[0250] Example 19. Synthesis of methyl 3,3,3-trifluoropropionate (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)3,3,3-trifluoropropionate (compound ATV016).

[0251]

[0252] Following the methods described in Examples 8 and 9, and replacing isobutyric acid with trifluoropropionic acid, 0.31 g of compound ATV016 was synthesized as a white solid, with an overall yield of 50.8% for both steps. The obtained compound ATV016 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0253] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.88 (q, J=4.6Hz, 2H), 4.89 (d, J=5.3H z, 1H), 4.54-4.50 (m, 1H), 4.42-4.38 (m, 2H), 4.15 (t, J=5.7Hz, 1H), 3.45-3.35 (m, 2H).

[0254] Carbon spectrum: 13C NMR (150MHz, CD3OD) δ (ppm): 164.3 (J=4.0Hz), 155.5, 146.9, 123.8 (q, J=273.6Hz), 124.1, 116.6, 116.2, 110.8, 101.2, 81.7, 80.2, 74.0, 70.6, 64.1.

[0255] Example 20. Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-3-methylbutyrate-2-yl)methyl ester (compound ATV017)

[0256]

[0257] Following the methods described in Examples 8 and 9, and replacing isovaleric acid with isovaleric acid, a total of 0.27 g of white solid, compound ATV017, was synthesized, with an overall yield of 47.2% for both steps. The obtained compound ATV017 was subjected to proton and carbon spectral analysis, and the results are as follows:

[0258] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.90-6.88 (q, J=4.6Hz, 2H), 4.87 (d, J=5.3Hz, 1H), 4.43-4.40 (m, 1H), 4.39-4 .35 (m, 2H), 4.31-4.29 (m, 1H), 4.14 (t, J=5.7Hz, 1H), 2.18-2.16 (m, 2H), 2.04-1.97 (m, 1H), 0.91-0.90 (q, J=3.2Hz, 6H).

[0259] Carbon spectrum: 13 C NMR (150MHz, CD3OD) δ (ppm): 155.9, 146.9, 124.3, 116.5, 116.2, 110.7, 101.1, 82.0, 80.0, 74.2, 70.7, 70.6, 62.8, 62.7, 42.6, 25.4, 21.3, 21.2.

[0260] Example 21. Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-neopentanoic acid-2-yl ester (compound ATV018)

[0261]

[0262] Following the methods described in Examples 8 and 9, and replacing isobutyric acid with neopentanoic acid, 0.22 g of compound ATV018 was synthesized as a white solid, with an overall yield of 38.4% for both steps. The obtained compound ATV018 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0263] Hydrogen spectrum: 1 H NMR (600MHz, CD3OD) δ (ppm): 7.86 (s, 1H), 6.89-6.87 (q, J=4.6Hz, 2H), 4.86 (d, J=5. 3Hz, 1H), 4.39-4.36 (m, 2H), 4.32-4.29 (m, 1H), 4.16 (t, J=5.6Hz, 1H), 1.15 (s, 9H).

[0264] Carbon spectrum: 13 C NMR (150MHz, CD3OD) δ (ppm): 155.9, 146.9, 124.3, 116.6, 116.2, 110.7, 101.1, 82.0, 79.9, 74.2, 70.6, 63.0, 38.5, 26.1.

[0265] Example 22. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepentan-4-yl)methyl(tert-butyl)-D-valine ester (compound 7)

[0266]

[0267] 1.80 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 1.18 g of (D)-Boc-valine and 66.48 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.22 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation was performed by column chromatography (elution buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 2.81 g of compound 14 (white solid, 97% yield). The obtained compound 14 was analyzed by 1H NMR, 1C NMR, and HPLC, and the results are as follows:

[0268] Hydrogen spectrum: 1H NMR (600MHz, Methanol-d4) δ7.79 (s, 1H), 6.79 (s, 2H), 5.39 (s, 1H), 4.90 (dd, J=6.5, 3.4Hz, 1H), 4.51 (q, J=4.1Hz, 1H), 4.29 (dd, J=12.0, 3.8Hz, 1H), 4.24 (dd, J=12.1, 5.2Hz, 1H), 3.77 (d, J=6.0Hz, 1H), 3.27-3.11 (m, 1H), 1.6 1 (s, 4H), 1.32 (d, J=2.5Hz, 9H), 1.24 (s, 3H), 0.73 (dd, J=19.0, 6.8Hz, 6H).

[0269] Carbon spectrum: 13 C NMR (151MHz, MeOD) δ172.00, 156.84, 155.83, 147.06, 123.47, 116.84, 116 .25, 115.65, 110.76, 101.11, 84.49, 82.89, 82.02, 81.17, 79.18, 63.54, 5 9.24, 53.42, 48.04, 47.91, 47.90, 47.84, 47.76, 47.62, 47.56, 47.48, 47. 33, 47.19, 33.37, 30.06, 27.32, 25.35, 25.14, 24.66, 24.14, 18.14, 16.90.

[0270] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound 14 was 3.293 min.

[0271] Example 23. ((2R,3S,4R,5R)-5-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl D-valine ester (compound ATV019).

[0272]

[0273] 2.50 g of compound 14 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation, and the solution was separated by column chromatography (eluent: methanol / ethyl acetate (V / V) = 1:20) to give 0.99 g of compound ATV019 (white solid, yield 54%). The proton NMR spectrum of the obtained compound ATV019 was analyzed, and the results are as follows:

[0274] Hydrogen spectrum: 1 H NMR (400MHz, Methanol-d4) δ7.76 (s, 1H), 6.80 (s, 2H), 4.79 (s, 1H), 4.42-4.24 (m, 3H), 4.08 (d, J=5 .5Hz, 1H), 3.23 (d, J=11.1Hz, 1H), 1.90-1.76 (m, 1H), 0.82 (d, J=6.9Hz, 3H), 0.74 (d, J=6.9Hz, 3H).

[0275] Example 24. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepentan-4-yl)methyl(tert-butyl)-L-valine ester (compound 6)

[0276]

[0277] 1.50 g of compound 5 was dissolved in 15 mL of dichloromethane, followed by the addition of 0.98 g of (L)-Boc-valine and 55.40 mg of 4-dimethylaminopyridine. After stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. Separation by column chromatography (eluting buffer: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded 2.28 g of compound 15 (white solid, 95% yield).

[0278] Example 25: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valine ester (compound ATV020)

[0279]

[0280] 2.28 g of compound 15 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran. The mixture was stirred for 6 hours, and sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Separation was performed by column chromatography (eluent: methanol / ethyl acetate (V / V) = 1:20) to obtain 0.85 g of compound ATV020 (white solid, 50% yield). The obtained compound ATV020 was analyzed by 1H NMR, 1C NMR, and HPLC. The results are as follows:

[0281] Hydrogen spectrum: 1H NMR (600MHz, Methanol-d4) δ7.76 (s, 1H), 6.80 (d, J = 1.6Hz, 2H), 4.81 (d, J = 5.3Hz, 1H), 4.42-4.26 (m, 3H), 4 .04 (t, J=5.8Hz, 1H), 3.25 (d, J=4.9Hz, 1H), 1.97-1.84 (m, 1H), 0.83 (d, J=6.9Hz, 3H), 0.79 (d, J=6.9Hz, 3H).

[0282] Carbon spectrum: 13 C NMR (151MHz, MeOD) δ173.76, 155.85, 146.93, 124.12, 116.62, 116.21, 110. 86, 101.11, 81.75, 80.16, 74.04, 70.76, 63.66, 59.27, 31.62, 17.75, 16.46.

[0283] High performance liquid chromatography: The mobile phase was water / acetonitrile (V / V) = 10 / 90, the flow rate was 0.8 mL / min, the detection wavelength was 254 nm, and the retention time of compound ATV020 was 2.594 min.

[0284] Example 26: Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-L-phenylalanine methyl ester (compound ATV021)

[0285]

[0286] Following the methods described in Examples 22 and 23, and replacing (D)-Boc-valine with N-Boc-L-phenylalanine, 0.1 g of compound ATV021 was synthesized as a white solid, with an overall yield of 16.9% for both steps. The obtained compound ATV021 was subjected to proton and carbon spectral analysis, and the results are as follows:

[0287] Hydrogen spectrum: 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.96 (br, 1H), 7.95 (s, 1H), 7.87 (br, 1H), 7.21 -7.13 (m, 5H), 6.93 (d, J = 4.5Hz, 1H), 6.81 (d, J = 4.5Hz, 1H), 6.33 (d, J = 6.2Hz, 1 H), 5.36 (br, 1H), 4.70 (t, J = 5.0Hz, 1H), 4.28-4.24 (m, 2H), 4.19-4.16 (m, 1H), 3.88 (t, J=5.5Hz, 1H), 3.57 (t, J=6.7Hz, 1H), 2.84-2.73 (m, 2H), 1.85 (br, 2H).

[0288] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 174.5, 155.4, 147.8, 137.5, 129.0, 127.9, 126. 1, 123.4, 116.8, 116.4, 110.1, 100.7, 81.1, 78.9, 73.8, 70.0, 63.1, 55.6, 40.4.

[0289] Example 27; Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-D-phenylalanine methyl ester (compound ATV022)

[0290]

[0291] Following the methods described in Examples 22 and 23, and replacing (D)-Boc-valine with N-Boc-D-phenylalanine, 0.1 g of compound ATV022 was synthesized as a white solid, with a two-step yield of 15.3%. The obtained compound ATV022 was subjected to proton and carbon spectral analysis, and the results are as follows:

[0292] Hydrogen spectrum: 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.85 (br, 1H), 7.25-7.14 (m, 5H), 6.90 (d, J = 4.5Hz, 1H), 6.80 (d, J = 4.5Hz, 1H), 6.33 (d, J = 5.9Hz, 1 H), 5.39 (d, J=5.6Hz, 1H), 4.71 (t, J=5.3Hz, 1H), 4.25-4.17 (m, 3H), 3.95-3.94 (m, 1H), 3.56 (t, J=6.7Hz, 1H), 2.86-2.71 (m, 2H), 1.75 (br, 2H).

[0293] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 175.2, 156.1, 148.4, 138.2, 129.7, 128.6, 12 6.8, 124.0, 117.4, 117.1, 110.8, 101.3, 81.7, 79.5, 74.5, 70.7, 63.9, 56.1.

[0294] Example 28: Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-L-isoleucine methyl ester (compound ATV023)

[0295]

[0296] Following the methods described in Examples 22 and 23, and replacing (D)-Boc-valine with N-Boc-L-isoleucine, 0.06 g of compound ATV023 was synthesized as a white solid, with a two-step yield of 10.2%. The obtained compound ATV023 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0297] Hydrogen spectrum: 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.95 (br, 1H), 7.92 (s, 1H), 7.87 (br, 1H), 6.92 (d, J=5.8Hz, 1H), 6.83 (d, J=5.8Hz, 1H), 6.35 (br, 1H), 5.40 (br, 1H), 4.73 (d, J=4.6Hz, 1H), 4.29-4.24(m, 3H), 3.96(t, J=5.0Hz, 1H), 3.18(d, J=4.2Hz, 1H) , 1.53-1.51(m, 1H), 1.39-1.32(m, 1H), 1.11-1.04(m, 1H), 0.80-0.74(m, 6H).

[0298] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 175.6, 156.1, 148.4, 124.0, 117.4, 117.0, 110.8, 101.3, 81.6, 79.5, 74.5, 70.7, 63.5, 59.1, 39.1, 24.6, 16.0, 11.8.

[0299] Example 29: Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-D-isoleucine methyl ester (compound ATV024)

[0300]

[0301] Following the methods described in Examples 22 and 23, and replacing (D)-Boc-valine with N-Boc-D-isoleucine, 0.06 g of compound ATV024 was synthesized as a white solid, with a two-step yield of 9.1%. The obtained compound ATV024 was subjected to proton and carbon spectroscopy, and the results are as follows:

[0302] Hydrogen spectrum: 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.86 (br, 2H), 6.92 (d, J = 5.8Hz, 1H), 6.83 (d, J = 5.8Hz, 1H), 6.33 (d, J = 4.7Hz, 1H), 5.39 (br, 1H), 4.71 (b r, 1H), 4.30-4.19 (m, 3H), 3.97 (t, J=5.1Hz, 1H), 3.15 (d, J=5.3Hz, 1H), 1. 53-1.50(m, 1H), 1.39-1.34(m, 1H), 1.11-1.04(m, 1H), 0.80-0.75(m, 6H).

[0303] Carbon spectrum: 13 C NMR (150MHz, DMSO-d6) δ (ppm): 175.6, 156.1, 148.4, 124.0, 117.4, 117.1, 110.8, 101.3, 81.7, 79.5, 74.5, 70.8, 63.8, 59.1, 39.0, 24.6, 16.1, 11.8.

[0304] Example 30. Synthesis of ((2R,3S,4R,5R)-5-(4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound ATV025).

[0305]

[0306] ATV006 (1 g, 2.77 mmol), Selectfluor (1.4 g, 5.5 mmol, 1-chloromethyl 4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt), and DMAP (0.34 g, 2.77 mmol) were added to 20 mL of a mixed solvent of acetonitrile-water (v / v = 9:1). The mixture was stirred at room temperature for 24 h, and monitored by TLC (mobile phase: DCM:MeOH = 10:1) until ATV006 was basically completely reacted. Acetonitrile was removed by vacuum distillation, and then water and ethyl acetate were added. The mixture was stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and washed successively with saturated sodium carbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a dark red oily substance. The substance was purified by column chromatography (DCM:MeOH = 50:1) to obtain 100 mg of a nearly white solid, with a yield of 9.5%. The proton and carbon spectra of the obtained compound ATV025 were analyzed, and the results are as follows:

[0307] Hydrogen spectrum: 1H NMR (600MHz, CD3OD) δ (ppm): 7.79 (s, 1H), 6.65 (s, 1H), 4.79 (d, J = 5.0Hz, 1H), 4 .40-4.30(m, 3H), 4.09(t, J=5.6Hz, 1H), 2.59-2.54(m, 1H), 1.14-1.13(m, 6H).

[0308] Carbon spectrum: 13 C NMR (150MHz, CD3OD) δ (ppm): 176.9, 154.5, 147.6, 144.0, 142.3, 121.0, 115. 7, 102.7, 102.5, 97.0, 96.9, 81.9, 79.6, 74.5, 70.5, 62.7, 33.7, 17.9, 17.8. 19 F NMR (600MHz, CD3OD) δ (ppm): -160.8.

[0309] Example 31: Synthesis of ((3aR,4R,6R,6aR)-6-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepentan-4-yl)methyl isobutyrate (compound 16)

[0310]

[0311] Compound 7 (0.5 g, 1.2 mmol) and N-iodosuccinimide (0.28 g, 1.2 mmol) were mixed with dichloromethane (10 mL), stirred at 25 °C, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluting agent: ethyl acetate / petroleum ether = 1 / 2 (VN)) to give compound 16 (red solid, 350 mg, yield 53.3%).

[0312] Example 32: Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl-5-deuterium)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxanepent-4-yl)methyl isobutyrate (compound 17)

[0313]

[0314] PdCl2(dppf)2 (32 mg, 0.04 mmol) was added to a D2O-DMSO-d6 (10 mL, D2O∶DMSO=1∶9 (V / V)) solution containing compound 16 (200 mg, 0.38 mmol) and cesium carbonate (247 mg, 0.76 mmol). The mixture was stirred at 80 °C for 10 hours, cooled to 25 °C, and slowly poured into water (10 mL). The mixture was then extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water, and concentrated under vacuum to give a red oil. The red oil was purified by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 2 (V / V)) to give compound 17 (pale red oil, 68 mg, yield 44.7%).

[0315] Example 33: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl-5-deuterium)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound ATV026)

[0316]

[0317] Compound 17 (68 mg, 0.17 mmol) was dissolved in a mixed solution of 6 mol / L hydrochloric acid aqueous solution (1 mL) and tetrahydrofuran (1.5 mL), stirred at 0-5 °C for 7 hours, the pH was adjusted to 8 with Na2CO3, the solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (eluting agent: ethyl acetate / petroleum ether = 1 / 1 (V / V)) to give compound ATV026 (grayish-white solid, 38 mg, yield 61.7%).

[0318] Example 34: Inhibitory effect of the compound on SARS-CoV replicons in HEK293T cells

[0319] HEK293T cells were seeded in 24-well plates. When the cells reached a density of 40-50%, 250 ng of SARS replicon plasmid was transfected using LIPO2000. 6-8 h after transfection, the cell supernatant was discarded, and fresh DMEM medium was added. The compounds listed in Table 1 were added to final concentrations of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.1 μM, or 0.01 μM. 60 h after transfection, the cell supernatant was discarded, and cellular RNA was collected using TRIZOL. Total RNA was extracted, and cDNA was obtained via reverse transcriptase. Finally, quantitative real-time PCR was used to detect the internal reference gene Gapdh and the SARS N gene subgenome in the cDNA to reflect viral replication in the SARS replicon. The inhibitory effect of different drug concentrations on the virus was calculated, and the IC50 of the drugs was determined. 50The inhibitory effects of different compounds on SARS replicons in HEK293T cells are shown in Table 1.

[0320] Table 1: Inhibitory effect of compounds on SARS replicons in HEK293T cells.

[0321]

[0322]

[0323] ＊ The compound was tested at a concentration of 5 μM.

[0324] Conclusion: The experimental results obtained from Example 27 above show that:

[0325] 1) The tested compounds all inhibited SARS-CoV replication to varying degrees in HEK293T cells. Among them, the viral inhibitory activity of ATV001 and ATV002 was significantly lower than that of the parent nucleus GS-441524, while the activity of compounds such as ATV004, ATV009, ATV010, and ATV011 was improved. This indicates that the inhibitory activity of the compounds against the virus is not obvious, and that simple ester monosubstituted esters at the C5 hydroxyl position have a significant effect on enhancing the viral inhibitory activity.

[0326] Example 35; Inhibitory effect of the compound on SARS-CoV-2 replicons in HEK293T cells

[0327] Take compounds GS-441524, ATV001, ATV002, ATV003, ATV004, ATV005, ATV006, ATV007, ATV008, ATV009, ATV010, ATV011, ATV012, ATV013, ATV014, ATV015, ATV016, ATV017, ATV018, ATV019, ATV020, ATV021, ATV022, ATV023, ATV024, ATV025, or remdesivir intermediate 5 as the test compounds, and perform the following procedures respectively:

[0328] HEK293T cells were seeded in 24-well plates. When the cells reached a density of 40-50%, 250 ng of SARS-CoV-2 replicon plasmid was transfected using LIPO2000 (liposome 2000). 6-8 h after transfection, the cell supernatant was discarded, and fresh DMEM medium was added. The test compound was added to final concentrations of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.1 μM, or 0.01 μM, respectively. 60 h after transfection, the cell supernatant was discarded, and cellular RNA was collected using TRIZOL. Total RNA was extracted, and cDNA was obtained via reverse transcriptase. Finally, quantitative real-time PCR was used to detect the internal reference gene Gapdh and the SARS-CoV-2N gene subgenome in the cDNA to reflect viral replication in the SARS-CoV-2 replicon. The inhibitory effect of different drug concentrations on the virus was calculated, and the IC50 of the drug was determined. 50 The results are shown in Table 2.

[0329] Table 2: Inhibitory effects of compounds on SARS-CoV-2 replicons in HEK293T cells

[0330]

[0331]

[0332] Conclusion: All tested compounds inhibited SARS-CoV-2 replication to varying degrees in HEK293T cells. ATV006 showed twice the activity of compound GS-441524, indicating a significant increase in activity. The inhibitory effects of different compounds on SARS-CoV-2 replicons in HEK293T cells are shown in [reference needed]. Figure 1 And as shown in Table 2.

[0333] Example 36; Inhibitory effect of the compound on SARS-CoV-2 in Vero-E6 cells

[0334] Compounds RDV, GS-441524, ATV006, ATV009, ATV010, ATV011, ATV013, ATV014, ATV017, and ATV018 were taken as test compounds and operated according to the following steps:

[0335] Vero-E6 cells were seeded in 48-well plates. When the cell density reached approximately 70-80%, the supernatant was discarded and replaced with fresh DMEM medium. Each compound was then added separately to the medium to final concentrations of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.5 μM, 0.25 μM, 0.1 μM, or 0.01 μM. Cells were infected with three SARS-CoV-2 mutants (B.1, B.1.351, and B.1.617.2) at a multiplicity of infection (MOI) of 0.05. Antiviral activity was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) to quantify the viral copy number in the supernatant 48 hours after infection. We calculated the inhibitory effects of different concentrations of the test drugs on viral replication and their IC50 values. The IC50 values ​​of different compounds against SARS-CoV-2 in Vero-E6 cells are shown below. Figure 2 And Table 3.

[0336] Table 3: Inhibitory effects of different compounds on SARS-CoV-2 in Vero-E6 cells

[0337]

[0338] Example 37: Metabolism of compounds ATV006, ATV014 and GS-441524 in rats

[0339] 1. Dosage and administration method for each group:

[0340] ATV006 intravenous injection group: 5 mg of ATV006 was injected intravenously per kg of mouse body weight.

[0341] ATV006 oral administration group: 25 mg of ATV006 per kg of mouse body weight was administered by gavage.

[0342] ATV014 intravenous injection group: 5 mg of ATV014 per kg of mouse body weight was injected intravenously.

[0343] ATV014 oral administration group: 25 mg of ATV014 per kg of mouse body weight was administered by gavage.

[0344] GS-441524 intravenous injection group: 5 mg of GS-441524 was injected intravenously per kg of mouse body weight.

[0345] GS-441524 oral administration group: 25 mg of GS-441524 per kg of mouse body weight was administered by gavage.

[0346] 2. Operation:

[0347] Sixteen male SD rats weighing 220g–250g were divided into four groups: ATV006 intravenous injection group, ATV006 oral administration group, ATV014 intravenous injection group, ATV014 oral administration group, GS-441524 intravenous injection group, and GS-441524 oral administration group, with four rats in each group (three rats in each ATV014 group). The rats were administered the drugs as described in Section 1, "Dosage and Administration for Each Group." Blood was collected from the jugular vein. Approximately 0.3 mL of blood was collected into heparin tubes at 0.083h (not collected in the oral administration group), 0.16h (not collected in the oral administration group), 0.25h, 0.5h, 1h (not collected in the intravenous injection group), 2h, 4h, 8h, 24h, and 48h after drug administration. The blood was centrifuged at 4000 rpm for 10 min at 4°C. The supernatant plasma was transferred and temporarily stored at approximately -20°C until analysis. Take 50 μL of plasma sample, add 100 μL of 90% methanol aqueous solution, and vortex mix; then add 350 μL of methanol-acetonitrile mixture (1:1, VN), and vortex mix; centrifuge at 10000 rpm for 10 min, and filter the supernatant through a 0.22 μm filter membrane before injection for detection; blood samples taken 0.5 hours after intravenous administration and 4 hours after oral administration are diluted 10-fold before injection for detection. The drug concentration in each sample is determined by high performance liquid chromatography (HPLC) / mass spectrometry (MS). Analytes are separated using a Waters UPLC / XEVO TQ-S column and an InertSustain AQ-C18HP column (3.0 mm x 50 mm, 3.0 μm, GL). Pharmacokinetic parameters are calculated using DAS (Drug and Statistics) 3.0 software.

[0348] Results: See Tables 4, 5, and 6. Figure 3 (A, B).

[0349] Table 4: Pharmacokinetic parameters of SD rats after administration of ATV006 (measured at GS-441524, mean ± standard deviation, n=4)

[0350]

[0351] Table 5: Pharmacokinetic parameters of SD rats after administration of ATV014 (measured at GS-441524, mean ± standard deviation, n = 3)

[0352]

[0353] Table 6: Pharmacokinetic parameters of SD rats after administration of GS-441524 (mean ± standard deviation, n = 4)

[0354]

[0355] in conclusion:

[0356] From Table 4, Table 5, Table 6 and Figure 3 (A, B) shows that after oral administration of ATV006 solution to SD rats, the oral bioavailability was 79.59% (calculated based on the metabolite GS-441524), the oral bioavailability of ATV014 was 49.08%, and the oral bioavailability of GS-441524 was 22.63%. This indicates that ATV006 and ATV014 have significantly improved oral bioavailability and better oral drug properties compared to GS-441524.

[0357] Example 38: Metabolism of compound ATV006 in cynomolgus monkeys

[0358] Three male cynomolgus macaques (3-5 years old) weighing 3-5 kg ​​were used. On day 1, a single oral administration of 10 mg / kg of compound ATV006 was administered via gavage. On day 5, a single intravenous injection of 5 mg / kg of compound ATV006 was administered. Blood was collected at an appropriate rate using a disposable syringe inserted into the jugular vein. Approximately 1 mL of blood was collected at 0 h before administration, immediately after administration (5 min), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h after administration. The collected blood was treated with the anticoagulant EDTA-K2, centrifuged at 2000g for 10 min at 4°C, and approximately 400 μL of the supernatant plasma was collected, or the maximum possible collection volume, and temporarily stored at -65°C until analysis. Plasma samples from all administered groups and samples from the control group collected before and 5 min after administration were analyzed using an LCMS system and the Watson LIMS 7.5SP1 analytical method. Microsoft Excel 2013 WinNonlin 6.3 (WNL-01) statistical software was used to calculate pharmacokinetic parameters.

[0359] Results: See Table 7 and... Figure 3 C.

[0360] Table 7. Metabolic data of compound ATV006 in cynomolgus monkeys (administered by gavage and injection).

[0361]

[0362] Conclusion: As shown in Table 7 and Figure 3 As shown in C, ATV006 is rapidly metabolized to the active product GS-441524 after administration by gavage or intravenous injection in cynomolgus monkeys. The oral bioavailability of the gavage-administered product is 30% (calculated based on the active product GS-441524), which is significantly improved compared with the pharmacokinetic data of GS-441524 in cynomolgus monkeys reported by NIH OpeData Portal (F = 8.3%).

[0363] Example 39: In vivo efficacy of compound ATV006 against mouse coronavirus (MHV-A59)

[0364] Laboratory mice: 80 male SPF-grade BALB / c mice, weighing 18-22g.

[0365] Procedure: The experimental mice were infected with MHV-A59 and randomly divided into 10 groups of 10 mice each. The information for each group is as follows:

[0366] Group A: Virus model control group, no drug was administered after MHV-A59 infection;

[0367] Group B1: Infected mice were administered compound ATV006 by gavage at a dose of 50 mg per kg of mouse body weight daily.

[0368] Group B2: Infected mice were administered compound ATV006 by gavage at a dose of 20 mg per kg of mouse body weight per day;

[0369] Group B3: Infected mice were administered compound ATV006 by gavage at a dose of 10 mg per kg of mouse body weight per day;

[0370] Group B4: Infected mice were administered compound ATV006 by gavage at a dose of 5 mg per kg of mouse body weight daily.

[0371] Group B5: Infected mice were administered compound ATV006 by gavage at a dose of 2 mg per kg of mouse body weight daily.

[0372] Group B6: Infected mice were administered remdesivir (RD) at a dose of 20 mg per kg of mouse body weight by gavage daily;

[0373] Group B7: Infected mice were administered 50 mg of GS-441524 per kg of mouse body weight by gavage daily;

[0374] Group C: The control group that was not infected with the virus, i.e., mice that were not infected with the virus were not given the drug and served as the control group for the other groups;

[0375] Group D: The uninfected control group corresponding to Group B1, i.e., uninfected mice were administered the drug in the same manner as Group B1.

[0376] Mice were monitored for disease symptoms, including weight, clinical signs, and mortality, daily for 14 days. Weight changes in mice from each treatment group after viral infection were recorded (results are shown in [link to results]). Figure 4 Figure A) and survival curves (see results) Figure 4 (Figure B in the middle). The viral titer in mouse livers 72 hours after viral infection was determined using real-time PCR (results are shown in Figure B). Figure 4 (Figure C in the middle)

[0377] Conclusion: From Figure 4 The results showed that compound ATV006 exhibited better in vitro anti-mouse coronavirus MHV-A59 activity compared to GS-441524 and remdesivir. The reasons are as follows:

[0378] (1) After infection, the body weight of the virus model control group (Group A) decreased significantly. Except for the 2 mg / kg group, the body weight of the other treatment groups of compound ATV006 decreased less than that of the virus model control group (Group A) and the positive drug GS-441524 (50 mg / kg) group. The body weight of the animals showed an upward trend 9 days after infection, indicating that the drug has a certain positive effect on body weight protection.

[0379] (2) Four days after infection, mice in the virus model control group (Group A) began to die. By the 8th day after infection, the mortality rate was 100% and the median mortality rate was 5 days. In contrast, the mortality rate in the ATV006 treatment group (Groups B1-B4) was 0% within 14 days, indicating that ATV006 at doses above 5 mg / kg had a significant positive effect on animal survival.

[0380] (3) Mice in the 2 mg / kg ATV006 treatment group (Group B5) began to die 4 days after infection, with a mortality rate of 100% by day 10 post-infection. The median mortality time was 6 days, which was significantly different from the virus model control group (Group A) (P = 0.0291). This indicates that compound ATV006, even at an ultra-low dose of 2 mg / kg, still has a positive effect on prolonging animal survival.

[0381] (4) The compound ATV006 (B1-B4 group) at doses of 5 mg / kg or higher significantly inhibited viral replication in the liver 72 h after viral infection, and the effect was dose-dependent.

[0382] Example 40: Therapeutic effect of compound ATV006 in mice with SARS-CoV-2

[0383] 1. The therapeutic effect of compound ATV006 on SARS-CoV-2 in mice.

[0384] Mice: 18 SPF-grade male C57BL / 6hACE2 humanized mice, weighing 18-22 grams.

[0385] Carrier solvent: Calculated by the total volume of the carrier solvent, it contains 20% by volume of 1,2-propanediol, 5% by volume of solubilol (polyethylene glycol-15 hydroxystearate), and 75% by volume of double-distilled sterilized water.

[0386] In our preliminary study, hACE2 transgenic mice were intranasally inoculated with SARS-CoV-2 (2 x 10⁻⁶ SARS-CoV-2 per mouse). 5 Plaque-forming unit (PFU) virus, starting 2 hours before viral inoculation. Figure 5 A) Treatment with the carrier solvent (blank control, by gavage, once daily), compound ATV006 (dose: 500 mg / kg (diluted with carrier solvent), by gavage, once daily) or compound ATV006 (dose: 250 mg / kg (diluted with carrier solvent), by gavage, once daily) continued for 4 days post-infection.

[0387] On day 4 post-infection (4 dpi), we assessed the abundance of viral genome (N gene) and subgenome viral RNA (subgenome N) in mouse lung tissue by qPCR. The number of viral genome and subgenomes in the drug treatment group was significantly lower than that in the control group. Figure 5 (B and 5C).

[0388] 2. The therapeutic effect of compound ATV006 in mice with SARS-CoV-2 mutant strain B.1.617.2

[0389] Mice: Six SPF-grade male C57BL / 6K18-hACE2 mice, weighing 18-22 grams.

[0390] Carrier solvent: Calculated by the total volume of the carrier solvent, it contains 20% by volume of 1,2-propanediol, 5% by volume of solubilol (polyethylene glycol-15 hydroxystearate), and 75% by volume of double-distilled sterilized water.

[0391] Each mouse was intranasally injected with 1x10 4 PFU SARS-CoV-2 mutant strain B.1.617.2 virus was used, and then, starting 2 hours before virus inoculation, the virus was treated with the vector solvent (blank control, by gavage, once daily) and compound ATV006 (dosage: 250 mg / kg (diluted with the vector solvent), by gavage, once daily). Figure 6 A), and this continues for up to 3 days after infection.

[0392] On day 3 post-infection (3 dpi), we assessed the abundance of viral genome (N gene) and subgenome viral RNA (subgenome N) in mouse lung tissue by qPCR. The number of viral genome and subgenomes in the drug treatment group was significantly lower than that in the control group. Figure 6 B and 6C).

[0393] Conclusion: Our results indicate that intragastric administration of ATV006 effectively inhibits the replication of SARS-CoV-2 and its variants B.1.617.2.

[0394] In summary: Based on the experimental results obtained in Examples 34, 35, 36, 37, 38, 3g, and 40 above, it can be concluded that:

[0395] (1) The compound ATV006 has good anti-SARS-CoV and anti-SARS-CoV-2 activity, and its anti-SARS-CoV-2 activity is twice that of GS-441524, which indicates that the compound ATV006 can effectively inhibit the replication and / or reproduction of the virus in cells.

[0396] (2) In vivo pharmacokinetic studies in rats and cynomolgus monkeys demonstrated that compound ATV006 possesses excellent oral pharmacokinetic properties. Low-dose ATV006 (2 mg / kg) maintained protective activity against mouse coronavirus MHV-A59 infection, prolonging the survival time of mice infected with MHV-A59. Medium- and high-dose ATV006 (5 mg / kg-50 mg / kg) showed good inhibitory effects against mouse coronavirus MHV-A59 in a dose-dependent manner. In particular, data from the B.1.617.2 variant in both mouse models indicated the potential of ATV006 as an oral antiviral agent against SARS-CoV-2 and its variants.

[0397] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises compound ATV014 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; the pharmaceutical composition is in the form of tablets, pills, creams, emulsions, ointments, suspensions, lyophilized preparations, capsules, sustained-release preparations, granules, powders, or sprays; the compound ATV014 is (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclohexanecarboxylate, having the following structural formula: 。

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