Nucleoside drugs and their use for treating or preventing coronavirus infections

Abstract

The present invention belongs to the field of pharmaceutical technology, in particular to a nucleoside drug and its use for treating or preventing coronavirus infection.The present invention further relates to a method for preparing a prodrug of a nucleoside drug.The nucleoside drug of formula (I) or (II) provided in the present invention is more suitable for oral administration to individuals in need thereof compared with other nucleoside drugs, such as injectable remdesivir. [Formula 1] JPEG2025514335000086.jpg41169

Description

Detailed Description of the Invention

[0001] This application claims priority to the following patent applications filed with the State Intellectual Property Office of the People's Republic of China: CN202210465512.X filed on April 25, 2022, CN202211217036.6 filed on September 30, 2022, and CN202211358613.3 filed on November 1, 2022, and also claims priority to the following applications filed with the United States Patent and Trademark Office: No. 63 / 363,499 filed on April 25, 2022, and No. 63 / 381,846 filed on November 1, 2022.

[0002] [Technical field] The present invention relates to the field of pharmaceutical technology, in particular to a nucleoside drug and its use for treating or preventing coronavirus infection. The present invention further relates to a method for preparing a prodrug of a nucleoside drug.

[0003] [Background technology] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also known as novel coronavirus or abbreviated as 'COVID-19') is a thin-walled virus containing a relatively large sense RNA genome coated with a nucleocapsid protein (N). Three transmembrane proteins are incorporated into the viral lipid envelope, namely the spike protein (S) and two smaller proteins, the membrane protein (M) and the envelope protein (E). COVID-19 infection begins with the binding of the spike protein (S protein) on the viral surface to the angiotensin-converting enzyme (ACE2) receptor on the cell surface, which then mediates viral uptake and fusion.

[0004] After invading the host cell, coronaviruses disassemble and release the nucleocapsid and viral RNA into the cytoplasm, and the viral RNA 5'-end open reading frame (ORF1a / b) encodes polyproteins (pp1a and pp1a / b). pp1a and pp1ab can be cleaved by papain-like protease (PLpro) and 3CL protease (3CLpro, also called Mpro) to produce nonstructural proteins (NSPs), such as RNA-dependent RNA polymerase (RdRp) and helicase. The viral RNA-dependent RNA polymerase (RdRp), also called nonstructural protein 12 (nsp 12), can combine with multiple other nonstructural proteins to form an efficient RNA synthesis "machine" to achieve the transcription and replication of genetic material RNA genome. As a core element of this transcription-replication machine, RNA polymerase is one of the most important antiviral drug targets, and it is expected that by disrupting its function, we can block viral replication and ultimately achieve the purpose of treatment. It is extremely important to develop drugs targeting the new coronavirus, especially RNA-dependent RNA polymerase, and to verify the mechanisms of efficacy.

[0005] At present, there is no clear therapeutic drug for SARS-CoV-2 infection, and clinical treatment often mainly involves isolation, antiviral, and symptomatic support, but these treatments still cannot meet clinical needs. Molnupiravir, an oral anti-COVID-19 drug made by Merck, has been approved as an emergency drug by the European Medicines Agency and is the first oral anti-COVID-19 drug in the world that has been approved for home use. Molnupiravir has already been approved for sale by the US FDA, but the drug still has side effects and is prone to drug resistance. Therefore, it is of great significance to conduct research into targeted drugs for SARS-CoV-2.

[0006] Remdesivir, as a drug with broad-spectrum anti-RNA virus activity, has been widely applied in the prevention and treatment of RNA virus diseases, but its use is limited by defects such as hepatotoxic side effects and the inability to be administered orally.

[0007] [Summary of the Invention] In view of the deficiencies existing in the prior art and the demands existing in this field, the present invention aims to provide a series of compounds whose viral inhibition mechanism is similar to that of Remdesivir, but whose inhibitory effect on coronaviruses, particularly SARS-CoV-2 virus, is stronger than that of Remdesivir, and / or whose advantages include low toxicity, good safety, and oral administration, can be used as drugs to effectively prevent, alleviate, and / or treat coronavirus infections in clinical practice. This objective is achieved by the subject matter of the present application described in the following aspects.

[0008] Accordingly, in a first aspect, the present application provides a compound of formula (X) or (XI) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof,

[0009] [ka]

[0010] Among them, U is independently H, D, halogen, C1-C 12 Alkyl group or C1-C 12 each m independently represents an integer of 0 to 3, preferably 0, 1 or 2, and more preferably 0 or 1; R x are independently H, OH, -OC1-C 12 Alkyl group, CN, nitro group, amino group, halogen, C1-C 12 represents a haloalkyl group, Wa and Wb are each independently H, OH, unsubstituted or optionally one, two or more groups Rw C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C2-C 12 Alkenylcarbonyloxy group, C2-C 12 Alkynylcarbonyloxy group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 Aryl groups, C1-C 12 Alkyloxycarbonyloxy group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12 Alkylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, C6-C 14 Arylcarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R w are each independently a di(C1-C6 alkyl)aminosulfonyl group, C1-C 12 alkyl group, hydroxy group, carboxy group, amino group, halogen, Q, X, Y and Z each independently represent O, S or NH; L 1 and L 2 are each independently a single bond, an unsubstituted or optionally one, two or more radicals R a C1-C substituted with 12 Alkylene group, C2-C 12 Alkenylene group, C2-C 12 Alkynylene group, C3-C 12 Cycloalkylene groups, C6-C 14Arylene group, 5-12 membered heteroarylene group, -(O-C1-C 12 Alkylene) n -,-(C1-C 12 Alkylene-O) n -, C1-C 12 Alkylene-NH-C1-C 12 Alkylene groups, C1-C 12 Alkylene-C6-C 14 Arylene group, C6-C 14 Arylene-C1-C 12 Represents an alkylene group, of which R a each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a phenyl group, an amino C1-C6 alkyl group, a di(C1-C6 alkyl)amino C1-C6 alkyl group, or a benzyloxycarbonylamino group; each n independently represents an integer of 1 to 6, and preferably an integer of 4 to 6; R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C2-C 12 Alkenylcarbonyloxy group, C2-C 12 Alkynylcarbonyloxy groups, C1-C 12 Alkyloxycarbonyl group, C2-C 12 Alkenyloxycarbonyl group, C2-C 12 Alkynyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 Aryl groups, C1-C 12 Alkyloxycarbonyloxy group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12Alkylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, C6-C 14 Arylcarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R b each independently represents a benzyloxycarbonylamino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, and is preferably Cl; L 3 is a single bond, unsubstituted or optionally one, two or more groups R c C1-C substituted with 12 Represents an alkylene group, of which R c each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen; R 3 is H, unsubstituted or containing one, two or more groups R d C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C1-C 12 Alkyloxycarbonyl group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 Arylcarbonyloxy groups, C1-C 12 Alkyloxycarbonyloxy group, 5-12 membered heterocyclylcarbonyloxy group, carboxy group, amino group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12 Alkylcarbonyloxy group, C3-C 12Cycloalkylcarbonyloxy group, C6-C 14 Aryloxycarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, C3-C 12 A cycloalkyloxycarbonyloxy group, of which R d each independently represents a di(C1-C6 alkyl)aminosulfonyl group, preferably a di-n-propylaminosulfonyl group, a C1-C6 alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen atom, and preferably Cl; R 4 , H, R 1 -L 1 -X or R 2 -L 2 -Y indicates R e and R f are independently C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, halogens, OH, CN, and -NO2.

[0011] In a second aspect, the present application provides a compound of formula (I) or (II) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof,

[0012] [ka]

[0013] Among them, U is independently H, D, halogen, C1-C 12 Alkyl group or C1-C 12 each m independently represents an integer of 0 to 3, preferably 0, 1 or 2, and more preferably 0 or 1; R x are independently H, OH, -OC1-C 12 Alkyl group, CN, nitro group, amino group, halogen, C1-C 12 represents a haloalkyl group, Wa and Wb are each independently H, OH, unsubstituted or optionally one, two or more groups R w C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C2-C 12 Alkenylcarbonyloxy group, C2-C 12 Alkynylcarbonyloxy group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 Aryl groups, C1-C 12 Alkyloxycarbonyloxy group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12 Alkylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, C6-C 14 Arylcarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R w are each independently a di(C1-C6 alkyl)aminosulfonyl group, C1-C 12 alkyl group, hydroxy group, carboxy group, amino group, halogen, Q, X, Y and Z each independently represent O, S or NH; L 1 and L 2are each independently a single bond, an unsubstituted or optionally one, two or more radicals R a C1-C substituted with 12 Alkylene group, C2-C 12 Alkenylene group, C2-C 12 Alkynylene group, C3-C 12 Cycloalkylene groups, C6-C 14 Arylene group, 5-12 membered heteroarylene group, -(O-C1-C 12 Alkylene) n -,-(C1-C 12 Alkylene-O) n -, C1-C 12 Alkylene-NH-C1-C 12 Alkylene groups, C1-C 12 Alkylene-C6-C 14 Arylene group, C6-C 14 Arylene-C1-C 12 Represents an alkylene group, of which R a each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a phenyl group, an amino C1-C6 alkyl group, a di(C1-C6 alkyl)amino C1-C6 alkyl group, or a benzyloxycarbonylamino group; each n independently represents an integer of 1 to 6, and preferably an integer of 4 to 6; R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C2-C 12 Alkenylcarbonyloxy group, C2-C 12 Alkynylcarbonyloxy groups, C1-C 12 Alkyloxycarbonyl group, C2-C 12 Alkenyloxycarbonyl group, C2-C 12Alkynyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 Aryl groups, C1-C 12 Alkyloxycarbonyloxy group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12 Alkylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, C6-C 14 Arylcarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R b each independently represents a benzyloxycarbonylamino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, and is preferably Cl; L 3 is a single bond, unsubstituted or optionally one, two or more groups R c C1-C substituted with 12 Represents an alkylene group, of which R c each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen; R 3 is H, unsubstituted or containing one, two or more groups R d C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C1-C 12 Alkyloxycarbonyl group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20Arylcarbonyloxy groups, C1-C 12 Alkyloxycarbonyloxy group, 5-12 membered heterocyclylcarbonyloxy group, carboxy group, amino group, C1-C 12 Alkylcarbonylthio group, C6-C 20 Aryl-C1-C 12 Alkylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, C6-C 14 Aryloxycarbonyloxy group, C3-C 12 Cycloalkyloxycarbonyl group, C3-C 12 A cycloalkyloxycarbonyloxy group, of which R d each independently represents a di(C1-C6 alkyl)aminosulfonyl group, preferably a di-n-propylaminosulfonyl group, a C1-C6 alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen atom, and preferably Cl; R 4 , H, R 1 -L 1 -X or R 2 -L 2 Indicates -Y.

[0014] In some preferred embodiments of the present application, the compound of formula (I) or (II) has the structure of formula (II) or (II-I):

[0015] [ka]

[0016] Among them, U is independently H, D, halogen, C1-C 12 Alkyl group or C1-C 12 each m independently represents an integer of 0 to 3, preferably 0, 1 or 2, and more preferably 0 or 1; R x are independently H, OH, -OC1-C 12 Alkyl group, CN, nitro group, amino group, halogen, C1-C 12represents a haloalkyl group, Wb each independently represents H or OH; Q, X, Y and Z each independently represent O, S or NH; L 1 and L 2 are each independently a single bond, an unsubstituted or optionally one, two or more radicals R a C1-C substituted with 12 Alkylene group, C2-C 12 Alkenylene group, C2-C 12 Alkynylene group, C3-C 12 Cycloalkylene groups, C6-C 14 Arylene group, 5-12 membered heteroarylene group, -(O-C1-C 12 Alkylene) n -, C1-C 12 Alkylene-NH-C1-C 12 Represents an alkylene group, of which R a each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a phenyl group, an amino C1-C6 alkyl group, or a di(C1-C6 alkyl)amino C1-C6 alkyl group; n each independently represents an integer of 1 to 6, and preferably an integer of 4 to 6; R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C1-C 12 Alkyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 Aryl groups, C1-C 12alkyloxycarbonyloxy group, carboxy group, amino group, 5- to 12-membered heteroarylcarbonyloxy group, and 5- to 12-membered heterocyclylcarbonyloxy group, among which R b each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, and is preferably Cl; L 3 is a single bond, unsubstituted or optionally one, two or more groups R c C1-C substituted with 12 represents an alkylene group, R 3 is H, unsubstituted or containing one, two or more groups R d C1-C substituted with 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C1-C 12 Alkyloxy group, C2-C 12 Alkenyloxy groups, C2-C 12 Alkynyloxy groups, C1-C 12 Alkylcarbonyloxy group, C1-C 12 Alkyloxycarbonyl group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 Arylcarbonyloxy groups, C1-C 12 alkyloxycarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, carboxy group, and amino group, among which R d each independently represents a di(C1-C6 alkyl)aminosulfonyl group, and is preferably a di-n-propylaminosulfonyl group, a C1-C6 alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, and is preferably Cl.

[0017] In some preferred embodiments according to the present invention, R 4 are each independently H.

[0018] In some preferred embodiments according to the present invention, one R 4 represents H, and the other R 4is R 1 -L 1 -X or R 2 -L 2 Indicates -Y.

[0019] In some preferred embodiments according to the present invention, the compound of formula (I) or (II) has the structure of formula (IA) or (IIA):

[0020] [ka]

[0021] Among them, R 1 , R 2 , R 3 , R 4 , R x , L 1 , L 2 , L 3 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II), preferably, U represents deuterium (D).

[0022] In some preferred embodiments according to the present invention, the compound of formula (I) or (II) has the structure of formula (IB) or (IIB):

[0023] [ka]

[0024] Among them, R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , R 4 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II), preferably, U represents deuterium (D).

[0025] In some preferred embodiments according to the present invention, the compound of formula (I) or (II) has the structure of formula (IC) or (IIC):

[0026] [ka]

[0027] Among them, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II), preferably, U represents deuterium (D).

[0028] In some preferred embodiments according to the present invention, Wa and Wb in formula (I), (II), (IA), (IB) or (IC) represent OH. In other embodiments, Wb in formula (II), (II-I), (IIA), (IIB) or (IIC) represents OH.

[0029] In some preferred embodiments according to the present invention, Wa and Wb are each independently H, OH, unsubstituted or one, two or more groups R w C1-C6 alkylcarbonyloxy group, C2-C6 alkenylcarbonyloxy group, C2-C6 alkynylcarbonyloxy group, C3-C 12 Cycloalkylcarbonyloxy group, 5-12 membered heteroarylcarbonyloxy group, C6-C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R weach independently represents a di(C1-C6 alkyl)aminosulfonyl group, preferably a di-n-propylaminosulfonyl group, a C1-C6 alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen; and preferably, Wa and Wb each independently represent OH, an acetoxy group, an isopropionyloxy group, an isobutyryloxy group, a 2-propylpentanoyloxy group, a 2,2-dimethylpropionyloxy group, a 4-(di-n-propylaminosulfonyl)benzoyloxy group, a pyridine-3-methanoyl group, an N-methylpyrrolidin-2-ylmethanoyl group, a prolyloxy group, or a cyclopentanemethanoyl group.

[0030] In some preferred embodiments according to the present invention, L 1 and L 2 are each independently a single bond, a C1-C6 alkylene group, a C6-C 10 Arylene group, C3-C6 cycloalkylene group, 5-8 membered heteroarylene group, -(O-C1-C6 alkylene) n It is preferable that L represents -, C1-C6 alkylene-NH-C1-C6 alkylene group, and more preferably, L 1 and L 2 each independently represents a single bond, a methylene group, an ethylidene group, a propylidene group, a phenylene group, a cyclopentylene group, a cyclohexylidene group, an oxadiazolediyl group, a pyrazolediyl group, an imidazolediyl group, a thiazolediyl group, -(OCH2CH2) n -, C1-C6 alkylene-NH-C1-C3 alkylene group, and most preferably L 1 and L 2 represent, independently of one another, a single bond, a methylene group, a 1,1-ethylidene group, a 2,2-propylidene group, a 2-phenyl-1,1-ethylidene group, a 1,4-phenylene group, 1,2,4-oxadiazole-3,5-diyl, -(OCH2CH2)4-, or pentylidene-N(C2H5)-CH2CH2-.

[0031] In some preferred embodiments according to the present invention, R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals Rb C1-C6 alkyl groups substituted with C6-C 12 Alkylcarbonyloxy group, C1-C6 alkyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C6-C 14 It is preferable that R represents an aryl group, a C1-C6 alkyloxycarbonyloxy group, a C3-C6 cycloalkylcarbonyloxy group, a C3-C6 cycloalkyloxycarbonyl group, a carboxy group, an amino group, a 5-12 membered heteroarylcarbonyloxy group, or a 5-12 membered heterocyclylcarbonyloxy group. b are each independently a benzyloxycarbonylamino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, fluorine, chlorine or bromine, and more preferably, R 1 and R 2 are each independently H, a methyl group, a heptylcarbonyloxy group, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, a butyloxycarbonyl group, a hexyloxycarbonyl group, a quinolylamino group, a benzamidine group, a propyloxycarbonyloxy group, a carboxy group, an amino group, a pyridinylformyloxy group, an N-methyl-hydroxypyrrolidinylformyl group, a cyclopentylcarbonyloxy group, or a cyclopentyloxycarbonyl group, and most preferably R 1 and R 2 are independent of each other. H, phenyl group, methyl group, carboxy group, amino group,

[0032] [ka]

[0033] is selected from the group consisting of atoms or groups:

[0034] In some preferred embodiments according to the present invention, R 1 and R 2 At the same time

[0035] [ka]

[0036] isn't it.

[0037] In some preferred embodiments according to the present invention, L 3 is a single bond or an unsubstituted or optionally one, two or more groups R c It is preferable that R represents a C1-C6 alkylene group substituted with c each independently represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen atom, and more preferably, L 3 represents a single bond, a methylene group or an ethylidene group, and most preferably, L 3 represents a single bond, a methylene group, or a 1,1-ethylidene group.

[0038] In some preferred embodiments according to the present invention, R 3 is H, unsubstituted or containing one, two or more groups R d C1-C6 alkyl groups substituted with C6-C 12 Alkylcarbonyloxy group, C1-C6 alkyloxycarbonyl group, 5-12 membered heteroarylcarbonyloxy group, benzamidine group, C6-C 14 Arylcarbonyloxy group, C1-C6 alkyloxycarbonyloxy group, 5-12 membered heterocyclylcarbonyloxy group, N-methyl-hydroxypyrrolidinylformyl group, carboxy group, amino group, C1-C6 alkylcarbonylthio group, C6-C 14 Aryl C1-C6 alkylcarbonyloxy group, C6-C 14 It is preferable that R represents an aryloxycarbonyloxy group or a C3-C6 cycloalkyloxycarbonyloxy group, and more preferably R 3represents H, a methyl group, a heptylcarbonyloxy group, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, a butyloxycarbonyl group, a hexyloxycarbonyl group, a propyloxycarbonyloxy group, an isopropyloxycarbonyloxy group, a benzoyl group, a pyridinylformyloxy group, a carboxy group, an amino group, a tert-butylcarbonylthio group, a phenylpropylcarbonyloxy group, a phenoxycarbonyloxy group, a cyclobutyloxycarbonyloxy group, or a cyclopentyloxycarbonyloxy group, and is most preferably R 3 is H, phenyl group, methyl group, carboxy group, amino group,

[0039] [ka]

[0040] is selected from the group consisting of atoms or groups:

[0041] In some preferred embodiments according to the present invention, R 1 -L 1 -X- and R 2 -L 2 -Y- are each independently

[0042] [ka]

[0043] This represents a group represented by the formula:

[0044] In some preferred embodiments according to the present invention, R 3 -L 3 -Q- is

[0045] [ka]

[0046] This represents a group represented by the formula:

[0047] In some preferred embodiments according to the present invention, the compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) is selected from the compounds in Tables 1 to 9 below.

[0048] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) as defined herein or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

[0049] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention may optionally further comprise at least one physiologically / pharmaceutical acceptable auxiliary agent.

[0050] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention may optionally further comprise another active ingredient, such as, for example, a fusion inhibitor, a viral entry inhibitor, a protease inhibitor, a polymerase inhibitor, an antiviral nucleoside drug different from remdesivir and its derivatives, a viral maturation inhibitor, a JAK inhibitor, an angiotensin-converting enzyme 2 (ACE2) inhibitor, a SARS-CoV-specific human monoclonal antibody, a compound that inhibits cytokine storm, preferably, ribavirin, sovosbuvir, GS-441524, palivizumab, motavizumab, etc.

[0051] In some preferred embodiments according to the present invention, pharmaceutical compositions according to the present invention comprise a therapeutically effective amount of a compound of Formula (I) or (II) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

[0052] In some preferred embodiments according to the invention, the pharmaceutical compositions according to the invention are capable of inhibiting the replication of an RNA virus, preferably an orthomyxovirus (e.g., influenza virus) or a paramyxovirus (e.g., coronavirus or respiratory syncytial virus).

[0053] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention is used for preventing or treating a coronavirus infection or a disease or condition caused by a coronavirus. Preferably, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus 229E (HCoV-229E), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), human coronavirus NL63, human coronavirus HKU1, and a coronavirus having a homology of more than 85% with any one of the above coronaviruses and having viral activity. More preferably, the coronavirus is novel coronavirus (SARS-CoV-2). Alternatively, the coronavirus is selected from porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV.

[0054] In some preferred embodiments according to the present invention, the disease or symptoms caused by coronavirus include respiratory infection caused by coronavirus, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, shivering, vomiting, headache, chills, rapid breathing, cytokine storm, and the like.

[0055] According to the present invention, the pharmaceutical compositions according to the present invention can be prepared by methods known in the art into dosage forms suitable for administration.

[0056] In a fourth aspect, the present invention provides the use of a compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof according to the present invention in the manufacture of a medicament.

[0057] In some preferred embodiments according to the present invention, the medicament may optionally further comprise another active ingredient, such as a fusion inhibitor, a viral entry inhibitor, a protease inhibitor, a polymerase inhibitor, an antiviral nucleoside drug different from remdesivir and its derivatives, a viral maturation inhibitor, a JAK inhibitor, an angiotensin-converting enzyme 2 (ACE2) inhibitor, a SARS-CoV-specific human monoclonal antibody, a compound that inhibits cytokine storm, preferably ribavirin, sovosbuvir, GS-441524, palivizumab, motavizumab, etc.

[0058] In some preferred embodiments according to the invention, the medicament is used to inhibit the replication of an RNA virus, preferably an orthomyxovirus (eg, influenza virus) or a paramyxovirus (eg, coronavirus or respiratory syncytial virus).

[0059] In some preferred embodiments according to the present invention, the medicament is used for preventing or treating coronavirus infection or a disease or condition caused by a coronavirus. Preferably, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus 229E (HCoV-229E), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), human coronavirus NL63, human coronavirus HKU1, and a coronavirus having a homology of more than 85% with any one of the above coronaviruses and having viral activity. More preferably, the coronavirus is novel coronavirus (SARS-CoV-2). Alternatively, the coronavirus is selected from porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV.

[0060] In a fifth aspect, the present invention provides a method for treating or preventing a disease or condition caused by an RNA virus, preferably an orthomyxovirus (e.g. influenza virus) or paramyxovirus (e.g. coronavirus or respiratory syncytial virus), the method comprising administering to an individual in need thereof a compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) according to the present invention or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

[0061] In some preferred embodiments according to the present invention, the compounds of the present invention can be administered by oral, parenteral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary, airway, vaginal, rectal, intraperitoneal, intralesional, perilesional, and the like routes.

[0062] In some preferred embodiments according to the present invention, the compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) according to the present invention or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof, may be administered to an individual in need thereof with the following active ingredients: fusion inhibitors, viral entry inhibitors, protease inhibitors, polymerase inhibitors, antiviral nucleoside drugs different from remdesivir and derivatives thereof, viral maturation inhibitors, JAK inhibitors, angiotensin-converting enzyme 2 (ACE2) inhibitors, SARS-CoV specific human monoclonal antibodies, compounds that inhibit cytokine storm, preferably ribavirin, sovosbuvir, GS-441524, palivizumab, motavizumab, etc.

[0063] The specific dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that are typically considered by the attending physician when determining the individualized regimen and dosage level most suitable for a particular patient. For example, the daily dosage of the compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) according to the present invention may be, in particular, 0.001 to 150 mg / kg body weight (e.g., 0.1 mg / kg body weight, 1 mg / kg body weight, 10 mg / kg body weight, or 100 mg / kg body weight).

[0064] The specific dosing frequency may be determined by one of skill in the art, for example, once per day, once per two days, once per three days, once per four days, once per five days, once per six days, twice per day, three times per day, etc.

[0065] In a sixth aspect, the present invention provides a compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof, for use in inhibiting the replication of an RNA virus, preferably an orthomyxovirus (e.g., influenza virus) or a paramyxovirus (e.g., coronavirus or respiratory syncytial virus) or for use in preventing or treating a coronavirus infection or a disease or condition caused by a coronavirus.

[0066] Preferably, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus 229E (HCoV-229E), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), human coronavirus NL63, human coronavirus HKU1, and a coronavirus having a homology of more than 85% with any one of the above coronaviruses and having viral activity. More preferably, the coronavirus is novel coronavirus (SARS-CoV-2). Alternatively, the coronavirus is selected from porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV).

[0067] In a seventh aspect, the present invention provides a method of forming a prodrug of a nucleoside drug, optionally comprising: (SA) reacting a p-nitrophenyl phosphate compound (V) with a (deoxy)nucleoside drug (VI) having a free hydroxy group at the C5 position to obtain a prodrug compound of formula (VII),

[0068] [ka]

[0069] Among them, R 1 , R 2 , R x , L 1 , L 2 , Wa, Wb, X, Y, Z are as defined above for the compound of formula (I) or any of its preferred embodiments, and the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; Preferably, the compound of formula (VI) is GS-441524, preferably, step (SA) is carried out under basic conditions, more preferably, step (SA) is carried out under basic conditions and in the presence of a Grignard reagent, most preferably, step (SA) is carried out in the presence of tert-butylmagnesium bromide, Or, (SB) reacting a (deoxy)nucleoside phosphate drug (IX) with a phenolic compound (VIII) to obtain a prodrug compound of formula (X),

[0070] [ka]

[0071] Among them, R 1 , R 2 , R x , L 1 , L 2 The definitions of Wa, Wb, and Z are as defined above for the compounds of formula (I) or any of its preferred embodiments, and L 1 is C6-C 14 An arylene group or a 5- to 12-membered heteroarylene group, preferably a C6-C 10an arylene group or a 5-8 membered heteroarylene group, more preferably a 1,4-phenylene group or a 1,2,4-oxadiazole-3,5-diyl; the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; Or, (SC) First, a (deoxy)nucleoside phosphate (XI) is converted to a silver salt (XII), and then the silver salt (XII) is reacted with a halide R 1 -L 1 -Hal and / or R 2 -L 2 -Hal to obtain a prodrug compound of formula (XIII),

[0072] [ka]

[0073] Among them, R 1 , R 2 , R x , L 1 , L 2 the definitions of W, X, Y, and Z are as defined above for the compound of formula (I) or any of its preferred embodiments; the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; Hal represents a halogen, preferably Br or I, more preferably I; and preferably said silver salt is silver carbonate; Or, (SD) Cyclic phosphate (deoxy)nucleoside drug (XIV) is reacted with halide R in the presence of a basic compound. 3 -L 3 -Hal to obtain a prodrug compound of formula (XV),

[0074] [ka]

[0075] Among them, R x , R 3 , L 3 and W are as defined above for the compound of formula (II) or any of its preferred embodiments, the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, Hal represents a halogen, preferably Br or Cl, more preferably Cl, and said basic compound is preferably an alkali metal carbonate, more preferably cesium carbonate; Or, (SE) First, a (deoxy)nucleoside phosphate (XVI) is converted to a silver salt (XVII), and then the silver salt (XVII) is reacted with a halide R 3 -L 3 -Hal to obtain a prodrug compound of formula (XV),

[0076] [ka]

[0077] Among them, R x , R 3 , L 3 and W are as defined above for the compound of formula (II) or any of its preferred embodiments, the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, Hal represents a halogen, preferably Br or I, more preferably I, Or, (SF) reacting phosphoramide compound (XVIII) with (deoxy)nucleoside drug (VI) having free hydroxy groups at the C3 and C5 positions to obtain a prodrug compound of formula (XIX),

[0078] [ka]

[0079] Among them, R x , R 3 , L 3 the definitions of and W are as defined above for the compound of formula (II) or any of its preferred embodiments, the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, preferably, step (SF) is carried out under basic conditions, more preferably, step (SF) is carried out under basic conditions and in the presence of a Grignard reagent, most preferably, step (SF) is carried out in the presence of tert-butylmagnesium bromide, Includes.

[0080] In some preferred embodiments of the methods of forming a prodrug of a nucleoside drug herein, W represents OH and R x represents a cyano group, and the base is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl. Thus, the nucleoside drug is preferably GS-441524.

[0081] The inventors unexpectedly found that by phosphorylating the hydroxy group at C5 or the hydroxy groups at C3 and C5 of the prodrug of a nucleoside drug, the nucleoside drug is converted into its prodrug form, which makes it more suitable for use as an oral drug. In particular, when the base of the nucleoside structure is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, a higher concentration of GS-443902 can be detected in lung tissue.

[0082] In this specification, when referring to the position of carbon atom in the molecule of nucleoside drug compound, the usual numbering system for carbon atom in this field is used.Take ribofuranose to form ribonucleoside glycosyl as an example, the carbon atom formed by condensation of aldehyde group is designated as C1 position, the carbon atom with primary hydroxyl group is designated as C5 position, and the remaining carbon atoms are numbered sequentially.

[0083] [ka]

[0084] Any of the reactants or intermediates in the above processes may be protected with a protecting group as necessary. After the corresponding reaction is completed, the protecting group is removed by further selecting an appropriate method.

[0085] The reactant materials in the above processes may be synthesized by conventional methods or purchased commercially. For example, the starting materials are generally derived from commercial sources such as Aldrich, or can be readily prepared by methods well known to those skilled in the art (available from SciFinder, Reaxys online database).

[0086] In the method of forming a prodrug of a nucleoside drug according to the present invention, suitable reaction conditions and raw materials can be selected according to each case, for example, in a one-step reaction, only one substituent may be replaced with another substituent according to the present invention, or multiple substituents may be replaced with other substituents according to the present invention in the same reaction step.

[0087] According to the present invention, in the method for forming a prodrug of a nucleoside drug, after the reaction is completed, the reaction product can be treated by a conventional post-treatment method, for example, separated and purified by conventional technical means such as preparative high performance liquid chromatography, preparative thin layer chromatography or recrystallization to obtain a prodrug compound of the desired purity.

[0088] Those skilled in the art will understand that the features listed in each aspect and each embodiment of the present invention can be freely combined as long as they do not conflict with each other.

[0089] Beneficial Effects of the Invention The present invention provides modified nucleoside drugs (prodrugs) that are more suitable for oral administration to individuals in need thereof compared to other nucleoside drugs, such as injectable remdesivir.In the study, it was found that in the compounds of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) according to the present invention, when the base of the nucleoside structure part is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, a higher concentration of GS-443902 (i.e., the triphosphate metabolite of remdesivir known in the art, which is itself an effective viral RNA-dependent RNA polymerase (RdRp) inhibitor) can be detected in lung tissue.

[0090] [Mode for carrying out the invention] The present invention will now be described in further detail.

[0091] Unless otherwise specified, the following terms used herein have the meanings as interpreted below, and they can be combined or combined with each other in any way, such as illustrative definitions, exemplary definitions, preferred definitions, definitions listed in the tables, definitions of specific compounds in the examples, etc., and terms that are not specifically interpreted should have the same meaning as commonly understood by those of ordinary skill in the art, and all patent and non-patent literature or other disclosed materials cited in whole or in part in this specification are incorporated herein by reference.

[0092] term In this specification, the terms "comprise", "include", and / or "contain" are open expressions, i.e., they include the contents specified in the present invention, but do not exclude the contents of other embodiments. When describing one / kind, two / kind or more / kinds, "more / more kinds" should refer to more than 2, for example, an integer of 3 or more, for example, 3, 4, 5, 6, 7, 8, 9 or 10 / kinds. The term "optionally" indicates that the two cases are present or absent in the described feature, which means that the event described thereafter may occur but may not occur, and thus includes the two cases of the event occurring or not occurring. For example, "heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may exist but may not exist, and thus includes the case of a heterocyclyl group substituted with an alkyl group and the case of a heterocyclyl group not substituted with an alkyl group. Expressions such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, and / or C," and "X is A, B, and / or C" all have the same meaning, i.e., X may be any one, two, or more of A, B, and C.

[0093] In this specification, the term "unsubstituted" indicates that one or some hydrogen atoms in an atom, residue, group, or moiety with which the term is used are not replaced with other atoms or groups of atoms other than hydrogen atoms (i.e., substituents), and thus the atom, residue, group, or moiety retains its original structure. The term "substituted" indicates that one, two or more hydrogen atoms, preferably at most five hydrogen atoms, more preferably one to three hydrogen atoms in a group, are each independently replaced with a corresponding number of substituents. When one or more substituents are replaced, these substituents are independent of each other, i.e., the one or more substituents may be the same as each other, but do not exclude the case where they may be the same. Unless specifically stated, one substituent may be replaced at any substitutable position of the group to be replaced. In a given structural formula, when multiple positions can be replaced with one, two or more substituents, these substituents may be replaced at these positions independently. Of course, the substituents are located only at their chemically possible positions, and a person skilled in the art can determine possible or impossible replacements without undue effort by experiment or theory. The phrase "independently of each other" should be understood to mean that each of the described individuals is independent of each other and may be independently selected from identical or different options. For example, "independently of each other" may mean that specific options represented by the same symbol in different groups do not affect each other, or may indicate that specific options represented by the same symbol in the same group do not affect each other.

[0094] In the present specification, a linking group may be described that is located in the middle of a compound structure and is connected to the remainder of the compound through at least two linking sites. A Markush variable listed for a linking group should be understood as a divalent group, i.e., a "subunit," of the variable. For example, if a compound structure defines a linking group and lists an "alkyl group" or an "aryl group" for the Markush group definition of the linking group, the "alkyl group" or "aryl group" should be understood to represent a linked alkylene group or arylene group, respectively.

[0095] In this specification, "C x -C y When used in conjunction with a group, the term "C1-C1" indicates the upper and lower ranges of the number of carbon atoms contained in that group. For example, "C1-C1 12 An "alkyl group" refers to an alkyl group containing a minimum of 1 and a maximum of 12 carbon atoms. One of ordinary skill in the art will understand that such numbers do not include the number of carbon atoms contained in the linked substituents when these groups are otherwise substituted. The term "X-Y membered", when used in conjunction with a cyclic group, indicates the upper and lower ranges of the number of ring atoms contained in the cyclic group. For example, a "3-20 membered" heterocyclyl group refers to a heterocyclyl group containing a minimum of 3 and a maximum of 20 ring atoms. One of ordinary skill in the art will understand that such numbers do not include the number of carbon atoms contained in the linked substituents when these heterocyclyl groups are otherwise substituted.

[0096] In this specification, the term "halogen" refers to fluorine, chlorine, bromine and / or iodine. Thus, the term "halogenated" refers to fluoro, chloro, bromo and / or iodo. In the scope of this specification, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be mono-, di- or poly-substituted, up to full substitution by halogen atoms.

[0097] The term "alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42- Examples of the branched chain isomers include 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2-ethylhexyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylhexyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

[0098] The term "alkenyl group" refers to a straight or branched chain monovalent unsaturated aliphatic hydrocarbon group containing one, two or more double bonds. It should be understood that when an alkenyl group contains more than one double bond, said double bonds may be separate or conjugated with each other. Non-limiting examples of alkenyl groups include vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1 ... (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop -2-enyl group, 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group These include (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl groups.

[0099] The term "alkylene group" refers to a divalent group obtained by removing one additional hydrogen atom from an "alkyl group." Similarly, "alkenylene group" and "alkynylene group" refer to divalent groups obtained by removing one additional hydrogen atom from an "alkenyl group" and an "alkynyl group," respectively.

[0100] The term "alkyloxy" refers to an -O-alkyl group, where alkyl is as defined herein. Non-limiting examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups can be unsubstituted or optionally substituted.

[0101] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O)2, but not including the -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms (e.g., 1, 2, 3 and 4), more preferably 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclyl group may be linked to the remainder of the molecule via any one of the carbon atoms or nitrogen atoms (if present) or oxygen or sulfur atoms (particularly when an onium salt is formed). The heterocyclyl group may contain fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl, etc., preferably piperidinyl and pyrrolidinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclyl groups, and may be benzo-fused heterocyclyl groups such as dihydroisoquinoline. The heterocyclyl group may be bicyclic, non-limiting examples of which include hexahydrocyclopenta[c]pyrrol-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. The heterocyclyl group may be partially unsaturated, i.e., it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

[0102] The term "aryl group / aromatic ring" refers to 6-14 membered all-carbon monocyclic or fused polycyclic (i.e. rings which share adjacent pairs of carbon atoms) groups having a conjugated electron system, preferably 6-10 membered rings, e.g., phenyl and naphthyl groups.

[0103] As used herein, the term "heteroaryl group / heteroheteroaryl ring" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-20 ring atoms, of which the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered. Non-limiting examples of heteroaryl groups include thienyl, furan, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, as well as benzo derivatives thereof, such as benzofuran, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazole, indole, isoindole, or pyrazolyl. These include, but are not limited to, quinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl groups, and benzo derivatives thereof, such as quinoline, quinazolinyl, isoquinoline, azocine, indolizinyl, purine groups, and benzo derivatives thereof, such as cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and / or phenoxazinyl groups.

[0104] Unless otherwise stated, the heterocyclyl group, heteroaryl group or heteroaryl ring includes all possible isomeric forms thereof, for example, positional isomers thereof.Thus, some illustrative non-limiting examples include those substituted or bonded to other groups at one, two or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present), and include pyridin-2-yl, pyridylidene-2-yl, pyridin-3-yl, pyridylidene-3-yl, pyridin-4-yl and pyridylidene-4-yl, thienyl or thienylidene groups, including thien-2-yl, thienylidene-2-yl, thien-3-yl and thienylidene-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0105] The aryl group / aromatic ring / heteroaryl group / heteroaryl ring may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups or carboxylate groups.

[0106] Unless otherwise specified, the definition of a term in this specification applies to expressions containing the term as well. For example, the definition of a C1-C6 alkyl group includes a C1C-6 alkyloxy group, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl group, -SO-C 1-6 Alkyl group or -S(O)2-C 1-6 This also applies to alkyl groups.

[0107] As used herein, "physiologically / pharmacologically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and has the desired biological activity.

[0108] Physiologically / pharmacologically acceptable salts include acid addition salts of the compounds of the present invention that have nitrogen atoms in the chain or ring and are sufficiently basic. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl groups; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl groups; aralkyl halides such as bromides of benzyl and phenethyl groups. Illustrative physiologically / pharmacologically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, hydrogen sulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts.

[0109] Since the compound of the present invention can have multiple salt-forming sites, the physiological / pharmacologically acceptable salts include not only salts formed at one salt-forming site in the compound of the present invention, but also salts formed at two, three or all of the salt-forming sites. Therefore, in the physiological / pharmacologically acceptable salts, the molar ratio of the compound of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) to the ion (anion) of an acid or the cation of a base required for salt formation can vary within a relatively wide range, for example, 4:1 to 1:4, for example, 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0110] As used herein, the term "nitrogen oxide" refers to the fact that, when a compound contains several nitrogen-containing functional groups, one or more of the nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or the N-oxides of nitrogen-containing heterocyclic nitrogen atoms. For example, the corresponding nitrogen-containing compound can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn.Comm.1977, 7,509-514), in which, for example, the nitrogen-containing compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0111] As used herein, the term "ester" refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxy or carboxy group. Such esters are, for example, physiologically / pharmacologically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol or acid. Compounds of formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC) contain a carboxy group and can form in vivo hydrolyzable esters with suitable groups, including, but not limited to, alkyl groups, arylalkyl groups, and the like.

[0112] Depending on the position and nature of different substituents, the compounds of the present invention may further contain one or more asymmetric centers. The asymmetric carbon atom may be present in (R) or (S) configuration, and when there is only one asymmetric center, a racemic mixture is produced, and when there are multiple asymmetric centers, a diastereoisomeric mixture is obtained. In some cases, asymmetry may occur because rotation around a particular bond is hindered, for example, when the central bond is attached to two substituted aromatic rings in a particular compound. And the substituent may exist in the form of cis or trans isomers.

[0113] The compounds of the present invention further include each and every possible stereoisomer, be it in the form of a single stereoisomer or any mixture of said stereoisomers in any ratio (e.g., R- or S-isomers, or E- or Z-isomers). Separation of single stereoisomers (e.g., single enantiomers or single diastereoisomers) of the compounds of the present invention can be achieved by any suitable conventional method (e.g., chromatography, in particular, e.g., chiral chromatography).

[0114] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may have an R or S configuration, and the various isomers formed thereby are optical isomers. Optical isomers include all diastereoisomers, enantiomers, meso forms, racemates or mixtures thereof. Optical isomers can be separated, for example, by chiral chromatography columns or by chiral synthesis.

[0115] The term "tautomer" refers to a functional isomer produced by the rapid shift of an atom in a molecule between two positions. The compounds of the present invention can exhibit the phenomenon of tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-shift tautomers are due to the shift of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium forms, and separation of single tautomers usually produces a mixture whose physicochemical properties match the mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention includes all tautomeric forms of the compounds.

[0116] The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as a cis isomer, a trans isomer, an E isomer, and a Z isomer. The geometric isomer includes the cis isomer, the trans isomer, the E isomer, the Z isomer, or a mixture thereof.

[0117] In the present invention, the compounds according to the present invention further include isotopically labeled compounds, which are the same as those shown in formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC), but one or more atoms therein are replaced with an atom whose atomic mass or mass number is different from the atomic mass or mass number usually found in nature. Illustrative examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, each of which can be, for example, 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 32 P, 35 S, 18 F and 36The isotopes of the present invention are preferably Cl. Compounds of the present invention, prodrugs thereof, or physiologically / pharmaceutical acceptable salts of the compounds or prodrugs thereof, containing the above isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Isotopically labeled compounds according to the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein. Certain isotopically labeled compounds of the present invention, such as compounds containing a radioactive isotope (e.g., 3 H and 14 Compounds incorporating tritium (i.e., 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred because they are easy to produce and can be detected. 2 Substitution with hydrogen (H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dosage) resulting from greater metabolic stability, and therefore is preferred in some cases. The compounds of the invention as claimed in the claims can be specifically limited to substitution with deuterium or tritium. Otherwise, hydrogen appearing in a substituent may also include deuterium or tritium, without indicating that deuterium or tritium is excluded unless the term deuterium or tritium is explicitly recited by itself.

[0118] As used herein, the term "prodrug" or "drug precursor" refers to a compound that is converted in vivo to the compound shown in formula (X) or (XI), formula (I) or (II), formula (II) or (II-I), formula (IA) or (IIA), formula (IB) or (IIB), formula (IC) or (IIC), or a specific compound. Such conversion is effected by the prodrug being hydrolyzed in blood or converted to the parent structure via enzymes in blood or tissue. The prodrug of the present invention may be an ester, and the esters that can be used as prodrugs in the present invention include phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in the present invention contains a hydroxy / carboxy group, i.e., it can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, for example, these phosphate ester compounds are obtained by phosphorylation of the hydroxy group in the parent.

[0119] As used herein, the term "metabolite" refers to a product obtained by metabolism in the body of a specific compound or its salt. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by testing methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, etc. of the administered compound. Thus, the present invention includes metabolites of a compound, including those produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

[0120] Abbreviations for any protecting groups, amino acids and other compounds used in the present invention follow their commonly used and widely accepted abbreviations or refer to the IUPAC-IUB Commission Biochemical Nomenclature, unless otherwise specified.

[0121] As used herein, the term "solvate" refers to the associated complex formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid and aminoethanol. Thus, the term "hydrate" refers to the associated complex formed by water solvent molecules.

[0122] As used herein, the term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutical acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutical acceptable carriers and excipients. Pharmaceutical compositions are intended to facilitate administration to the living body and contribute to the absorption of the active ingredients to further exert biological activity. The term "physiologically / pharmaceutical acceptable" refers to molecular entities and compositions that can be physiologically tolerated when administered to humans and generally do not cause allergic or similar undesirable reactions, such as gastrointestinal discomfort, dizziness, etc. The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These drug carriers may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water, aqueous solutions, saline solutions, aqueous glucose and glycerin solutions are preferably used as carriers, especially injectable solutions.

[0123] As used herein, the term "treatment" of any disease or condition, in some embodiments thereof, refers to ameliorating the disease or condition (i.e., slowing, arresting, or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to modulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treatment" refers to preventing or delaying the onset, development, or worsening of the disease or condition.

[0124] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described in the present invention sufficient to achieve the expected application (including, but not limited to, the treatment of diseases as defined below). The therapeutically effective amount can vary depending on the expected application (in vitro or in vivo), or the subject and disease or condition to be treated, such as the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art. The specific dosage can vary depending on the particular compound selected, the method of administration followed, whether or not it is administered in combination with other compounds, the time schedule of administration, the tissue to which it is administered, and the physical delivery system it is carrying.

[0125] In some preferred embodiments according to the present invention, the pharmaceutical adjuvant may be an adjuvant widely adopted in the field of drug manufacturing. The adjuvant is primarily for providing a safe, stable and functional pharmaceutical composition, and may also provide a method for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting the effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical adjuvant may be an inert filler, or may provide some function, such as stabilizing the pH value of the entire composition, or preventing the active ingredient of the composition from decomposing. The pharmaceutical adjuvant may include one or more of the following adjuvants: adhesive, suspending agent, emulsifying agent, diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, anti-adherent, glidant, wetting agent, gelling agent, absorption retarder, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, coloring agent, flavoring agent, and sweetening agent.

[0126] Substances which can be used as physiologically / pharmacologically acceptable auxiliary agents are: ion exchangers, aluminium, aluminium stearate, lecithin, serum proteins, e.g. human serum proteins, buffer substances, e.g. phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g. protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, e.g. lactose, glucose, sucrose, starches, e.g. corn starch and potato starch, cellulose and its derivatives, e.g. carboxymethylcellulose. In one embodiment, the pharmaceutical composition may include, but is not limited to, sodium stearate, ethylcellulose and cellulose acetate, gum powder, malt, gelatin, talc powder, adjuvants such as cocoa butter and suppository wax, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycolic compounds such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic salts, Ringer's solution, ethanol, phosphate buffer solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, releasing agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0127] The pharmaceutical compositions of the present invention can be prepared based on the disclosed content by any method known to those skilled in the art, for example, conventional mixing, dissolving, granulating, emulsifying, pulverizing, encapsulating, embedding or lyophilizing processes.

[0128] The dosage form of the drug of the present invention can be selected according to the specific situation. The dosage form of the drug is often composed of a drug, an excipient, and a container / closure system. The addition of one or more excipients (also called inactive ingredients) to the compound of the present invention can improve or facilitate the manufacture, stability, administration, and safety of the drug, and can also provide a method to obtain a desired drug release curve. Therefore, the type of excipient added to the drug is determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing steps. Pharmaceutical excipients that exist in the art and are described in various pharmacopoeias are included.

[0129] The pharmaceutical compositions of the present invention may contain one or more physiologically acceptable inactive ingredients, which facilitate processing of the active molecule into a formulation for pharmaceutical use.

[0130] The suitable formulation is determined by the desired route of administration. The routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, etc. For oral administration, the compounds may be prepared in liquid or solid dosage forms and may be in immediate release or controlled release / sustained release formulations. Suitable dosage forms for oral administration to an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions.

[0131] Solid oral dosage forms can be obtained using excipients, including fillers, disintegrants, adhesives (dry and wet), dissolution inhibitors, lubricants, glidants, anti-adherents, cation exchange resins, humectants, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water can be used as granulation aids. In some cases, it is necessary to coat the tablets, for example, with a taste-masking film, an anti-gastric acid film, or a sustained release film. Natural and synthetic polymers are often combined with colorants, sugars, and organic solvents or water to coat tablets, resulting in dragees.When capsules are preferred over tablets, the drug powder, suspension, or solution can be delivered in a compatible hard or soft shell capsule form.

[0132] The therapeutically effective amount can be estimated initially using various methods well known in the art. The initial dose used in animal studies can be based on the effective concentration established in cell culture assays. The dose range suitable for humans can be determined, for example, by data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as pharmaceutical agents for oral administration.

[0133] Appropriate formulations, routes of administration, dosages and interval times between doses can be selected in accordance with methods known in the art, taking into account the particularities of an individual's situation.

[0134] Working Example The manufacturing method of the present invention will be described in more detail with reference to the following specific examples. It should be understood that the following examples are merely illustrative and interpretive of the present invention and should not be interpreted as limiting the scope of the claims of the present invention. Any technical solutions realized based on the content of the present invention are included in the scope of the claims of the present invention.

[0135] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods in the art, and the reagents, raw materials, instruments, equipment, etc. used in the following examples are all commercially available.

[0136] Abbreviation or abbreviation DCM Dichloromethane TEA Triethanolamine Et2O Diethyl ether n-Bu4NOH Tetra-n-butylammonium hydroxide DMF N,N-Dimethylformamide EA Ethyl acetate PE Petroleum Ether THF Tetrahydrofuran NMP N-Methylpyrrolidone DIEA N,N-Diisopropylethylamine ACN Acetonitrile MeOH Methanol Bu Butyl TEAB Triethylamine-Carbonate Buffer TBHP tert-butyl hydroperoxide RT retention time TLC Thin Layer Chromatography Manufacturing Example Preparation Example 1 Preparation of Compound 001, Compound 070 and Compound 071

[0137] [ka]

[0138] Preparation of Compound 001-3 To a mixture of compound 001-4 (15 g, 71.527 mmol, 1 eq.) and chlorophosphonyl chloride 4-nitrophenyl ester (18.31 g, 71.527 mmol, 1 eq.) in DCM (300 mL) was added TEA (14.48 g, 143.054 mmol, 2 eq.) in DCM at -78 °C under argon gas atmosphere. The resulting mixture was stirred at -78 °C for 1 h and then allowed to warm to room temperature within 2 h. The reaction mixture was concentrated and the residue was diluted with Et2O (150 mL) and stirred at room temperature for 1 h. The formed solid was removed by filtration and the filtrate was concentrated under reduced pressure to provide compound 001-3 (30 g) in crude product form, which was used directly in the next step. Confirmed by LC-MS.

[0139] Preparation of Compound 001-2 To a mixture of compound 001-3 (10 g, 25.460 mmol, 1 equiv.) in Et2O (60 mL) at 0°C under argon gas atmosphere, n-Bu4NOH aqueous solution (15 mL, 30.552 mmol, 1.2 equiv., 40 wt%) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase flash chromatography eluted with 0-20% MeCN in 10 mM NH4HCO3 aqueous solution to give compound 001-2 (4.7 g, 29.98% yield) as a yellow oil. The properties were confirmed by LC-MS and H / P NMR.

[0140] Preparation of Compound 001-1 A solution of compound 001-2 (1 g, 1.621 mmol, 1 equiv.) in DMF (10 mL) was added with a solution of compound 003-2 (506.73 mg, 1.783 mmol, 1.1 equiv.) in DMF (1 mL) at 0° C. under argon gas atmosphere, and the resulting mixture was stirred at 20° C. for 1 h. The reaction was quenched with hydrochloric acid (1 wt%, 20 mL), extracted with EA (200 mL), and the organic layer was washed with water (30 mL) and brine (saturated, 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 23% EA in PE to give compound 001-1 (500 mg, 58.14% yield) as a white solid. It was confirmed by LC-MS, H / P NMR.

[0141] Preparation of Compound 001, Compound 070 and Compound 071 Under argon gas atmosphere, a solution of compound 001 (2.91 g, 9.990 mmol, 1 equiv.) in NMP (50 mL) was added with tert-butyl magnesium chloride (1 M in THF, 20 mL, 19.980 mmol, 2 equiv.) at 0° C., and the resulting mixture was stirred for 30 min. A solution of compound 001-1 (5.3 g, 9.990 mmol, 1 equiv.) in NMP (10 mL) was added to the mixture, and the resulting mixture was stirred at 20° C. for 2 h. The reaction was quenched with aqueous NH4Cl (saturated, 50 mL), extracted with EA (500 mL), and the organic layer was washed with brine (saturated, 3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give compound 001 (5 g) in the form of a racemic mixture, which was separated by preparative chiral supercritical fluid chromatography under the following conditions: column: CHIRALPAK IG, 5×25 cm, 10 μm, mobile phase A: CO2, mobile phase B: MEOH (0.1% 2 M NH3-MEOH), flow rate: 200 mL / min, gradient: isocratic 40%B, column temperature (°C): 35, back pressure (bar): 100, wavelength: 220 nm, RT1: 7.66 min to give compound 070 (2.61 g) as a white solid, and RT2: 10.22 min to give compound 071 (890 mg) as a white solid. Confirmed by LCMS, H NMR, P NMR.

[0142] Compound 070 1 H NMR: (400 MHz, CD3OD) δ 7.91 (s, 1H), 6.95-6.89 (m, 2H), 5.57-5.53 (m, 2H), 4.88-4.83 (m, 1H), 4.37-4.34 (m, 2H), 4.25-4.20 (m, 2H), 4.09-1.08(m, 1H), 4.07-4.05 (m, 1H), 4.05-3.99 (m, 1H), 2.40-2.38 (m, 1H), 1.61-1.56 (m, 5H), 1.58-1.29 (m, 12H), 0.91-0.85 (m, 12H). Compound 071 1H NMR: (400 MHz, CD3OD) δ 7.88 (s, 1H), 6.94-6.88 (m, 2H), 5.64-5.55 (m, 2H), 4.35-4.21 (m, 2H), 4.07-4.03 (m, 2H), 3.96-3.94 (m, 1H), 3.93-3.92 (m, 2H), 2.42-2.40 (m, 1H), 1.60-1.59 (m, 2H), 1.58-1.57 (m, 3H), 1.36-1.27 (m, 11H), 0.90-0.85 (m, 12H). According to the present invention, other exemplary compounds were synthesized with reference to the methods in Preparation Example 1 above, and are shown in Table 1 below.

[0143] [Table 1] JPEG2025514335000022.jpg215169 JPEG2025514335000023.jpg231169 JPEG2025514335000024.jpg209169 JPEG2025514335000025.jpg232169 JPEG2025514335000026.jpg209169 JPEG2025514335000027.jpg250169 JPEG2025514335000028.jpg231169 JPEG2025514335000029.jpg209169 JPEG2025514335000030.jpg230169 JPEG2025514335000031.jpg159169

[0144] Preparation Example 2 Preparation of Compound 016

[0145] [ka]

[0146] To a stirred solution of compound 001-2 (20 mg, 0.038 mmol, 1.0 equiv.), HATU (21.67 mg, 0.057 mmol, 1.5 equiv.), and compound 2 (13.52 mg, 0.038 mmol, 1.0 equiv.) in DMF (0.5 mL, 25.00 equiv.) was added dropwise under argon gas at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 20 mL / min, gradient: 60%B to 65%B within 4.5 min, detector: UV 254 / 210 nm, RT(min) was 4.35 to give compound 016 (11 mg, 33.50%) as a pale yellow solid. The properties were confirmed by LCMS, H NMR, and P NMR.

[0147] 1 H NMR:(400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.44-8.42 (m, 2H), 7.93-7.89 (m, 4H), 7.58-7.55 (m, 1H), 7.45-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.22-7.18 (m, 1H), 6.91-6.79 (m, 3H), 6.34-6.31 (m, 1H), 6.20-6.14 (m, 1H), 5.40-5.36 (m, 1H), 4.68-4.66 (m, 1H), 4.29-4.26 (m, 2H), 4.18-4.12 (m, 1H), 4.02-3.77 (m, 4H), 3.66-3.46 (m, 2H), 2.53-2.51 (m, 4H), 1.50-1.40 (m, 1H), 1.32-1.22 (m, 7H), 0.98-0.94 (m, 6H), 0.84-0.78 (m, 6H). The racemic mixture of compound 016 (75 mg, 0.087 mmol) was separated by preparative chiral high performance liquid chromatography under the following conditions: column: CHIRAL ART Cellulose-SC, 3×25 cm, 5 μm; mobile phase A: MtBE (0.5% 2 M NH3-MeOH)-HPLC; mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 15%B to 15%B within 13 min; wavelength: 254 / 220 nm; sample solvent: EtOH-HPLC; injection volume: 0.8 mL; run number: 5. RT1 was 5.81 min to provide compound 062 (39.5 mg, 50.33%) as a pale yellow solid; RT2 was 10.64 min to provide compound 063 (25.8 mg, 31.89%) as a pale yellow solid. 1 Confirmed by 1 H NMR.

[0148] According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 2 above, and are shown in Table 2 below.

[0149] [Table 2] JPEG2025514335000034.jpg126169

[0150] Preparation Example 3 Preparation of Compound 003

[0151] [ka]

[0152] Preparation of Compound 003-4 To a stirred solution of NaHCO3 (1165.03 mg, 13.867 mmol, 2.5 equiv.) and Bu4NHSO4 (376.70 mg, 1.109 mmol, 0.2 equiv.) in DCM (0.80 mL) and water (4.00 mL) under argon gas atmosphere at room temperature, a solution of valproic acid (800 mg, 5.547 mmol, 1.00 equiv.) in DCM (1.20 mL) was added. Then, a solution of chloromethyl chlorosulfate (1098.23 mg, 6.656 mmol, 1.2 equiv.) in DCM (6.00 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for another 15 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (2 × 50 mL), dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA in PE (0%-50%) to give compound 003-4 (663 mg, 3.45 mmol, 62.03%) as a colorless oil, confirmed by H NMR.

[0153] Preparation of Compound 003-3 A mixture of compound 003-4 (420 mg, 2.180 mmol, 1.00 equiv), NaI (1.31 g, 8.720 mmol, 4 equiv) and TBAI (1 mg) in ACN (5 mL) was stirred for 15 h at 40 °C under argon gas atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (50 mL) and washed with saturated NaHCO3 (50 mL), saturated aqueous Na2S2O3 (50 mL) and saturated aqueous NaCl (2 × 50 mL), and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to provide compound 003-3 (470 mg, 75.89%) as a pale yellow oil. The solubility was confirmed by H NMR.

[0154] Preparation of Compound 003-2 To a mixture of compound 1 (300 mg, 0.716 mmol, 1.00 equiv) in trimethyl phosphate (5 mL) at 0 °C was added POCl3 (219.47 mg, 1.432 mmol, 2 equiv). The resulting mixture was stirred at 0 °C for 4 h. The reaction was quenched by buffering with TEAB to pH = 7, and the resulting mixture was stirred for an additional 30 min. The resulting mixture was diluted with CHCl3 (10 mL) and water (10 mL). The aqueous phase was extracted with CHCl3 (2 × 10 mL) and then concentrated under reduced pressure. The residue was purified by preparative HPLC using an XBridge Shield RP18 OBD column, 30×150 mm, 5 μm, mobile phase A was 10 mM NH4HCO3 aqueous solution, mobile phase B was ACN, flow rate was 35 mL / min, gradient was 0% to 20% B within 11 min, detector was 254 / 210 nm, RT was 10.2 min to give compound GID17-003-2 (200 mg, 0.539 mmol, 52.2%) as an off-white solid. The product was confirmed by LC-MS, H NMR and P NMR.

[0155] Preparation of Compound 003-1 A mixture of compound 003-2 (100 mg, 0.269 mmol, 1.00 equiv) and Ag2CO3 (148.49 mg, 0.538 mmol, 2 equiv) in ACN (1 mL) and water (1 mL) was stirred for 2 h at 25 °C. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 003-1 (100 mg, 0.171 mmol, 63.46%) as a light brown solid.

[0156] Preparation of Compound 003 To a mixture of compound 003-1 (100 mg, 0.17 mmol, 1.00 equiv) in NMP (1.5 mL) at 0° C., a solution of compound PH-GHDI-003-2 (485.15 mg, 1.7 mmol, 10 equiv) in NMP (0.5 mL) was added. The resulting mixture was stirred at 25° C. for 2 h. The mixture was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm, mobile phase A: 10 mM NH4HCO3 aqueous solution, mobile phase B: ACN, flow rate: 20 mL / min, gradient: 59% B to 59% B within 11 min, detector: 254 / 210 nm, RT1: 8.5 min, to give compound 003 (10 mg, 0.014 mmol, 8.61% yield) as an off-white solid. The product was confirmed by LC-MS, H NMR and P NMR.

[0157] 1 H NMR: (300 MHz, CD3OD) δ 7.89 (s, 1H), 6.94-6.88 (m, 2H), 5.64-5.59 (m, 4H), 4.88-4.83 (m, 1H), 4.43-4.34 (m, 3H), 4.19-4.15 (m, 1H), 2.43-2.40 (m, 2H), 1.64-1.54 (m, 4H), 1.48-1.38 (m, 4H), 1.34-1.24 (m, 8H), 0.91-0.84 (m, 12H). Preparation of Compound 251

[0158] [ka]

[0159] To a solution of compound 003 (148 mg, 0.216 mmol, 1 equiv) in DMF (2.5 mL) was added isobutyric acid (57.07 mg, 0.648 mmol, 3 equiv) and DIC (81.75 mg, 0.648 mmol, 3 equiv) at 0° C. under Ar gas, the resulting mixture was stirred at room temperature for 15 min, and DMAP (13.19 mg, 0.108 mmol, 0.5 equiv) was added to the above mixture. After the mixture was stirred at room temperature for 15 h, the main desired compound was detected by LCMS. The mixture was purified by reversed-phase flash chromatography under the conditions of column C18 silica gel, mobile phase MeCN aqueous solution, gradient 0% to 70% in 25 min, detector 254 nm / 210 nm to give compound 251.

[0160] Compound 212 (deuterium compound) was synthesized with reference to compounds 208 and 209.

[0161] According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 3 above, and are shown in Table 3 below.

[0162] [Table 3] JPEG2025514335000038.jpg213169 JPEG2025514335000039.jpg148169

[0163] Preparation Example 4 Preparation of Compound 057

[0164] [ka]

[0165] Preparation of compound 057-2 To a mixture of compound 1 (1 g, 3.433 mmol, 1.00 equiv.) in NMP (40 mL) was added 1H-imidazole-4,5-dicarbonitrile (810.93 mg, 6.866 mmol, 2 equiv.) and a solution of 3-{[bis(diisopropylamino)phosphino]oxy}propionitrile (1552.26 mg, 5.149 mmol, 1.5 equiv.) in ACN (5 mL) at room temperature under argon gas atmosphere. The mixture was stirred at room temperature for 1 h. Then, TBHP (3094.10 mg, 34.330 mmol, 10 equiv.) was added to the above mixture. The mixture was stirred at the same temperature for 30 min. The product was detected as 55% by LCMS. The solvent was removed under reduced pressure and the residue was purified by reverse-phase flash chromatography eluting with 0-50% MeCN in 5 mM aqueous NH4HCO3 to yield compound 057-2 (560 mg, 40.15% yield) as a white solid.

[0166] Preparation of Compound 094 To a stirred mixture of compound 057-2 (560 mg, 1.378 mmol, 1 equiv, 70%) in ACN (8 mL) was added NH3.H2O (8 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The main desired product was detected by LCMS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC with XBridge Prep C18 OBD column, 19×150 mm, 5 μm, mobile phase A was 10 mM NH4HCO3 in water, mobile phase B was ACN, flow rate was 20 mL / min, gradient was 10% B to 30% B within 7.5 min, detector was UV 254 / 210 nm, RT was 7.2 min. The product-containing fractions were concentrated under reduced pressure to yield compound 094 (320 mg, 0.91 mmol, 65.73% yield) as a white solid. Confirmed by LCMS 1 H NMR, 3 P NMR.

[0167] Preparation of Compound 057 Compound 003-4 (44.73 mg, 0.232 mmol, 2.05 equiv.) was added to a stirred mixture of compound 094 (40 mg, 0.113 mmol, 1 equiv.) and Cs2CO3 (75.64 mg, 0.232 mmol, 2.05 equiv.) in DMF (0.4 mL) at room temperature under argon gas. The mixture was stirred at 50 °C for 15 h. The desired mass was 38% detected by LCMS. The mixture was purified by preparative HPLC under the following conditions: column was XBridge Prep C18 OBD column, 19 × 150 mm, 5 μm, mobile phase A was 10 mM aq. NH4HCO3, mobile phase B was ACN, flow rate was 20 mL / min, gradient was 30% B to 50% B within 6.5 min, detector was UV 254 / 210 nm, RT was 5.8 min. The fractions containing the product were directly lyophilized to yield compound 057 (8 mg, 0.017 mmol, 14.74% yield) as a white solid, as confirmed by LCMS, H NMR, and P NMR.

[0168] Compound 094 1 H NMR: (400 MHz, CD3OD) δ 7.801 (s, 1H), 6.804-6.792 (d, J phosphoryl 4.8 Hz, 1H), 6.707-6.696 (d, J phosphoryl 4.4 Hz, 1H), 4.688-4.679 (m, 1H), 4.390-4.285 (m, 3H), 4.199-4.130 (m, 1H). Compound 057 1 H NMR: (300 MHz, CD3OD) δ 7.84 (s, 1H), 6.91-6.85 (m, 2H), 5.96 (d, J = 6.0 Hz, 1H), 4.71-4.67 (m, 1H), 4.50-4.27 (m, 3H), 2.59-2.55 (m, 1H), 1.78-1.72 (m, 2H), 1.58-1.37 (m, 6H), 0.97-0.91 (m, 6H).

[0169] [Table 4] JPEG2025514335000042.jpg125169

[0170] Preparation Example 5 Preparation of Compounds 077 and 145

[0171] [ka]

[0172] Preparation of compound 077-2 To a stirred solution of chloromethyl isopropyl carbonate (5 g, 32.772 mmol, 1 equiv.) in ACN (70 mL) at room temperature under argon gas atmosphere, NaI (19.7 g, 131.426 mmol, 4.01 equiv.) and TBAI (5 mg) were added. The resulting mixture was stirred at 40 °C for 16 h and then cooled to room temperature. The resulting mixture was diluted with DCM (200 mL), washed with saturated aqueous NaHCO3 (50 mL), saturated aqueous Na2S2O3 (50 mL) and saturated aqueous NaCl (2 × 50 mL), and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to provide compound 077-2 (7.3 g, 0.030 mol, 91.28%) as a pale yellow oil. The solubility was confirmed by H NMR.

[0173] Preparation of Compound 077-1 To a stirred solution of compound 094 (1 g, 2.831 mmol, 1 equiv.) in ACN (10 mL) and H2O (10 mL) at room temperature was added Ag2CO3 (858.70 mg, 3.114 mmol, 1.1 equiv.). The resulting mixture was stirred at room temperature for 2 h and then filtered. The filtrate was directly lyophilized to yield compound 077-1 (1.3 g, 2.830 mmol, 99.81%) as a pale yellow solid.

[0174] Preparation of Compound 077 and Compound 145 To a stirred solution of compound 077-1 (90 mg, 0.196 mmol, 1 equiv.) in NMP (1.5 mL) at 0° C. under an argon atmosphere, a solution of compound 077-2 (143.21 mg, 0.588 mmol, 3 equiv.) in NMP (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The desired mass was determined to be 40% by LCMS. The mixture was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: 10 mM NH4HCO3 aqueous solution; mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35%B to 35%B within 5.8 min; detector: 254 / 210 nm; RT1: 4.8 min, yielding compound 077 (4.3 mg, 0.009 mmol, 4.68%) as a white solid; and RT2: 5.5 min, yielding compound 145 (6.6 mg, 0.014 mmol, 7.18%) as a white solid. Characterization was performed by LC-MS, H NMR, and P NMR.

[0175] Compound 077 1 H NMR: (300 MHz, CD3OD) δ 7.90 (s, 1H), 6.91-6.87 (m, 2H), 5.76-5.65 (m, 2H), 4.83-4.52 (m, 6H), 1.34-1.32 (m, 6H). compound 145 1 H NMR: (300 MHz, CD3OD) δ 7.91 (s, 1H), 6.91-6.85 (m, 2H), 5.69-5.64 (m, 2H), 4.72-4.43 (m, 6H), 1.26-1.20 (m, 3H), 1.16-1.14 (m, 3H). Preparation of compound 245

[0176] [ka]

[0177] To a solution of compound 129 (110 mg, 0.216 mmol, 1 equiv.) in DMF (2.5 mL) was added isobutyric acid (57.07 mg, 0.648 mmol, 3 equiv.) and DIC (81.75 mg, 0.648 mmol, 3 equiv.) at 0° C. under Ar gas, the resulting mixture was stirred at room temperature for 15 min, and DMAP (13.19 mg, 0.108 mmol, 0.5 equiv.) was added to the above mixture. After the mixture was stirred at room temperature for 15 h, the main desired compound was detected by LCMS. The mixture was purified by reversed-phase flash chromatography under the conditions of column C18 silica gel, mobile phase MeCN aqueous solution, gradient 0% to 70% in 25 min, detector 254 nm / 210 nm to give compound 245.

[0178] Compounds 210 and 211 were synthesized with reference to the synthesis methods of compounds 208 and 209.

[0179] According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 5 above, and are shown in Table 5 below.

[0180] [Table 5] JPEG2025514335000046.jpg234169 JPEG2025514335000047.jpg225169 JPEG2025514335000048.jpg215169 JPEG2025514335000049.jpg87169

[0181] Preparation Example 6 Preparation of Compounds 126 and 140

[0182] [ka]

[0183] Preparation of compound 126-2 To a stirred mixture of L-alanine (10 g, 112.241 mmol, 1 equiv.) in 2-ethylbutanol (100 mL) at 0 °C under argon gas, SOCl2 (26.70 g, 224.482 mmol, 2 equiv.) was added. The mixture was stirred at 90 °C for 15 h. TLC checked for the main desired product. The solvent was removed under reduced pressure, and the residue was coevaporated with toluene (4 × 100 mL) and triturated with Et2O (100 mL) to yield compound 126-2 (11.5 g, 55.0 mmol, 48.86% yield) as a white solid.

[0184] Preparation of Compound 126-1 To a stirred mixture of chlorophosphonyl chloride 4-nitrophenyl ester (610.30 mg, 2.384 mmol, 1 equiv.) and compound 126-2 (500 mg, 2.384 mmol, 1 equiv.) in DCM (10 mL) was added TEA (241.26 mg, 2.384 mmol, 1 equiv.) under argon gas at 0° C. The mixture was stirred at 20° C. for 2 h. Then, to the mixture was added pentafluorophenol (438.86 mg, 2.384 mmol, 1 equiv.) and TEA (241.26 mg, 2.384 mmol, 1 equiv.) at 0° C. The mixture was stirred at 20° C. for 2 h. The desired mass was 70% by LCMS. Et2O (15 mL) was added to the reaction mixture, filtered, and the filtrate was concentrated under reduced pressure to give compound 126-1 (834.87 mg) in crude form, which was used directly in the next step without purification.

[0185] Preparation of Compound 126 and Compound 140 To a stirred mixture of (2R,3R,4S,5R)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (300 mg, 1.030 mmol, 1.00 equiv.) in NMP (9 mL) was added tert-butylmagnesium chloride (1.29 mL, 2.575 mmol, 2.5 equiv.) under argon gas at -10°C. The mixture was stirred at -10°C for 30 min. Then, a solution of compound 126-1 (834.87 mg, 1.545 mmol, 1.5 equiv.) in NMP (9 mL) was added to the above mixture. The resulting mixture was stirred at 0°C for 15 h. The desired product was detected at 14% by LCMS. The reaction was quenched with saturated NH4Cl and diluted with EA (100 mL), the organic layer was washed with water (2×50 mL), NaCl (2×50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (0-8%) in DCM to yield the crude product. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 19×150 mm, 5 μm, mobile phase A was 10 mM NH4HCO3 aqueous solution, mobile phase B was ACN, flow rate was 20 mL / min, gradient was 30%B to 50%B within 5.5 min, detector was 254 / 210 nm, RT1 was 4.8 min, yielding compound 140 (14.1 mg, 0.028 mmol, 2.81% yield) as a white solid, and RT2 was 5.2 min, yielding compound 126 (4.1 mg, 0.008 mmol, 0.76% yield) as a white solid. Confirmed by LCMS, H NMR, and P NMR.

[0186] Compound 126 1H NMR: (400 MHz, CD3OD) δ 7.82 (s, 1H), 6.90-6.84 (m, 2H), 4.89-4.88 (m, 1H), 4.71-4.69 (m, 2H), 4.69-4.59 (m, 2H), 4.12-4.04 (m, 2H), 3.99-3.95 (m, 1H), 1.56-1.51 (m, 1H), 1.44-1.41 (m, 6H), 1.39-1.37 (m, 1H), 0.94-0.87 (m, 6H). Compound 140 1H NMR: (400 MHz, CD3OD) δ 7.82 (s, 1H), 6.91-6.84 (m, 2H), 4.89-4.88 (m, 1H), 4.72-4.68 (m, 2H), 4.66-4.60 (m, 1H), 4.58-4.55 (m, 1H), 4.07-4.05 (m, 2H), 3.89-3.85 (m, 1H), 1.52-1.51 (m, 1H), 1.38-1.28 (m, 7H), 0.93-0.82 (m, 6H). Production Example 7 Production of Compounds 143 and 144

[0187]

change

[0188] Manufacturing of compound 143-2 A solution of 1H-imidazole-4,5-dicarbonitrile (0.81 g, 6.866 mmol, 2 eq.) and compound 2 (1.45 g, 4.806 mmol, 1.4 eq.) in ACN (5 mL) was added to a mixture of compound 1 (1 g, 3.433 mmol, 1.00 eq.) in NMP (35 mL) at room temperature under argon gas atmosphere. The mixture was stirred at room temperature for 1 h. Then, (E)-N,N-dimethyl-N'-(5-thio-1,2,4-thiadiazol-3-yl)carboxamidine (3.52 g, 17.165 mmol, 5 eq.) was added to the above mixture. The mixture was stirred at the same temperature for 30 min. The product was detected as 55% by LCMS. The solvent was removed under reduced pressure and the residue was purified by reverse-phase flash chromatography eluting with 0-50% MeCN in water to yield compound 2, compound 143-2 (650 mg, 30.48% yield) as a white solid.

[0189] Preparation of Compound 143-1 To a stirred mixture of compound 143-2 (600 mg, 1.421 mmol, 1 equiv.) in ACN (6 mL) was added NH3.H2O (6.00 mL) under argon gas at 0 °C. The mixture was stirred at room temperature for 1 h. The main desired product was detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography eluting with 0-50% MeCN in 5 mM aqueous NH4HCO3 to afford compound 143-1 (300 mg, 0.813 mmol, 57.31% yield) as a white solid. The product was confirmed by LC-MS, H NMR and P NMR.

[0190] Preparation of Compound 143 and Compound 144 A solution of compound 143-1 (80 mg, 0.217 mmol, 1 eq.) and molecular sieves (12 mg) in NMP (1.4 mL) was stirred at room temperature under argon gas for 5 min. DIEA (84.00 mg, 0.651 mmol, 3 eq.) in NMP (0.3 mL) and compound 003-3 (184.66 mg, 0.651 mmol, 3 eq.) in NMP (0.3 mL) were added dropwise to the above mixture at 0° C. for 5 min. The resulting mixture was stirred at room temperature for 2 h. The desired product was detected at 42.9% by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Shield RP18 OBD column, 19×150 mm, 5 μm, mobile phase A: water (10 mM ammonium acetate), mobile phase B: ACN, flow rate: 20 mL / min, gradient: 40% B to 60% B within 6.5 min, wavelength: 254 / 210 nm, RT1: 5.2 min to give compound 143 (5 mg, 0.010 mmol, 4.39% yield) as a white solid, and RT2: 6.5 min to give compound 144 (8 mg, 0.015 mmol, 7.04% yield) as a white solid. Characterization was performed by SFC-MS, H NMR, and P NMR.

[0191] compound 143 1 H NMR:(300 MHz, CD3OD) δ 7.88 (s, 1H), 6.92-6.86 (m, 2H), 5.57-5.41 (m, 2H), 4.76-4.56 (m, 5H), 2.32-2.26 (m, 1H), 1.54-1.15 (m, 8H), 0.90-0.73 (m, 6H). compound 144 1H NMR:(400 MHz, CD3OD) δ 7.88 (s, 1H), 6.91-6.87 (m, 2H), 5.56-5.49 (m, 2H), 4.96-4.80 (m, 3H), 4.69-4.64 (m, 2H), 2.48-2.46 (m, 1H), 1.64-1.61 (m, 2H), 1.50-1.43 (m, 2H), 1.37-1.31 (m, 4H), 0.94-0.91 (m, 6H). According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 7 above, and are shown in Table 6 below.

[0192] [Table 6]

[0193] Preparation Example 8 Preparation of Compounds 156 and 157

[0194] [ka]

[0195] Preparation of compound 156-3 To a stirred solution of 4-(chlorosulfonyl)benzoic acid (10 g, 45.454 mmol, 1 equiv.) in DCM (150 mL) at 0° C. under argon gas atmosphere, a solution of dipropylamine (13.77 g, 136.4 mmol, 3 equiv.) in DCM (30 mL) was added dropwise, and the resulting mixture was stirred at 25° C. for 18 h. LCMS confirmed the desired product at 95%. The resulting mixture was washed with hydrochloric acid (1 M, 100 mL) and water (2×100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield compound 156-3 (11 g, 38.6 mmol, 84.9%) as a white solid, which was used directly in the next step without purification. LCMS, H NMR confirmed.

[0196] Preparation of compound 156-2 To a stirred mixture of compound 156-3 (2.5 g, 8.761 mmol, 1 equiv), BuNHSO (0.15 g, 0.438 mmol, 0.05 equiv), and NaHCO (2.32 g, 21.902 mmol, 2.5 equiv) in DCM (38 mL) and H0 (38 mL) was added a solution of chloromethyl chlorosulfate (1.73 g, 10.513 mmol, 1.2 equiv) in DCM (38 mL) at 0 °C under argon gas atmosphere, and the mixture was stirred at room temperature for 18 h. The main desired product was detected by LCMS. The reaction mixture was diluted with DCM (100 mL), washed with saturated NaHCO (2 × 50 mL), brine (saturated, 50 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with (0-18%) EA in PE to give compound 156-2 (2.3 g, 6.91 mmol, 78.64%) as a white solid, confirmed by LCMS, H NMR.

[0197] Preparation of Compound 156-1 To a stirred mixture of compound 156-2 (1.8 g, 5.392 mmol, 1 equiv.) in ACN (8 mL) at room temperature under argon gas atmosphere, NaI (2.42 g, 16.176 mmol, 3 equiv.) was added, and the resulting mixture was stirred at 60 °C for 3 h. The main desired product was detected by LCMS. The reaction mixture was diluted with DCM (100 mL), washed with aqueous Na2S2O3 (saturated, 2 × 50 mL), dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to yield compound 156-1 (2.2 g, 5.17 mmol, 95.94%) as a white solid. Confirmed by LCMS, H NMR.

[0198] Preparation of Compound 156 and Compound 157 To a stirred mixture of compound 003-1 (300 mg, 0.652 mmol, 1 equiv.) in NMP (6 mL) at 0° C. under argon gas atmosphere, a solution of compound 156-1 (831.90 mg, 1.956 mmol, 3 equiv.) in NMP (6 mL) was added, and the resulting mixture was stirred at room temperature for 3 h. LCMS showed 43% of the desired product. The mixture was purified by reversed-phase flash chromatography, eluting with 0-80% ACN in 5 mM aqueous NH4HCO3 to yield the racemic mixture (220 mg, 0.338 mmol, 46.67%) as a white solid. The racemic mixture was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: 10 mM NH4HCO3 aqueous solution; mobile phase B: ACN; flow rate: 20 mL / min; gradient: 45%B to 60%B within 6 min; detector: UV 254 / 210 nm; RT1: 5.55 min to produce compound 156 (50 mg, 22.73%) as a white solid; and RT2: 6.17 min to produce compound 157 (41 mg, 18.64%) as a white solid. Characterization was performed by LCMS, H NMR, and P NMR.

[0199] compound 156 1 H NMR: (300 MHz, CD3OD) δ 8.25-8.09 (m, 2H), 7.97-7.88 (m, 2H), 3.16-3.02 (m, 4H), 1.61-1.48 (m, 4H), 0.90-0.84 (m, 6H). Compound 157 1H NMR: (300 MHz, CD3OD) δ 8.32-8.28 (m, 2H), 7.98-7.95 (m, 2H), 7.88 (s, 1H), 6.90-6.86 (m, 2H), 6.03-6.02 (m, 1H), 5.98-5.95 (m, 1H), 4.92-4.89 (m, 2H), 4.85-4.73 (m, 2H), 4.58-4.52 (m, 1H), 3.15-3.10 (m, 4H), 1.62-1.49 (m, 4H), 0.90-0.85 (m, 6H). Preparation Example 9 Preparation of Compounds 208 and 209

[0200] [ka]

[0201] Synthesis of compound 208-3 Compound 208-4 (2 g, 1 eq) was dissolved in DMF (20 mL), and iodine (2 eq) was added in portions and reacted at room temperature overnight. TLC / LCMS showed that 80% product was obtained and a small amount of starting material remained. The reaction solution was added to a mixture of sodium sulfite and sodium carbonate, extracted with EA, and the organic phase was separated. The organic phase was washed with water and saturated saline in turn, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to produce pure product 208-3 (1.7 g) as a white solid, and 600 mg of crude product with a purity of 70%, with a yield of 81%.

[0202] Synthesis of compound 208-2 Compound 208-3 (200mg, 1eq) was added to a mixture of dried THF (15mL) and deuterium oxide (3mL), the solution was concentrated, and then dissolved in the same volume of THF and deuterium oxide. Pd(dppf)Cl2-DCM (0.1eq) and TMEDA (0.2eq) were added in sequence, and the mixture was stirred for 10min after addition was complete. NaBD4 (5eq) was then added in several portions, and the mixture was allowed to react at room temperature for 2h. TLC showed that the raw materials had completely reacted. The reaction solution was added to water, extracted with EA, and the organic phase was separated. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain the product compound 208-2 (130mg), with a yield of 80%.

[0203] Synthesis of compound 208-1 Compound 208-2 (130 mg) was dissolved in DCM (15 mL) and added dropwise with BCl3 (1 M in DCM, 3.5 eq) at -60°C. After addition was complete, the mixture was stirred at -40°C for 3 hours. TLC showed complete reaction, and LCMS showed that the main target product signal was observed. Methanol (0.15 mL) was added to the reaction solution, and TEA was added to adjust the pH of the reaction solution to 7-8. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 208-1.

[0204] Synthesis of compounds 208 and 209 The crude product was obtained by replacing compound 1 with compound 208-1 in a similar manner to preparation example 4. The crude product was purified by preparative high performance liquid chromatography under the following conditions: column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: 10 mM HCOONH4 aqueous solution; mobile phase B: CAN; flow rate: 20 mL / min; gradient: 25%B to 40%B within 5.5 min; detector: UV 254 / 210 nm; RT1: 5.2 min, yield: white solid compound 209 (1.0 mg, 0.002 mmol, yield 0.92%); and RT2: 5.3 min, yield: white solid compound 208 (2.9 mg, 0.006 mmol, yield 2.67%). 1Confirmed by 1 H NMR.

[0205] compound 208 1 H NMR: (300 MHz, DO) δ 7.82 (d, J = 3.3 Hz, 1H), 6.86-6.82 (m, 1H), 5.89 (d, J = 4.2 Hz, 1H), 4.41-4.35 (m, 3H), 4.20-4.14 (m, 1H), 2.70-2.60 (m, 1H), 1.95-1.75 (m, 2H), 1.62-1.50 (m, 2H), 1.47-1.42 (m, 4H), 0.84-0.79 (m, 6H). compound 209 1 H NMR: (300 MHz, DO) δ 7.92 (s, 1H), 6.94 (d, J = 3.0 Hz, 1H), 5.84-5.80 (m, 1H), 5.58-5.53 (m, 1H), 4.45-4.27 (m, 3H), 2.06-1.96 (m, 1H), 0.96-0.84 (m, 6H), 0.63-0.53 (m, 8H). Preparation Example 10 Preparation of Compounds 236 and 237

[0206] [ka]

[0207] Synthesis of S-(2-((diisopropylamino)phosphono)oxy)ethyl) 2,2-dimethylthiopropionate (compound 236-1) To a stirred solution of 1-chloro-N,N,N',N'-tetraisopropylphosphinediamine (1.5 g, 5.622 mmol, 1.00 equiv) in ethyl ether (5.5 mL) at -40 °C under Ar gas was added a mixture of S-(2-hydroxyethyl) 2,2-dimethylpropanethioic acid (0.91 g, 5.622 mmol, 1 equiv) and TEA (0.63 g, 6.184 mmol, 1.1 equiv) in Et2O (0.5 mL), and the resulting mixture was stirred at room temperature for 3 h and showed 80% product by P NMR. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step.

[0208] Synthesis of S-(2-((((2R,4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-7-hydroxy-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphoryl-2-oxy)ethyl)2,2-dimethylpropane sodium hydrogen sulfate (compounds 236 / 237) Compound 1 (300 mg, 1.030 mmol, 1 eq.) was added with NMP (1.5 mL), DCI (304.10 mg, 2.575 mmol, 2.5 eq.), and a solution of compound 236-1 (525.66 mg, 1.339 mmol, 1.3 eq.) in NMP (1.5 mL) was added dropwise at 0° C. under Ar atmosphere, and the mixture was stirred at room temperature for 2 hours. Then, TBHP (0.94 mL, 5.150 mmol, 5 eq.) was added to the above mixture at 0° C. The mixture was stirred at room temperature for 30 minutes. The desired mass was detected by LCMS at 20%. The mixture was purified by reversed-phase flash chromatography under the following conditions, the column was C18 silica gel, the mobile phase was MeCN aqueous solution, the gradient was 0% to 35% in 20 minutes, and the detector was UV 254 / 210 nm, and the crude product was obtained. The crude product was purified by preparative HPLC using the following conditions. The column was an XBridge Prep C18 OBD column, 19 × 150 mm, 5 μm, mobile phase A was 10 mM CH3COONH4, mobile phase B was ACN, the flow rate was 25 mL / min, the gradient was 30% B to 50% B in 6 min, the detector was 254 / 210 nm, RT1 was 5.3 min to give compound 236 (69.3 mg, 0.139 mmol, 13.53%) as a white solid, and RT2 was 6.2 min to give compound 237 (14.3 mg, 0.029 mmol, 2.79%) as a white solid.

[0209] 236 1 H-NMR: (300 MHz, CD3CN) δ 7.90 (d, J = 3.0 Hz, 1H), 6.84 - 6.78 (m, 2H), 6.37 (s, 2H), 4.89 - 4.71 (m, 2H), 4.66 - 4.63 (m, 1H), 4.50 - 4.41 (m, 2H), 4.38 - 4.32 (m, 1H), 4.13 - 4.05 (m, 2H), 3.14 - 3.10 (m, 2H), 1.11 (d, J = 3.0 Hz, 9H). 237 1 H-NMR: (300 MHz, CD3CN) δ 7.94 (d, J = 3.0 Hz, 1H), 6.83 - 6.77 (m, 2H), 6.36 (s, 2H), 4.89 - 4.84 (m, 2H), 4.75 - 4.63 (m, 3H), 4.47 - 4.38 (m, 1H), 4.18 - 4.11 (m, 2H), 3.19 - 3.15 (m, 2H), 1.23 - 1.19 (m, 9H). Preparation of Compounds 278 / 279

[0210] [ka]

[0211] To a solution of compound 236 / 237 (107 mg, 0.216 mmol, 1 equiv.) in DMF (2.5 mL) was added isobutyric acid (57.07 mg, 0.648 mmol, 3 equiv.) and DIC (81.75 mg, 0.648 mmol, 3 equiv.) at 0° C. under Ar gas, the resulting mixture was stirred at room temperature for 15 min, and DMAP (13.19 mg, 0.108 mmol, 0.5 equiv.) was added to the above mixture. After the mixture was stirred at room temperature for 15 h, the main desired compound was detected by LCMS. The mixture was purified by reversed-phase flash chromatography under the conditions of column: C18 silica gel, mobile phase: aqueous MeCN, gradient: 0% to 70% in 25 min, detector: 254 nm / 210 nm to give compound 278 / 279.

[0212] According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 10 above, and are shown in Table 7 below.

[0213] [Table 7] JPEG2025514335000058.jpg215169 JPEG2025514335000059.jpg52169

[0214] Preparation Example 11 Synthesis of Compounds 214 / 215

[0215] [ka]

[0216] Synthesis of 4-nitrophenylphosphonium chloride (compound 214-6) To a stirred mixture of compound 214-7 (2 g, 9.480 mmol, 1 eq.) and compound 2 (1.32 g, 9.480 mmol, 1 eq.) in DCM (20 mL) at -78 °C, TEA (1.92 g, 18.960 mmol, 2 eq.) was added dropwise, and the resulting mixture was stirred at -78 °C for 1 h and at room temperature for another 2 h, monitored by LCMS as 56% of the desired product. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in Et2O (100 mL) and stirred for 30 min. The resulting mixture was filtered, and the filter cake was washed with Et2O (50 mL). The filtrate was concentrated under reduced pressure to give compound 214-6 (2.8 g, crude product). The crude product was used directly in the next step without further purification.

[0217] Synthesis of 4-nitrophenyl phosphate tetra tert-butylammonium salt (compound 214-5) To a stirred mixture of compound 214-6 (2.8 g, 8.928 mmol, 1 equiv) in ethyl ether (28 mL) was added a solution of n-Bu4NOH (2.32 g, 8.928 mmol, 1 equiv) in ethyl ether (28 mL). At 0° C., water (28 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 h and monitored by LCMS, which was 56% of the desired product. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography under the conditions of column C18 silica gel, mobile phase ACN in water (10 mM NH4HCO3), gradient 0% to 50% in 30 min, detector UV 254 nm to give compound 215-5 (3.5 g, 73.05%) as a yellow oil. Confirmed by LC-MS.

[0218] Synthesis of methyl ((4-nitrophenoxy)(phenoxy)phosphoryl)oxy)pivalate (compound 214-3) To a stirred solution of compound 214-5 (1 g, 1.863 mmol, 1 equiv) in DMF (10 mL) at 0° C., compound 3 (0.68 g, 2.795 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature for 2 h and monitored by LCMS, which showed 73% of the desired product. The reaction mixture was quenched with a solution of hydrochloric acid (0.01%, 100 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The organic layer was washed with brine (2×20 mL) and dried over anhydrous Na2SO4. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (0-30%) to give compound 214-3 (436 mg, 57.16%) as a colorless oil. Confirmed by LCMS.

[0219] Synthesis of (((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxy-4-yl)methoxy)(phenoxy)phosphoryl)oxy)methyl pivalate (compound 214-2) To a stirred solution of compound 214-4 (100 mg, 0.302 mmol, 1.00 equiv) in NMP (2 mL) at 0° C. under argon gas, tert-butyl magnesium chloride (0.60 mL, 0.604 mmol, 2 equiv) was added dropwise, and the resulting mixture was stirred at 0° C. for 30 min under Ar gas. To the above mixture was added a solution of compound 214-3 (185.31 mg, 0.453 mmol, 1.5 equiv) in NMP (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for another 2 h and monitored by LCMS, showing 20% ​​of the desired product. The resulting mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The organic layer was washed with water (3×50 mL) and brine (2×25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0220] Synthesis of (((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)oxy)methyl pivalate (compound 214-1) A solution of compound 214-2 (200 mg, 0.332 mmol, 1 equiv) in HCOOH (2 mL, 46.653 mmol, 140.32 equiv, 88%) was stirred at room temperature with argon gas for 6 h and monitored by LCMS, which showed 34% of the desired product. The resulting mixture was azeotroped with toluene (3×3 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (0-10%) to give compound 214-1 (50 mg, 26.78%) as a pale yellow solid. Confirmed by LC-MS.

[0221] Preparation of ((S)-(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)oxy)methyl pivalate (Compound 214) Compound 214-1 (55 mg, 0.098 mmol, 1 equiv.) was purified by preparative HPLC under the following conditions (column is Lux 3 μ cellulose-4, 4.6 × 50 mm, 3 μm, mobile phase A is Hex (0.1% DEA):EtOH = 70:30, flow rate is 1 mL / min, gradient is 0% B to 0% B, injection volume is 5 μL mL, RT is 3.836) to give compound 214 (11.9 mg) as a white solid, RT is 5.589, and compound 215 (14.1 mg, 25.64%) as a white solid. 1 Confirmed by 1 H NMR.

[0222] 214 1 H-NMR 1 H NMR: (300 MHz, CD3OD) δ 7.88 - 7.81 (m, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.24 - 7.11 (m, 3H), 6.91 - 6.82 (m, 2H), 5.67 (ddd, J = 13.2, 7.3, 5.0 Hz, 2H), 4.56 - 4.36 (m, 3H), 4.18 (t, J = 5.4 Hz, 1H), 3.31 (s, 4H), 1.17 - 1.11 (m, 8H). 215 1 H-NMR 1 H NMR: (300 MHz, CD3OD) δ 7.84 (s, 1H), 7.30 (s, 5H), 7.15 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.90 - 6.84 (m, 2H), 5.71 - 5.63 (m, 2H), 5.12 - 5.04 (m, 3H), 4.49 - 4.31 (m, 4H), 4.20 - 4.16 (m, 1H), 3.08 - 3.04 (m, 1H), 2.94 - 2.91 (m, 1H), 2.39 - 2.37 (m, 1H), 1.79 - 1.21 (m, 17H), 0.84 (t, J = 7.2 Hz, 6H). According to the present invention, further exemplary compounds were synthesized with reference to the methods in Preparation Example 11 above, and are shown in Table 8 below.

[0223] [Table 8] JPEG2025514335000062.jpg214169 JPEG2025514335000063.jpg231169

[0224] Preparation Example 12 Preparation of Compound 155

[0225] [ka]

[0226] Under Ar gas atmosphere, a mixture of compound 003-1 (100 mg, 0.17 mmol, 1 equiv.) and molecular sieves (4A) (40 mg) in NMP (2 mL) was stirred at 25° C. for 5 min. To the above mixture was added a solution of PH-GHDI-003-2 (500 mg, 1.7 mmol, 10 equiv.) in NMP (0.5 mL) at 0° C. for 5 min. The resulting mixture was stirred at 25° C. for another 2 h. The reaction was quenched with water (0.5 mL), extracted with EA (150 mL), and the organic layer was washed with aqueous NaHCO3 (saturated, 50 mL) and brine (saturated, 5×20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column was SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm, mobile phase A was water (0.1% FA), mobile phase B was ACN, flow rate was 20 mL / min, gradient was 50% B to 70% B within 5.5 min, wavelength was 254 / 210 nm, RT was 5.2 min to give compound 155 (10 mg, 61.33% yield) as an off-white semisolid.

[0227] [Table 9]

[0228] Biological Examples Biological Example 1 Cytopathic Epithelial Cell Death (CPE) Experiments Cells were seeded at a certain density in a microplate and cultured overnight in a 5% CO2, 37°C incubator. The following day, diluted compounds and viruses were added. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with virus, no compound treatment) and culture medium controls (culture medium only) were set up. The final concentration of DMSO in the culture medium was 0.5%. Cells were cultured in an incubator for 3 (229E) or 7 (OC43) days. The conditions for the cytotoxicity experiment were the same as those for the antiviral experiment, but without virus infection. Cell activity was detected using the cell activity detection reagent kit Cell Titer Glo (Promega).

[0229] The antiviral activity and cytotoxicity of the compounds are expressed as the inhibition rate (%) of the compounds at different concentrations against the cytopathic effect of the virus and the cell viability (%), respectively. Nonlinear fitting analysis was performed on the inhibition rate and cell viability of the compounds using GraphPad Prism, and the half effective concentration (EC 50 ), 90% effective concentration (EC 90 ), half cytotoxic concentration (CC 50 ) and 90% cytotoxic concentration (EC 90 ) values ​​were calculated.

[0230] Activity results for exemplary compounds are shown in Table I below.

[0231] [Table 10] JPEG2025514335000067.jpg237169 JPEG2025514335000068.jpg245169 JPEG2025514335000069.jpg245169 JPEG2025514335000070.jpg25169

[0232] Among them, A indicates <0.1 μM, B indicates >0.1 μM and <0.5 μM, and C indicates >0.5 μM.

[0233] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention are intended to be included in the scope of the claims of the present invention.

Claims

1. A compound of formula (X) or (XI) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof, 【Chemistry 1】 Among them, U is independently H, D, halogen, C 1 -C 12 Alkyl group or C 1 -C 12 m represents, independently of each other, an integer from 0 to 3, preferably 0, 1 or 2, more preferably 0 or 1; R x are independently H, OH, -OC 1 -C 12 Alkyl group, CN, nitro group, amino group, halogen, C 1 -C 12 represents a haloalkyl group, Wa and Wb are each independently H, OH, unsubstituted or optionally one, two or more groups R w C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 2 -C 12 Alkenylcarbonyloxy group, C 2 -C 12 Alkynylcarbonyloxy group, 5-12 membered heteroarylamino group, benzamidine group, C 6 -C 14 Aryl group, C 1 -C 12 Alkyloxycarbonyloxy group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Arylcarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R w are independent of each other. 1 -C 6 alkyl)aminosulfonyl group, C 1 -C 12 alkyl group, hydroxy group, carboxy group, amino group, halogen, Q, X, Y and Z each independently represent O, S or NH; L 1 and L 2 are each independently a single bond, an unsubstituted or optionally one, two or more radicals R a C replaced with 1 -C 12 Alkylene group, C 2 -C 12 Alkenylene group, C 2 -C 12 Alkynylene group, C 3 -C 12 Cycloalkylene group, C 6 -C 14 Arylene group, 5- to 12-membered heteroarylene group, -(OC 1 -C 12 Alkylene) n -, -(C 1 -C 12 Alkylene-O) n -, C 1 -C 12 Alkylene-NH-C 1 -C 12 Alkylene group, C 1 -C 12 Alkylene-C 6 -C 14 Arylene group, C 6 -C 14 Arylene-C 1 -C 12 Represents an alkylene group, of which R a are C 1 -C 6 Alkyl group, C 1 -C 6 Haloalkyl group, phenyl group, amino C 1 -C 6 Alkyl group, di(C 1 -C 6 Alkyl)amino C 1 -C 6 an alkyl group or a benzyloxycarbonylamino group, and n is each independently an integer of 1 to 6, preferably an integer of 4 to 6; R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 2 -C 12 Alkenylcarbonyloxy group, C 2 -C 12 Alkynylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyl group, C 2 -C 12 Alkenyloxycarbonyl group, C 2 -C 12 Alkynyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C 6 -C 14 Aryl group, C 1 -C 12 Alkyloxycarbonyloxy group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Arylcarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R b are each independently a benzyloxycarbonylamino group, C 1 -C 6 Alkyl group, C 1 -C 6 represents a haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, or a halogen, and is preferably Cl; L 3 is a single bond, unsubstituted or optionally one, two or more groups R c C replaced with 1 -C 12 Represents an alkylene group, of which R c are C 1 -C 6 Alkyl group, C 1 -C 6 A haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, or a halogen atom. R 3 is H, unsubstituted or containing one, two or more groups R d C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyl group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 Arylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, carboxy group, amino group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Aryloxycarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, C 3 -C 12 A cycloalkyloxycarbonyloxy group, of which R d are independent of each other. 1 -C 6 alkyl)aminosulfonyl group, preferably di-n-propylaminosulfonyl group, C 1 -C 6 an alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, preferably Cl; R 4 , H, R 1 -L 1 -X or R 2 -L 2 -Y indicates R e and R f are each independently C 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy groups, halogens, OH, CN, -NO 2 Showing, A compound of formula (X) or (XI) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

2. A compound of formula (I) or (II) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof, 【Chemistry 2】 Among them, U is independently H, D, halogen, C 1 -C 12 Alkyl group or C 1 -C 12 m represents, independently of each other, an integer from 0 to 3, preferably 0, 1 or 2, more preferably 0 or 1; R x are independently H, OH, -OC 1 -C 12 Alkyl group, CN, nitro group, amino group, halogen, C 1 -C 12 represents a haloalkyl group, Wa and Wb are each independently H, OH, unsubstituted or optionally one, two or more groups R w C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 2 -C 12 Alkenylcarbonyloxy group, C 2 -C 12 Alkynylcarbonyloxy group, 5-12 membered heteroarylamino group, benzamidine group, C 6 -C 14 Aryl group, C 1 -C 12 Alkyloxycarbonyloxy group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Arylcarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R w are independent of each other. 1 -C 6 alkyl)aminosulfonyl group, C 1 -C 12 alkyl group, hydroxy group, carboxy group, amino group, halogen, Q, X, Y and Z each independently represent O, S or NH; L 1 and L 2 are each independently a single bond, an unsubstituted or optionally one, two or more radicals R a C replaced with 1 -C 12 Alkylene group, C 2 -C 12 Alkenylene group, C 2 -C 12 Alkynylene group, C 3 -C 12 Cycloalkylene group, C 6 -C 14 Arylene group, 5- to 12-membered heteroarylene group, -(OC 1 -C 12 Alkylene) n -, -(C 1 -C 12 Alkylene-O) n -, C 1 -C 12 Alkylene-NH-C 1 -C 12 Alkylene group, C 1 -C 12 Alkylene-C 6 -C 14 Arylene group, C 6 -C 14 Arylene-C 1 -C 12 Represents an alkylene group, of which R a are C 1 -C 6 Alkyl group, C 1 -C 6 Haloalkyl group, phenyl group, amino C 1 -C 6 Alkyl group, di(C 1 -C 6 Alkyl)amino C 1 -C 6 an alkyl group or a benzyloxycarbonylamino group, and n is each independently an integer of 1 to 6, preferably an integer of 4 to 6; R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 2 -C 12 Alkenylcarbonyloxy group, C 2 -C 12 Alkynylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyl group, C 2 -C 12 Alkenyloxycarbonyl group, C 2 -C 12 Alkynyloxycarbonyl group, 5-12 membered heteroarylamino group, benzamidine group, C 6 -C 14 Aryl group, C 1 -C 12 Alkyloxycarbonyloxy group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Arylcarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, carboxy group, amino group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R b are each independently a benzyloxycarbonylamino group, C 1 -C 6 Alkyl group, C 1 -C 6 represents a haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, or a halogen, and is preferably Cl; L 3 is a single bond, unsubstituted or optionally one, two or more groups R c C replaced with 1 -C 12 Represents an alkylene group, of which R c are C 1 -C 6 Alkyl group, C 1 -C 6 A haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, or a halogen atom. R 3 is H, unsubstituted or containing one, two or more groups R d C replaced with 1 -C 12 Alkyl group, C 2 -C 12 Alkenyl group, C 2 -C 12 Alkynyl group, C 1 -C 12 Alkyloxy group, C 2 -C 12 Alkenyloxy group, C 2 -C 12 Alkynyloxy group, C 1 -C 12 Alkylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyl group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 Arylcarbonyloxy group, C 1 -C 12 Alkyloxycarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, carboxy group, amino group, C 1 -C 12 Alkylcarbonylthio group, C 6 -C 20 Aryl-C 1 -C 12 Alkylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, C 6 -C 14 Aryloxycarbonyloxy group, C 3 -C 12 Cycloalkyloxycarbonyl group, C 3 -C 12 A cycloalkyloxycarbonyloxy group, of which R d are independent of each other. 1 -C 6 alkyl)aminosulfonyl group, preferably di-n-propylaminosulfonyl group, C 1 -C 6 an alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, preferably Cl; R 4 , H, R 1 -L 1 -X or R 2 -L 2 -Y indicates A compound of formula (I) or (II) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

3. The compound of formula (I) or (II) has the structure of formula (IA) or (IIA): 【Chemistry 3】 Among them, R 1 , R 2 , R 3 , R 4 , R x , L 1 , L 2 , L 3 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II); A compound of formula (I) or (II) according to claim 2, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

4. The compound of formula (I) or (II) has the structure of formula (IB) or (IIB): 【Chemistry 4】 Among them, R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , R 4 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II); A compound of formula (I) or (II) according to claim 2 or 3, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

5. The compound of formula (I) or (II) has the structure of formula (IC) or (IIC): 【Chemistry 5】 Among them, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , Q, U, Wa, Wb, X, Y, Z are as defined in formula (I) or (II); A compound of formula (I) or (II) according to any one of claims 1 to 4, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

6. Wa and Wb each independently represent H, OH, an unsubstituted or one, two or more groups R w C replaced with 1 -C 6 Alkylcarbonyloxy group, C 2 -C 6 Alkenylcarbonyloxy group, C 2 -C 6 Alkynylcarbonyloxy group, C 3 -C 12 Cycloalkylcarbonyloxy group, 5- to 12-membered heteroarylcarbonyloxy group, C 6 -C 20 arylcarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, of which R w are independent of each other. 1 -C 6 alkyl)aminosulfonyl group, preferably di-n-propylaminosulfonyl group, C 1 -C 6 an alkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen; and preferably, Wa and Wb each independently represent OH, an acetoxy group, an isopropionyloxy group, an isobutyryloxy group, a 2-propylpentanoyloxy group, a 2,2-dimethylpropionyloxy group, a 4-(di-n-propylaminosulfonyl)benzoyloxy group, a pyridinyl-3-methanoyl group, an N-methylpyrrolidin-2-ylmethanoyl group, a prolyloxy group, or a cyclopentanemethanoyl group; A compound of formula (I) or (II) according to any one of claims 1 to 5, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

7. L 1 and L 2 are each independently a single bond, C 1 -C 6 Alkylene group, C 6 -C 10 Arylene group, C 3 -C 6 Cycloalkylene group, 5- to 8-membered heteroarylene group, -(OC 1 -C 6 Alkylene) n -, C 1 -C 6 Alkylene-NH-C 1 -C 6 It is preferable that L represents an alkylene group, and more preferably, L 1 and L 2 each independently represents a single bond, a methylene group, an ethylidene group, a propylidene group, a phenylene group, a cyclopentylene group, a cyclohexylidene group, an oxadiazolediyl group, a pyrazolediyl group, an imidazolediyl group, a thiazolediyl group, -(OCH 2 CH 2 ) n -, C 1 -C 6 Alkylene-NH-C 1 -C 3 It represents an alkylene group, and most preferably L 1 and L 2 each independently represents a single bond, a methylene group, a 1,1-ethylidene group, a 2,2-propylidene group, a 2-phenyl-1,1-ethylidene group, a 1,4-phenylene group, a 1,2,4-oxadiazole-3,5-diyl group, -(OCH 2 CH 2 ) 4 -, pentylidene-N (C 2 H 5 )-CH 2 CH 2 - and / or R 1 and R 2 are each independently H, unsubstituted or one, two or more radicals R b C replaced with 1 -C 6 Alkyl group, C 6 -C 12 Alkylcarbonyloxy group, C 1 -C 6 Alkyloxycarbonyl group, 5- to 12-membered heteroarylamino group, benzamidine group, C 6 -C 14 Aryl group, C 1 -C 6 Alkyloxycarbonyloxy group, C 3 -C 6 Cycloalkylcarbonyloxy group, C 3 -C 6 It is preferable that R represents a cycloalkyloxycarbonyl group, a carboxy group, an amino group, a 5- to 12-membered heteroarylcarbonyloxy group, or a 5- to 12-membered heterocyclylcarbonyloxy group. b are each independently a benzyloxycarbonylamino group, C 1 -C 6 Alkyl group, C 1 -C 6 R represents a haloalkyl group, a hydroxyl group, a carboxyl group, an amino group, a fluorine group, a chlorine group, or a bromine group, and more preferably R 1 and R 2 are each independently H, methyl, heptylcarbonyloxy, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, hexyloxycarbonyl, quinolylamino, benzamidine, propyloxycarbonyloxy, carboxy, amino, pyridinylformyloxy, N-methyl-hydroxypyrrolidinylformyl, cyclopentylcarbonyloxy, or cyclopentyloxycarbonyl, and most preferably R 1 and R 2 are independent of each other. H, phenyl group, methyl group, carboxy group, amino group, 【Chemistry 6】 and / or L 3 is a single bond or an unsubstituted or optionally one, two or more groups R c C replaced with 1 -C 6 It is preferable that R represents an alkylene group. c are C 1 -C 6 Alkyl group, C 1 -C 6 It represents a haloalkyl group, a hydroxy group, a carboxy group, an amino group, or a halogen, and more preferably, L 3 represents a single bond, a methylene group or an ethylidene group, and most preferably, L 3 represents a single bond, a methylene group, a 1,1-ethylidene group, and / or R 3 is H, unsubstituted or containing one, two or more groups R d C replaced with 1 -C 6 Alkyl group, C 6 -C 12 Alkylcarbonyloxy group, C 1 -C 6 Alkyloxycarbonyl group, 5- to 12-membered heteroarylcarbonyloxy group, benzamidine group, C 6 -C 14 Arylcarbonyloxy group, C 1 -C 6 Alkyloxycarbonyloxy group, 5- to 12-membered heterocyclylcarbonyloxy group, N-methyl-hydroxypyrrolidinylformyl group, carboxy group, amino group, C 1 -C 6 Alkylcarbonylthio group, C 6 -C 14 Aryl C 1 -C 6 Alkylcarbonyloxy group, C 6 -C 14 Aryloxycarbonyloxy group, C 3 -C 6 It is preferable that R represents a cycloalkyloxycarbonyloxy group, and more preferably R 3 represents H, a methyl group, a heptylcarbonyloxy group, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, a butyloxycarbonyl group, a hexyloxycarbonyl group, a propyloxycarbonyloxy group, an isopropyloxycarbonyloxy group, a benzoyl group, a pyridinylformyloxy group, a carboxy group, an amino group, a tert-butylcarbonylthio group, a phenylpropylcarbonyloxy group, a phenoxycarbonyloxy group, a cyclobutyloxycarbonyloxy group, or a cyclopentyloxycarbonyloxy group, and is most preferably R 3 is H, phenyl group, methyl group, carboxy group, amino group, 【Chemistry 7】 is selected from the group consisting of: A compound of formula (I) or (II) according to any one of claims 1 to 5, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

8. R 1 -L 1 -X- and R 2 -L 2 -Y- are each independently 【Chemistry 8】 and / or R 3 -L 3 -Q- is 【Chemistry 9】 Showing the group: A compound of formula (I) or (II) according to any one of claims 1 to 6, or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof.

9. A compound of formula (I) or (II) according to any one of claims 1 to 7 or an isotopically labeled compound, an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharma- ceutically acceptable salt, a prodrug, a metabolite, a crystalline polymorph or a solvate thereof, and / or optionally at least one physiologically / pharmacologically acceptable auxiliary, and / or optionally another active ingredient, preferably said another active ingredient being, for example, a fusion inhibitor, a viral entry inhibitor, a protease inhibitor, a polymerase inhibitor, an antiviral nucleoside drug different from remdesivir and its derivatives, a viral maturation inhibitor, a JAK inhibitor, an angiotensin-converting enzyme 2 (ACE2) inhibitor, a SARS-CoV specific human monoclonal antibody, a compound that inhibits cytokine storm, preferably ribavirin, sovosbuvir, GS-441524, palivizumab, motavizumab, Pharmaceutical compositions.

10. Use of a compound of formula (I) or (II) according to any one of claims 1 to 7 or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharma- ceutically acceptable salt, prodrug, metabolite, crystalline polymorph or solvate thereof, in the manufacture of a medicament, preferably the medicament optionally comprises another active ingredient, preferably selected from fusion inhibitors, viral entry inhibitors, protease inhibitors, polymerase inhibitors, antiviral nucleoside drugs different from remdesivir and derivatives thereof, viral maturation inhibitors, JAK inhibitors, angiotensin-converting enzyme 2 (ACE2) inhibitors, SARS-CoV specific human monoclonal antibodies, compounds that inhibit cytokine storm, more preferably ribavirin, sovosbuvir, GS-441524, palivizumab, motavizumab, preferably the medicament is an RNA virus, preferably an orthomyxovirus (e.g. influenza orthomyxovirus (e.g. influenza virus) or paramyxovirus (e.g. coronavirus or respiratory syncytial virus) replication and / or for preventing or treating an RNA virus, preferably an orthomyxovirus (e.g. influenza virus) or paramyxovirus (e.g. coronavirus) infection or a disease or condition caused by an RNA virus, preferably an orthomyxovirus (e.g. influenza virus) or paramyxovirus (e.g. coronavirus or respiratory syncytial virus), more preferably said coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus 229E (HCoV-229E), coronavirus OC43 (HCoV-OC43), murine hepatitis coronavirus (MHV), human coronavirus NL63, human coronavirus HKUl, human coronavirus NL63 ...HKUl) and a coronavirus having a homology of more than 85% with any one of the coronaviruses and having viral activity; or the coronavirus is selected from porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV), and most preferably, the coronavirus is a novel coronavirus (SARS-CoV-2); use.

11. 1. A method of forming a prodrug of a nucleoside drug, optionally comprising: (SA) reacting a p-nitrophenyl phosphate compound (V) with a (deoxy)nucleoside drug (VI) having a free hydroxy group at the C5 position to obtain a prodrug compound of formula (VII), 【Chemistry 10】 Among them, R 1 , R 2 , R x , L 1 , L 2 , Wa, Wb, X, Y, Z are defined as defined in any one of claims 1 to 6, and the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; Preferably, step (SA) is carried out under basic conditions, more preferably, step (SA) is carried out under basic conditions and in the presence of a Grignard reagent, and most preferably, step (SA) is carried out in the presence of tert-butylmagnesium bromide; Or, (SB) reacting a (deoxy)nucleoside phosphate (VIII) with a phenolic compound (IX) to obtain a prodrug compound of formula (X), 【Chemistry 11】 Among them, R 1 , R 2 , R x , L 2 , Wa, Wb, Z are defined as defined in any one of claims 1 to 6, and L 1 is C 6 -C 14 represents an arylene group or a 5- to 12-membered heteroarylene group, preferably C 6 -C 10 an arylene group or a 5-8 membered heteroarylene group, more preferably a 1,4-phenylene group or a 1,2,4-oxadiazole-3,5-diyl; the base may be selected from a purine or pyrimidine base or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine base or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; Or, (SC) First, a (deoxy)nucleoside phosphate (XI) is converted to a silver salt (XII), and then the silver salt (XII) is reacted with a halide R 1 -L 1 -Hal and / or R 2 -L 2 -Hal to obtain a prodrug compound of formula (XIII), 【Chemistry 12】 Among them, R 1 , R 2 , R x , L 1 , L 2 , Wa, Wb, X, Y, Z are defined as defined in any one of claims 1 to 6, the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, Hal represents a halogen, preferably Br or I, more preferably I, and preferably said silver salt is silver carbonate; Or, (SD) Cyclic phosphate (deoxy)nucleoside drug (XIV) is reacted with halide R in the presence of a basic compound. 3 -L 3 -Hal to obtain a prodrug compound of formula (XV), 【Chemistry 13】 Among them, R 3 , R x , L 3 and W are defined as defined in any one of claims 1 to 6, the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, Hal represents a halogen, preferably Br or Cl, more preferably Cl, said basic compound is preferably an alkali metal carbonate, more preferably cesium carbonate, Or, (SE) First, the (deoxy)nucleoside phosphate (XVI) is converted to a silver salt (XVII), and then the silver salt (XVII) is reacted with a halide R 3 -L 3 -Hal to obtain a prodrug compound of formula (XV), 【Chemistry 14】 Among them, R 3 , R x , L 3 and W are defined as defined in any one of claims 1 to 6, the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, Hal denotes halogen, preferably Br or I, more preferably I, Or, (SF) reacting a phosphoramide compound (XVIII) with a (deoxy)nucleoside drug (VI) having free hydroxy groups at the C3 and C5 positions to obtain a prodrug compound of formula (XIX), 【Chemistry 15】 Among them, R 3 , R x , L 3 and W are defined as defined in any one of claims 1 to 6, the base may be selected from purine or pyrimidine bases or any basic hetero(aryl) group, preferably selected from guanine, adenine, thymine, uracil, cytosine bases or 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, preferably step (SF) is carried out under basic conditions, more preferably step (SF) is carried out under basic conditions and in the presence of a Grignard reagent, most preferably step (SF) is carried out in the presence of tert-butylmagnesium bromide, A method comprising:

12. Wb represents OH, Rx represents a cyano group, and the base is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl; The method of claim 10.

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