Nucleoside drugs for the treatment or prevention of coronavirus infection and their uses

A compound of formula (I) or (II) or an isotopically-labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof,

• wherein,
• U, independently of each other, represents H, D, halogen, C1-C12 alkyl or C1-C12 haloalkyl;
• m, independently of each other, represents an integer from 0 to 3, preferably represents 0, 1 or 2, more preferably represents 0 or 1;
• RX, independently of each other, represents H, OH, —OC1-C12 alkyl, CN, nitro, amino, halogen, C1-C12 haloalkyl;
• Wa and Wb, independently of each other, represent H, OH, the following groups unsubstituted or substituted with one, two or more RW:
• C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 alkyloxy, C2-C12 alkenyloxy, C2-C12 alkynyloxy, C1-C12 alkylcarbonyloxy, C2-C12 alkenylcarbonyloxy, C2-C12 alkynylcarbonyloxy, 5-12 membered heteroarylamino, benzimidamido, C6-C14 aryl, C1-C12 alkyloxycarbonyloxy, C1-C12 alkylcarbonylthio, C6-C20 aryl-C1-C12 alkylcarbonyloxy, C3-C12 cycloalkylcarbonyloxy, C6-C14 arylcarbonyloxy, C3-C12 cycloalkyloxycarbonyl, carboxyl, amino, 5-12 membered heteroarylcarbonyloxy, C6-C20 arylcarbonyloxy, 5-12 membered heterocyclylcarbonyloxy;
• wherein, Rw, independently of each other, represents di(C1-C6 alkyl)aminosulfonyl, C1-C12 alkyl, hydroxyl, carboxyl, amino, halogen;
• Q, X, Y and Z, independently of each other, represents O, S or NH,
• L1 and L2, independently of each other, represents a single bond, the following groups unsubstituted or optionally substituted with one, two or more Ra:
• C1-C12 alkylene, C2-C12 alkenylene, C2-C12 alkynylene, C3-C12 cycloalkylene, C6-C14 arylene, 5-12 membered heteroarylene, —(O—C1-C12 alkylene)n—, —(C1-C12 alkylene—O—)n—, C1-C12 alkylene—NH—C1-C12 alkylene, C1-C12 alkylene-C6-C14 arylene, C6-C14 arylene-C1-C12 alkylene;
• wherein, Ra, independently of each other, represents C1-C6 alkyl, C1-C6 haloalkyl, phenyl, aminoC1-C6 alkyl, di(C1-C6 alkyl)aminoC1-C6 alkyl, benzyloxycarbonylamino;
• n, independently of each other, represents an integer from 1 to 6, preferably an integer from 4 to 6;
• R1 and R2, independently of each other, represents H, the following groups unsubstituted or substituted with one, two or more Rb:
• C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 alkyloxy, C2-C12 alkenyloxy, C2-C12 alkynyloxy, C1-C12 alkylcarbonyloxy, C2-C12 alkenylcarbonyloxy, C2-C12 alkynylcarbonyloxy, C1-C12 alkyloxycarbonyl, C2-C12 alkenyloxycarbonyl, C2-C12 alkynyloxycarbonyl, 5-12 membered heteroarylamino, benzimidamido, C6-C14 aryl, C1-C12 alkyloxycarbonyloxy, C1-C12 alkylcarbonylthio, C6-C20 aryl-C1-C12 alkylcarbonyloxy, C3-C12 cycloalkylcarbonyloxy, C6-C14 arylcarbonyloxy, C3-C12 cycloalkyloxycarbonyl, carboxyl, amino, 5-12 membered heteroarylcarbonyloxy, C6-C20 arylcarbonyloxy, 5-12 membered heterocyclylcarbonyloxy;
• wherein, Rb, independently of each other, represents benzyloxycarbonylamino, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, carboxyl, amino, halogen, preferably C1;
• L3 represents a single bond, C1-C12 alkylene unsubstituted or optionally substituted with one, two or more group Rc;
• wherein Rc, independently of each other, represents C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, carboxyl, amino, halogen;
• R3 represents H, the following groups unsubstituted or substituted with one, two or more group Rd:
• C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 alkyloxy, C2-C12 alkenyloxy, C2-C12 alkynyloxy, C1-C12 alkylcarbonyloxy, C1-C12 alkyloxycarbonyl, 5-12 membered heteroarylcarbonyloxy, C6-C20 arylcarbonyloxy, C1-C12 alkyloxycarbonyloxy, 5-12 membered heterocyclylcarbonyloxy, carboxyl, amino, C1-C12 alkylcarbonylthio, C6-C20 aryl-C1-C12 alkylcarbonyloxy, C3-C12 cycloalkylcarbonyloxy, C6-C14 aryloxycarbonyloxy, C3-C12 cycloalkyloxycarbonyl, C3-C12 cycloalkyloxycarbonyloxy;
• wherein, Rd, independently of each other, represents di(C1-C6 alkyl)aminosulfonyl, preferably di-(n-propyl)aminosulfonyl, C1-C6 alkyl, hydroxyl, carboxyl, amino, halogen, preferably C1;
• R4 represents H, R1-L1-X or R2-L2-Y.

A method of forming a prodrug of a nucleoside drug, optionally comprising the steps of:

• (S-A) reacting the p-nitrophenyl phosphate compound (V) with a (deoxy)nucleoside drug (VI) having free hydroxyl groups at positions C5 to obtain a prodrug compound of formula (VII),
• wherein, R1, R2, RX, L1, L2, Wa, Wb, X, Y, Z are as defined in formula (I) or (II) or any preferred embodiment thereof, 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 (S-A) is performed under basic conditions;
• more preferably, step (S-A) is performed under basic conditions and in the presence of a Grignard reagent;
• most preferably, step (S-A) is performed in the presence of tert-butylmagnesium bromide;
• or,
• (S-B) reacting the (deoxy)nucleoside drug phosphate (IX) with a phenolic compound (VIII) to obtain a prodrug compound of formula (X),
• wherein, R1, R2, RX, L1, L2, Wa, Wb, Z are as defined in formula (I) or (II) or any preferred embodiment thereof, L1 represents C6-C14 arylene or 5-12 membered heteroarylene, preferably C6-C10 arylene or 5-8 membered heteroarylene, more preferably 1,4-phenylene or 1,2,4-oxadiazol-3,5-diyl, 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;
• or,
• (S-C) converting the (deoxy)nucleoside drug phosphate (XI) into a silver salt (XII) firstly and then reacting the silver salt (XII) with the halides R1-L1-Hal and/or R2-L2-Hal, to obtain a prodrug compound of formula (XIII),
• wherein, R1, R2, RX, L1, L2, Wa, Wb, X, Y, Z are as defined in formula (I) or any preferred embodiment thereof, 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 halogen, preferably Br or I, more preferably I;
• preferably, the silver salt is silver carbonate;
• or,
• (S-D) reacting cyclic (deoxy)nucleoside drug phosphate (XIV) with halide R3-L3-Hal in the presence of a basic compound, to obtain a prodrug compound of formula (XV),
• wherein, RX, R3, L3 and Wb are as defined in formula (II) or any preferred embodiment thereof, 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 halogen, preferably Br or C1, more preferably C1;
• the basic compound is preferably an alkali metal carbonate, more preferably cesium carbonate;
• or,
• (S-E) converting the (deoxy)nucleoside drug phosphate (XVI) into a silver salt (XVII) firstly and then reacting the silver salt (XVII) with the halide R3-L3-Hal, to obtain a prodrug compound of formula XV),
• wherein, RX, R3, L3 and Wb are as defined in formula (II) or any preferred embodiment thereof, 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 halogen, preferably Br or I, more preferably I;
• or,
• (S-F) reacting the phosphoramidite compound (XVIII) with a (deoxy)nucleoside drug (VI) having free hydroxyl groups at positions C3 and C5 to obtain a prodrug compound of formula (XIX),
• wherein, RX, R3, L3 and Wb are as defined in formula (II) or any preferred embodiment thereof, 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 (S-F) is performed under basic conditions;
• more preferably, step (S-F) is performed under basic conditions and in the presence of a Grignard reagent;
• most preferably, step (S— F) is performed in the presence of tert-butylmagnesium bromide.