Macrolide brefeldin a ester derivatives and use thereof

An ester derivative of brefeldin A, wherein the ester derivative of brefeldin A is a compound represented by Formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite or a pharmaceutical acceptable salt of the compound represented by Formula (I), or a prodrug thereof,

• wherein R1 and R2 are each independently H or
• R1 and R2 are not H simultaneously;
• Z is selected from the group consisting of benzene ring, pyridine ring, quinoline ring, and isoquinoline ring;
• R3 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, alkyl, haloalkyl, alkoxy, alkylamino, alkanoyl, hydroxyalkoxy, hydroxyalkylamino, hydroxyalkanoyl, haloalkoxy, haloalkylamino, haloalkanoyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkanoyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkanoyl, aryl, aryloxy, aroyl, arylamino, arylalkoxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroaroyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heteroarylalkanoyl, heterocycloalkyl, heterocyclyloxy, heterocyclylamino, heterocyclylanoyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkanoyl, azidoalkoxy, fused bicyclyl, fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclyl aliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclylalkoxy, fused heterobicyclylalkoxy, fused bicyclylalkylamino, fused heterobicyclylalkylamino, fused bicycloxyalkoxy, fused heterobicycloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fused heterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fused bicyclylaminoC(═O)—, fused heterobicyclylamino-C(═O)—, fused bicyclyl-C(═O)N(R4)—, fused heterobicyclyl-C(═O)N(R4)—, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino, spiro heterobicyclylamino, spiro bicyclylalkoxy, spiro heterobicyclylalkoxy, spiro bicyclylalkylamino, spiro heterobicyclylalkylamino, spiro bicycloxyalkoxy, spiro heterobicycloxyalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl-C(═O)—, spiro bicyclyl-C(═O)O—, Spiro heterobicyclyl-C(═O)—, Spiro heterobicyclyl-C(═O)O—, Spiro bicyclylamino-C(═O)—, Spiro heterobicyclylamino-C(═O)—, Spiro bicyclyl-C(═O)N(R4)—, Spiro heterobicyclyl-C(═O)N(R4)—, R5R4N—, —C(═O)NR4R5, —OC(═O)NR4R5, —OC(═O)OR4, —N(R4)C(═O)NR4R5, —N(R4)C(═O)OR5, —N(R4)C(═O)—R5, R4R5N—S(═O)t-, R4S(═O)t—, R4S(═O)tN(R5)—, R5R4N-alkyl, R4S(═O)t-alkyl, R4R5N—C(═O)-alkyl, R5R4N-alkoxy, R4S(═O)t-alkoxy, R4R5N—C(═O)-alkoxy, aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, and cycloalkyl-(CH2)p-G-(CH2)m—, wherein G is selected from the group consisting of O, S, NR6, S(═O), S(═O)2, C(═O), —C(═O)N(R4)—, —OC(═O)N(R4)—, —OC(═O)—, —N(R4)C(═O)N(R4)—, —(R4)N—S(═O)t-, —OS(═O)t-, and —OS(═O)tN(R4)—, wherein each t is 1 or 2, p and m are each independently 0, 1, 2, 3 or 4, wherein the aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, or cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more substituents selected from the group consisting of F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy and cyano;
• when Z is a benzene ring, R3 is not H;
• R6 is selected from the group consisting of hydrogen, R5R4NC(═O)—, R5OC(═O)—, R5C(═O)—, R5R4NS(═O)—, R5OS(═O)—, R5S(═O)—, R5R4NS(═O)2—, R5OS(═O)2—, R5S(═O)2—, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl and carbocyclyl;
• R5 and R4 are each independently selected from the group consisting of hydrogen, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl and cycloalkyl;
• with the proviso that where R5 and R4 are bonded to a same nitrogen atom, R5 and R4 together with the nitrogen atom optionally form an optionally substituted 3-8 membered ring, an optionally substituted fused bicyclic ring or an optionally substituted spiro bicyclic ring,
• wherein hetero atoms in the heterocyclyl, heteroaryl, fused heterobicyclyl and/or spiro heterobicyclyl are independently selected from the group consisting of N, O, S, and/or Se, and number of the hetero atoms is 1-5;
• wherein R3, R4, R5, R6 are optionally substituted by one or more substituents selected from the group consisting of hydroxyl, hydroxymethyl, carboxyl, acetylamino, alkyl, alkoxy, alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, thiol, halogen, nitro, amino, azido (—N3), guanidyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (—C═O), oxo (═O), thio (═S), sulfonyl, aryl, heteroaryl, and heterocyclyl.