Homoharringtonine alkaloid derivatives and their pharmaceutical compositions, preparation methods and uses

Abstract

This invention relates to holoharbine derivatives and their pharmaceutical compositions, preparation methods, and uses, belonging to the field of pharmaceutical compounds. The holoharbine derivatives and their pharmaceutical compositions provided by this invention exhibit excellent antitumor activity. Furthermore, the preparation methods of these derivatives have advantages such as inexpensive and readily available raw materials and simple operation.

Description

[0001] This application claims priority to the prior art patent application filed by the applicant on September 22, 2022 with the China National Intellectual Property Administration, application number 202211161020.8, entitled "Triharbine Base Derivatives and Pharmaceutical Compositions Thereof, Preparation Methods and Uses Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to thiamethoxam alkaloid derivatives and their pharmaceutical compositions, preparation methods and uses, belonging to the field of pharmaceutical compounds. Background Technology

[0003] Harringtonine alkaloids, such as homoharringtonine (HT), deoxyharringtonine (DHT), and isoharringtonine (IHT), are known anticancer drugs.

[0004]

[0005] Homoharringtonine 2 was included in the Chinese Pharmacopoeia in 1990 for the clinical treatment of acute non-lymphocytic leukemia and has been used clinically ever since.

[0006] Currently, medicinal cephalotaxine alkaloids are isolated from plants of the *Cephalotaxus* genus. However, natural cephalotaxine alkaloids constitute only a small portion of total alkaloids, and are primarily found in the non-renewable parts of the plant. Besides existing in low concentrations in natural plant materials, cephalotaxine alkaloids also mix with many structurally similar congeners, making the isolation of high-purity cephalotaxine alkaloids from natural products extremely difficult. Furthermore, due to the drastic decline in the number of *Cephalotaxus* plants, which have become rare and protected species, the isolation of cephalotaxine alkaloids from plants is far from meeting the needs of clinical applications.

[0007] The inventor previously obtained a Chinese patent ZL201510925650.1 that reported a class of cephalotaxine alkaloids, their synthesis methods and uses, in which some of the compounds in the examples showed certain inhibitory activity against HL-60 human leukemia cells.

[0008] Currently, further research is needed on derivatives of these compounds in order to develop drug compounds with improved anticancer activity. Summary of the Invention

[0009] To address the aforementioned technical problems, the present invention provides compounds of formula (I), their racemates, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters, or prodrug compounds thereof:

[0010]

[0011] Among them, R S Selected from (R) N ) m -G-(CH2) n -or (R) Q ) m -G-(CH2) n -:

[0012] R N This represents a substituent containing a nitrogen atom, such as a nitro group, an unsubstituted group, or optionally a group with one, two, or more R atoms. a The following groups are substituted: -NR 6 R 7 -NR 6’ -C(=YR 4 )-NR 6 R 7 ;

[0013] Each R 6 R 6’ and R 7 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. b The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy group, 3-20 membered heterocyclic oxy group, C 6-20 aryloxy group, 5-20 member heteroaryloxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 3-20 cycloalkylthio, C 3-20 Cycloalkenylthio, 3-20 membered heterocyclic thio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, R 10 C(=O)-、R 10 C(=O)O-、R10 C(=O)NH-、R 10 OC(=O)-、R 10 NHC(=O)-、R 10 S(O)2-、R 10 S(O)2O-、R 10 OS(O)2-、R 10 S(O)-, tris(C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl;

[0014] R Q Represents H, halogen, -OH, -CN, unsubstituted or optionally substituted with one, two or more Rs. c The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy group, 3-20 membered heterocyclic oxy group, C 6-20 aryloxy group, 5-20 member heteroaryloxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 3-20 cycloalkylthio, C 3-20 Cycloalkenylthio, 3-20 membered heterocyclic thio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, R 10 C(=O)-、R 10 C(=O)O-、R 10 OC(=O)-、R 10 S(O)2-、R 10 S(O)2O-、R 10 OS(O)2-、R 10 S(O)-, tris(C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl;

[0015] G represents chemical bond, C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20Aryl, 5-20 membered heteroaryl; the condition is that when G is not a chemical bond, the positions of the different groups attached to G on G can be spaced 1-10 atoms apart, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms apart; for example, when G is phenyl, the positions of the different groups attached to G on G can be spaced 1, 2, 3, 4 or 5 carbon atoms apart, for example, the different groups on G are ortho-substituted, meta-substituted and / or para-substituted, preferably meta-substituted and / or para-substituted;

[0016] Each m is either the same or different, and each is independently selected from integers greater than 1;

[0017] Each n is either the same or different, and is independently selected from integers greater than 1;

[0018] Each Y is either identical or different, and is independently selected from O, S, or N, provided that when Y is selected from O or S, R 4 It does not exist;

[0019] R 1 and R 2 They are either the same or different, and are independently selected from H and C. 1-6 Alkyl or halogen;

[0020] R 3 Selected from R 8 R 8 -O-、R 8 -S-;

[0021] R 4 It does not exist, or is selected from H, without substitution, or is optionally occupied by one, two, or more R. d The following groups are substituted: R 8 -O-、R 8 -S-、R 9 C(=O)O-、R 10 OC(=O)O-、R 10 NHC(=O)-、R 10 NHC(=O)O-、R 10 C(=O)NH-;

[0022] R 5 Selected from H or C 1-6 alkyl;

[0023] Each R a R b R c and R d They may be identical or different, and are independently selected from halogens, -OH, -CN, -NO2, oxo (=O), unsubstituted or optionally substituted by one, two or more R groups. e The following groups are substituted: C1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy group, 3-20 membered heterocyclic oxy group, C 6-20 aryloxy group, 5-20 member heteroaryloxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 3-20 cycloalkylthio, C 3-20 Cycloalkenylthio, 3-20 membered heterocyclic thio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, R 11 C(=O)-、R 11 C(=O)O-、R 11 C(=O)NH-、R 11 OC(=O)-、R 11 NHC(=O)-、R 11 S(O)2-、R 11 S(O)2O-、R 11 OS(O)2-、R 11 S(O)-、-NR 12 R 13 -NH-C(=Y)-NR 12 R 13 3 (C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl;

[0024] Each R 8 R 9 R 10 and R 11 They are either the same or different, and are independently selected from H and C. 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 quinone heteroaryl, R 11’ C(=O)-、R 11’ C(=O)O-、R 11’ C(=O)NH-、R 11’ OC(=O)-、R 11’ NHC(=O)-、R 11’S(O)2-、R 11’ S(O)2O-、R 11’ OS(O)2-、R 11’ S(O)-、-NR 12 R 13 -NH-C(=Y)-NR 12 R 13 3 (C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl;

[0025] Each R 11’ R 12 and R 13 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. f The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl;

[0026] Each R e and R f They may be identical or different, and are independently selected from halogens, -OH, -CN, -NO2, -NH2, oxo (=O), unsubstituted or optionally substituted by one, two or more R groups. g The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy group, 3-20 membered heterocyclic oxy group, C 6-20 aryloxy group, 5-20 member heteroaryloxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 3-20 cycloalkylthio, C 3-20 Cycloalkenylthio, 3-20 membered heterocyclic thio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, R 14 C(=O)-、R 14 C(=O)O-、R 14 OC(=O)-、R 14S(O)2-、R 14 S(O)2O-、R 14 OS(O)2-、R 14 S(O)-;

[0027] Each R 14 Same or different, selected independently from C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl;

[0028] Each R g They may be the same or different, and are independently selected from halogens, -OH, -CN, -NO2, -NH2, oxo (=O), and C. 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy group, 3-20 membered heterocyclic oxy group, C 6-20 aryloxy group, 5-20 member heteroaryloxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 3-20 cycloalkylthio, C 3-20 Cycloalkenylthio, 3-20 membered heterocyclic thio, C 6-20 Arylthio, 5-20 membered heteroarylthio;

[0029] Optionally, the C 3-20 One, two or more carbon atoms of a cycloalkyl or 3-20 membered heterocyclic group may optionally be substituted with oxygen to form a carbonyl group.

[0030] According to an embodiment of the present invention, G represents a chemical bond, C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 membered heteroaryl, such as chemical bonds, C 1-8 Alkyl, C 2-8 Alkenyl, phenyl, naphthyl.

[0031] According to an embodiment of the present invention, m represents an integer from 1 to 20, preferably an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0032] According to an embodiment of the present invention, n represents an integer from 1 to 20, preferably an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0033] According to embodiments of the present invention, halogens represent F, Cl, Br, or I.

[0034] According to an embodiment of the present invention, Y is selected from O, N or S.

[0035] According to an embodiment of the present invention, R 3 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyl-O-, C 2-8 alkenyl-O-, C 3-15 cycloalkyl-O-, C 3-15 Cycloalkenyl-O-, 3-15 membered heterocyclic-O-, C 6-15 Aryl-O-, 5-15 heteroaryl-O-, C 1-8 Alkyl-S-, C 2-8 alkenyl-S-, C 3-15 cycloalkyl-S-, C 3-15 Cycloalkenyl-S-, 3-15 membered heterocyclic-S-, C 6-15 Aryl-S-, 5-15 heteroaryl-S-.

[0036] According to an embodiment of the present invention, R 4 It does not exist or is selected from H.

[0037] According to an embodiment of the present invention, R N This represents a substituent containing a nitrogen atom, such as a nitro group, an unsubstituted group, or optionally a group with one, two, or more R atoms. a The following groups are substituted: -NR 6 R 7 -NH-C(=YR) 4 )-NR 6 R 7 .

[0038] According to an embodiment of the present invention, R N Represents nitro, unsubstituted, or optionally substituted with one, two, or more R groups. a The following groups are substituted: -NR6 R 7 -NH-C(=YR) 4 )-NR 6 R 7 Where Y is selected from O, N, or S, and R 4 It does not exist or is selected from H.

[0039] According to an embodiment of the present invention, R N Selected from -NR 6 R 7 -NH-C(=O)-NR 6 R 7 -NH-C(=S)-NR 6 R 7 or -NH-C(=NH)-NR 6 R 7 .

[0040] Or, according to an embodiment of the present invention, R N Selected from nitro, amino, or phenyl groups substituted at the ortho, meta, and / or para positions with nitro or amino groups, wherein the amino group is unsubstituted or substituted with one, two, or more groups selected from C 1-8 alkyl carbonyl, C 1-8 Alkyloxycarbonyl, C 3-8 cycloalkyl carbonyl, C 3-8 Cycloalkyloxycarbonyl, C 6-10 aryl carbonyl, C 6-10 aryloxycarbonyl, C 2-8 Alkenyl substituent substitution.

[0041] According to an embodiment of the present invention, R 6 Selected from H, without substitution, or optionally by one, two, or more Rs b The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 quinone heteroaryl, R 10 C(=O)-、R 10 C(=O)O-、R 10 OC(=O)-、R 10 S(O)2-、R 10 S(O)2O-、R 10 OS(O)2-、R 10 S(O)-, tris(C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl;

[0042] According to an embodiment of the present invention, R 7 Selected from H, without substitution, or optionally by one, two, or more Rs b The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 quinone heteroaryl, R 10 C(=O)-、R 10 C(=O)O-、R 10 OC(=O)-、R 10 S(O)2-、R 10 S(O)2O-、R 10 OS(O)2-、R 10 S(O)-, tris(C) 1-20 Alkyloxy)silyl C 1-20 Alkyl, tri(C) 1-20 Alkyl)silyl.

[0043] According to an embodiment of the present invention, R 7 Selected from H, without substitution, or optionally by one, two, or more Rs b The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, R 10 C(=O)-、R 10 C(=O)O-、R 10 OC(=O)-、R 10 S(O)2-、R 10 S(O)2O-、R 10 OS(O)2-、R 10 S(O)-, tris(C) 1-8 Alkyloxy)silyl C 1-8 Alkyl, tri(C) 1-8 Alkyl)silyl.

[0044] According to an embodiment of the present invention, R 10 Selected from C 1-8 Alkyl, C 2-8 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, NH2.

[0045] According to an embodiment of the present invention, each R a and R b They may be the same or different, and are independently selected from halogens, -OH, -CN, -NO2, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyloxy, C 2-8 alkenyloxy group, C 3-15 Cycloalkyloxy, C 3-15 Cycloalkenyloxy group, 3-15 membered heterocyclic oxy group, C 6-15 aryloxy group, 5-15 membered heteroaryloxy group, C 1-8 Alkyl thio, C 2-8 alkenyl thio, C 3-15 cycloalkylthio, C 3-15 Cycloalkenylthio, 3-15 membered heterocyclic thio, C 6-15 arylthio, 5-15 membered heteroarylthio, R 11 C(=O)-、R 11 C(=O)O-、R 11 OC(=O)-、R 11 S(O)2-、R 11 S(O)2O-、R 11 OS(O)2-、R 11 S(O)-、-NR 12 R 13 -NH-C(=Y)-NR 12 R 13 ; Three (C) 1-20 Alkyloxy)silyl C 1-20 alkyl;

[0046] According to an exemplary embodiment of the present invention, R 7 Selected from, for example, H, unsubstituted, or optionally by one, two, or more Rs e The following groups are substituted: C 1-8 Alkyl, C3-8 cycloalkyl, C 2-8 alkenyl, tri(C) 1-8 Alkyloxy)silyl C 1-8 Alkyl, phenyl, biphenyl, naphthyl.

[0047] For example, R 7 Selected from H, without substitution, or optionally by one, two, or more Rs eThe following groups are substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, allyl, phenyl.

[0048] According to an embodiment of the present invention, the compound represented by formula (I) may be selected from the compounds represented by formula (I-1) below:

[0049]

[0050] Among them, R 7 G, n, R 3 Each of the options is independently selected from the definitions described above, where Y represents O, S, or NH.

[0051] According to an embodiment of the present invention, R Q Selected from H, halogen, -OH, -CN, unsubstituted or optionally substituted with one, two or more R c The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyloxy, C 2-8 alkenyloxy group, C 3-15 Cycloalkyloxy, C 3-15 Cycloalkenyloxy group, 3-15 membered heterocyclic oxy group, C 6-15 aryloxy group, 5-15 membered heteroaryloxy group, C 1-8 Alkyl thio, C 2-8 alkenyl thio, C 3-15 cycloalkylthio, C 3-15 Cycloalkenylthio, 3-15 membered heterocyclic thio, C 6-15 Arylthio, 5-15 membered heteroarylthio.

[0052] According to an embodiment of the present invention, R Q Selected from H, halogen, -OH, -CN, unsubstituted or optionally substituted with one, two or more R c The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, such as unsubstituted or optionally substituted with one, two or more R groups.c The following groups may be substituted: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, trifluoromethyl-methyl, pentafluoroethyl, phenyl, naphthyl, thiophene, and dihydrobenzofuranyl.

[0053] According to an exemplary embodiment of the present invention, R Q The group is selected from halogens or groups substituted with halogens.

[0054] According to an embodiment of the present invention, R 3 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyl-O-, C 2-8 alkenyl-O-, C 3-15 cycloalkyl-O-, C 3-15 Cycloalkenyl-O-, 3-15 membered heterocyclic-O-, C 6-15 Aryl-O-, 5-15 heteroaryl-O-, C 1-8 Alkyl-S-, C 2-8 alkenyl-S-, C 3-15 cycloalkyl-S-, C 3-15 Cycloalkenyl-S-, 3-15 membered heterocyclic-S-, C 6-15 Aryl-S-, 5-15 heteroaryl-S-.

[0055] According to an exemplary embodiment of the present invention, R 3 Selected from H, methyl, methoxy, and methylthio.

[0056] According to an embodiment of the present invention, the compound represented by formula (I) may be selected from the compounds represented by formulas (I-2), (I-4), or (I-5):

[0057]

[0058] Among them, R Q G, n, R 3 Each is selected independently from the definition described above.

[0059]

[0060] Among them, R 6 R 7 G, n, R 3 Each is selected independently from the definition described above;

[0061]

[0062] Among them, R 6 R 10 G, n, R 3 Each is selected independently from the definition described above.

[0063] According to an embodiment of the present invention, Y is selected from N.

[0064] According to an embodiment of the present invention, R Q Selected from H, without substitution, or optionally by one, two, or more Rs c The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 heteroaryl.

[0065] According to an exemplary embodiment of the present invention, R Q Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, such as unsubstituted or optionally substituted with one, two or more R groups. c The following groups may be substituted: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, thiophene, and dihydrobenzofuranyl.

[0066] According to an embodiment of the present invention, R 3 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 heteroaryl.

[0067] According to an embodiment of the present invention, R 4 Selected from unsubstituted or arbitrarily assigned to one, two or more R d The following groups are substituted: R 8 -O-、R 8 -S-、R 9 C(=O)O-.

[0068] According to an embodiment of the present invention, each R 8 and R 9 They are either the same or different, and are independently selected from H and C. 1-8Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, -NR 12 R 13 ;

[0069] According to an embodiment of the present invention, each R 12 and R 13 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. f The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 heteroaryl.

[0070] According to an embodiment of the present invention, R 12 Selected from H, R 13 Selected from unsubstituted or arbitrarily assigned to one, two or more R f The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, -NR 12 R 13 For example, it is selected from cyclopentyl.

[0071] According to an embodiment of the present invention, R 8 Selected from H, -OH, acryloyl, isobutyryl, isopentyl,

[0072] According to an embodiment of the present invention, R 9 Selected from C 1-8 Alkyl, C 2-8 Alkenyl, NH2.

[0073] According to an embodiment of the present invention, each R d They may be the same or different, and are independently selected from halogens, -OH, -CN, -NO2, unsubstituted, or optionally substituted by one, two, or more R groups. e The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15aryl, 5-15 aryl, for example selected from unsubstituted or optionally surrounded by one, two or more R groups. e The following groups can be substituted: phenyl, naphthyl, etc.

[0074] According to an embodiment of the present invention, each R e They may be the same or different, and are independently selected from halogens, -OH, -CN, -NO2, unsubstituted, or optionally substituted by one, two, or more R groups. e The following groups are substituted: C 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyloxy, C 2-8 alkenyloxy group, C 3-15 Cycloalkyloxy, C 3-15 Cycloalkenyloxy group, 3-15 membered heterocyclic oxy group, C6- 15 aryloxy group, 5-15 membered heteroaryloxy group, C 1-8 Alkyl thio, C 2-8 alkenyl thio, C 3-15 cycloalkylthio, C 3-15 Cycloalkenylthio, 3-15 membered heterocyclic thio, C 6-15 Arylthio, 5-15 membered heteroarylthio.

[0075] According to an embodiment of the present invention, each R f They may be the same or different, and are independently selected from halogens, -OH, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocyclic groups, C 6-15 Aryl, 5-15 quinone heteroaryl, C 1-8 Alkyloxy, C 2-8 alkenyloxy group, C 3-15 Cycloalkyloxy, C 3-15 Cycloalkenyloxy group, 3-15 membered heterocyclic oxy group, C 6-15 aryloxy group, 5-15 membered heteroaryloxy group, C 1-8 Alkyl thio, C 2-8 alkenyl thio, C 3-15 cycloalkylthio, C 3-15 Cycloalkenylthio, 3-15 membered heterocyclic thio, C 6-15 Arylthio, 5-15 membered heteroarylthio.

[0076] According to an embodiment of the present invention, the compound shown in formula (I) may be selected from the compounds shown in formulas (I-3) below:

[0077]

[0078] Among them, R Q G, n, R 3 R 4 Each is selected independently from the definition described above.

[0079] According to an exemplary embodiment of the present invention, the compound represented by formula (I) described above may be selected from the following compounds:

[0080]

[0081] Among them, groups R, G, R 4 and n have the definitions described in the following table:

[0082]

[0083] According to an exemplary embodiment of the present invention, the compound represented by formula (I) described above may be selected from the following compounds:

[0084]

[0085] Among them, groups R and R 3 and n have the definitions described in the following table:

[0086]

[0087] According to an exemplary embodiment of the present invention, the compound represented by formula (I) described above may be selected from the following compounds:

[0088]

[0089] Among them, groups R and R 3 and R 8 It has the definitions described in the table below:

[0090]

[0091] Unless otherwise stated, although the definitions of the above groups are used to describe the specific compound structures covered by the general formula, those skilled in the art should understand that this specification also contains an independent definition of each of the above groups, which may be used alone or together with other groups to further define one, two or more corresponding substituents in the general formula, thereby further defining the general formula.

[0092] The present invention also provides a method for preparing the compound of formula (I), its racemate, stereoisomer, tautomer, isotope label, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or prodrug compound thereof, wherein the preparation method may include one selected from the following methods:

[0093] Method (1)

[0094]

[0095] Among them, R 1 R 2 R 4 R 5 Y has the definition described above;

[0096] R 3 Selected from R 8 -O-;

[0097] Step (1) involves alkali and R 8 The reaction is carried out in the presence of -OH to prepare compound (I).

[0098] Method (2)

[0099] When the substituent R of compound of formula (I) S When an amino group is present, the corresponding nitro compound is used as a substrate to prepare compound (I) by reduction.

[0100] Preferably, the reduction is carried out in the presence of Zn and AcOH.

[0101] Method (3)

[0102] When the substituent R of compound of formula (I) S When an acylamino group is present, the corresponding amino compound is used as a substrate to prepare compound (I) through an acylation reaction.

[0103] Method (4)

[0104] When the substituent R of compound of formula (I) S When a compound contains a urea group, the corresponding amino compound is used as a substrate to prepare compound (I) by reacting it with an isocyanate compound.

[0105] Method (5)

[0106] When the substituent R of compound of formula (I) S When a guanidine group is present, the corresponding amino compound is used as a substrate to prepare compound (I) by reacting it with nitrile amines, acyl nitrile amines, or carbodiimides with different substitutions.

[0107] Method (6)

[0108]

[0109] Among them, R 1 R 2 R 3 R 5 It has the definition described above;

[0110] R 4 Selected from hydroxyl groups;

[0111] Y is selected from N;

[0112] Step (1) is carried out in the presence of a base and hydroxylamine hydrochloride to prepare compound (I).

[0113] Method (7)

[0114]

[0115] Among them, R 1 R 2 R 3 R 5 It has the definition described above;

[0116] R 4 Selected from R 9 C(=O)O-;

[0117] Y is selected from N;

[0118] Step (1) involves alkali and C. 1-20 Alkyl-C(O)-OC(O)-C 1-20 The reaction is carried out in the presence of alkyl groups to prepare compound (I).

[0119] Method (8)

[0120]

[0121] Among them, R 1 R 2 R 3 R 5 It has the definition described above;

[0122] R 4 Selected from R 9 C(=O)O-;

[0123] Y is selected from N;

[0124] Step (1) involves alkali and R 9 C(=O)Cl or R 9 The reaction is carried out in the presence of C(=O)OH to prepare compound (I).

[0125] Method (9)

[0126]

[0127] Among them, R 1 R 2 R 3 R 5 It has the definition described above;

[0128] R 4 Selected from R 8 -O-;

[0129] R 8 Selected from C 1-20 Alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl;

[0130] Y is selected from N;

[0131] Step (1) involves alkali and R 8 The reaction was carried out in the presence of -L to prepare compound (I);

[0132] L is a leaving group, such as a halogen, preferably Br or I.

[0133] Method (10)

[0134]

[0135] Among them, R 1 R 2 R 3 R 5 It has the definition described above;

[0136] R 4 Selected from R 10 NHC(=O)O-;

[0137] Y is selected from N;

[0138] The step (1) in R 10 The reaction is carried out in the presence of -N=C=O to prepare compound (I).

[0139] Optionally, the preparation method further includes the step of reacting the prepared compound of formula (I) with a pharmaceutically acceptable acid or base to form a salt.

[0140] The present invention also provides a pharmaceutical composition comprising at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, an isotope label, an N-oxide, a hydrate, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a prodrug compound thereof.

[0141] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, an isotope label, an N-oxide, a hydrate, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a prodrug compound thereof.

[0142] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0143] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0144] The present invention also provides the use of at least one of the compounds of formula (I), racemates, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof in the preparation of pharmaceuticals.

[0145] According to embodiments of the present invention, the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound, the drug or the pharmaceutical composition thereof is used for the prevention and / or treatment of diseases caused by uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, or diseases accompanied by uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, particularly, said diseases being, for example, hematologic malignancies, solid tumors and / or their metastases, such as leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, thoracic tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary system tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and / or their metastases.

[0146] The present invention also provides the use of the compound of formula (I), its racemate, stereoisomer, tautomer, isotope label, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound, the drug or the drug composition thereof for inhibiting tumor cells, wherein the tumor cells are selected from tumor cells of hematologic malignancies and / or solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, doxorubicin-resistant strains of leukemia cells, glioblastoma cells, cervical cancer cells, colon cancer cells and / or brain microvascular endothelial cells.

[0147] This invention also provides the use of the compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope label, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound, and the use of the drug or the pharmaceutical composition in the preparation of a drug, the drug being used to treat hyperproliferative disorders in mammals, or to inhibit, block, reduce, or decrease cell proliferation and / or cell division and / or induce apoptosis. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other skin hyperplasia, benign prostatic hyperplasia (BpH), solid tumors such as breast cancer, respiratory tract cancer, lung cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. The disorders also include lymphoma, sarcoma, and leukemia.

[0148] The drug can also be used to inhibit tumor cells, wherein the tumor cells are selected from hematologic malignancies and / or solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, doxorubicin-resistant strains of leukemia cells, glioblastoma cells, cervical cancer cells, colon cancer cells and / or brain microvascular endothelial cells.

[0149] According to an embodiment of the present invention, the examples of tumor cells may be selected from at least one of human breast cancer cells MCF-7, liver cancer cells HepG2, lung adenocarcinoma cells A549, human leukemia cells HL-60, human leukemia cells doxorubicin-resistant strain HL-60 / ADR, human glioblastoma cells U-87MG, human cervical cancer cells HeLa, human colon cancer cells HCT-116, human colon cancer cells Sw620, human colon cancer cells LoVo, and human brain microvascular endothelial cells hCMEC / D3.

[0150] When administered as a medicine, the compounds of the present invention may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical field and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and formulations may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powder formulations, and powders. Conventional drug carriers, water, powder or oily bases, thickeners, etc., may be necessary or required.

[0151] In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or contained in a carrier such as a capsule, pouch, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance, serving as a solvent, carrier, or medium for the active ingredient. Therefore, the compositions can be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in a liquid solvent); ointments containing, for example, up to 10% by weight of the active compound; soft and hard gelatin capsules; suppositories; sterile injectable solutions; and sterile packaged powders.

[0152] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may also contain: lubricants such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The compositions of the present invention can be formulated using methods known in the art to provide immediate, sustained, or delayed release of the active ingredient upon administration to a patient.

[0153] Compositions can be formulated in unit dosage forms, each containing approximately 5 to 1000 mg, more typically approximately 100 to 500 mg of active ingredient. The term "unit dosage form" refers to a physically isolated single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, when mixed with suitable pharmaceutical excipients.

[0154] The effective dose range of an active compound can be quite wide, and it is usually administered at the pharmaceutically effective dose. However, it is understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the patient's age, weight, and response, and the severity of the patient's symptoms.

[0155] For the preparation of solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preform composition containing a homogeneous mixture of the compounds of the present invention. When these preform compositions are referred to as homogeneous, it means that the active ingredient is generally uniformly distributed throughout the composition, such that the composition can be readily divided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preform is then divided into unit dosage forms of the type described above, containing, for example, about 0.1 to 1000 mg of the active ingredient of the present invention.

[0156] The tablets or pills of this invention can be coated or compounded to obtain dosage forms that provide the advantage of long-lasting action. For example, the tablets or pills contain an internal dose and an external dose component, the latter being a coated form of the former. The two components can be separated by an enteric coating layer, which is used to prevent disintegration in the stomach, allowing the internal component to pass through the duodenum intact or to delay release. A variety of substances can be used for such enteric coatings or coatings, including a variety of high molecular weight acids and mixtures of high molecular weight acids with such substances such as shellac, cetyl alcohol, and cellulose acetate.

[0157] The compounds and compositions of the present invention may be incorporated into liquid forms for oral or injectable administration, including aqueous solutions, suitably flavored syrups, water or oil suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutical solvents.

[0158] Compositions for inhalation or inhalation include solutions and suspensions, and powders, dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve local or systemic effects. The composition can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer, or the nebulizer can be connected to a face mask or intermittent positive pressure ventilation machine. Solutions, suspensions, or powder compositions can be administered orally or nasally by a device that delivers the formulation in a suitable manner.

[0159] The amount of compound or composition given to a patient is not fixed and depends on the drug being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, the method of administration, etc. In therapeutic applications, a sufficient amount of the composition may be given to a patient with an existing disease to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose should depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0160] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized using conventional sterilization techniques or filterable sterilization. The aqueous solutions may be used as is, or lyophilized; prior to administration, the lyophilized formulation may be mixed with a sterile aqueous carrier. The pH of the compound formulation is typically 3–11, more preferably 5–9, and most preferably 7–8. It is understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of drug salts.

[0161] The therapeutic dose of the compounds of this invention may be determined based on, for example, the specific therapeutic use, the manner of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compounds of this invention in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of this invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% (w / v) of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

[0162] The present invention provides the use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotope labels, N-oxides, hydrates, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters, or prodrug compounds in an analytical test for identifying compounds capable of inhibiting one or more tumor cells.

[0163] More preferably, the competitive binding assay includes contacting the compound of the invention with tumor cells and detecting any changes in the interaction between the compound of the invention and the tumor cells.

[0164] Beneficial effects

[0165] The holoharbine derivatives and their pharmaceutical compositions provided by this invention exhibit excellent antitumor activity. Furthermore, the preparation method of these derivatives has advantages such as inexpensive and readily available raw materials and simple operation.

[0166] Terminology Definitions and Explanations

[0167] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0168] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when certain numerical ranges are defined as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "numbers from 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0169] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0170] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0171] Term "C" 1-20 "Alkyl" should be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8"Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0172] Term "C" 2-20 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-8 "Alkenyl". "C" 2-8 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, particularly 2 or 3 carbon atoms ("C"). 2-3The term "alkenyl" should be understood to refer to a group containing more than one double bond, where the double bonds can be separable or conjugated. The alkenyl group is, for example, 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. -alkenyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (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, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl 1,1-dimethylprop-2-enyl, (Z)-1-methylbut-2-enyl, (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, 1-isopropylvinyl.

[0173] Term "C" 3-20 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0174] Term "C" 5-20"Cycloalkenyl" should be understood as representing a conjugated or non-conjugated monocyclic or bicyclic hydrocarbon ring with an unsaturation degree of 1, 2, or 3, having 5 to 20 carbon atoms, preferably "C". 5-10 "Cycloalkenyl". The term "C" 5-10 "Cycloalkenyl" should be understood as representing an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 5-10 The cycloalkenyl group can be a monocyclic hydrocarbon group, such as 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 2,4-cyclopentadienyl, 2,5-cyclohexadienyl, or 1,3,5-cycloheptanetrienyl or 1,3,6-cycloheptanetrienyl, or a bicyclic hydrocarbon group, such as hexahydronaphthyl or octahydronaphthyl. Unless otherwise specified, the term "C" is used. 5-20 "Cycloalkenyl" includes all its possible isomers, such as its positional isomers or configurational isomers.

[0175] Unless otherwise defined, the term "3-20 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9- or 7-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The heterocyclic group may be connected to the rest of the molecule by any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group may include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl. Alternatively, it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-10 membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the ring of the 3-10 membered heterocyclic group can be linked to other groups. For example, when the 3-10 membered heterocyclic group is selected from piperazineyl, the nitrogen atom on the piperazineyl group can be linked to other groups. Or when the 3-10 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at its para position can be linked to other groups.

[0176] Term "C" 6-20 "Aryl" should preferably be understood to represent a monocyclic or bicyclic (e.g., fused, bridged, or spirocyclic) hydrocarbon ring having 6 to 20 carbon atoms and possessing monovalent aromatic or partially aromatic properties. It can be a monoaromatic ring or a polyaromatic ring fused together, particularly a ring with 6 carbon atoms ("C6 aryl"), such as phenyl or biphenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), for example, naphthyl. When the C6-10 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0177] The term "5-20-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, preferably 1 to 3 heteroatoms independently selected from N, O, and S, and in each case may be benzofused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthidyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-pyrrinyl, 2-, 4-, 6- or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazole, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbazole, 1-, 2-, 3-, 4-, 6-, 7-, 8- 9- or 10-phenanthidyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3- 4, 5, 6, 7, 8, 9, or 10-benzoisoquinolinyl, 2, 3, 4, or thieno[2,3-b]furanyl, 2, 3, 5, 6, 7, 8, 9, 10, or 11-7H-pyrazino[2,3-c]carbazole, 2, 3, 5, 6, or 7-2H-furano[3,2-b]-pyranyl, 2, 3, 4, 5, 7, or 8-5H-pyrido[2,3-d]-o-azinyl, 1, 3, or 5-1H-pyrazolo[4,3-d]-azole, 2, 4, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazolel, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiophene, 2-, 4-, 5-, 6- or 7-benzozolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-10-membered heteroaryl group is linked to other groups to form the compounds of this invention, the carbon atom on the 5-10-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-10-membered heteroaryl ring may be linked to other groups. When the 5-10-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0178] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0179] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0180] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0181] Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may include those in which one, two, or more of the following positions (if present): substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene groups including thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; and pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0182] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0183] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-20 The definition of alkyl also applies to C 1-20 Terms such as alkyloxy groups.

[0184] In the term "three (C)" 1-20 "alkyloxy)silyl" and the term "tris(C)" 1-20 In "alkyl)silyl", each C 1-20 Alkyl groups may be the same as or different from each other, and are independently selected from the definitions described above.

[0185] The abbreviations of groups used in this article have meanings well known in the art, such as Me for methyl, Et for ethyl, Ph for phenyl, TMS for trimethylsilyl, i-Pr for isopropyl, and Ac for acetyl.

[0186] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0187] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0188] The compounds of the present invention can exist in the form of stereoisomers, which can be enantiomers and cis-trans isomers, or enantiomers and diastereomers.

[0189] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0190] The term "cis-trans isomers" refers to isomers with different orientations of the substituent atoms associated with the carbon-carbon double bond. The substituent atoms (not H) on either side of the carbon-carbon double bond can be E or Z configurations. In the "E" (opposite) or "chair" configuration, the substituent is on the opposite side of the carbon-carbon double bond; in the "Z" (same-side) or "boat" configuration, the substituent is oriented on the same side of the carbon-carbon double bond. Compounds having a mixture of "cis" and "trans" configurations are designated as "cis / trans".

[0191] The symbols “R”, “S”, “E”, “Z”, “cis”, “trans”, etc., described in this article are used to indicate the atomic configuration relative to the core molecule and are used in the manner defined in IUPAC Recommendations for Fundamental Stereochemistry (Section E) (Pure Appl. Chem., 1976, 45:13-30).

[0192] Individual isomers of the compounds of this invention can be prepared by isomer-specific synthesis or by resolution of mixtures of isomers. Conventional resolution techniques include using optically active salts to form the free bases of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free base), using esters or amides to form the isomers in an isomer pair (followed by chromatographic separation and removal of chiral excipients), or using preparative TLC (thin-layer chromatography) or chiral HPLC columns to resolve mixtures of isomers of either the starting material or the final product.

[0193] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0194] The term “therapeutic effective dose” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Therapeutic effective doses can initially be estimated by cell culture assays or by estimating the initial dose from in vivo data. Using these initial guidelines, those skilled in the art can determine the effective dose for humans. Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, e.g., by determining the LD50. 50 and ED 50 .

[0195] Examples of the "excipients" described in this invention can be found in "Handbook of Pharmaceutical Excipients, 2nd Edition, 1994, edited by A Wade and PJ Weller".

[0196] The “carrier” or “diluent” described in this invention is well known in the pharmaceutical field and has been described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro, 1985).

[0197] The choice of drug carrier, excipient, or diluent can be made based on the intended route of administration and standard pharmaceutical practice. A pharmaceutical composition may contain, or additionally contain, any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidants), etc., as a carrier, excipient, or diluent, and substances included to make the formulation isotonic with the recipient's blood.

[0198] For pharmaceutical formulations suitable for oral administration, where the carrier is solid, the most preferred form is a unit-dose formulation, such as pills, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active compound in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, lubricating substance, surfactant, or dispersant. Molded tablets can be prepared by molding the active compound and an inert liquid diluent. Tablets can optionally be coated, and if not coated, symbols can optionally be printed. Capsules can be prepared by filling the active compound alone or mixed with one or more excipients into a capsule shell and then sealing it in a conventional manner. Flat capsules are similar to capsules, wherein the active compound, along with any excipients, is sealed in a rice paper film. The active compound can also be formulated into dispersible granules, for example, which can be suspended in water or sprinkled on food before administration. Granules can be packaged, for example, in sachets. The carrier can be a liquid formulation suitable for oral administration, and can be presented as a solution or suspension in an aqueous or non-aqueous liquid form, or as an oil-in-water liquid emulsion.

[0199] The term "pharmaceutically acceptable salt" includes its suitable acid addition salt or base salt. For information on suitable pharmaceutical salts, see JPharm Sci, 66, 199, 1977, Berge et al.

[0200] The term "pharmaceutically acceptable ester" refers to an ester formed by the use of an organic acid or alcohol / hydroxide with an esterifiable functional group in the structure of the compounds of this invention.

[0201] The term "isotope label" indicates that at least one atom in the compounds of this invention is replaced by an isotope. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, as appropriate. 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35S, 18 F and 36 Cl. Using isotopes such as deuterium (i.e. 2 H) substitution can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom.

[0202] The term "prodrug compound" refers to a covalently bonded compound that releases an active parent drug according to general formula (I) in vivo. Such prodrugs are typically compounds of the present invention in which one or more suitable groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversal is usually achieved by enzymes naturally present in such subjects, although a second drug agent may be administered with this prodrug to facilitate reversal in vivo. Examples of such modifications include pharmaceutically acceptable esters as described above, where such reversal can be achieved by esterases, etc.

[0203] The term "polymorph" refers to the various crystalline, polycrystalline, and hydrated forms of the compounds of this invention. It is well known in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by purification and / or separation of the solvents used in the synthetic preparation of such compounds.

[0204] The term "administration" indicates that the pharmaceutical compositions of the present invention are suitable for administration rectally, intranasally, intrabronchially, topically (including orally and sublingually), vaginally or parenterally (including subcutaneously, intramuscularly, intravenously, intra-arterially, and intradermally), intraperitoneally, or intrathecally. Preferably, the formulation is an orally administered formulation. The formulation can be conveniently presented in unit dosage forms, i.e., in the form of discrete portions comprising a unit dose or multiple units or subunits of a unit dose. As examples, the formulation can be in the form of tablets and sustained-release capsules, and can be prepared by any method well known in the pharmaceutical field.

[0205] The formulations for oral administration of the present invention may take the form of: discrete units, such as capsules, gels, drops, sachets, pills, or tablets, each containing a predetermined amount of an active agent; as powders or granules; as solutions, emulsions, or suspensions of the active agent in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions; or as bolus formulations, etc. Preferably, each dose of these compositions contains 1 to 250 mg, more preferably 10 to 100 mg, of the active ingredient.

[0206] For compositions intended for oral administration (e.g., tablets and capsules), solvents and / or common excipients are also included, such as binders like syrups, gum arabic, gelatin, sorbitol, astragalus gum, polyvinylpyrrolidone (polyvinyl ether), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose, and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginate; and lubricants such as magnesium stearate, sodium stearate, and other metal stearates, glyceryl stearate, stearic acid, silicone fluids, talc, oils, and colloidal silica. Flavoring agents such as peppermint, wintergreen oil, and cherry flavoring may also be used. Coloring agents may be added to make the dosage form easily identifiable. Tablets may also be coated using methods well known in the art.

[0207] Other formulations suitable for oral administration include tablets containing a flavoring matrix, typically sucrose and active agents in gum arabic or astragalus gum; soft tablets containing an inert matrix such as gelatin and glycerin, or sucrose and gum arabic, containing active agents in a suitable liquid carrier; and mouthwashes containing active agents in a suitable liquid carrier.

[0208] Other forms of administration include solutions or emulsions prepared from sterile or sterile solutions for intravenous, intra-arterial, intrathecal, subcutaneous, intradermal, intraperitoneal, or intramuscular injection. Injectable formulations typically contain 10-1000 mg, preferably 10-250 mg, of the active ingredient per dose.

[0209] The administration method can also be combination administration, that is, combining one or more compounds of the present invention with one or more other active agents. In this case, the compounds of the present invention and one or more other active agents can be administered continuously, simultaneously, or sequentially. Detailed Implementation

[0210] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0211] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0212] Analytical methods

[0213] At room temperature, in the solvent, using a Bruker AV 400 spectrometer. 11H nuclear magnetic resonance (NMR) spectra, unless otherwise specified. In all cases, NMR data are consistent with the presented structure. Use conventional abbreviations for specifying the main peak, and give the characteristic chemical shift (δ) in parts per million: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet; br, broad. Mass spectra were recorded using an Agilent 1290 Infinity / 6460 triple Quad LCMS. When using thin-layer chromatography (TLC), it refers to silica gel TLC.

[0214] Example 1: Synthesis of thiabendazole base analogs containing nitro-substituted benzene rings

[0215] Step 1.1

[0216] Preparation of compound 5

[0217]

[0218] Under argon protection, p-nitrobenzaldehyde (0.18 g, 1 mmol), NC·TMS (0.12 g, 1.2 mmol), and IMESCL (0.03 g, 0.1 mmol) were dissolved in THF (5 mL). t-BuOK (0.01 g, 0.1 mmol) was added with stirring at room temperature, and the reaction was carried out for 5 min at room temperature. After the reaction was monitored by TLC plate until complete, the solution was concentrated, quenched with EtOAc (10 mL) and 2M HCl (5 mL), separated, extracted with EtOAc (2 × 10 mL), and the organic phases were combined. The solutions were washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Column separation was performed with a PE:EA ratio of 4:1.

[0219] Compound 5: pale yellow liquid, 1.90 g, yield 94%. 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),4.49(t,J=6.5H z,1H),3.26(s,1H),2.97(t,J=7.8Hz,2H),2.20(ddd,J=11.4,8.9,5.6Hz,2H)ppm.

[0220] Same as step 1.1, except that m-nitrobenzenepropionaldehyde and 3-nitrobenzenepropionaldehyde were used instead of p-nitrobenzenepropionaldehyde, yielding the following compounds 6 and 7 respectively:

[0221]

[0222] Compound 6: pale yellow liquid, 8.10 g, yield 94%. 1H NMR (400MHz, CDCl3) δ8.11 (dd, J=7.6, 1.4Hz, 2H), 7.56 (dt, J=7.7, 1.5Hz, 1H), 7.50 (td ,J=7.5,1.1Hz,1H),4.51(t,J=6.5Hz,1H),2.98(t,J=7.8Hz,2H),2.30–2.15(m,2H)ppm.

[0223]

[0224] Compound 7: colorless liquid, 7.2 g, yield 79%. 1 H NMR (400MHz, CDCl3) δ4.75–4.61(m,2H),4.61–4.51(m,1H),2.64–2.54(m,1H),2.53–2.42(m,1H)ppm.

[0225] Step 1.2

[0226] Preparation of compound 8

[0227]

[0228] General procedure: Under argon protection, compound 5 (1.90 g, 9.21 mmol) was dissolved in CH3OH (30 mL) solution, and concentrated HCl (6.5 mL) was added. The mixture was heated to 80 °C and refluxed overnight. After the reaction was monitored by TLC plate to ensure complete reaction, it was cooled to room temperature, concentrated, and quenched with EtOAc (20 mL) and H2O. The mixture was separated, extracted with EtOAc (2 × 20 mL), and the organic phases were combined. The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated.

[0229] Compound 8

[35] Pale yellow liquid, 2.15g, yield 98%. 1 H NMR (400MHz, CDCl3) δ8.15(d,J=8.7Hz,2H),7.37(d,J=8.8Hz,2H),4.19(dd,J=8.1,3.8Hz,1H),3.77(s,3H),2.97–2.76(m,2H),2.24–2.08(m,2H)ppm.

[0230] Similar to step 1.2, except that raw material 5 is replaced with 6 and 7, which can be used to prepare compounds 9 and 10 respectively:

[0231]

[0232] Compound 9: pale yellow liquid, 9.38 g, yield 98%. 1H NMR (400MHz, CDCl3) δ8.11–8.02(m,2H),7.55(d,J=7.5Hz,1H),7.45(t,J=7.8Hz,1H),4.19(dd,J=8.0,3. 9Hz,1H),3.77(s,3H),2.97–2.79(m,2H),2.16(dddd,J=13.7,9.7,7.2,3.9Hz,1H),2.06–1.92(m,1H)ppm.

[0233]

[0234] Compound 10: Yellow liquid, 6.7 g, yield 60%. 1 H NMR (400MHz, CDCl3) δ4.63–4.47(m,2H),4.31(dd,J=8.7,4.1Hz,1H),3.82(s,3H),2.58(ddd,J=14.6,11.5,7.2Hz,1H),2.27(dt,J=14.8,7.6Hz,1H)ppm.

[0235] Step 1.3

[0236] Preparation of compound 11

[0237]

[0238] Compound 8 (2.15 g, 9.00 mmol) was dissolved in 80 mL of CH₂Cl₂ solution, and Dess-Martin (11.45 g, 27.0 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by TLC plate to confirm its completion, saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (1:1) were added to quench the reaction. The mixture was separated, extracted with CH₂Cl₂ (2 × 40 mL), and the organic phases were combined. The mixture was washed with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Column separation was performed with a PE:EA ratio of 4:1.

[0239] Compound 11: pale yellow liquid, 1.37 g, yield 64%. 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 8.7Hz, 2H), 7.38 (d, J = 8.7Hz, 2H), 3.87 (s, 3H), 3.24 (t, J = 7.1Hz, 2H), 3.07 (t, J = 7.3Hz, 2H) ppm.

[0240] Similar to step 1.3, except that raw material 8 is replaced with 9 and 10, which can be used to prepare compounds 12 and 13 respectively:

[0241]

[0242] Compound 12: pale yellow liquid, 6.82 g, yield 73%. 1 H NMR (400MHz, CDCl3) δ8.08 (dd, J=7.5, 1.4Hz, 2H), 7.56 (d, J=7.6Hz, 1H), 7.47 ( t,J=8.1Hz,1H),3.87(s,3H),3.26(t,J=7.3Hz,2H),3.08(t,J=7.3Hz,2H)ppm.

[0243]

[0244] Compound 13: colorless liquid, 4.5 g, yield 68%. 1 H NMR (400MHz, CDCl3) δ4.73 (t, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.53 (t, J = 5.9 Hz, 2H) ppm.

[0245] Step 1.4

[0246] Preparation of compound 14

[0247]

[0248] General procedure: A CH3OH solution of p-nitrophenyl ring side chain ketone ester 11 (2.00 g, 8.40 mmol) in 2 mL was added dropwise to a 2 M NaOH aqueous solution (0.67 g, 16.80 mmol). The reaction was allowed to proceed at room temperature (approximately 2 h). After the reaction was completed as monitored by TLC, the solution was concentrated (to remove methanol), and Et2O (10 mL) was added. The mixture was separated, and the aqueous phase was quenched with 2 M HCl (10 mL), adjusted to pH < 1, extracted with Et2O (3 × 10 mL), and the organic phases were combined, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated.

[0249] Compound 14

[36] Pale yellow liquid, 1.00g, yield 99%. 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 8.7Hz, 2H), 7.39 (d, J = 8.8Hz, 2H), 3.31 (t, J = 7.3Hz, 2H), 3.09 (t, J = 7.2Hz, 2H) ppm.

[0250] Similar to step 1.4, except that raw material 11 is replaced with 12 and 13, which can be used to prepare compounds 15 and 16 respectively:

[0251]

[0252] Compound 15: pale yellow liquid, 1.00 g, 99% yield. 1 H NMR (400MHz, CDCl3) δ8.13–8.07(m,2H),7.56(d,J=7.6Hz,1H),7.51–7.46(m,1H),3.36(t,J=7.3Hz,2H),3.11(t,J=7.3Hz,2H)ppm.

[0253]

[0254] Compound 16: 4.3 g of colorless liquid, yield 96%. 1 H NMR (400MHz, CDCl3) δ4.66 (t, J = 5.9 Hz, 2H), 3.48 (t, J = 5.9 Hz, 2H) ppm.

[0255] Step 1.5

[0256] Preparation of compound 17

[0257]

[0258] General procedure: Under argon protection, add DMF (0.01 g, 0.02 mmol) and oxaloyl chloride (0.25 g, 2.0 mmol) dropwise to a CH2Cl2 (10 mL) solution of p-nitrophenyl side-chain α-keto acid 14 (0.23 g, 1 mmol) at 0 °C. Let the mixture react overnight at room temperature. After the reaction is complete as monitored by TLC, concentrate the solution. The crude product is obtained and can be used directly in the next step without further purification.

[0259] Under argon protection, CET (0.16 g, 0.5 mmol) was dissolved in pyridine (1 mL) and CH2Cl2 (5 mL) solutions. A CH2Cl2 (5 mL) solution of the previously generated p-nitrophenyl side-chain ketoacyl chloride (0.48 g, 2.00 mmol) was added dropwise at 0 °C, and the reaction was carried out overnight at 0 °C. The mixture was then heated to room temperature, washed with copious amounts of water, separated, and extracted with CH2Cl2 (2 × 10 mL). The combined organic phases were washed with sodium bicarbonate solution and sodium chloride solution, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and separated by gradient column chromatography (CH2Cl2:Et2O = 200:1–100:1).

[0260] Compound 17: pale yellow amorphous solid, 552 mg, yield 26%. 1H NMR (400MHz, CDCl3) δ8.12(d,J=8.5Hz,2H),7.24(d,J=8.7Hz,2H),6.56(s,1H),6.45(s,1H),5.88(d,J=9.3 Hz,1H),5.80(s,1H),5.75(s,1H),5.11(s,1H),3.82(d,J=9.4Hz,1H),3.70(s,3H),3.21–3.09(m,1H),3.10– 3.02(m,2H),2.94–2.85(m,1H),2.81(t,J=7.3Hz,2H),2.65(dt,J=7.2,3.1Hz,1H),2.61–2.54(m,2H),2.30( dd,J=14.6,7.0Hz,1H),2.00(dd,J=8.4,3.5Hz,1H),1.94–1.86(m,1H),1.78–1.71(m,2H)ppm.HRMS(ESI)m / z calcd for C 28 H 29 N₂O₈, [M+H] + 521.1918, found 521.1945.

[0261] Similar to step 1.5, except that raw material 14 is replaced with 15 and 16, which can be used to prepare compounds 18 and 19 respectively:

[0262]

[0263] Compound 18: pale yellow amorphous solid, 3.916 g, yield 52%. 1H NMR (400MHz, CDCl3) δ7.89(dt,J=6.6,2.5Hz,1H),7.80(s,1H),7.27(d,J=6.5Hz,2H),6.38(s,1H),6.24(s,1H),5.7 1(d,J=9.2Hz,1H),5.60(d,J=1.4Hz,1H),5.55(d,J=1.4Hz,1H),4.93(s,1H),3.65(d,J=9.4Hz,1H),3.53(s,3H),3.0 3–2.94(m,1H),2.92–2.87(m,1H),2.75–2.70(m,1H),2.64(t,J=7.3Hz,2H),2.48–2.38(m,4H),2.14(dd,J=14.5,7.0 Hz,1H),1.88–1.81(m,1H),1.72(ddd,J=12.2,7.6,4.6Hz,1H),1.57(dd,J=11.1,5.7Hz,2H)ppm.HRMS(ESI)m / zcalcd for C 28 H 29 N₂O₈, [M+H] + 521.1918, found 521.1919.

[0264]

[0265] Compound 19: Pale yellow amorphous solid, 2.84 g, yield 67%. HRMS(ESI) m / z calcd for C 22 H 25 N₂O₈, [M+H] + 445.1605, found 445.1610.

[0266] Step 1.6

[0267] Preparation of compound 20

[0268]

[0269] General Procedure: Under argon protection, boron trifluoride diethyl ether (0.57 g, 4 mmol) was added dropwise to a CH2Cl2 (10 mL) solution of p-nitrophenylcephalotaxine α-ketoester 17 (0.52 g, 1 mmol) at 0 °C. After 20 min, a CH2Cl2 (10 mL) solution of TMS-ketene (0.25 g, 0.5 mmol) was added dropwise, and the reaction was allowed to proceed overnight at 0 °C. After the reaction was complete as monitored by TLC, sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to 9. The mixture was then extracted with CH2Cl2 (3 × 10 mL). The organic phases were combined, washed with sodium chloride solution, and concentrated to remove the solvent, yielding the intermediate product. At room temperature, the intermediate product was dissolved in CH3CN (10 mL) solution, and KF·2H2O (0.47 g, 5 mmol) was added. The reaction was allowed to proceed for approximately 4 h. After the reaction was complete as monitored by TLC, the mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated. Column separation: PE:EA = 4:1, 0.5% TEA.

[0270] Compound 20: pale yellow amorphous solid, 40 mg, yield 22%. 1 H NMR (400MHz, CDCl3) δ8.15(d,J=8.6Hz,2H),7.28(d,J=8.6Hz,2H),6.61(s,1H),6.58(s,1H) ,5.92(dd,J=9.5,0.9Hz,1H),5.77(d,J=1.5Hz,1H),5.60(d,J=1.5Hz,1H),5.13(s,1H),3.8 4(d,J=9.5Hz,1H),3.73(s,3H),3.15–3.00(m,3H),2.98–2.84(m,2H),2.65–2.51(m,4H),2. 43–2.20(m,3H),2.08–1.97(m,1H),1.96–1.88(m,1H),1.82–1.71(m,2H)ppm.HRMS(ESI)m / z calcd forC 30 H 31 N₂O₉, [M+H] + 563.2024, found 563.2026.

[0271] Similar to step 1.6, except that raw material 17 is replaced with 18 and 19, which can be used to prepare compounds 21 and 22 respectively:

[0272]

[0273] Compound 21: pale yellow amorphous solid, 708 mg, yield 16%. 1H NMR (400MHz, CDCl3) δ8.09(dt,J=5.9,2.3Hz,1H),8.01(s,1H),7.47(d,J=5.2Hz,2H),6.63(s,1H),6.57(s,1H),5.94(dd,J=9 .4,0.9Hz,1H),5.79(d,J=1.5Hz,1H),5.65(d,J=1.5Hz,1H),5.15(s,1H),3.86(d,J=9.5Hz,1H),3.76(s,3H),3.16–3.05(m,2H ),3.01(d,J=16.5Hz,1H),2.93(td,J=11.5,6.9Hz,1H),2.80(d,J=16.5Hz,1H),2.72(td,J=12.9,4.5Hz,1H),2.64–2.56(m,3H ),2.46(dd,J=14.2,6.8Hz,1H),2.36–2.25(m,1H),2.15–2.06(m,1H),1.97–1.88(m,2H),1.79–1.73(m,2H)ppm.HRMS(ESI)m / z calcd for C 30 H 31 N₂O₉, [M+H] + 563.2024, found 563.2024.

[0274]

[0275] Compound 22: Pale yellow amorphous solid, 1.20 g, yield 76%. HRMS (ESI) m / z calcd for C 24 H 27 N₂O₉, [M+H] + 487.1711, found 487.1712.

[0276] Step 1.7

[0277] Preparation of compound I-2-1

[0278]

[0279] General Procedure: Under argon protection, slowly add a freshly prepared CH3ONa CH3OH solution (0.05 g, 1 mmol) to a CH3OH solution of p-nitrophenylcephalin 20 (0.56 g, 1 mmol) at room temperature (approximately 20 min). After the reaction is complete as monitored by TLC, quench with a saturated ammonium chloride solution (10 mL). Concentrate (to remove methanol), add 10 mL of water and 10 mL of CH2Cl2, stir, and separate the phases. Extract the aqueous phase with CH2Cl2 (3 × 10 mL), combine the organic phases, and concentrate to remove some solvent. Wash with a buffer solution of pH 6.8 (2 × 10 mL) until the cephalin is completely removed, wash with sodium bicarbonate solution and sodium chloride solution, and dry with anhydrous sodium sulfate. Filter and concentrate. Column separation: PE:EA = 4:1, 0.5% TEA.

[0280] Compound I-2-1: pale yellow amorphous solid, 25 mg, yield 52%. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.6Hz,2H),7.25(d,J=8.4Hz,2H),6.58(s,1H),6.56(s,1H),6.04(d,J=9.7Hz,1H),5 .83(d,J=1.6Hz,1H),5.74(d,J=1.6Hz,1H),5.11(s,1H),3.81(d,J=9.8Hz,1H),3.69(s,3H),3.65(s,1H),3.59(s,3H ),3.19–3.05(m,2H),2.94(td,J=11.6,6.9Hz,1H),2.75(td,J=12.7,5.3Hz,1H),2.66–2.54(m,2H),2.49–2.32(m,2H ),2.29(d,J=16.4Hz,1H),2.11–1.96(m,2H),1.92(ddd,J=12.2,7.6,4.6Hz,1H),1.82–1.69(m,4H)ppm.HRMS(ESI)m / z calcd for C 31 H 35 N2O 10 [M+H] + 595.2286, found 595.2288.

[0281] Same as step 1.7, except that raw material 20 is replaced with 21 and 22 to prepare compounds I-2-2 to I-2-4 respectively:

[0282]

[0283] Compound I-2-2: pale yellow amorphous solid, 516 mg, yield 69%. 1 H NMR (400MHz, CDCl3) δ8.05(d,J=7.0Hz,1H),7.96(s,1H),7.47–7.41(m,2H),6.57(s,1H),6.56(s,1H),6.06(d,J=9.7Hz,1 H),5.83(s,1H),5.76(s,1H),5.14(s,1H),3.83(d,J=9.8Hz,1H),3.73(s,3H),3.68(s,1H),3.59(s,3H),3.21–3.07(m,2H) ,2.98(td,J=11.8,10.8,6.3Hz,1H),2.78(td,J=13.0,5.1Hz,1H),2.70–2.59(m,2H),2.46(td,J=13.1,4.4Hz,1H),2.38( dd,J=14.0,6.8Hz,1H),2.28(d,J=16.6Hz,1H),2.12–2.04(m,1H),2.00–1.90(m,3H),1.82–1.72(m,3H)ppm.HRMS(ESI)m / z calcd for C 31 H 35 N2O 10 [M+H] + 595.2286, found 595.2284.

[0284]

[0285] Compound I-2-3: pale yellow amorphous solid, 720 mg, yield 75%. HRMS (ESI) m / z calcd for C 25 H 31 N2O 10 [M+H] + 519.1973, found 519.1970.

[0286]

[0287] Compound I-2-4: pale yellow amorphous solid, 680 mg, yield 70%. HRMS (ESI) m / z calcd for C 26 H 33 N2O 10 [M+H] + 533.2130, found 533.2135.

[0288] Example 2: Preparation of the base analogue I-2-5 of thiamethoxam

[0289]

[0290] I-2-2 (1 mmol) was dissolved in 1 mL of AcOH, and Zn powder (20 mmol) was added. The reaction was carried out at room temperature. After the reaction was completed by TLC, the mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with CH2Cl2 to obtain the filtrate. CH2Cl2 and sodium bicarbonate solution were added to the filtrate, and the mixture was stirred for 30 min. The liquid was separated, and the aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried, filtered, and concentrated. Column chromatography was performed to obtain the pale yellow solid product of the title compound I-2-5 (yield 93%). 1 H NMR (400MHz, CDCl3) δ7.05(t,J=7.7Hz,1H),6.59(s,1H),6.55(s,1H),6.53–6.48(m,2H),6.44(t,J=2.0Hz,1 H),6.05(d,J=9.8Hz,1H),5.84(d,J=1.6Hz,1H),5.75(d,J=1.6Hz,1H),5.08(s,1H),3.80(d,J=9.8Hz,1H),3 .70(s,3H),3.58(s,4H),3.20–3.09(m,2H),3.02–2.93(m,1H),2.64–2.50(m,3H),2.38(dd,J=14.2,6.8Hz,1 H),2.33–2.23(m,2H),2.07–1.92(m,3H),1.82–1.74(m,2H),1.70(dt,J=11.9,5.7Hz,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 37 N₂O₈, [M+H] + 565.2544, found 565.2541.

[0291] Example 3 Preparation of compounds I-2-6 to I-2-8

[0292] Referring to Example 2, the difference is that the raw material I-2-2 was replaced with I-2-1, I-2-3 and I-2-4 to prepare compounds I-2-6 to I-2-8 respectively.

[0293]

[0294] Compound I-2-6: Pale yellow amorphous product, 90% yield. HRMS(ESI) m / z calcd for C 31 H 37N₂O₈, [M+H] + 565.2544, found 565.2540.

[0295]

[0296] The product of compound I-2-7 was a pale yellow amorphous solid in 88% yield. HRMS(ESI) m / z calcd for C 25 H 33 N₂O₈, [M+H] + 489.2231, found 489.2230.

[0297]

[0298] The product of compound I-2-8 is a pale yellow amorphous solid in 92% yield. HRMS (ESI) m / z calcd for C 26 H 35 N₂O₈, [M+H] + 503.2388, found 503.2392.

[0299] Example 4: Preparation of the base analogue I-2-9 of cephalotaxine

[0300]

[0301] Under argon protection, TEA (3 mmol) and acetyl chloride (1.1 mmol) were added dropwise one at a time to 1 mmol of CH2Cl2 (5 mL) of I-2-5 at 0 °C. After the addition was complete, the mixture was allowed to react overnight at room temperature. After the reaction was monitored by TLC, sodium bicarbonate solution was added to quench the reaction, the pH was adjusted to 8, and the mixture was extracted with CH2Cl2. The organic phases were combined, dried, filtered, and concentrated. Column chromatography yielded a pale yellow solid product of the title compound (I-2-9) (93% yield). 1H NMR (400MHz, CDCl3) δ7.32(d,J=7.9Hz,1H),7.25(s,2H),7.20(t,J=7.8Hz,1H),6.84(d,J=7.5Hz,1H),6.59(s,1H), 6.55(s,1H),6.04(d,J=9.7Hz,1H),5.83(d,J=1.4Hz,1H),5.72(d,J=1.5Hz,1H),5.09(s,1H),3.80(d,J=9.8Hz,1H) ,3.70(s,3H),3.58(s,4H),3.20–3.06(m,2H),3.01–2.89(m,1H),2.66–2.56(m,3H),2.38(dd,J=14.2,6.9Hz,1H),2 .33–2.27(m,2H),2.16(s,3H),2.06–1.97(m,3H),1.96–1.87(m,2H),1.72(dt,J=11.9,5.7Hz,2H)ppm.HRMS(ESI)m / z calcd for C 33 H 39 N₂O₉, [M+H] + 607.2650, found 607.2651.

[0302] Example 5 Preparation of compounds I-2-10 and I-2-12

[0303] Referring to Example 4, the difference is that raw material I-2-5 was replaced with I-2-6 to I-2-8 to prepare compounds I-2-10 to I-2-12 respectively.

[0304]

[0305] Compound I-2-10: Pale yellow solid product, 90% yield. HRMS(ESI) m / z calcd for C 33 H 39 N₂O₉, [M+H] + 607.2650, found 607.2651.

[0306]

[0307] Compound I-2-11: Pale yellow solid product, 88% yield. HRMS(ESI) m / z calcd for C 27 H 35 N₂O₉, [M+H] + 531.2337, found 531.2339.

[0308]

[0309] Compound I-2-12: Pale yellow solid product, 88% yield. HRMS(ESI) m / z calcd for C 28 H 37 N₂O₉, [M+H] + 545.2494, found 545.2490.

[0310] Example 6 Preparation of compounds I-2-13 to I-2-22

[0311] The preparation method of compound I-2-9 in Example 5 is the same, except that different acyl chlorides are used instead of acetyl chlorides to react with compounds I-2-7 or I-2-8 to prepare compounds I-2-13 to I-2-22 respectively.

[0312]

[0313]

[0314] Example 7 Preparation of compounds I-2-23 to I-2-28 and I-1-100

[0315] Referring to Example 4, the difference is that different acyl chlorides were used instead of acetyl chloride to react with compound I-2-5 to prepare compounds I-2-23 to I-2-28 and I-1-100, respectively.

[0316]

[0317] Example 8: Preparation of Cephalotaxine Base Analog I-1-1

[0318]

[0319] Under argon protection, 1 mmol of p-toluene isocyanate was added dropwise to 5 mL of CH2Cl2 containing 1 mmol of I-2-5. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete, and then concentrated. Column chromatography yielded a pale yellow solid product of the title compound I-1-1 (96% yield). 1H NMR (400MHz, CDCl3) δ7.23(d,J=8.4Hz,3H),7.19(d,J=7.9Hz,1H),7.13(d,J=8.2Hz,2H),7.04(s,1H),6.83(d,J=6.8Hz,1H), 6.70(d,J=7.5Hz,1H),6.56(s,1H),6.54(s,1H),6.02(d,J=9.7Hz,1H),5.82(d,J=1.4Hz,1H),5.71(d,J=1.4Hz,1H),5.07(s, 1H),3.79(d,J=9.8Hz,1H),3.68(s,3H),3.58(s,3H),3.20–3.03(m,2H),3.00–2.85(m,1H),2.68–2.52(m,3H),2.36(dd,J=14 .2,6.8Hz,2H),2.32(s,3H),2.28(d,J=6.1Hz,1H),2.08–1.97(m,3H),1.97–1.85(m,2H),1.72–1.65(m,2H)ppm.HRMS(ESI)m / z calcd for C 39 H 44 N3O9, [M+H] + 698.3072, found 698.3072.

[0320] Example 9: Preparation of cephalotaxine base analogs I-1-2, I-1-7, I-1-9, I-1-12, I-1-22, I-1-97, I-1-98 and I-1-99

[0321] Referring to Example 8, except that cyclopentyl isocyanate, cyclopropyl isocyanate, cyclohexyl isocyanate, tert-butyl isocyanate, benzyl isocyanate, 4-methoxyphenyl isocyanate, 3-chloro-4-tolyl isocyanate, 3,5-ditrifluoromethylphenyl isocyanate, and 4-fluorophenyl isocyanate are used instead of p-tolyl isocyanate to prepare compounds I-1-2, I-1-7, I-1-9, I-1-12, I-1-22, I-1-26, I-1-97, I-1-98, and I-1-99, respectively.

[0322]

[0323] The title compound I-1-2 is a pale yellow solid product (yield 69%). 1H NMR (400MHz, CDCl3) δ7.17(d,J=4.9Hz,2H),7.00(s,1H),6.78(d,1H),6.58(s,1H),6.54(s,1H),6.03(d,J=9 .7Hz,1H),5.82(d,J=1.4Hz,1H),5.72(d,J=1.3Hz,1H),5.08(s,1H),3.79(d,J=9.8Hz,1H),3.68(s,3H),3.5 8(s,3H),3.20–3.03(m,3H),3.00–2.87(m,1H),2.65–2.54(m,3H),2.37(dd,J=14.0,6.8Hz,2H),2.29(d,J=1 6.5Hz,2H),2.03(d,J=8.7Hz,2H),2.01–1.90(m,4H),1.77–1.66(m,4H),1.66–1.58(m,4H)ppm.HRMS(ESI)m / z calcd for C 37 H 46 N3O9, [M+H] + 676.3229, found 676.3226.

[0324]

[0325] The title compound I-1-7 is a pale yellow solid product (yield 92%). 1H NMR(400MHz,Chloroform-d)δ7.24-7.20(m,1H),7.11(t,J=7.8Hz,1H),7.04(s,2H),6.71(d,J=7.5Hz,1H),6.52(s,1H),6.48(s,1H),5.97 (d,J=9.7Hz,1H),5.76(d,J=1.6Hz,1H),5.65(d,J=1.6Hz,1H),5.20(s,1H),5.02(s,1H),3.73(d,J=9.8Hz,1H),3.63(s,3H),3.58(s,1H), 3.51(s,3H),3.15–2.99(m,2H),2.88(td,J=11.5,6.8Hz,1H),2.64–2.48(m,4H),2.36–2.29(m,1H),2.24(dd,J=17.4,6.2Hz,2H),2.05–1. 93(m,2H),1.93–1.84(m,1H),1.73(d,J=8.0Hz,2H),1.69–1.60(m,2H),0.73(q,J=4.7Hz,2H),0.54(q,J=5.1,4.7Hz,2H)ppm.HRMS(ESI)m / z calcd for C 35 H 42 N3O9, [M+H] + 648.2916, found 648.2915.

[0326]

[0327] The title compound I-1-9 is a pale yellow solid product (yield 89%). 1H NMR (400MHz, Chloroform-d) δ7.20–7.13(m,2H),7.01(s,1H),6.84(s,1H),6.76(d,J=6.7Hz,1H),6.58(s,1H),6.54(s,1H),6.02(d,J=9.7H z,1H),5.82(d,J=1.6Hz,1H),5.72(d,J=1.6Hz,1H),5.08(s,1H),3.79(d,J=9.8Hz,1H),3.67(s,3H),3.64(s,1H),3.59-3.63(s,1H),3.58( s,3H),3.19–3.05(m,2H),2.92(td,J=11.5,6.9Hz,1H),2.59(ddt,J=17.6,12.4,6.6Hz,3H),2.41–2.34(m,1H),2.35–2.25(m,2H),2.08–1. 96(m,3H),1.95–1.89(m,3H),1.79–1.64(m,6H),1.57(dd,J=10.5,6.4Hz,1H),1.37–1.28(m,2H),1.17–1.06(m,3H)ppm.HRMS(ESI)m / zcalcd for C 38 H 48 N3O9, [M+H] + 690.3385, found 690.3382.

[0328]

[0329] The title compound I-1-12 is a pale yellow solid product (90% yield). 1H NMR (400MHz, Chloroform-d) δ7.12-7.04(m,2H),6.95(s,1H),6.76(d,J=12.6Hz,1H),6.66(d,J=6.8Hz,1H),6.51(s,1H),6.47(s, 1H),5.96(d,J=9.7Hz,1H),5.76(d,J=1.5Hz,1H),5.66(d,J=1.6Hz,1H),5.07-4.98(m,2H),3.72(d,J=9.8Hz,1H),3.62-3.57(m,4H ),3.50(s,3H),3.12–2.98(m,2H),2.86(td,J=11.6,7.0Hz,1H),2.60–2.47(m,3H),2.31(dd,J=14.4,6.7Hz,1H),2.23(dd,J=14.7 ,6.9Hz,2H),2.02–1.92(m,2H),1.90–1.82(m,1H),1.70(dd,J=12.1,5.4Hz,2H),1.67–1.61(m,2H),1.28(s,9H)ppm.HRMS(ESI)m / z calcd forC 36 H 46 N3O9, [M+H] + 664.3229, found 664.3226.

[0330]

[0331] The title compound I-1-17 is a pale yellow solid product (93% yield). 1H NMR(400MHz,Chloroform-d)δ7.24–7.17(m,5H),7.09(d,J=6.4Hz,2H),6.95(s,1H),6.82(s,1H),6.71(d,J=6.7Hz,1H),6.47(s,1H),6 .43(s,1H),5.93(d,J=9.6Hz,1H),5.71(d,J=1.6Hz,1H),5.59(d,J=1.6Hz,1H),5.48(s,1H),5.00(s,1H),4.40–4.28(m,2H),3.69(d,J= 9.7Hz,1H),3.60(s,3H),3.54(s,1H),3.50(s,3H),3.12–2.99(m,2H),2.86(td,J=11.5,6.7Hz,1H),2.63–2.43(m,3H),2.30(dd,J=14.2 ,6.6Hz,1H),2.25–2.17(m,2H),2.01–1.91(m,2H),1.89–1.82(m,1H),1.74–1.66(m,J=7.7Hz,2H),1.64–1.57(m,2H)ppm.HRMS(ESI)m / z calcd for C 39 H 44 N3O9, [M+H] + 698.3072, found 698.3070.

[0332]

[0333] The title compound I-1-22 is a pale yellow solid product (90% yield). 1H NMR(400MHz,Chloroform-d)δ7.42-7.38(m,2H),7.23-7.15(m,3H),7.10(t,J=7.7Hz,1H),7.03(s,1H),6.80–6.75(m,2H ),6.72(d,J=7.5Hz,1H),6.50(d,J=12.4Hz,2H),5.99(d,J=9.7Hz,1H),5.80(s,1H),5.69(s,1H),5.04(s,1H),3.76(s,1H ),3.72(s,3H),3.69(s,1H),3.64(s,3H),3.54(s,3H),3.16–3.04(m,2H),2.88(td,J=11.6,6.9Hz,1H),2.66–2.49(m,3H) ,2.33(td,J=6.7Hz,J=12.0,1H),2.30–2.23(m,2H),2.03–1.87(m,3H),1.74(m,2H),1.69–1.61(m,2H)ppm.HRMS(ESI)m / z calcd for C 39 H 44 N3O 10 [M+H] + 714.3021, found 714.3023.

[0334]

[0335] Compound I-1-97, as titled, is a pale yellow solid product (yield 88%). 1H NMR(400MHz,Chloroform-d)δ7.70(d,J=13.8Hz,2H),7.37(d,J=2.2Hz,1H),7.23–7.16(m,1H),7.15–7.08(m,2H),7.07–6.98( m,2H),6.73(d,J=7.5Hz,1H),6.57(s,1H),6.52(s,1H),6.02(d,J=9.7Hz,1H),5.82(d,J=1.5Hz,1H),5.73(d,J=1.6Hz,1H),5. 07(s,1H),3.80(s,1H),3.77(d,J=9.7Hz,1H),3.65(s,3H),3.55(s,3H),3.18–3.03(m,2H),2.95–2.85(m,1H),2.65–2.50(m,3 H),2.39–2.29(m,2H),2.25(s,3H),2.18-2.12(m,1H),2.07–1.87(m,3H),1.80–1.73(m,2H),1.73–1.66(m,2H).HRMS(ESI)m / z calcd for C 39 H 43 ClN3O9,[M+H] + 732.2682, found 732.2678.

[0336]

[0337] The title compound I-1-98 is a pale yellow solid product (yield 84%). 1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),8.00(s,2H),7.95(s,1H),7.46(s,1H),7.42(d,J=7.3Hz1H),7.16(t,J=7.8Hz,1H),7.03(s,1H ),6.73(d,J=7.6Hz,1H),6.60(s,1H),6.51(s,1H),6.04(d,J=9.7Hz,1H),5.83(d,J=1.5Hz,1H),5.75(d,J=1.5Hz,1H),5.11(s,1H),4.04 (s,1H),3.78(d,J=9.7Hz,1H),3.64(s,3H),3.54(s,3H),3.18–3.05(m,2H),2.93(td,J=11.4,6.9Hz,1H),2.63(ddd,J=16.4,13.4,7.8Hz ,3H),2.42(ddt,J=13.9,10.5,7.1Hz,2H),2.30(d,J=16.9Hz,1H),2.10–1.97(m,2H),1.97–1.88(m,1H),1.82-1.70(m,4H).HRMS(ESI)m / z calcd for C 40 H 40 F6N3O9,[M+H] + 820.2663, found 820.2652.

[0338]

[0339] The title compound I-1-99 is a pale yellow solid product (yield 84%). 1H NMR (400MHz, Chloroform-d) δ7.85–7.62(m,2H),7.32–7.22(m,2H),7.19(d,J=8.1Hz,1H),7.12(t,J=7.6Hz,1H),7.05(s,1H),6.90(t,J=8.0 Hz,2H),6.74(d,J=7.6Hz,1H),6.55(s,1H),6.50(s,1H),6.01(d,J=9.7Hz,1H),5.82(d,J=1.6Hz,1H),5.72(d,J=1.6Hz,1H),5.06(s,1H),3.7 7(d,J=9.8Hz,1H),3.66(s,3H),3.59(s,1H),3.55(s,3H),3.19–3.05( m,2H),2.90(td,J=11.5,6.8Hz,1H),2.69–2.48(m,3H),2.40–2.28(m,2 H),2.27(d,J=16.7Hz,1H),2.07–1.99(m,1H),1.97(d,J=16.9Hz,1H),1.95–1.85(m,1H),1.83–1.70(m,2H),1.73–1.64(m,2H).HRMS(ESI)m / z calcd for C 38 H 41 FN3O9,[M+H] + 702.2821, found 702.2829.

[0340]

[0341] Example 10: Preparation of thiabendazole alkaloid analogs I-1-3 to I-1-36 (compounds other than those in Example 9)

[0342] Referring to Example 8, the difference is that compounds I-1-3 to I-1-33 were prepared using isocyanates with different substitutions.

[0343]

[0344] Example 11: Preparation of basalt analogues I-1-34 to I-1-63

[0345] Referring to Example 8, the difference is that compounds I-1-34 to I-1-63 were prepared by reacting compound I-2-7 with isocyanates of different substitutions.

[0346]

[0347] Example 12: Preparation of thiabendazole alkaloid analogs I-1-64 to I-1-72

[0348] Referring to Example 8, the difference is that compounds I-1-64 to I-1-72 were prepared by reacting compound I-2-8 with isocyanates of different substitutions.

[0349]

[0350] Example 13: Preparation of thiabendazole alkaloid analog I-1-73

[0351] Referring to Example 8, the difference is that benzoyl isocyanate was used instead of p-tolyl isocyanate to react with compound I-2-5 to prepare compound I-1-73.

[0352]

[0353] The pale yellow solid product of the title compound I-1-73 (yield 92%). 1 H NMR (400MHz, CDCl3) δ10.80(s,1H),8.75(s,1H),7.94(s,1H),7.82(d,J=8.6Hz,1H),7.65(d,J=7.4Hz,1H),7.54(t,J=7.6Hz,2H),7 .51–7.43(m,2H),6.91(s,1H),6.60(s,1H),6.56(s,1H),6.06(d,J=9.9Hz,1H),5.84(d,J=1.4Hz,1H),5.75(d,J=1.4Hz,1H),5.13( s,1H),3.81(d,J=9.8Hz,1H),3.73(s,3H),3.64(s,1H),3.59(s,3H),3.27–3.00(m,2H),3.00–2.88(m,1H),2.85–2.47(m,3H),2.46 –2.34(m,1H),2.31(d,J=16.6Hz,1H),2.08–1.97(m,2H),1.94(d,J=10.2Hz,1H),1.88–1.65(m,3H),1.58(s,2H)ppm.HRMS(ESI)m / z calcd for C 39 H 42 N3O 10 [M+H] + 712.2865, found 712.2865.

[0354] Example 14: Preparation of thiabendazole alkaloid analogs I-1-74 to I-1-81

[0355] Referring to Example 8, the difference is that different acyl isocyanates were used instead of p-tolyl isocyanates to react with compounds I-2-5, I-2-7, or I-2-8 respectively to prepare compounds I-1-74 to I-1-81.

[0356]

[0357] Example 15: Preparation of thiabendazole alkaloid analog I-1-82

[0358] Referring to Example 8, except that benzenesulfonyl isocyanate was used instead of p-tolyl isocyanate to prepare compound I-1-82.

[0359]

[0360] The pale yellow solid product of the title compound I-1-82 (yield 83%). 1 H NMR(400MHz, CDCl3) δ7.79(d,J=7.1Hz,2H),7.25–7.11(m,3H),7.10–7.00(m,1H),6.70(d,J=5.8Hz,1H),6.55( s,1H),6.47(s,1H),6.00(d,J=9.4Hz,1H),5.80(d,J=1.4Hz,1H),5.68(d,J=1.4Hz,1H),5.08(s,1H),3.82(d,J =9.1Hz,1H),3.60(s,3H),3.54(s,3H),3.41–3.27(m,1H),3.27–3.12(m,2H),3.12–3.00(m,1H),2.61–2.39(m, 2H),2.36(s,3H),2.31–2.13(m,3H),2.09–1.89(m,3H),1.89–1.72(m,2H),1.72–1.54(m,2H)ppm.HRMS(ESI)m / z calcd forC 39 H 44 N3O 11 S,[M+H] + 762.2691, found 762.2691.

[0361] Example 16: Preparation of thiabendazole alkaloid analogs I-1-83 to I-1-96

[0362] Referring to Example 8, the difference is that compounds I-2-5, I-2-7, or I-2-8 were reacted with different substituted nitrile amines, acyl nitrile amines, or different substituted carbodiimides to prepare compounds I-1-83 to I-1-96 respectively.

[0363]

[0364] Example 17: Preparation of β-cyclic lactone holoharponenolate alkaloids 23-40

[0365] Referring to step 1.6 of Example 1, the difference is that trimethylsilyl ketenes with different side chain substitutions were reacted with trimethylsilyl ketenes to prepare compounds 23-40.

[0366]

[0367] Compound 23: pale yellow solid, yield 23%. (c 0.45, CHCl3). 1 H NMR (400MHz, CDCl3) δ6.60(d,J=2.6Hz,2H),5.92(d,J=9.6Hz,1H),5.86(dd,J=7.3,1.5Hz,2H),5 .09(s,1H),3.82(d,J=9.5Hz,1H),3.69(s,3H),3.13–3.03(m,2H),3.00(d,J=16.5Hz,1H),2.95– 2.89(m,1H),2.74(d,J=16.5Hz,1H),2.62–2.57(m,2H),2.35(dd,J=14.2,6.8Hz,1H),2.09–2.00 (m,3H),1.91(ddd,J=12.1,7.6,4.2Hz,2H),1.80–1.71(m,3H),1.56–1.47(m,2H).HRMS(ESI)m / z calcd for C 26 H 29 F3NO7,[M+H] + 524.1891, found 524.1889.

[0368]

[0369] Compound 24: Pale yellow solid product (yield 30%). (c 0.7, CHCl3). 1H NMR(400MHz, CDCl3) δ6.60(d,J=4.2Hz,2H),5.90(d,J=9.5Hz,1H),5.87(dd,J=10.3,1.5Hz,2H),5.11 (s,1H),3.82(d,J=9.4Hz,1H),3.68(s,2H),3.11–3.03(m,2H),3.04(d,J=16.4Hz,1H),2.93(td,J=11 .9,11.4,6.8Hz,1H),2.80(d,J=16.4Hz,1H),2.62–2.56(m,2H),2.36(dd,J=14.0,6.5Hz,1H),2.28–2 .20(m,1H),2.04(ddd,J=12.6,10.8,7.0Hz,3H),1.97–1.88(m,3H),1.75–1.72(m,2H).HRMS(ESI)m / z calcd for C 26 H 27 F5NO7,[M+H] + 560.1702, found 560.1700.

[0370]

[0371] Compound 25: pale yellow amorphous solid, yield 50%. 1 H NMR (400MHz, CDCl3) δ7.09(dd,J=7.9,5.7Hz,2H),6.98(t,J=8.6Hz,2H),6.63(s,1H),6.59(s,1H),5.95(d,J=9.5Hz,1H) ,5.81(s,1H),5.61(s,1H),5.14(s,1H),3.86(d,J=9.5Hz,1H),3.74(s,3H),3.17–3.06(m,2H),3.01(d,J=16.5Hz,1H),2. 94(td,J=11.7,7.1Hz,1H),2.83(d,J=16.5Hz,1H),2.64–2.56(m,2H),2.48(td,J=12.6,4.7Hz,1H),2.37(dd,J=14.3,6.9 Hz,1H),2.32–2.26(m,1H),2.25–2.17(m,1H),2.10–2.03(m,1H),1.97–1.88(m,2H),1.81–1.74(m,2H)ppm.HRMS(ESI)m / z calcd for C 30 H 31 FNO7, [M+H] +536.2082, found 536.2085.

[0372]

[0373] Compound 26: pale yellow amorphous solid, yield 80%. 1 H NMR (400MHz, CDCl3) δ7.54(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),6.62(s,1H),6.58(s,1H),5.94(dd,J=9.5,0.9Hz,1H),5. 78(d,J=1.5Hz,1H),5.57(d,J=1.5Hz,1H),5.13(d,J=0.9Hz,1H),3.85(d,J=9.5Hz,1H),3.73(s,3H),3.10(ddt,J=13.3,8.9, 6.7Hz,2H),3.02(d,J=16.5Hz,1H),2.93(td,J=11.6,6.9Hz,1H),2.86(d,J=16.5Hz,1H),2.67–2.47(m,3H),2.42–2.28(m,2H ),2.22(ddd,J=14.1,12.1,4.7Hz,1H),2.05(dt,J=12.3,9.6Hz,1H),1.98–1.86(m,2H),1.83–1.70(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 31 F3NO7,[M+H] + 586.2047, found 586.2053.

[0374]

[0375] Compound 27: pale yellow amorphous solid, 97% yield. 1H NMR(400MHz, CDCl3)δ7.07(q,J=8.1Hz,1H),6.84–6.72(m,2H),6.61(s,1H),6.56(s,1H),5.93(d,J=9.5Hz,1H),5.8 0(s,1H),5.64(s,1H),5.11(s,1H),3.83(d,J=9.6Hz,1H),3.71(s,3H),3.16–3.04(m,2H),3.01(d,J=16.5Hz,1H),2 .92(td,J=11.5,7.0Hz,1H),2.81(d,J=16.6Hz,1H),2.63–2.55(m,2H),2.49(dd,J=12.5,4.7Hz,1H),2.40–2.30(m, 2H),2.17(td,J=13.1,12.4,4.9Hz,1H),2.08–2.01(m,1H),1.95–1.85(m,2H),1.79–1.72(m,2H)ppm.HRMS(ESI)m / z calcd forC 30 H 30 F2NO7,[M+H] + 554.1987, found 554.1990.

[0376]

[0377] Compound 28: pale yellow amorphous solid, yield 50%. 1 H NMR (400MHz, CDCl3) δ6.71–6.56(m,5H),5.93(d,J=9.5Hz,1H),5.81(d,J=1.6Hz,1H),5.69(d,J=1.5 Hz,1H),5.13(s,1H),3.85(d,J=9.5Hz,1H),3.74(s,3H),3.12–3.05(m,2H),2.99(d,J=16.5Hz,1H),2 .92(td,J=11.9,7.2Hz,1H),2.78(d,J=16.5Hz,1H),2.63–2.55(m,2H),2.49(td,J=12.8,12.3,5.0H z,1H),2.38–2.14(m,3H),2.06–2.01(m,1H),1.96–1.88(m,2H),1.80–1.73(m,2H)ppm.HRMS(ESI)m / z calcd for C 30 H 30 F2NO7,[M+H] +554.1979, found 554.1990.

[0378]

[0379] Compound 29: Pale yellow amorphous solid, 95% yield. 1 H NMR (400MHz, CDCl3) δ6.98–6.92(m,1H),6.91–6.82(m,2H),6.62(s,1H),6.56(s,1H),5.95(d,J=9 .5Hz,1H),5.81(d,J=1.5Hz,1H),5.68(d,J=1.5Hz,1H),5.12(s,1H),3.88–3.81(m,1H),3.73(s,3H ),3.15–3.05(m,2H),3.04–2.92(m,2H),2.79(d,J=16.5Hz,1H),2.63–2.55(m,3H),2.40–2.30(m, 2H),2.23–2.12(m,1H),2.10–2.00(m,1H),1.98–1.86(m,2H),1.81–1.72(m,2H)ppm.HRMS(ESI)m / z calcd for C 30 H 30 F2NO7,[M+H] + 554.1983, found 554.1990.

[0380]

[0381] Compound 30: pale yellow amorphous solid, 97% yield. 1H NMR(400MHz, CDCl3)δ7.05–6.96(m,2H),6.87(t,J=7.1Hz,1H),6.61(s,1H),6.56(s,1H),5.93(d,J=9.5Hz,1H),5 .80(s,1H),5.66(s,1H),5.11(s,1H),3.84(d,J=9.5Hz,1H),3.72(s,3H),3.15–3.06(m,2H),3.01(d,J=16.5Hz,1H ),2.92(td,J=11.8,7.0Hz,1H),2.79(d,J=16.5Hz,1H),2.66–2.52(m,3H),2.46(dt,J=18.0,9.1Hz,1H),2.35(dd, J=14.2,6.8Hz,1H),2.26–2.19(m,1H),2.07–1.99(m,1H),1.95–1.86(m,2H),1.81–1.69(m,2H)ppm.HRMS(ESI)m / z calcd for C 30 H 30 F2NO7,[M+H] + 554.1983, found 554.1990.

[0382]

[0383] Compound 31: Pale yellow amorphous solid, yield 89%. 1H NMR (400MHz, CDCl3) δ7.61 (dd, J=7.9, 1.4Hz, 1H), 7.48 (dd, J=8.3, 6.9Hz, 1H), 7.32 (t, J=7.7Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 6.61 (s, 1H), 6.54(s,1H),5.97(dd,J=9.5,1.0Hz,1H),5.78(d,J=1.5Hz,1H),5.57(d,J=1.5Hz,1H),5.11(d,J=1.0Hz,1H),3.84(d,J=9.6Hz,1H),3.72( s,3H),3.16–3.06(m,2H),3.02(d,J=16.5Hz,1H),2.92(td,J=11.7,7.0Hz,1H),2.80(d,J=16.5Hz,1H),2.70(td,J=13.0,4.6Hz,1H),2.63 –2.54(m,3H),2.34(dd,J=14.3,6.9Hz,1H),2.23–2.15(m,1H),2.07–2.02(m,1H),1.94–1.88(m,2H),1.79–1.73(m,2H)ppm.HRMS(ESI)m / z calcdfor C 31 H 31 F3NO7,[M+H] + 586.2045, found 586.2053.

[0384]

[0385] Compound 32: pale yellow amorphous solid, yield 80%. 1H NMR (400MHz, CDCl3) δ7.48(d,J=7.7Hz,1H),7.45–7.36(m,2H),7.31(d,J=7.6Hz,1H),6.62(s,1H),6.57(s,1H),5.96(d,J= 9.5Hz,1H),5.79(d,J=1.5Hz,1H),5.61(d,J=1.5Hz,1H),5.13(s,1H),3.85(d,J=9.5Hz,1H),3.73(s,3H),3.18–3.04(m,2H) ,2.98(d,J=16.5Hz,1H),2.93(td,J=11.5,6.9Hz,1H),2.81(d,J=16.5Hz,1H),2.69–2.49(m,3H),2.42–2.30(m,1H),2.23( td,J=12.9,12.2,4.7Hz,1H),2.11–1.99(m,1H),1.96–1.87(m,1H),1.79–1.72(m,2H),1.71–1.62(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 31 F3NO7,[M+H] + 586.2044, found 586.2053.

[0386]

[0387] Compound 33: pale yellow amorphous solid, yield 56%. 1H NMR(400MHz, CDCl3)δ7.32(dd,J=9.1,2.7Hz,1H),7.26–7.22(m,1H),7.18(td,J=8.1,2.6Hz,1H),6.61(s,1H),6.55(s,1H), 5.95(d,J=9.5Hz,1H),5.79(d,J=1.5Hz,1H),5.59(d,J=1.6Hz,1H),5.11(s,1H),3.84(d,J=9.5Hz,1H),3.72(s,3H),3.17–3. 03(m,2H),3.01(d,J=16.6Hz,1H),2.92(td,J=11.6,7.0Hz,1H),2.80(d,J=16.5Hz,1H),2.72–2.44(m,4H),2.34(dd,J=14.3 ,6.9Hz,1H),2.18(ddd,J=14.3,12.1,4.8Hz,1H),2.08–1.98(m,1H),1.97–1.79(m,2H),1.82–1.70(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 30 F4NO7, [M+H] + 604.1952, found 604.1958.

[0388]

[0389] Compound 34: pale yellow amorphous solid, yield 63%. 1H NMR (400MHz, CDCl3) δ7.54(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),6.62(s,1H),6.58(s,1H),5.94(dd,J=9.5,0.9Hz,1H),5. 78(d,J=1.5Hz,1H),5.57(d,J=1.5Hz,1H),5.13(d,J=0.9Hz,1H),3.85(d,J=9.5Hz,1H),3.73(s,3H),3.10(ddt,J=13.3,8.9, 6.7Hz,2H),3.02(d,J=16.5Hz,1H),2.93(td,J=11.6,6.9Hz,1H),2.86(d,J=16.5Hz,1H),2.67–2.47(m,3H),2.42–2.28(m,2H ),2.22(ddd,J=14.1,12.1,4.7Hz,1H),2.05(dt,J=12.3,9.6Hz,1H),1.98–1.86(m,2H),1.83–1.70(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 34 NO7, [M+H] + 532.2331, found 532.2335.

[0390]

[0391] Compound 35: pale yellow amorphous solid, yield 89%. 1H NMR (400MHz, CDCl3) δ7.98–7.91(m,1H),7.86(dd,J=7.1,2.2Hz,1H),7.74(d,J=8.2Hz,1H),7.56–7.44(m,2H),7.39(dd,J=8.2,7. 0Hz,1H),7.7.29–7.25(m,1H),6.64(s,1H),6.50(s,1H),6.04(dd,J=9.5,0.9Hz,1H),5.72(d,J=1.5Hz,1H),5.42(d,J=1.5Hz,1H), 5.16(s,1H),3.88(d,J=9.6Hz,1H),3.73(s,3H),3.27–3.13(m,1H),3.15–3.05(m,1H),3.01–2.82(m,4H),2.80(d,J=16.5Hz,1H),2 .69–2.56(m,2H),2.46–2.29(m,2H),2.10–2.00(m,1H),2.00–1.90(m,1H),1.83–1.73(m,2H),1.72–1.67(m,1H)ppm.HRMS(ESI)m / z calcd for C 34 H 34 NO7, [M+H] + 568.2326, found 568.2335.

[0392]

[0393] Compound 36: pale yellow amorphous solid, yield 85%. 1H NMR (400MHz, CDCl3) δ7.84–7.73(m,3H),7.56(s,1H),7.48–7.41(m,2H),7.25(d,J=8.5Hz,1H),6.63(s,1H),6.5 8(s,1H),5.98(d,J=9.5Hz,1H),5.74(s,1H),5.51(s,1H),5.13(s,1H),3.86(d,J=9.5Hz,1H),3.75(s,3H),3.21 –3.04(m,2H),3.01(d,J=16.5Hz,1H),2.98–2.89(m,1H),2.86(d,J=16.5Hz,1H),2.68–2.54(m,3H),2.45(dt,J= 13.0,6.4Hz,1H),2.41–2.26(m,2H),2.09–1.97(m,2H),1.98–1.87(m,1H),1.83–1.71(m,2H)ppm.HRMS(ESI)m / z calcd for C 34 H 34 NO7, [M+H] + 568.2321, found 568.2335.

[0394]

[0395] Compound 37: pale yellow amorphous solid, yield 89%. 1H NMR (400MHz, CDCl3) δ7.03(d,J=8.2Hz,2H),6.82(d,J=8.1Hz,2H),6.61(s,1H),6.58(s,1H),5.94(d,J=9.5Hz,1H),5.80(d,J=1.6Hz,1H ),5.61(d,J=1.6Hz,1H),5.12(s,1H),3.84(d,J=9.5Hz,1H),3.78(s,3H),3.73(s,3H),3.18–3.03(m,2H),2.96(d,J=16.7Hz,1H),2.97–2 .87(m,1H),2.78(d,J=16.5Hz,1H),2.66–2.54(m,2H),2.45(td,J=12.8,4.8Hz,1H),2.35(dd,J=14.2,6.9Hz,1H),2.26(td,J=13.1,12. 6,4.6Hz,1H),2.16(ddd,J=16.5,11.7,4.7Hz,1H),2.05(dt,J=12.8,9.6Hz,1H),1.95–1.86(m,2H),1.86–1.70(m,2H)ppm.HRMS(ESI)m / z calcd forC 31 H 34 NO8, [M+H] + 548.2276, found 548.2284.

[0396]

[0397] Compound 38: pale yellow amorphous solid, yield 69%. 1 H NMR (400MHz, CDCl3) 1H NMR (400MHz, CDCl3) δ7.11 (s, 4H), 6.63 (s, 1H), 6.59 (s, 1H), 5.89 (dd, J = 37.7, 9.1Hz, 1H), 5.74 (d, J = 10.2Hz, 1H), 5.50(d,1H),5.13(d,J=14.4Hz,1H),3.88(d,J=9.4Hz,1H),3.76(s,3H),3.18(ddt,J=13.5,8.9,6,5Hz,2H),3.08(d ,J=16.5Hz,1H),2.97(td,J=11.4,6.7Hz,1H),2.72(d,J=16.5Hz,1H),2.50–2.27(m,3H),2.24–2.16(m,2H),2.00( ddd,J=14.2,12.2,4.8Hz,1H),1.98(dtJ=12.4,9.7Hz,1H),1.98–1.87(m,2H),1.82–1.67(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 31 F3NO8,[M+H] + 602.2002, found 602.1993.

[0398]

[0399] Compound 39: Pale yellow amorphous solid, yield 89%. 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.2Hz,2H),7.04(d,J=8.3Hz,2H),6.61(s,1H),6.58(s,1H),5.94(dd,J=9.5,0.9Hz,1H) ,5.80(d,J=1.6Hz,1H),5.59(d,J=1.5Hz,1H),5.11(d,J=0.9Hz,1H),3.84(d,J=9.5Hz,1H),3.72(s,3H),3.17–3.05(m,2H ),2.98(d,J=16.5Hz,1H),2.92(dt,J=12.0,5.8Hz,1H),2.83(d,J=16.5Hz,1H),2.63–2.55(m,2H),2.49–2.40(m,4H),2. 35(dd,J=14.2,6.9Hz,1H),2.30–2.13(m,2H),2.09–2.01(m,1H),1.95–1.85(m,2H),1.80–1.70(m,2H)ppm.HRMS(ESI)m / z calcd for C31 H 34 NO7S, [M+H] + 564.2056, found 564.2038.

[0400]

[0401] Compound 40: pale yellow amorphous solid, yield 87%. 1 H NMR (400MHz, CDCl3) δ7.58(d,J=8.2Hz,2H),7.52(d,J=8.0Hz,2H),7.44(t,J=7.5Hz,2H),7.39–7.30(m,1H),7.20(d,J=8 .0Hz,2H),6.63(s,1H),6.59(s,1H),5.97(d,J=9.5Hz,1H),5.80(s,1H),5.60(s,1H),5.12(s,1H),3.86(d,J=9.5Hz,1H), 3.74(s,3H),3.18–3.06(m,2H),3.02(d,J=16.6Hz,1H),2.94(td,J=11.7,7.9Hz,1H),2.84(d,J=16.5Hz,1H),2.66–2.48 (m,3H),2.40–2.31(m,1H),2.30–2.18(m,1H),2.12–1.97(m,2H),1.99–1.88(m,2H),1.83–1.71(m,2H)ppm.HRMS(ESI)m / z calcd for C 36 H 36 NO7, [M+H] + 594.2478, found 594.2492.

[0402] Example 18: Preparation of Cephalotaxine Alkaloids I-2-29 to I-2-46

[0403] Referring to step 1.7 of Example 1, the difference is that compounds 23-40 are used for ring-opening methyl esterification reactions to prepare compounds I-2-29 to I-2-46 respectively:

[0404]

[0405] Compound I-2-29: Pale yellow solid product (yield 67%). (c 1,CHCl3). 1H NMR (400MHz, CDCl3) δ6.62(s,1H),6.53(s,1H),6.01(dd,J=9.8,1.0Hz,1H),5.86(dd,J=5.9,1.5Hz,2H) ,5.05(s,1H),3.77(d,J=9.8Hz,1H),3.72(s,1H),3.66(s,3H),3.57(s,3H),3.14–3.04(m,2H),2.94(td ,J=11.4,6.8Hz,1H),2.62–2.56(m,3H),2.37(dd,J=14.0,6.7Hz,1H),2.24(d,J=16.5Hz,1H),2.05–2.0 2(m,2H),1.95–1.86(m,2H),1.87(d,J=16.5Hz,1H),1.81–1.70(m,3H),1.53–1.49(m,2H).HRMS(ESI)m / z calcd for C 27 H 33 F3NO8,[M+H] + 556.2153, found 556.2145.

[0406]

[0407] Compound I-2-30: pale yellow solid product (yield 85%). (c 1.1,CHCl3). 1 H NMR (400MHz, CDCl3) δ6.64(s,1H),6.53(s,1H),6.03(d,J=9.8Hz,1H),5.87(d,J=5.5Hz,2H) ,5.07(s,1H),3.78(d,J=9.9Hz,1H),3.70(s,1H),3.63(s,3H),3.58(s,3H),3.13–3.03(m,2 H),2.95(td,J=11.4,6.6Hz,1H),2.63–2.56(m,2H),2.39(dd,J=13.9,6.5Hz,1H),2.29(d,J =16.6Hz,1H),2.08–2.00(m,2H),1.97–1.87(m,3H),1.78–1.67(m,4H).HRMS(ESI)m / zcalcd for C 27 H 31 F5NO8,[M+H] + 592.1965, found 592.1962.

[0408]

[0409] Compound I-2-31: pale yellow amorphous solid, yield 55%. 1 H NMR (400MHz, CDCl3) δ7.05(dd,J=8.5,5.6Hz,2H),6.95(t,J=8.7Hz,2H),6.58(s,1H),6.55(s,1H),6.05(dd,J =9.8,0.9Hz,1H),5.84(d,J=1.6Hz,1H),5.73(d,J=1.6Hz,1H),5.09(s,1H),3.81(d,J=9.8Hz,1H),3.69(s,3H ),3.61(s,1H),3.59(s,3H),3.21–3.06(m,2H),2.97(td,J=11.3,6.7Hz,1H),2.68–2.55(m,3H),2.42–2.25(m ,2H),2.30(d,J=16.4Hz,1H),2.12–1.88(m,3H),1.98(d,J=16.4Hz,1H),1.83–1.65(m,4H)ppm.HRMS(ESI)m / z calcd for C 31 H 35 FNO8, [M+H] + 568.2341, found 568.2347.

[0410]

[0411] Compound I-2-32: pale yellow amorphous solid, yield 50%. 1H NMR (400MHz, CDCl3) δ7.52(d,J=7.9Hz,2H),7.21(d,J=7.9Hz,2H),6.58(s,1H),6.56(s,1H),6.06(d,J=9.8Hz,1H),5.83(d,J =1.5Hz,1H),5.71(d,J=1.5Hz,1H),5.10(s,1H),3.81(d,J=9.8Hz,1H),3.69(s,3H),3.64(s,1H),3.59(s,3H),3.21–3.05(m,2 H),2.95(td,J=11.6,6.9Hz,1H),2.71(td,J=12.8,5.2Hz,1H),2.61(dd,J=10.7,7.7Hz,2H),2.47–2.34(m,2H),2.30(d,J=16 .5Hz,1H),2.10–2.02(m,1H),1.99(d,J=16.4Hz,1H),1.92(ddd,J=12.2,7.7,4.5Hz,1H),1.82–1.68(m,4H)ppm.HRMS(ESI)m / z calcd for C 29 H 29 F3NO6,[M+H] + 618.2305, found 618.2315.

[0412]

[0413] Compound I-2-33: pale yellow amorphous solid, yield 82%. 1H NMR (400MHz, CDCl3) δ7.07(q,J=8.1Hz,1H),6.82–6.70(m,2H),6.59(s,1H),6.54(s,1H),6.04(d,J=9.8Hz,1H),5.85(d ,J=1.6Hz,1H),5.75(d,J=1.6Hz,1H),5.08(s,1H),3.80(d,J=9.8Hz,1H),3.67(s,3H),3.64(s,1H),3.58(s,3H),3.23– 3.05(m,2H),2.95(td,J=11.5,7.0Hz,1H),2.66–2.54(m,3H),2.46(dd,J=12.0,5.7Hz,1H),2.36(dd,J=14.2,6.9Hz,1H ),2.28(d,J=16.5Hz,1H),2.09–1.99(m,1H),1.96–1.87(m,2H),1.80–1.72(m,2H),1.73–1.65(m,2H)ppm.HRMS(ESI)m / z calcd for C 31 H 34 F2NO8,[M+H] + 586.2248, found 586.2252.

[0414]

[0415] Compound I-2-34: pale yellow amorphous solid, yield 70%. 1 H NMR (400MHz, CDCl3) δ6.66–6.58(m,3H),6.58(s,1H),6.56(s,1H),6.04(d,J=9.5Hz ,1H),5.84(m,1H),5.78(s,1H),5.11(s,1H),3.81(d,J=9.6Hz,1H),3.70(s,3H),3. 63(s,1H),3.59(s,3H),3.20–3.00(m,2H),2.94(td,J=11.6,7.2Hz,1H),2.66–2.49 (m,3H),2.41–2.24(m,3H),2.09–1.86(m,3H),1.82–1.68(m,4H)ppm.HRMS(ESI)m / z calcd for C 31 H 34 F2NO8,[M+H] + 586.2246, found 586.2252.

[0416]

[0417] Compound I-2-35: pale yellow amorphous solid, yield 41%. 1 H NMR (400MHz, CDCl3) δ6.93(td,J=8.7,4.4Hz,1H),6.89–6.77(m,2H),6.59(s,1H),6.54(d,J=5.7Hz,1H),6.04(d,J=9 .8Hz,1H),5.85(d,J=1.6Hz,1H),5.77(d,J=1.6Hz,1H),5.09(s,1H),3.80(d,J=9.8Hz,1H),3.68(s,3H),3.65(s,1H) ,3.58(s,3H),3.22–3.07(m,2H),2.94(td,J=11.6,7.0Hz,1H),2.66–2.54(m,3H),2.48–2.32(m,2H),2.28(d,J=16.5 Hz,1H),2.09–2.00(m,1H),1.96–1.88(m,2H),1.82–1.72(m,2H),1.70(dd,J=9.8,7.4Hz,2H)ppm.HRMS(ESI)m / zcalcd for C 31 H 34 F2NO8,[M+H] + 586.2243, found 586.2252.

[0418]

[0419] Compound I-2-36: pale yellow amorphous solid, yield 47%. 1H NMR (400MHz, CDCl3) δ7.03–6.93(m,2H),6.87(dd,J=8.3,5.3Hz,1H),6.59(s,1H),6.54(s,1H),6.05(d,J=9.7H z,1H),5.85(d,J=1.5Hz,1H),5.76(d,J=1.6Hz,1H),5.09(s,1H),3.80(d,J=9.8Hz,1H),3.69(s,3H),3.66(s,1H ),3.59(s,3H),3.23–3.06(m,2H),2.95(td,J=11.6,7.0Hz,1H),2.71–2.48(m,4H),2.37(dd,J=14.2,6.9Hz,1H ),2.28(d,J=16.6Hz,1H),2.05(td,J=12.4,9.5Hz,1H),1.96–1.86(m,2H),1.80–1.64(m,4H)ppm.HRMS(ESI)m / z calcd forC 31 H 34 F2NO8,[M+H] + 586.2254, found 586.2252.

[0420]

[0421] Compound I-2-37: pale yellow amorphous solid, 118 mg, yield 47%. 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.9Hz,1H),7.38(t,J=7.7Hz,1H),7.34(s,1H),7.30(d,J=7.5Hz,1H),6.58(s,1H),6.56(s, 1H),6.07(d,J=9.8Hz,1H),5.84(d,J=1.7Hz,1H),5.75(d,J=1.7Hz,1H),5.12(s,1H),3.82(d,J=9.9Hz,1H),3.69(s,3H),3. 66(s,1H),3.59(s,3H),3.21–3.07(m,2H),3.00–2.90(m,1H),2.73(td,J=13.0,5.0Hz,1H),2.62(t,J=9.2Hz,2H),2.47–2.3 3(m,2H),2.28(d,J=16.5Hz,1H),2.06(q,J=10.1Hz,1H),1.98–1.91(m,2H),1.76(dd,J=12.2,7.5Hz,4H)ppm.HRMS(ESI)m / z calcd for C29 H 29 F3NO6,[M+H] + 618.2307, found 618.2315.

[0422]

[0423] Compound I-2-38: pale yellow amorphous solid, yield 60%. 1 H NMR (400MHz, CDCl3) δ7.59(d,J=7.8Hz,1H),7.45(t,J=7.5Hz,1H),7.27(q,J=8.0Hz,2H),6.56(s,1H),6.53(s,1H),6.03(d,J=9.8Hz,1H),5.84(d ,J=1.6Hz,1H),5.71(d,J=1.6Hz,1H),5.08(s,1H),3.79(d,J=9.8Hz,1H) ,3.69(s,3H),3.68(s,1H),3.60(s,3H),3.17(td,J=12.0,11.3,6.7Hz,1H ),3.15–3.05(m,1H),2.94(td,J=11.6,7.0Hz,1H),2.82(td,J=13.0,4.3 Hz,1H),2.66–2.52(m,3H),2.35(dd,J=14.2,6.9Hz,1H),2.28(d,J=16.5 Hz,1H),2.08–1.98(m,1H),1.92(dt,J=9.0,4.7Hz,1H),1.86(d,J=16.5Hz,1H),1.75(dt,J=13.8,5.1Hz,2H),1.68–1.59(m,2H)ppm.HRMS(ESI)m / z calcd for C 32 H 35 F3NO8,[M+H] + 618.2312, found 618.2315.

[0424]

[0425] Compound I-2-39: pale yellow amorphous solid, yield 84%. 1H NMR(400MHz, CDCl3)δ7.30(dd,J=9.4,2.7Hz,1H),7.26–7.18(m,1H),7.20–7.11(m,1H),6.57(s,1H),6.53(s,1H),6.02(d,J=9 .8Hz,1H),5.84(d,J=1.6Hz,1H),5.73(d,J=1.6Hz,1H),5.09(s,1H),3.79(d,J=9.8Hz,1H),3.69(s,3H),3.68(s,1H),3.60(s,3 H),3.22–3.05(m,2H),2.94(td,J=11.6,7.0Hz,1H),2.78(td,J=13.3,4.7Hz,1H),2.64–2.45(m,3H),2.35(dd,J=14.2,6.9Hz, 1H),2.27(d,J=16.5Hz,1H),2.08–1.96(m,1H),1.95–1.89(m,1H),1.86(d,J=16.6Hz,1H),1.81–1.63(m,4H)ppm.HRMS(ESI)m / z calcd for C 32 H 34 F4NO8,[M+H] + 636.2212, found 636.2221.

[0426]

[0427] Compound I-2-40: pale yellow amorphous solid, yield 60%. 1 H NMR (400MHz, CDCl3) δ7.11 (s, 4H), 6.58 (s, 1H), 6.56 (s, 1H), 6.05 (d, J = 10.0Hz, 1H), 5.83 (d ,J=1.5Hz,1H),5.71(d,J=1.6Hz,1H),5.10(s,1H),3.81(d,J=9.8Hz,1H),3.69(s,3H),3.59 (s,3H),3.56(s,1H),3.20–3.03(m,2H),2.96(td,J=11.4,6.9Hz,1H),2.68–2.54(m,3H),2. 43–2.26(m,3H),2.09–1.96(m,2H),1.98–1.87(m,1H),1.82–1.67(m,4H)ppm.HRMS(ESI)m / z calcd forC 32 H 35 F3NO9,[M+H] +634.2263, found 634.2264.

[0428]

[0429] Compound I-2-41: pale yellow amorphous solid, yield 56%. 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.2Hz,2H),7.03(d,J=8.2Hz,2H),6.59(s,1H),6.55(s,1H),6.06(d,J =9.8Hz,1H),5.84(d,J=1.6Hz,1H),5.73(d,J=1.6Hz,1H),5.09(s,1H),3.80(d,J=9.8Hz,1H),3.69(s, 3H),3.61(s,1H),3.58(s,3H),3.20–3.06(m,2H),2.95(td,J=11.6,7.0Hz,1H),2.66–2.56(m,3H),2.4 6(s,3H),2.41–2.26(m,3H),2.10–2.01(m,1H),2.00–1.88(m,2H),1.81–1.64(m,4H)ppm.HRMS(ESI)m / z calcd for C 32 H 38 NO8S, [M+H] + 596.2313, found 596.2318.

[0430]

[0431] Compound I-2-42: pale yellow amorphous solid, yield 71%. 1 H NMR (400MHz, CDCl3) δ7.10(d,J=7.6Hz,2H),7.02(d,J=7.7Hz,2H),6.60(s,1H),6.57(s,1H),6. 08(d,J=9.8Hz,1H),5.84(d,J=1.6Hz,1H),5.74(d,J=1.6Hz,1H),5.11(s,1H),3.82(d,J=9.8Hz, 1H),3.71(s,4H),3.59(s,3H),3.26–3.06(m,2H),2.99(dt,J=12.6,6.2Hz,1H),2.76–2.54(m,3H ),2.44–2.27(m,6H),2.15–2.02(m,1H),2.01–1.89(m,2H),1.84–1.68(m,4H)ppm.HRMS(ESI)m / z calcd for C32 H 38 NO8, [M+H] + 564.2591, found 564.2597.

[0432]

[0433] Compound I-2-43: pale yellow amorphous solid, yield 60%. 1 H NMR (400MHz, CDCl3) δ8.09–7.85(m,2H),7.75(d,J=8.2Hz,1H),7.51(dd,J=6.3,3.3Hz,2H),7.42(t,J=7.6Hz,1H),7.36–7.26(m,1H),6 .59(s,1H),6.55(s,1H),6.20(d,J=9.9Hz,1H),5.91–5.82(m,1H),5.71(d,J=1.6Hz,1H),5.21(s,1H),3.88(d,J=9.9Hz,1H),3.82(s,1 H),3.71(s,3H),3.64(s,3H),3.33(td,J=13.1,7.7Hz,1H),3.22–3.07(m,2H),3.09–2.90(m,2H),2.80–2.63(m,2H),2.39(dd,J=14.3, 6.9Hz,1H),2.32(d,J=16.6Hz,1H),2.17–2.06(m,1H),2.05–1.92(m,2H),1.90(d,J=16.5Hz,1H),1.87–1.76(m,3H)ppm.HRMS(ESI)m / z calcd for C 35 H 38 NO8, [M+H] + 600.2592, found 600.2597.

[0434]

[0435] Compound I-2-44: pale yellow amorphous solid, 153 mg, yield 61%. 1H NMR (400MHz, CDCl3) δ7.83–7.70(m,3H),7.54(s,1H),7.50–7.37(m,2H),7.25(d,J=9.0Hz,1H),6.59(s,1H),6.57(s, 1H),6.09(d,J=9.7Hz,1H),5.81(s,1H),5.69(s,1H),5.11(s,1H),3.83(d,J=9.6Hz,1H),3.71(s,3H),3.67(s,1H),3 .60(s,3H),3.20(td,J=13.1,7.9Hz,1H),3.11(q,J=8.0,7.3Hz,1H),2.96(td,J=11.5,7.0Hz,1H),2.82(td,J=12.8, 5.3Hz,1H),2.68–2.47(m,3H),2.44–2.30(m,2H),2.05(dt,J=25.3,13.3Hz,2H),1.97–1.73(m,5H)ppm.HRMS(ESI)m / z calcd for C 35 H 38 NO8, [M+H] + 600.2600, found 600.2597.

[0436]

[0437] Compound I-2-45: pale yellow amorphous solid, yield 56%. 1 H NMR (400MHz, CDCl3) δ7.02(d,J=8.3Hz,2H),6.82(d,J=8.5Hz,2H),6.59(s,1H),6.55(s,1H),6.06(d,J=9.8Hz,1H ),5.83(d,J=1.6Hz,1H),5.73(d,J=1.6Hz,1H),5.09(s,1H),3.81(d,J=9.9Hz,1H),3.78(s,4H),3.70(s,3H),3.58 (s,3H),3.21–3.07(m,2H),2.97(td,J=11.3,6.5Hz,1H),2.65–2.57(m,3H),2.41–2.26(m,3H),2.30(d,J=16.4Hz, 1H),2.06(dt,J=12.0,9.6Hz,1H),1.99–1.89(m,2H),1.96(d,J=16.4Hz,1H),1.81–1.67(m,4H)ppm.HRMS(ESI)m / z calcd forC 32 H38 NO9, [M+H] + 580.2544, found 580.2547.

[0438]

[0439] Compound I-2-46: pale yellow amorphous solid, yield 50%. 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.0Hz,2H),7.51(d,J=7.9Hz,2H),7.43(t,J=7.5Hz,2H),7.33(t,J=6.8Hz,1H),7.18(d,J=7 .8Hz,2H),6.60(s,1H),6.56(s,1H),6.08(d,J=9.8Hz,1H),5.84(d,J=1.6Hz,1H),5.73(d,J=1.7Hz,1H),5.10(s,1H),3.82(d ,J=9.8Hz,1H),3.72(s,3H),3.64(s,1H),3.59(s,3H),3.24–3.06(m,2H),2.96(td,J=11.6,6.9Hz,1H),2.76–2.55(m,3H),2. 47–2.28(m,3H),2.10–2.02(m,1H),1.99(d,J=16.5Hz,1H),1.93(dd,J=9.6,5.5Hz,1H),1.83–1.72(m,4H)ppm.HRMS(ESI)m / z calcd for C 37 H 40 NO8, [M+H] + 626.2746, found 626.2754.

[0440] Example 19: Preparation of ketoxime compounds

[0441]

[0442] General procedure: Under argon protection, 0.16 mmol of cinquercetin catalyst and 0.8 mmol of m-nitrobenzoic acid were added to a 4 mmol acetone (5 mL) solution of α-keto ester at room temperature. After reacting for 8 h, most of the solvent was removed and the mixture was separated by column chromatography to obtain the ketone analog.

[0443] At room temperature, the ketone compound (2 mmol) was dissolved in CH3CN / H2O (v / v = 9:1, 5 mL), and hydroxylamine hydrochloride (2 mmol) and sodium acetate (2.5 mmol) were added with stirring. After the reaction was complete as monitored by TLC, saturated NaHCO3 was added to quench the reaction, followed by extraction with CH2Cl2. The organic phases were combined, washed with saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the E / Z ketoxime analog.

[0444] Following the method described above, the following compounds were obtained:

[0445]

[0446] Compound I-2-47: Column chromatography with PE:EA = 7:1 and 0.5% TEA yielded a yellow amorphous solid (yield 87%). 1 H NMR (400MHz, CDCl3): δ6.60(s,1H),6.55(s,1H),5.98(d,J=9.8Hz,1H),5.85(dd,J=13.6,1.5Hz,2H),5.79–5.64(m ,1H),5.03(s,1H),5.00–4.87(m,2H),3.76(d,J=9.8Hz,1H),3.67(s,3H),3.57(s,1H),3.10(ddd,J=23.8,13.2,7.6 Hz,2H),2.92(td,J=11.6,7.0Hz,1H),2.63–2.52(m,2H),2.46(d,J=17.5Hz,1H),2.36(dd,J=14.1,6.9Hz,1H),2.22 (d,J=17.5Hz,1H),2.11–1.95(m,2H),1.89(s,3H),1.87–1.67(m,4H),1.55–1.38(m,2H)ppm; HRMS-ESI(m / z):Calcd for C 27 H 34 NO7[M+H] + 484.2336.Found 484.2257.

[0447]

[0448] Compound I-2-48: Column chromatography with PE:EA = 7:1 and 0.5% TEA yielded a yellow amorphous solid (96% yield). 1H NMR (400MHz, CDCl3): δ6.60(s,1H),6.54(s,1H),5.96(d,J=9.8Hz,1H),5.87–5.80(m,2H),5.02(s,1H),5.03–4. 94(m,1H),3.75(d,J=9.8Hz,1H),3.66(s,3H),3.56(s,1H),3.20–3.02(m,2H),2.92(td,J=11.5,6.9Hz,1H),2.62 –2.51(m,2H),2.42(d,J=17.3Hz,1H),2.36(dd,J=14.2,7.0Hz,1H),2.13(d,J=17.4Hz,1H),2.07–1.93(m,3H),1 .91–1.85(m,1H),1.88(s,3H),1.75(dt,J=13.8,7.5Hz,4H),1.65(s,3H),1.56(s,3H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 38 NO7[M+H] + 512.2649.Found 512.2570.

[0449]

[0450] Compound I-2-49: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (yield 88%). 1 H NMR (400MHz, CDCl3): δ7.10 (dd, J=5.1, 1.2Hz, 1H), 6.90 (dd, J=5.2, 3.4Hz, 1H), 6.73 (d, J=2.3Hz, 1H), 6.60 (s, 1H), 6. 56(s,1H),6.04(d,J=9.8Hz,1H),5.80(dd,J=11.2,1.5Hz,2H),5.05(s,1H),3.78(d,J=9.9Hz,1H),3.70(s,1H),3.67(s ,3H),3.22–3.04(m,2H),3.00–2.82(m,2H),2.65–2.53(m,3H),2.49(d,J=17.6Hz,1H),2.38(dd,J=14.2,6.9Hz,1H),2 .20(d,J=17.6Hz,1H),2.10–1.97(m,1H),1.94–1.88(m,1H),1.89(s,3H),1.84–1.69(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 29H 34 NO7S[M+H] + 540.2057.Found540.1987.

[0451]

[0452] Compound I-2-50: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (98% yield). 1 H NMR (400MHz, CDCl3): δ6.94(s,1H),6.82(d,J=8.1Hz,1H),6.68(d,J=8.0Hz,1H),6.57(d,J=3.2Hz,2H),6.03(d,J=9.8Hz,1H),5.77(dd,J =26.9,1.5Hz,2H),5.07(s,1H),4.53(t,J=8.6Hz,2H),3.79(d,J=9.8Hz,1H),3.69(s,3H),3.66(s,1H),3.16(t,J=8.6Hz,2H),3.14–3.04( m,2H),2.93(td,J=11.5,7.0Hz,1H),2.65–2.48(m,3H),2.46(d,J=17.5Hz,1H),2.36(dd,J=14.1,6.9Hz,1H),2.33–2.21(m,1H),2.19(d,J =17.5Hz,1H),2.10–1.99(m,1H),1.94–1.88(m,1H),1.90(s,3H),1.75(p,J=9.2,8.1Hz,2H),1.72–1.59(m,2H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 38 NO8[M+H] + 576.2598.Found 576.2519.

[0453]

[0454] Compound I-2-51: Column chromatography (PE:EA = 5:1, 0.5% TEA) yielded a yellow amorphous solid (95% yield). HRMS-ESI (m / z): Calculated for C 28 H 38 NO8[M+H] + 500.2643.Found 500.2648.

[0455]

[0456] Compound I-3-1: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (yield 37%). 1 HNMR (400MHz, CDCl3): δ8.06(s,1H),6.58(s,1H),6.55(s,1H),5.85(d,J=3.3Hz,2H),5.79–5.66(m,1H) ,5.04(s,1H),5.00–4.88(m,2H),3.77(d,J=9.9Hz,1H),3.67(s,3H),3.21–3.02(m,2H),2.99–2.86(m,1H ),2.65–2.53(m,2H),2.38(dd,J=14.1,6.9Hz,1H),2.10(d,J=16.0Hz,1H),2.05–1.98(m,2H),1.95–1.89 (m,1H),1.78–1.71(m,1H),1.63(s,3H),1.59–1.47(m,1H),0.91–0.80(m,6H)ppm.HRMS-ESI(m / z):Calcd for C 27 H 35 N₂O₇[M+H] + 499.2445.Found 499.2366.

[0457]

[0458] Compound I-3-2: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (yield 42%). 1 HNMR (400MHz, CDCl3): δ6.60(s,1H),6.58(s,1H),5.93(d,J=9.6Hz,1H),5.83(d,J=19.6Hz,2H),5.06 (s,1H),5.05–4.96(m,2H),3.81(s,1H),3.67(s,3H),3.35(s,1H),3.20–3.05(m,2H),2.94(d,J=8.5H z,1H),2.90–2.75(m,1H),2.63–2.48(m,3H),2.39(dd,J=14.3,6.8Hz,1H),2.18–2.00(m,3H),1.89(d ,J=24.0Hz,4H),1.72(s,3H),1.66(d,J=5.6Hz,3H),1.57(d,J=6.1Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 39 N₂O₇[M+H]+ 527.2758.Found 527.2679.

[0459]

[0460] Compound I-3-3: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (30% yield). 1 HNMR (400MHz, CDCl3): δ7.60(s,1H),6.58(s,1H),6.55(s,1H),5.93(d,J=9.7Hz,1H),5.84(dd,J=8.9,1 .6Hz,2H),5.04(s,1H),5.04–4.95(m,1H),3.77(d,J=9.7Hz,1H),3.67(s,3H),3.63(s,1H),3.22–3.03( m,2H),2.98–2.86(m,1H),2.63–2.52(m,2H),2.37(dd,J=14.2,7.0Hz,1H),2.07(d,J=15.9Hz,1H),2.04 –1.83(m,4H),1.82–1.69(m,3H),1.65(s,6H),1.56(s,3H),1.53–1.36(m,2H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 39 N₂O₇[M+H] + 527.2758.Found 527.2679.

[0461]

[0462] Compound I-3-5: Column chromatography with PE:EA = 4:1 and 0.5% TEA yielded a yellow amorphous solid (yield 46%). 1HNMR (400MHz, CDCl3): δ7.09 (dd, J=5.1, 1.2Hz, 1H), 6.89 (dd, J=5.1, 3.4Hz, 1H), 6.73 (d, J=2.4Hz, 1H), 6.58 (s, 1H), 6.56(s,1H),5.99(d,J=9.7Hz,1H),5.77(dd,J=34.4,1.6Hz,2H),5.06(s,1H),3.87(s,1H),3.78(d,J=9.7Hz,1H),3.6 7(s,3H),3.24–3.02(m,2H),2.99–2.83(m,2H),2.65–2.53(m,2H),2.55–2.42(m,1H),2.39(dd,J=14.5,7.0Hz,1H),2. 13(d,J=18.6Hz,1H),2.10–1.95(m,3H),1.95–1.79(m,3H),1.82–1.68(m,4H),1.63(s,3H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 35 N₂O₇S[M+H] + 555.2166.Found 555.2087.

[0463]

[0464] Compound I-3-5: Column chromatography with PE:EA = 4:1 and 0.5% TEA yielded a yellow amorphous solid (yield 45%). 1HNMR (400MHz, CDCl3): δ6.95(s,1H),6.84(d,J=8.1Hz,1H),6.67(d,J=8.1Hz,1H),6.57(s,1H),6.56(s,1H),5.99(d,J=9.7Hz,1H),5 .73(dd,J=54.7,1.7Hz,2H),5.08(s,1H),4.53(t,J=8.6Hz,2H),3.80(d,J=9.8Hz,1H),3.70(s,3H),3.23–3.14(m,1H),3.16(t,J=8.6 ,7.7Hz,2H),3.14–3.03(m,1H),3.00–2.87(m,1H),2.66–2.46(m,3H),2.38(dd,J=14.2,7.0Hz,1H),2.22–2.08(m,1H),2.12(d,J=17. 4Hz,1H),2.08–1.95(m,2H),1.99(d,J=17.4Hz,1H),1.96–1.84(m,2H),1.82–1.69(m,4H),1.66(s,3H)ppm.HRMS-ESI(m / z):Calcdfor C 33 H 39 N₂O₈S[M+H] + 591.2707.Found 591.2628.

[0465]

[0466] Compound I-3-6: Column chromatography with PE:EA = 4:1 and 0.5% TEA yielded a yellow amorphous solid (35% yield). 1HNMR (400MHz, CDCl3): δ6.94(s,1H),6.82(d,J=8.1Hz,1H),6.68(d,J=8.1Hz,1H),6.57(s,1H),6.57(s,1H),6.03(d,J=9.8Hz,1H ),5.77(dd,J=28.7,1.5Hz,2H),5.07(s,1H),4.54(t,J=8.7Hz,2H),3.79(d,J=9.9Hz,1H),3.69(s,3H),3.65(s,1H),3.23–3.04( m,3H),3.19(t,J=8.6,7.7Hz,2H),3.00–2.86(m,1H),2.65–2.48(m,4H),2.46(d,J=17.5Hz,1H),2.36(dd,J=14.1,6.9Hz,1H),2. 28(dd,J=25.2,12.5Hz,1H),2.19(d,J=17.4Hz,1H),1.90(s,4H),1.82–1.69(m,2H),1.69–1.60(m,2H)ppm.HRMS-ESI(m / z):Calcd forC 33 H 39 N₂O₈S[M+H] + 591.2707.Found 591.2628.

[0467] Example 20: Preparation of Aldoxime Compounds

[0468]

[0469] General procedure: Under argon protection, at -60°C, thioenol silyl ether (2 mmol) was added dropwise to a CH2Cl2 (15 mL) solution of α-keto ester (1 mmol). After 10 min, BF3·OEt2 (3 mmol) was added dropwise. After the reaction was monitored by TLC plate until complete, saturated NaHCO3 was added to quench the reaction, followed by extraction with CH2Cl2. The organic phases were combined, washed with saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the thioester intermediate.

[0470] At room temperature, Pd / C (0.1 mmol) and Et3SiH (2.5 mmol) were added to a 5 mL CH2Cl2 solution of the thioester, and the reaction was monitored until complete. The mixture was quenched with saturated NaHCO3, filtered through diatomaceous earth, extracted with CH2Cl2, and the organic phases were combined, washed with saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the aldehyde analog.

[0471] At room temperature, the intermediate aldehyde (2 mmol) was dissolved in CH3CN / H2O (v / v = 9:1, 5 mL), and hydroxylamine hydrochloride (2 mmol) and sodium acetate (2.5 mmol) were added with stirring. The reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO3, extracted with CH2Cl2, and the organic phases were combined, washed with saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to give the E / Z aldoxime analog.

[0472] Following the method described above, the following compounds were obtained:

[0473]

[0474] Compound I-2-52: gave a pale pink amorphous solid (yield 98%). 1 H NMR (400MHz, CDCl3): δ6.61(s,1H),6.52(s,1H),6.00(d,J=9.8Hz,1H),5.86(dd,J=6.5,1.7Hz,2H),5.04(s,1H), 3.78(d,J=9.8Hz,1H),3.67(s,3H),3.39(s,1H),3.15–3.03(m,2H),2.98–2.89(m,1H),2.61–2.55(m,2H),2.52(d ,J=16.0Hz,1H),2.36(dd,J=14.1,6.8Hz,1H),2.22(s,3H),2.00(d,J=16.0Hz,1H),1.94–1.86(m,1H),1.81–1.69 (m,2H),1.51–1.34(m,3H),1.33–1.21(m,2H),0.99–0.92(m,1H),0.82(t,J=6.4Hz,6H)ppm.HRMS-ESI(m / z):Calcd forC 28 H 38 NO7S[M+H] + 532.2370.Found 532.2291.

[0475]

[0476] Compound I-2-53: gave a pale pink amorphous solid (90% yield). 1H NMR (400MHz, CDCl3): δ6.58(s,1H),6.50(s,1H),5.98(d,J=9.8Hz,1H),5.82(dd,J=6.5,1.7Hz,2H),5.69(tt,J=13.1,5.1 Hz,1H),5.03(s,1H),4.98–4.85(m,2H),3.76(d,J=9.8Hz,1H),3.65(s,3H),3.41(s,1H),3.12–3.00(m,2H),2.97–2.83(m ,1H),2.61–2.52(m,2H),2.50(d,J=16.0Hz,1H),2.34(dd,J=14.1,6.8Hz,1H),2.19(s,3H),2.11–2.02(m,1H),2.07(d,J= 16.0Hz,1H),1.93–1.75(m,3H),1.72(p,J=5.9,4.8Hz,2H),1.51(tdd,J=25.4,13.5,4.8Hz,2H)ppm.HRMS-ESI(m / z):Calcd for C 24 H 34 NO7[M+H] + 516.2057.Found 516.1978.

[0477]

[0478] Compound I-2-54: gave a pale pink amorphous solid (yield 82%). 1 H NMR (400MHz, CDCl3): δ6.59(s,1H),6.50(s,1H),5.99(d,J=9.8Hz,1H),5.83(d,J=13.7Hz,2H),5.03(s,1H),5.02–4. 96(m,1H),3.77(d,J=9.8Hz,1H),3.65(s,3H),3.39(s,1H),3.16–3.01(m,2H),2.98–2.85(m,1H),2.62–2.52(m,2H), 2.48(d,J=15.9Hz,1H),2.35(dd,J=14.2,6.8Hz,1H),2.21(s,3H),2.01–1.94(m,1H),1.98(d,J=15.9Hz,1H),1.92–1 .85(m,1H),1.74(dd,J=13.7,7.9Hz,3H),1.64(s,3H),1.54(s,3H),1.52–1.35(m,3H)ppm.HRMS-ESI(m / z):Calcdfor C29 H 38 NO7S[M+H] + 544.2370.Found 544.2291.

[0479]

[0480] Compound I-2-55: gave a pink amorphous solid (yield 82%). 1 H NMR (400MHz, CDCl3): δ7.10 (dd, J=5.1, 1.3Hz, 1H), 6.90 (dd, J=5.1, 3.4Hz, 1H), 6.73 (d, J=2.4Hz, 1H), 6.61 (s, 1H), 6.54 (s,1H),6.06(d,J=9.8Hz,1H),5.82(dd,J=24.8,1.6Hz,2H),5.08(s,1H),3.81(d,J=9.8Hz,1H),3.68(s,3H),3.53(s,1H) ,3.12(ddd,J=21.9,13.8,7.7Hz,2H),3.01–2.84(m,2H),2.66–2.51(m,4H),2.38(dd,J=14.0,6.7Hz,1H),2.23(s,3H),2. 11(d,J=16.0Hz,1H),2.09–1.98(m,1H),1.98–1.83(m,2H),1.78(ddt,J=17.6,8.9,4.7Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 34 NO7S2[M+H] + 572.1777.Found 572.1698.

[0481]

[0482] Compound I-2-56: gave a pale pink amorphous solid (yield 89%). 1H NMR (400MHz, CDCl3): δ6.94(s,1H),6.82(d,J=8.1Hz,1H),6.68(d,J=8.1Hz,1H),6.58(s,1H),6.55(s,1H),6.06(d,J=9.7Hz,1H),5.8 0(dd,J=33.6,1.7Hz,2H),5.09(s,1H),4.53(t,J=8.7Hz,2H),3.81(d,J=9.8Hz,1H),3.70(s,3H),3.49(s,1H),3.16(t,J=8.9Hz,2H),3 .11(t,J=6.1Hz,2H),3.01–2.86(m,1H),2.66–2.54(m,3H),2.52(d,J=16.1Hz,1H),2.36(dd,J=14.1,6.9Hz,1H),2.32–2.26(m,1H),2. 23(s,3H),2.09(d,J=16.1Hz,1H),2.07–1.98(m,1H),1.92(ddd,J=12.1,7.6,4.5Hz,1H),1.83–1.61(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 38 NO8S[M+H] + 608.2319.Found 607.2240.

[0483]

[0484] Compound I-2-57: Column chromatography with PE:EA = 7:1 and 0.5% TEA yielded a yellow amorphous solid (yield 49%). 1H NMR (400MHz, CDCl3): δ8.98(d,J=2.9Hz,1H),6.60(s,1H),6.55(s,1H),5.98(d,J=8.8Hz,1H),5.87(dd,J=8.4,5.6Hz,2H),5.06(s,1H ),3.78(d,J=9.8Hz,1H),3.67(s,3H),3.31(s,1H),3.13–3.04(m,2H),2.94(ddd,J=12.4,10.8,6.7Hz,1H),2.58(td,J=9.3,7.3Hz,2H ),2.36(dd,J=13.9,6.7Hz,1H),2.29(dt,J=17.0,2.7Hz,1H),2.06–2.01(m,1H),1.99(s,1H),1.90(ddd,J=12.1,7.8,4.3Hz,1H),1.7 5(ddt,J=9.5,8.1,5.0Hz,3H),1.67–1.62(m,1H),1.52–1.44(m,2H),1.12–1.01(m,1H),0.90–0.82(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 26 H 34 NO7[M+H] + 472.2336.Found 471.2257.

[0485]

[0486] Compound I-2-58: Column chromatography with PE:EA = 7:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 51%). 1H NMR (400MHz, CDCl3): δ8.98(d,J=2.9Hz,1H),6.59(s,1H),6.55(s,1H),5.98(d,J=9.7Hz,1H),5.86(s,2H) ,5.06(s,1H),5.00(t,J=7.2Hz,1H),3.79(d,J=9.7Hz,1H),3.67(s,3H),3.37(s,1H),3.15–3.01(m,2H),2. 97–2.89(m,1H),2.64–2.52(m,2H),2.36(dd,J=14.0,6.7Hz,1H),2.27(dd,J=17.1,3.1Hz,1H),2.10–1.95( m,3H),1.95–1.84(m,2H),1.84–1.70(m,4H),1.65(t,J=2.3Hz,3H),1.56(s,3H)ppm.HRMS-ESI(m / z):Calcd forC 28 H 36 NO7[M+H] + 498.2493.Found 498.2414.

[0487]

[0488] Compound I-2-59: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (yield 54%). 1 H NMR (400MHz, CDCl3): δ9.00(d,J=2.5Hz,1H),7.09(d,J=5.2Hz,1H),6.92–6.83(m,1H),6.73(d,J =3.4Hz,1H),6.58(s,1H),6.55(s,1H),6.02(d,J=9.7Hz,1H),5.82(d,J=9.8Hz,2H),3.79(d,J=9. 8Hz,1H),3.67(s,3H),3.43(s,1H),3.14–3.00(m,2H),2.97–2.83(m,2H),2.61-2.52(m,4H),2.41 –2.28(m,2H),2.10–1.95(m,2H),1.94–1.82(m,3H),1.78–1.70(m,2H)ppm.HRMS-ESI(m / z):Calcd for C 28 H 32 NO7S[M+H] + 526.1900Found 526.1821.

[0489]

[0490] Compound I-2-60: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (62% yield). 1 H NMR (400MHz, CDCl3): δ9.01(s,1H),6.96(s,1H),6.85(d,J=8.2Hz,1H),6.68(d,J=8.1Hz,1H),6.58 (s,2H),6.05(d,J=9.7Hz,1H),5.82(d,J=18.7Hz,2H),5.11(s,1H),4.54(t,J=8.6Hz,2H),3.82(d,J =9.8Hz,1H),3.72(s,3H),3.43(s,1H),3.24–3.02(m,4H),3.01–2.87(m,1H),2.65–2.55(m,3H),2. 41–2.25(m,2H),2.08–1.98(m,3H),1.98–1.85(m,1H),1.82–1.70(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 32 H 36 NO8[M+H] + 562.2442Found562.2363.

[0491]

[0492] Compound I-2-61: Column chromatography (PE:EA = 5:1, 0.5% TEA) yielded a yellow amorphous solid (68% yield). HRMS-ESI (m / z): Calcd for C 27 H 36 NO7[M+H] + 486.2486Found 486.2480.

[0493]

[0494] Compound I-2-62: Column chromatography (PE:EA = 5:1, 0.5% TEA) yielded a yellow amorphous solid (65% yield). HRMS-ESI (m / z): Calcd for C 26 H 32 NO7[M+H] + 470.2173 Found 470.2170.

[0495]

[0496] Compound I-3-7: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 42%). 1 HNMR(400MHz, CDCl3):6.63–6.51(m,3H),5.96(d,J=10.6Hz,1H),5.06(s,1H),3.79(d,J=9.7Hz ,1H),3.71(s,1H),3.68(s,3H),3.18–3.04(m,3H),2.94(td,J=11.6,7.0Hz,1H),2.59(q,J=9.4, 8.8Hz,2H),2.38(dd,J=14.3,6.9Hz,1H),2.14–1.98(m,3H),1.95–1.84(m,1H),1.82–1.70(m,3 H),1.63–1.34(m,4H),1.01–0.88(m,1H),0.84(dd,J=6.6,2.2Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 27 H 37 N₂O₇[M+H] + 501.2602.Found 501.2523.

[0497]

[0498] Compound I-3-8: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 32%). 1HNMR (400MHz, CDCl3): δ8.11(s,1H),6.63(s,1H),6.59(s,1H),6.29(dd,J=6.5,3.6Hz,1H),5.96(d,J=9.7Hz,1H),5.88(q,J=1.7Hz,2 H),5.09(s,1H),3.82(d,J=9.7Hz,1H),3.70(s,3H),3.20–3.06(m,3H),2.97(td,J=11.5,6.8Hz,1H),2.66–2.57(m,2H),2.55(dd,J=1 6.7,6.6Hz,1H),2.41(dd,J=14.1,6.7Hz,1H),2.06–2.02(m,1H),1.92(ddd,J=12.2,8.0,4.1Hz,1H),1.78(tq,J=8.5,4.2,3.7Hz,2H) ,1.68(dd,J=16.8,3.6Hz,1H),1.64–1.44(m,4H),0.96(td,J=12.4,6.2Hz,1H),0.86(dd,J=6.6,2.5Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 27 H 37 N₂O₇[M+H] + 501.2602.Found 501.2523.

[0499]

[0500] Compound I-3-9: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 22%). 1HNMR (400MHz, CDCl3): δ6.57(dd,J=6.8,3.2Hz,3H),5.95(d,J=9.7Hz,1H),5.86(dd,J=12.8,1.7Hz,2H),5.06(s,1H) ,5.02(t,J=7.0Hz,1H),3.79(d,J=9.7Hz,1H),3.67(s,3H),3.32(s,1H),3.10(ddd,J=21.7,13.9,7.9Hz,2H),2.93(td ,J=11.6,6.9Hz,1H),2.63–2.53(m,2H),2.37(dd,J=14.1,6.8Hz,1H),2.11–1.92(m,2H),1.89(ddd,J=12.1,7.9,4.2 Hz,1H),1.82–1.67(m,2H),1.65(s,3H),1.57(s,3H),1.54–1.39(m,1H),0.92–0.80(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 28 H 37 N₂O₇[M+H] + 513.2602.Found 513.2523.

[0501]

[0502] Compound I-3-10: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 23%). 1 H NMR (400MHz, CDCl3): δ6.60(s,2H),6.56(s,1H),6.27(dd,J=6.5,3.7Hz,1H),5.93(d,J=9.5Hz,1H),5.87–5. 80(m,2H),5.07(s,1H),5.02(t,J=7.9Hz,1H),3.79(d,J=9.6Hz,1H),3.68(s,3H),3.16–3.03(m,2H),2.94(td ,J=11.5,6.8Hz,1H),2.63–2.54(m,2H),2.50(dd,J=16.7,6.6Hz,1H),2.43–2.32(m,1H),2.10–1.98(m,1H), 1.93–1.86(m,1H),1.83–1.68(m,2H),1.65(s,3H),1.57(s,3H),0.92–0.80(m,4H)ppm.HRMS-ESI(m / z):Calcd forC 28 H 37N₂O₇[M+H] + 513.2602.Found 513.2523.

[0503]

[0504]

[0505] Compound I-3-11: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 28%). 1 H NMR (400MHz, CDCl3): δ6.59(s,1H),6.58(s,1H),6.53(dd,J=7.9,4.2Hz,1H),5.95(d,J=9.5Hz,1H),5.87(d d,2H),5.05(s,1H),3.79(d,J=9.7Hz,1H),3.67(s,3H),3.29(s,1H),3.18–3.03(m,2H),2.94(td,J=11.5,6 .9Hz,1H),2.64–2.53(m,2H),2.37(dd,J=14.1,6.8Hz,1H),2.14–1.98(m,3H),1.90(ddd,J=12.1,8.1,4.1H z,1H),1.76(ddt,J=14.3,8.8,4.4Hz,4H),1.61–1.40(m,3H),0.92–0.80(m,4H)ppm.HRMS-ESI(m / z):Calcd forC 26 H 35 N₂O₇[M+H] + 487.2445.Found 487.2366.

[0506]

[0507] Compound I-3-12: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 35%). 1H NMR (400MHz, CDCl3): δ6.61(s,1H),6.56(s,1H),6.26(dd,J=6.5,3.6Hz,1H),5.93(d,J=9.8Hz,1H) ,5.86(d,J=1.8Hz,2H),5.06(s,1H),3.79(d,J=9.7Hz,1H),3.68(s,3H),3.13–3.05(m,2H),2.99–2. 90(m,1H),2.64–2.48(m,3H),2.39(dd,J=14.1,6.8Hz,1H),2.11–1.98(m,1H),1.95–1.84(m,1H),1. 83–1.60(m,4H),1.61–1.44(m,2H),1.09–0.99(m,1H),0.91–0.80(m,5H)ppm.HRMS-ESI(m / z):Calcd for C 26 H 35 N₂O₇[M+H] + 487.2445.Found487.2366.

[0508] Example 21: Preparation of oxime ester compounds

[0509]

[0510] General procedure: Under Ar atmosphere, at 0°C, Et3N (3 mmol) was added dropwise to a CH2Cl2 (5 mL) solution of oxime (1 mmol), followed by acetic anhydride (1.2 mmol). After the addition was complete, the solution was moved to room temperature, and the reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO3, extracted with CH2Cl2, and the organic phases were combined. The mixture was washed with saturated NaCl and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the crude oxime acetate product.

[0511] Following the method described above, the following compounds were obtained:

[0512]

[0513] Compound I-3-13: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (87% yield). HRMS-ESI (m / z): Calcd for C 29 H 38 N₂O₈[M+H] + 543.2707.Found 543.2628. 1H NMR (400MHz, CDCl3): δ6.82(dd,J=8.8,3.8Hz,1H),6.53(d,J=3.7Hz,2H),5.85(d,J=8.8Hz,1H),5.81(dd,J=18.3,1.6Hz,2H),5 .01(s,1H),3.74(d,J=9.7Hz,1H),3.64(s,1H),3.61(s,3H),3.05–2.97(m,4H),2.87(td,J=11.5,6.8Hz,1H),2.57–2.49(m,2H), 2.29(ddd,J=18.0,14.2,7.8Hz,3H),2.06(s,3H),1.82(ddd,J=14.9,10.6,4.4Hz,2H),1.70(dt,J=13.1,7.4Hz,2H),1.55(td,J =13.0,4.3Hz,1H),1.40(td,J=13.5,13.1,5.1Hz,1H),0.88–0.82(m,1H),0.77(dd,J=6.6,2.4Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 29 H 39 N₂O₈[M+H] + 543.2707.Found 543.2628.

[0514]

[0515] Compound I-3-14: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (55% yield). 1H NMR (400MHz, CDCl3): δ6.89(dd,J=8.8,3.8Hz,1H),6.60(s,1H),6.59(s,1H),5.92(d,J=9.7Hz,1H),5.87(dd,J =17.3,1.6Hz,2H),5.07(s,1H),3.80(d,J=9.7Hz,1H),3.68(s,3H),3.13–3.06(m,2H),3.04(s,1H),2.98–2.89( m,1H),2.60(t,J=8.4Hz,2H),2.43–2.29(m,2H),2.13(s,3H),2.10–1.97(m,2H),1.95–1.85(m,2H),1.80–1.70 (m,3H),1.66–1.55(m,3H),1.47(td,J=13.5,12.7,3.9Hz,1H),0.86(t,J=7.1Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 28 H 37 N₂O₈[M+H] + 529.2551.Found 528.2472.

[0516]

[0517] Compound I-3-15: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 49%). 1 H NMR (400MHz, CDCl3): δ6.92(dd,J=8.8,3.9Hz,1H),6.60(s,1H),6.58(s,1H),5.91(d,J=9.7Hz,1H),5.86(dd, J=9.7,1.6Hz,2H),5.08(s,1H),5.06–4.97(m,1H),3.81(d,J=9.7Hz,1H),3.68(s,3H),3.14–3.03(m,2H),3.09 (s,1H),2.92(td,J=11.5,6.8Hz,1H),2.62–2.54(m,2H),2.42–2.26(m,2H),2.13(s,3H),2.10–1.97(m,2H),1. 97–1.79(m,3H),1.81–1.71(m,3H),1.65(s,3H),1.56(s,3H),1.55–1.43(m,1H)ppm.HRMS-ESI(m / z):Calcdfor C 30 H 39 N₂O₈[M+H]+ 555.2707.Found 555.2628.

[0518] Example 22: Preparation of oxime ester compounds

[0519]

[0520] General procedure: Under Ar atmosphere, Et3N (3 mmol) was added dropwise to a 1 mmol CH2Cl2 (5 mL) solution of oxime, followed by the addition of acyl chloride (1.2 mmol). The reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO3, extracted with CH2Cl2, and the organic phases were combined. The mixture was washed with saturated NaCl and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the crude oxime ester.

[0521] Following the method described above, the following compounds were obtained:

[0522]

[0523] Compound I-3-16: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 44%). 1 H NMR (400MHz, CDCl3): δ6.58(d,J=17.9Hz,2H),6.50(d,J=17.5Hz,1H),6.22(ddd,J=17.4,10.5,1.9Hz,1H),5.97–5.80(m,4H),5.03 (s,1H),3.80(d,J=8.8Hz,1H),3.66(s,3H),3.36(s,1H),3.11(dd,J=23.9,8.5Hz,2H),2.92(q,J=10.5Hz,1H),2.62–2.54(m,2H),2 .39(d,J=14.8Hz,1H),2.33(d,J=16.9Hz,1H),2.09–1.96(m,1H),1.93–1.81(m,2H),1.79(d,J=1.8Hz,3H),1.76–1.66(m,3H),1.55 –1.48(m,1H),1.43(dt,J=11.8,5.1Hz,1H),1.30–1.21(m,1H),0.97–0.87(m,1H),0.83(d,J=6.7Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 31 H 41 N₂O₈[M+H] + 569.2864.Found 569.2785.

[0524]

[0525] Compound I-3-17: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 57%). 1 H NMR (400MHz, CDCl3): δ6.61(s,1H),6.56(s,1H),5.93(d,J=9.7Hz,1H),5.85(dd,J=13.7,1.5Hz,2H),5.03(s,1H),3.79(d,J=9.7 Hz,1H),3.66(s,3H),3.35(s,1H),3.21–3.04(m,2H),2.93(q,J=11.2Hz,1H),2.67(p,J=7.0Hz,1H),2.62–2.54(m,2H),2.38(dd,J =14.2,6.9Hz,1H),2.30(d,J=15.0Hz,1H),2.10–1.96(m,1H),1.93–1.86(m,1H),1.82(d,J=15.0Hz,1H),1.75(s,3H),1.57–1.36 (m,4H),1.23(dd,J=7.0,1.2Hz,6H),1.18–1.06(m,1H),0.95–0.87(m,2H),0.83(dd,J=6.6,2.7Hz,6H)ppm.HRMS-ESI(m / z):Calcd forC 32 H 45 N₂O₈[M+H] + 585.3177.Found 584.3098.

[0526]

[0527] Compound I-3-18: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 87%). 1H NMR (400MHz, CDCl3): δ7.09(d,J=5.1Hz,1H),6.90(dd,J=5.1,3.5Hz,1H),6.73(t,J=4.2Hz,1H),6.60(s,1H),6.56(s,1 H),6.01(d,J=9.3Hz,1H),5.79(d,J=17.8Hz,2H),5.06(s,1H),3.81(d,J=9.8Hz,1H),3.67(s,3H),3.53(s,1H),3.18(dt ,J=13.0,6.5Hz,1H),3.15–3.04(m,1H),3.00–2.79(m,2H),2.73–2.48(m,4H),2.40(dd,J=14.2,6.9Hz,1H),2.33(d,J=1 5.2Hz,1H),2.02(dd,J=20.7,11.0Hz,2H),1.96–1.81(m,3H),1.63(s,1H),1.27–1.21(m,6H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 41 N₂O₈S[M+H] + 625.2581.Found 625.2505.

[0528]

[0529] Compound I-3-19: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a white amorphous solid (yield 89%). 1H NMR (400MHz, CDCl3): δ6.95 (s, 1H), 6.84 (d, J = 8.1Hz, 1H), 6.67 (d, J = 8.1Hz, 1H), 6. 59(s,1H),6.58(s,1H),6.51(dd,J=17.4,1.4Hz,1H),6.22(dd,J=17.4,10.5Hz,1H) ,5.99(d,J=9.7Hz,1H),5.91(dd,J=10.5,1.5Hz,1H),5.75(dd,J=40.8,1.6Hz,2H), 5.08(s,1H),4.53(t,J=8.6Hz,2H),3.82(d,J=9.7Hz,1H),3.68(s,3H),3.46(s,1H) ,3.32–3.14(m,1H),3.16(t,J=8.8Hz,2H),3.09(td,J=8.5,5.1Hz,1H),2.93(td,J= 11.7,7.0Hz,1H),2.64–2.56(m,2H),2.49(td,J=12.9,4.9Hz,1H),2.40(dd,J=14.4 ,6.7Hz,1H),2.36(d,J=17.4Hz,1H),2.19(td,J=13.0,4.7Hz,1H),2.08–1.85(m,2H ),1.96(d,J=17.4Hz,1H),1.83(s,3H),1.80–1.65(m,4H)ppm.HRMS-ESI(m / z):Calcd for C 36 H 41 N₂O₉[M+H] + 645.2810.Found 645.2734.

[0530]

[0531] Compound I-3-20: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 38%). 1H NMR (400MHz, CDCl3): δ6.96 (s, 1H), 6.84 (d, J = 8.1Hz, 1H), 6.67 (d, J = 8.1Hz, 1H),6.58(d,J=6.3Hz,2H),5.99(d,J=9.7Hz,1H),5.76(dd,J=33.8,1.6Hz,2 H),5.08(s,1H),4.53(t,J=8.6Hz,2H),3.83(d,J=9.7Hz,1H),3.69(s,3H),3 .44(s,1H),3.16(t,J=8.8Hz,2H),3.13–3.04(m,2H),2.94(td,J=11.5,6.9Hz ,1H),2.72–2.54(m,3H),2.56–2.44(m,1H),2.40(dd,J=13.7,7.2Hz,1H),2. 33(d,J=15.0Hz,1H),2.22(td,J=12.9,4.5Hz,1H),2.08–1.98(m,1H),1.90( dd,J=13.2,5.1Hz,2H),1.79(s,3H),1.74(dd,J=12.7,5.4Hz,3H),1.68–1.4 8(m,1H),1.23(d,J=7.0Hz,6H),1.20–1.08(m,2H)ppm.HRMS-ESI(m / z):Calcd for C 37 H 45 N₂O₉[M+H] + 661.3120.Found 661.3122.

[0532]

[0533] Compound I-3-21: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 30%). 1H NMR (400MHz, CDCl3): δ6.92(s,1H),6.82(d,J=8.1Hz,1H),6.66(d,J=8.1Hz,1H),6.59(d,J=8.7Hz,2H),5.99(d,J=9.6Hz,1H),5.74( dd,J=54.6,1.6Hz,2H),5.12(s,1H),4.53(t,J=8.7Hz,2H),3.85(d,J=9.6Hz,1H),3.71(s,3H),3.15(t,J=8.8Hz,2H),3.21–3.06(m, 2H),3.05(s,1H),2.95(dt,J=11.5,5.5Hz,1H),2.74(d,J=13.7Hz,1H),2.67–2.52(m,3H),2.45–2.41(m,1H),2.38(dd,J=13.7,7.2H z,1H),2.15–1.98(m,2H),1.99–1.91(m,1H),1.90(s,3H),1.86–1.61(m,5H),1.16(dd,J=15.8,7.0Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 37 H 45 N₂O₉[M+H] + 661.3120.Found, 661.3122.

[0534]

[0535] Compound I-3-22: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a yellow amorphous solid (yield 89%). 1 H NMR (400MHz, CDCl3): δ6.63-6.45(m,3H),6.14(dd,J=17.3,10.5Hz,1H),5.96–5.83(m,3H),5.8 0(d,J=11.5Hz,2H),5.06(s,1H),3.78(d,J=9.6Hz,1H),3.65(s,3H),3.17–3.01(m,3H),3.00–2 .87(m,1H),2.66–2.54(m,2H),2.42–2.29(m,2H),2.11–1.96(m,1H),1.95–1.82(m,1H),1.80–1 .67(m,2H),1.66–1.51(m,2H),1.51–1.30(m,4H),0.87–0.77(m,6H)ppm.HRMS-ESI(m / z):Calcd for C 30 H39 N₂O₈[M+H] + 555.2707.Found 555.2628.

[0536]

[0537] Compound I-3-23: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 43%). 1 H NMR (400MHz, CDCl3): δ7.03(dd,J=8.9,3.8Hz,1H), 6.58(d,J=7.0Hz,2H), 5.91(d,J=9.7Hz,1H), 5.84(dd,J=9.8,1.5Hz,2H), 5.06(s,1H),3.79(d,J=9.7Hz,1H),3.66(s,3H),3.12–3.03(m,3H),2.92(td,J=11.5,6.8Hz,1H),2.63–2.53(m,4H),2.40–2. 28(m,2H),1.89(ddd,J=12.2,7.8,4.4Hz,1H),1.76(ddd,J=17.9,11.8,5.5Hz,4H),1.59(td,J=13.1,4.3Hz,1H),1.49–1.39( m,2H),1.20(dd,J=7.0,1.5Hz,6H),0.89(ddd,J=12.3,7.5,4.5Hz,1H),0.82(dd,J=6.6,3.1Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 31 H 43 N₂O₈[M+H] + 571.3020.Found 571.2941.

[0538]

[0539] Compound I-3-24: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 43%). 1H NMR (400MHz, CDCl3): δ7.03(dd,J=8.9,3.8Hz,1H), 6.58(d,J=7.0Hz,2H), 5.91(d,J=9.7Hz,1H), 5.84(dd,J=9.8,1.5Hz,2H), 5.06(s,1H),3.79(d,J=9.7Hz,1H),3.66(s,3H),3.12–3.03(m,3H),2.92(td,J=11.5,6.8Hz,1H),2.63–2.53(m,4H),2.40–2. 28(m,2H),1.89(ddd,J=12.2,7.8,4.4Hz,1H),1.76(ddd,J=17.9,11.8,5.5Hz,4H),1.59(td,J=13.1,4.3Hz,1H),1.49–1.39( m,2H),1.20(dd,J=7.0,1.5Hz,6H),0.89(ddd,J=12.3,7.5,4.5Hz,1H),0.82(dd,J=6.6,3.1Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 30 H 41 N₂O₈[M+H] + 557.2860.Found 557.2785.

[0540]

[0541] Compound I-3-25: Column chromatography with PE:EA = 5:1 and 0.5% TEA yielded a white amorphous solid (yield 87%). 1H NMR (400MHz, CDCl3): δ7.09(dd,J=8.8,3.9Hz,1H),6.59(s,1H),6.59(s,1H),5.90(d,J=5.1Hz,1H),5.85(dd,J=1.6Hz,2H),5.08( s,1H),5.02(t,J=6.8Hz,1H),3.81(d,J=9.7Hz,1H),3.68(s,3H),3.08(q,J=6.0Hz,3H),2.93(td,J=11.5,7.0Hz,1H),2.61(dt,J=1 3.9,7.0Hz,3H),2.38(dd,J=14.0,6.7Hz,1H),2.31(dd,J=14.8,8.8Hz,1H),2.10–1.97(m,1H),1.95–1.87(m,1H),1.82–1.71(m,4 H),1.65(s,3H),1.56(s,3H),1.55–1.42(m,1H),1.22(dd,J=7.0,1.3Hz,6H),0.85(d,J=6.6,3.5Hz,2H)ppm.HRMS-ESI(m / z):Calcd for C 32 H 43 N₂O₈[M+H] + 583.3020.Found 583.2941.

[0542] Example 23: Preparation of oxime ester compounds

[0543]

[0544] General procedure: Under Ar atmosphere, add dropwise naproxen (1 mmol), EDCI (1.1 mmol), and DMAP (0.2 mmol) in CH2Cl2 (2 mL) to a 1 mmol CH2Cl2 solution of oxime. Monitor the reaction on a TLC plate until complete. Quench with saturated NaHCO3, extract with CH2Cl2, combine the organic phases, wash with saturated NaCl, and dry with anhydrous Na2SO4. Remove the solvent by rotary evaporation to obtain the crude oxime ester product.

[0545] Following the method described above, the following compounds were obtained:

[0546]

[0547] Compound (I-3-26): Column chromatography with PE:EA = 4:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 44%). 1H NMR (400MHz, CDCl3): δ7.70(d,J=9.0Hz,3H),7.42(dd,J=8.4,1.9Hz,1H),7.16–7.09(m,2H),6.56(s,1H),6.47(s,1H),5.90(d,J=9 .6Hz,1H),5.69(dd,J=23.7,1.5Hz,2H),5.01(s,1H),3.91(s,3H),3.72(d,J=8.9Hz,1H),3.64(s,3H),3.28(s,1H),3.15–3.03(m,2H ),2.95–2.85(m,1H),2.61–2.53(m,2H),2.34(dd,J=14.1,6.8Hz,1H),2.25(d,J=15.0Hz,1H),2.04(s,3H),2.02–1.93(m,2H),1.92– 1.81(m,2H),1.79–1.71(m,3H),1.63(d,J=7.2Hz,3H),1.54–1.36(m,4H),0.82(dd,J=6.6,2.7Hz,6H)ppm.HRMS-ESI(m / z):Calcdfor C 42 H 51 N₂O₉[M+H] + 727.3594.Found 727.3516.

[0548]

[0549] Compound I-3-27: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 45%). 1H NMR (400MHz, CDCl3): δ7.71(d,J=9.1Hz,3H),7.43(d,J=8.4Hz,1H),7.12(ddd,J=15.9,12.3,3.8Hz,3H),6.89(dd,J=5.1,3.4Hz,1H),6 .73(d,J=3.3Hz,1H),6.56(s,1H),6.48(s,1H),5.98(d,J=9.7Hz,1H),5.65(dd,J=55.3,1.5Hz,2H),5.04(s,1H),3.91(s,3H),3.75(s,1 H),3.64(s,3H),3.51(s,1H),3.17–3.04(m,2H),2.98–2.80(m,2H),2.65–2.48(m,3H),2.37(dd,J=14.1,6.7Hz,1H),2.28(d,J=15.3Hz ,1H),2.00(dd,J=12.9,8.9Hz,1H),1.95–1.81(m,4H),1.81–1.70(m,3H),1.63(d,J=7.2Hz,3H),1.57(s,3H)ppm.HRMS-ESI(m / z):Calcd for C 43 H 47 N₂O₉S[M+H] + 767.2999.Found 767.2964.

[0550]

[0551] Compound I-3-28: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 31%). 1H NMR (400MHz, CDCl3): δ7.68–7.62(m,3H),7.38(dd,J=8.4,1.8Hz,1H),7.14–7.03(m,3H),6.86(dd,J=5.2,3.4Hz,1H),6.60(d,J=3.7Hz,1H),6.50 (s,1H),6.49(s,1H),5.97(d,J=9.5Hz,1H),5.73(dd,J=53.8,1.6Hz,2H) ,5.08(s,1H),3.89(s,3H),3.76(d,J=9.4Hz,1H),3.66(s,3H),3.53–3.43 (m,1H),3.14–3.02(m,2H),2.92(dd,J=11.2,7.0Hz,1H),2.87(s,1H),2. 65–2.53(m,3H),2.52(d,J=14.1Hz,1H),2.36–2.22(m,2H),2.02–1.98(m ,1H),1.91(td,J=12.4,11.9,5.2Hz,2H),1.78(s,3H),1.77–1.73(m,2H),1.70(d,J=14.1Hz,2H),1.63(d,J=7.1Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 43 H 47 N₂O₉S[M+H] + 767.2999.Found 767.2964.

[0552]

[0553] Compound I-3-29: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 40%). 1H NMR (400MHz, CDCl3): δ7.70(d,J=8.9Hz,2H),7.42(d,J=8.6Hz,1H),7.17–7.08(m,2H),6.94(s,1H),6.83(d,J=7.9Hz,1H),6.67(d,J=8.1Hz,1H),6. 52(d,J=16.3Hz,2H),5.96(d,J=9.7Hz,1H),5.71(s,1H),5.54(s,1H),5.0 6(s,1H),4.53(t,J=8.6Hz,2H),3.91(s,3H),3.76(d,J=9.8Hz,1H),3.66( s,3H),3.40(s,1H),3.15(t,J=8.7Hz,2H),3.12–3.02(m,2H),2.91(td,J= 11.6,7.0Hz,1H),2.63–2.55(m,2H),2.53–2.42(m,1H),2.35(dd,J=14.3, 6.9Hz,1H),2.29(d,J=15.0Hz,1H),2.26–2.14(m,1H),2.00(s,2H),1.94– 1.70(m,6H),1.63(d,J=7.1Hz,3H),1.59(s,3H)ppm.HRMS-ESI(m / z):Calcd forC 47 H 51 FN2O 10 [M+H] + 803.3542.Found 803.3465.

[0554]

[0555] Compound I-3-30: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 20%). 1H NMR (400MHz, CDCl3): δ7.64(d,J=8.8Hz,2H),7.58(d,J=8.5Hz,1H),7.34(d,J=8.3Hz,1H),7.09(d,J=9.0Hz,1H),7.04(s,1H),6.81(s,1H),6.73(d ,J=8.2Hz,1H),6.66(t,J=7.2Hz,1H),6.50(dd,J=12.3,2.5Hz,2H),5.98 (d,J=9.5Hz,2H),5.79(d,J=10.4Hz,1H),5.58(s,1H),5.10(s,1H),4.53( t,J=8.6Hz,2H),3.89(s,3H),3.78(d,J=9.7Hz,1H),3.69(s,3H),3.21–3 .05(m,4H),2.95–2.87(m,1H),2.85(s,1H),2.65–2.49(m,3H),2.32–2.20 (m,2H),2.07–1.97(m,2H),1.93–1.88(m,1H),1.82(s,3H),1.79–1.72(m,3H),1.72–1.64(m,2H),1.61(d,J=7.2Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 47 H 51 FN2O 10 [M+H] + 803.3542.Found 803.3465.

[0556]

[0557] Compound I-3-31 was subjected to column chromatography with PE:EA = 2:1 and 0.5% TEA to give a pale yellow amorphous solid (yield 20%). 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.2Hz,3H),7.44(d,J=8.5Hz,1H),7.14(dd,J=13.0,4.1Hz,2H),7.01(dd,J=8.9,3.8Hz,1H),6.51(d,J=10 .7Hz,2H),5.93–5.88(m,1H),5.52(d,J=22.8Hz,2H),5.05(s,1H),3.9 1(s,3H),3.77–3.72(m,1H),3.65(s,3H),3.12–2.98(m,3H),2.89(td, J=11.4,6.9Hz,1H),2.57(q,J=8.5Hz,2H),2.30(td,J=14.8,7.8Hz,2H),2.08–1.95(m,1H),1.94–1.82(m,1H),1.74(ddd,J=18.9,12.4,5.4H z,4H),1.61(d,J=7.1Hz,3H),1.50(ddd,J=49.4,13.4,6.0Hz,3H),0.94–0.86(m,2H),0.83(dd,J=6.7,3.1Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 41 H 49 N₂O₉[M+H] + 713.3439.Found713.3360.

[0558]

[0559] Compound I-3-32: Column chromatography with PE:EA = 4:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 54%). 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.2Hz,3H),7.44(d,J=8.5Hz,1H),7.14(dd,J=13.0,4.1Hz,2H),7.01(dd,J=8.9,3.8Hz,1H),6.51(d,J=10 .7Hz,2H),5.93–5.88(m,1H),5.52(d,J=22.8Hz,2H),5.05(s,1H),3.9 1(s,3H),3.77–3.72(m,1H),3.65(s,3H),3.12–2.98(m,3H),2.89(td, J=11.4,6.9Hz,1H),2.57(q,J=8.5Hz,2H),2.30(td,J=14.8,7.8Hz,2H),2.08–1.95(m,1H),1.94–1.82(m,1H),1.74(ddd,J=18.9,12.4,5.4H z,4H),1.61(d,J=7.1Hz,3H),1.50(ddd,J=49.4,13.4,6.0Hz,3H),0.94–0.86(m,2H),0.83(dd,J=6.7,3.1Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 40 H 47 N₂O₉[M+H] + 699.3203.Found699.3280.

[0560]

[0561] Compound I-3-33: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 58%). 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.6Hz,3H),7.43(dd,J=8.4,1.8Hz,1H),7.18–7.06(m,3H),7.00(dd,J=8.6,4.0Hz,1H),6.89 (dd,J=5.1,3.4Hz,1H),6.75–6.71(m,1H),6.52(d,J=4.7Hz,2H),5.96(d,J=9.6Hz,1H),5.46(dd,J=46.8,1.5Hz,2H),5.08(s, 1H),3.92(s,3H),3.77(d,J=9.6Hz,1H),3.67(s,3H),3.14–3.00(m,3H),2.88(ddt,J=17.7,13.6,5.8Hz,2H),2.62–2.52(m,3H ),2.39–2.25(m,2H),2.09–1.95(m,2H),1.98–1.82(m,3H),1.84–1.70(m,3H),1.61(d,J=7.1Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 42 H 45 N₂O₉S[M+H] + 753.2845.Found 753.2768.

[0562]

[0563] Compound I-3-34: Column chromatography with PE:EA = 2:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 83%). 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.6Hz,3H),7.43(dd,J=8.3,1.9Hz,1H),7.16–7.10(m,2H),7.04(dd,J=8.7,4.0Hz,1H),6.95(s,1H),6.84(d, J=8.8Hz,1H),6.67(d,J=8.1Hz,1H),6.53(s,1H),6.51(s,1H),5.95(d,J=9.6Hz,1H),5.48(dd,J=48.8,1.6Hz,2H),5.09(s,1H),4.53(t,J=8.7 Hz,2H),3.92(s,3H),3.79(d,J=9.7Hz,1H),3.69(s,3H),3.16(t,J=8.7 Hz,2H),3.11–3.02(m,2H),3.08(s,1H),2.90(td,J=11.5,6.8Hz,1H),2 .64–2.47(m,4H),2.36–2.20(m,4H),2.09–1.97(m,1H),1.93–1.85(m,1H),1.82–1.71(m,4H),1.61(d,J=7.1Hz,3H)ppm.HRMS-ESI(m / z):Calcd for C 46 H 49 N2O 10 [M+H] + 789.3385.Found 789.3309.

[0564] Example 24: Preparation of ketoxime ether compounds

[0565]

[0566] General procedure: Under Ar atmosphere, isopentyl bromide (1.2 mmol) was added dropwise to a DMF (2 mL) solution containing 1 mmol of oxime (2 mmol) of K₂CO₃, and the reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO₃, extracted with Et₂O, and the organic phases were combined. The mixture was washed successively with H₂O and saturated NaCl, and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation to obtain the crude ketoxime ether product.

[0567] Following the method described above, the following compounds were obtained:

[0568]

[0569] Compound I-3-35: Column chromatography with PE:EA = 7:1 and 0.5% TEA yielded a pale yellow amorphous solid (63% yield). 1H NMR (400MHz, CDCl3): δ6.59(s,1H),6.55(s,1H),5.93(d,J=9.0Hz,1H),5.85(dd,J=9.2,1.6Hz,2H),5.02(s,1H),3.76(d,J=9. 8Hz,1H),3.72(s,1H),3.66(s,3H),3.21–3.10(m,1H),3.13–3.02(m,1H),2.92(td,J=11.6,7.1Hz,1H),2.63–2.52(m,2H),2.37 (dd,J=14.1,6.9Hz,1H),2.11–1.96(m,3H),1.94–1.82(m,2H),1.74(ddd,J=17.1,8.7,4.6Hz,3H),1.61(s,3H),1.54–1.35(m, 3H),1.34–1.22(m,5H),1.13(dt,J=13.1,6.9Hz,1H),0.90–0.86(m,3H),0.83(dt,J=6.6,3.4Hz,8H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 49 N₂O₇[M+H] + 585.3541.Found 584.3462.

[0570]

[0571] General procedure: Under Ar atmosphere, isopentyl bromide (1.2 mmol) was added dropwise to a DMF (2 mL) solution containing 1 mmol of oxime (1.2 mmol) and NaH, and the reaction was monitored by TLC until complete. The reaction was quenched with half-saturated NH4Cl, extracted with Et2O, and the organic phases were combined and washed successively with H2O and saturated NaCl, then dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the crude aldehyde oxime ether product.

[0572]

[0573] Compound I-3-36: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (66% yield). 1H NMR (400MHz, CDCl3): δ6.57(d,J=4.4Hz,2H),6.23(dd,J=6.7,3.5Hz,1H),5.92(d,J=9.7Hz,1H),5.87(s,2H),5.06(s,1H),4.07(td,J =7.0,2.2Hz,2H),3.79(d,J=9.7Hz,1H),3.68(s,3H),3.15–3.06(m,2H),3.01(s,1H),2.98–2.89(m,1H),2.60(t,J=8.3Hz,2H),2.50( dd,J=16.7,6.7Hz,1H),2.37(dd,J=14.1,6.7Hz,1H),2.03(t,J=10.4Hz,1H),1.90(ddd,J=12.2,8.1,4.1Hz,1H),1.79–1.59(m,6H),1 .49(dq,J=37.9,6.8Hz,6H),0.93(dd,J=6.7,2.2Hz,6H),0.89(d,J=6.7Hz,1H),0.84(dd,J=6.6,2.2Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 32 H 47 N₂O₇[M+H] + 571.3384.Found 570.3305.

[0574]

[0575] Compound I-3-37: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 35%). 1H NMR (400MHz, CDCl3) δ6.60(s,1H),6.58(s,1H),5.93(d,J=9.8Hz,1H),5.86(d,J=13.8Hz,2H),5.05(s,1H),4.20–4.01 (m,1H),3.99(t,J=7.0Hz,2H),3.79(d,J=9.6Hz,1H),3.67(s,3H),3.19–3.04(m,2H),2.94(dd,J=21.0,9.1Hz,1H),2. 64–2.53(m,2H),2.38(dd,J=13.7,6.7Hz,1H),2.15–1.97(m,2H),1.95–1.84(m,1H),1.83–1.69(m,3H),1.70–1.39(m, 5H),1.27(h,J=8.6,7.5Hz,6H),1.16–0.98(m,1H),0.90(d,J=6.8Hz,6H),0.89–0.80(m,3H)ppm.HRMS-ESI(m / z):Calcd forC 31 H 45 N₂O₇[M+H] + 557.3225.Found 557.3149.

[0576]

[0577] Compound I-3-38: Column chromatography with PE:EA = 3:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 40%). 1H NMR (400MHz, CDCl3): δ7.10(dd,J=5.2,1.2Hz,1H),6.90(dd,J=5.2,3.4Hz,1H),6.74(d,J=2.2Hz,1H),6.58(s,1H),6.58(s,1H ),6.23(dd,J=6.7,3.6Hz,1H),5.98(d,J=9.6Hz,1H),5.83(dd,J=26.4,1.7Hz,2H),5.09(s,1H),4.07(td,J=7.0,2.4Hz,2H),3 .82(d,J=9.7Hz,1H),3.70(s,3H),3.19–3.05(m,3H),3.01–2.80(m,2H),2.66–2.49(m,4H),2.38(dd,J=14.2,6.8Hz,1H),2.12 –1.99(m,1H),1.97–1.85(m,3H),1.81–1.72(m,3H),1.73–1.61(m,3H),0.91(dd,J=6.6,4.0Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 43 N₂O₇S[M+H] + 611.2789.Found 611.2713.

[0578] Example 25: Preparation of carbamate oxime compounds

[0579]

[0580] General procedure: Under Ar atmosphere, cyclopentylcarbamate (1.2 mmol) was added dropwise to a CH2Cl2 (2 mL) solution of oxime (1 mmol) and reacted for 12 h. The reaction was quenched with saturated NaHCO3, extracted with CH2Cl2, and the organic phases were combined, washed with saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to obtain the crude carbamate oxime product.

[0581] Following the method described above, the following compounds were obtained:

[0582]

[0583] Compound I-3-39: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous product (yield 32%). 1H NMR (400MHz, CDCl3): δ6.49(s,1H),6.42(s,1H),6.07(d,J=7.2Hz,1H),5.96(d,J=9.7Hz,1H),5.88(d,J=1.6Hz,2H),5.05(s,1H), 4.09(h,J=6.9Hz,1H),3.71(d,J=9.3Hz,1H),3.67(s,3H),3.30(s,1H),3.18–3.00(m,2H),2.90(td,J=11.5,7.0Hz,1H),2.63–2.51 (m,2H),2.34(dd,J=14.1,7.0Hz,1H),2.27(d,J=17.5Hz,1H),2.13(d,J=17.5Hz,1H),2.11–1.93(m,4H),1.96–1.83(m,2H),1.85–1 .74(m,2H),1.74(s,3H),1.72–1.51(m,6H),1.52–1.42(m,2H),1.41–1.28(m,1H),0.86(d,J=6.6Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 34 H 48 N3O8[M+H] + 626.3438.Found 626.3363.

[0584]

[0585] Compound I-3-40: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 41%). 1 H NMR (400MHz, CDCl3): δ6.68(s,1H),6.63(s,1H),6.21(d,J=7.4Hz,1H),5.97(d,J=9.6Hz ,1H),5.85(s,2H),5.08(s,1H),4.08(h,J=6.8Hz,1H),3.85(d,J=9.7Hz,1H),3.69(s,3H) ,3.21–2.99(m,4H),2.75–2.55(m,3H),2.13–1.89(m,6H),1.79(s,3H),1.73–1.53(m,6H ),1.55–1.41(m,3H),1.43–1.30(m,4H),0.82(d,J=6.6Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 34 H 48 N3O8[M+H] +626.3438.Found 626.3363.

[0586]

[0587] Compound (I-3-41): Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 32%). 1 H NMR (400MHz, CDCl3): δ6.48(s,1H),6.42(s,1H),6.03(d,J=1.7Hz,1H),5.97(d,J=9.7Hz,1H),5.86(d,J=1.7Hz,1H),5.86–5.68 (m,1H),5.06(s,1H),5.05–4.90(m,2H),4.17–4.04(m,1H),3.69(d,J=10.1Hz,1H),3.67(s,3H),3.31(d,J=1.5Hz,1H),3.18–3. 01(m,3H),2.97–2.85(m,1H),2.63–2.52(m,2H),2.34(dd,J=13.6,6.3Hz,1H),2.30(d,J=17.3Hz,1H),2.24–2.15(m,1H),2.18( d,J=17.3Hz,1H),2.13–1.87(m,6H),1.85–1.76(m,2H),1.76(s,3H),1.75(s,1H),1.72–1.52(m,6H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 44 N3O8[M+H] + 610.3126.Found 610.3050.

[0588]

[0589] Compound I-3-42: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 42%). 1H NMR (400MHz, CDCl3): δ6.48(s,1H),6.42(s,1H),6.03(s,1H),5.97(d,J=9.7Hz,1H),5.86(s,1H),5.85–5.68(m,1H), 5.05(s,1H),5.04–4.88(m,2H),4.08(dd,J=8.4,4.9Hz,1H),3.69(d,J=10.1Hz,1H),3.67(s,3H),3.41–3.27(m,1H), 3.18–2.99(m,2H),2.98–2.81(m,1H),2.64–2.52(m,3H),2.40–2.25(m,2H),2.18(d,J=17.3Hz,2H),2.12–1.94(m,4H ),1.96–1.84(m,2H),1.87–1.75(m,2H),1.75(s,3H),1.76–1.69(m,1H),1.73–1.54(m,6H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 44 N3O8[M+H] + 610.3126.Found 610.3050.

[0590]

[0591] Compound I-3-43: Column chromatography with PE:EA = 3:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 21%). 1H NMR (400MHz, CDCl3): δ7.09(dd,J=5.2,1.2Hz,1H),6.89(dd,J=5.2,3.4Hz,1H),6.73(d,J=3.4Hz,1H),6.68(s,1H),6.63(s,1H),6.17(d ,J=7.4Hz,1H),6.01(d,J=9.6Hz,1H),5.80(dd,J=14.1,1.5Hz,2H),5.09(s,1H),4.07(h,J=7.3Hz,1H),3.86(d,J=9.6Hz,1H),3.67(s,3 H),3.23(s,1H),3.17–3.07(m,2H),2.94(td,J=11.6,6.8Hz,1H),2.89–2.76(m,1H),2.67(d,J=14.2Hz,1H),2.66–2.53(m,3H),2.06–1. 86(m,5H),1.81(s,3H),1.74(dd,J=13.1,4.7Hz,2H),1.71–1.55(m,6H),1.53–1.40(m,2H),1.43–1.31(m,1H)ppm.HRMS-ESI(m / z):Calcd for C 35 H 44 N3O8S[M+H] + 666.2680.Found 666.2771.

[0592]

[0593] Compound I-3-44: Column chromatography with PE:EA = 3:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 18%). 1H NMR (400MHz, CDCl3): δ7.11(dd,J=5.1,1.2Hz,1H),6.92(dd,J=5.2,3.4Hz,1H),6.76(d,J=2.2Hz,1H),6.49(s,1H),6.44(s,1H),6.06( d,J=7.2Hz,1H),6.02(d,J=1.7Hz,1H),5.86(d,J=1.7Hz,1H),5.07(s,1H),4.10(h,J=6.8Hz,1H),3.72(d,J=9.7Hz,1H),3.65(s,3H),3 .41(d,J=1.6Hz,1H),3.18–3.01(m,2H),3.02–2.87(m,2H),2.70(td,J=13.6,4.6Hz,1H),2.62–2.55(m,2H),2.35(dd,J=14.4,7.0Hz,1 H),2.22(d,J=17.5Hz,1H),2.20(d,J=17.5Hz,1H),2.11–1.95(m,4H),1.98–1.85(m,3H),1.86–1.78(m,2H),1.77(s,3H),1.73–1.55(m 6H)ppm.HRMS-ESI(m / z):Calcd for C 35 H 44 N3O8S[M+H] + 666.2680.Found 666.2771.

[0594]

[0595] Compound I-3-45: Column chromatography with PE:EA = 3:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 44%). 1H NMR (400MHz, CDCl3): δ6.94(s,1H),6.83(d,J=8.1Hz,1H),6.66(d,J=8.1Hz,1 H),6.66(s,1H),6.62(s,1H),6.17(d,J=7.4Hz,1H),6.00(d,J=9.6Hz,1H),5.7 8(dd,J=22.7,1.6Hz,2H),5.11(s,1H),4.53(t,J=8.6Hz,2H),4.06(q,J=6.9H z,1H),3.86(d,J=9.7Hz,1H),3.70(s,3H),3.20(s,1H),3.16(t,J=8.5Hz,2H), 3.15–3.04(m,2H),2.94(td,J=11.5,6.9Hz,1H),2.70(d,J=14.1Hz,1H),2.60 (td,J=14.5,6.9Hz,3H),2.49(td,J=12.8,4.7Hz,1H),2.24(td,J=13.7,13.2, 3.9Hz,1H),2.10–1.95(m,2H),1.91(dt,J=8.4,5.2Hz,2H),1.82(s,3H),1.82 –1.71(m,2H),1.72–1.54(m,6H),1.53–1.40(m,3H)ppm.HRMS-ESI(m / z):Calcd for C 39 H 48 N3O9[M+H] + 702.3388.Found 702.3312.

[0596]

[0597] Compound I-3-46: Column chromatography with PE:EA = 6:1 and 0.5% TEA yielded a pale yellow amorphous solid (yield 38%). 1H NMR (400MHz, CDCl3): δ6.64(s,1H),6.60(s,1H),5.94(d,J=9.7Hz,1H),5.91–5.88(m,2H),5.09(s,1H),3.81( d,J=9.7Hz,1H),3.68(s,4H),3.34(s,1H),3.13–3.01(m,2H),3.01–2.89(m,2H),2.66–2.54(m,2H),2.38(dd, J=13.6,6.3Hz,1H),2.10–2.01(m,2H),2.00–1.85(m,2H),1.80–1.71(m,4H),1.67–1.53(m,4H),1.47(dt,J=1 3.2,6.5Hz,1H),1.40–1.23(m,4H),0.97–0.88(m,3H),0.85(dd,J=6.6,4.5Hz,6H)ppm.HRMS-ESI(m / z):Calcd for C 33 H 46 N3O8[M+H] + 612.3286.Found 612.3207.

[0598] Example 26: In vitro bioactivity test

[0599] Test cells

[0600] Human breast cancer cells MCF-7, liver cancer cells HepG2, and lung adenocarcinoma cells A549 were all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. Human leukemia cells HL-60, human leukemia cells resistant to doxorubicin HL-60 / ADR, and human glioblastoma cells U-87MG were purchased from Shanghai Chuanqiu Biotechnology Co., Ltd. Human cervical cancer cells HeLa were purchased from Shanghai Jikai Gene Chemical Technology Co., Ltd. Human colon cancer cells HCT-116 and human brain microvascular endothelial cells hCMEC / D3 were preserved by Tianjin Shangde Pharmaceutical Technology Co., Ltd. Human colon cancer cells Sw620 and LoVo were provided by the Affiliated Hospital of Tianjin Medical University.

[0601] Main instruments and consumables

[0602] Carbon dioxide constant temperature cell incubator, Thermo Fisher Scientific, USA;

[0603] Inverted biological microscope, Chongqing Aote Optical Instrument Co., Ltd.;

[0604] ELISA reader, Thermo Fisher Scientific, USA;

[0605] Precision adjustable micropipettes, Eppendorf (Germany);

[0606] 96-well cell culture plate, Wuxi NiceLife Technology Co., Ltd.;

[0607] Cell culture dish, Wuxi Nice Life Technology Co., Ltd.

[0608] Main reagents

[0609] Fetal bovine serum, BI, Israel;

[0610] Trypsin, Gibco;

[0611] Bispecific antibody, Gibco;

[0612] DMEM medium, BI, Israel;

[0613] DMSO, Tianjin Bohua Chemical Reagent Co., Ltd.

[0614] MTT, Shanghai Yuanye Biotechnology Co., Ltd.

[0615] The experimental steps are as follows:

[0616] Cell culture

[0617] Human breast cancer cells MCF-7, liver cancer cells HepG2, lung adenocarcinoma cells A549, human leukemia cells HL-60, human leukemia cells (doxorubicin-resistant strain HL-60 / ADR), human glioblastoma cells U-87MG, human cervical cancer cells HeLa, human colon cancer cells HCT-116, human colon cancer cells Sw620, human colon cancer cells LoVo, and human brain microvascular endothelial cells HCMEC / D3 were cultured in DMEM medium. The culture medium contained 10% fetal bovine serum and 1% penicillin + streptomycin. The culture environment was a 5% CO2 incubator at 37°C. When the cells reached approximately 80%-90% confluence, they were passaged.

[0618] Preparation of working solution

[0619] Preparation of MTT solution: Weigh 50 mg of MTT, dissolve it in 10 mL of phosphate buffered saline (PBS), aliquot, and store at 4°C protected from light. It is effective for two weeks.

[0620] Preparation of test drugs: Take a series of compounds and dilute them with culture medium to prepare a 1 mg / ml stock solution. Before use, accurately pipette an appropriate amount of the sample stock solution and dilute it with culture medium to prepare working solutions with different concentration gradients, such as 100 μg / ml, 10 μg / ml, 1 μg / ml, 0.1 μg / ml, 0.01 μg / ml, 0.001 μg / ml, etc.

[0621] Determination methods

[0622] 1. Take cells in the logarithmic growth phase, digest, centrifuge, and resuspend. Add culture medium to adjust the cell density to 1×10⁶ cells / year. 5 100 μL of prepared cell suspension was added to each well of a 96-well cell culture plate and then placed in a cell culture incubator for culture.

[0623] 2. After 24 hours of culture, 2 μl of a series of compounds with concentrations of 100 μg / ml, 10 μg / ml, 1 μg / ml, 0.1 μg / ml, 0.01 μg / ml, and 0.001 μg / ml were added to the experimental group, with 4 replicates for each concentration. A positive control group (etoposide) and a blank control group were also included.

[0624] 3. After culturing the 96-well plate for 48 hours, add 20 μl of MTT solution (concentration of 5 mg / ml) to each well and continue culturing in the incubator for 4 hours.

[0625] 4. Remove the 96-well plate from the incubator, carefully aspirate the culture medium from the wells with a micropipette, add 150 μL of dimethyl sulfoxide to each well, shake to completely dissolve the crystals, and then use an ELISA reader to measure the absorbance (OD) value at a wavelength of 492 nm.

[0626] 5. The experiment was repeated three times consecutively, and the cell inhibition rate was calculated using the following formula: Cell inhibition rate (%) = [1 - OD value of experimental group / OD value of blank control group] × 100%, and the half-maximal inhibitory concentration (IC50) for inhibiting cell growth was calculated. 50 value.

[0627] Experimental results showed that solvents below 0.1 v% DMSO had negligible effects on cells, and the IC50 value was [missing information]. 50 The experimental results are summarized in Table 1.

[0628] Table 1: Activity data (IC50) of the compounds in the examples 50 (nM))

[0629]

[0630] The exemplary embodiments of the present invention have been described above. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A compound of formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof: （I-1） in, R 6 Selected from H or C 1-8 Alkyl; R 6’ Selected from H; R 7 Selected from one, two or more R b The following groups are substituted: C5-8 cycloalkyl, phenyl; each R b Same or different, selected independently from C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 alkyl thio, halogen, and with one, two or more R e Replacement C 1-8 Alkyl; R e Selected from halogens; G is selected from phenyl; n is 2 or 3; R 3 Selected from R 8 -O-;R 8 Selected from C 1-8 alkyl; Y represents O; （I-2） Among them, R Q Selected from one, two or more R c Replacement C6- 10 Aryl; R c Selected from halogens, -NO2, -NH2, C 1-8 Alkyl C(=O)NH-, C 1-8 alkyl thiols, C substituted with one or two or more halogens 1-8 alkyl; G is selected from chemical bonds; n is 2 or 3; R 3 Selected from R 8 -O-;R 8 Selected from C 1-8 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, In equation (I-1), R 3 Selected from R 8 -O-;R 8 Selected from C 1-4 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, In equation (I-2), R Q Selected from one, two or more R c Replacement C6- 10 Aryl; R c Selected from halogens, -NO2, -NH2, C 1-6 Alkyl C(=O)NH-, C 1-6 alkyl thiols, C substituted with one or two or more halogens 1-6 alkyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, In equation (I-2), R 3 Selected from R 8 -O-;R 8 Selected from C 1-4 alkyl.

5. The following compounds or their pharmaceutically acceptable salts:

6. The following compounds or their pharmaceutically acceptable salts:

7. The following compounds or their pharmaceutically acceptable salts: 。 8. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

9. Use of at least one of the compounds of any one of claims 1-7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting breast cancer cells, liver cancer cells, lung adenocarcinoma cells or leukemia cells.

10. Use of at least one of the compounds of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein, The compound is the compound represented by formula (I-1); the drug is used to inhibit human colon cancer cells.

11. Use of at least one of the compounds of claim 5 or 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein, The drug is used to inhibit human colon cancer cells.

12. Use of at least one of the compounds of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein, The compound is the compound shown in formula (I-2); the drug is used to inhibit cervical cancer cells.

13. Use of at least one of the compounds of claim 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein, The drug is used to inhibit cervical cancer cells.

Images