Camptothecin derivatives and their preparation methods and applications

Abstract

The present invention provides a novel camptothecin derivative compound, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, and a preparation method and use thereof. The compound has a structure shown in formula (I) and has good anti-cancer activity.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a series of camptothecin derivatives with novel structures, as well as preparation methods and applications thereof. Background Art

[0002] Camptothecin (CPT), a natural product originally extracted from the Chinese plant Camptotheca acuminata by American scientists Wall and Wani, is a water-insoluble, cytotoxic quinoline alkaloid with broad-spectrum anti-tumor activity. Its mechanism of action is believed to be binding to topoisomerase Top1, forming a complex with DNA, inhibiting Top1 activity, blocking DNA replication and protein synthesis, and thus leading to cell apoptosis. Camptothecin has shown significant therapeutic effects in the treatment of gastric cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic myeloid leukemia, choriocarcinoma, lung cancer, and bladder cancer. Despite their excellent anti-tumor activity, only two camptothecin compounds have been developed as anti-tumor drugs worldwide to date: irinotecan, which is used for colorectal cancer and small cell lung cancer (SCLC), and topotecan, which is used for lung and ovarian cancer. Belotecan, another camptothecin derivative, is only approved in South Korea for the treatment of SCLC and ovarian cancer. Camptothecin's cytotoxicity, poor solubility, and drug resistance have hindered its wider application in tumor treatment.

[0003] Therefore, the development of camptothecin derivatives with low toxicity, water solubility and resistance to drug resistance is necessary and has broad application value. Summary of the Invention

[0004] The object of the present invention is to provide a novel camptothecin derivative with anticancer activity.

[0005] In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof:

[0006]

[0007] Where,

[0008] R is -CH2NR1R2, wherein R1 and R2 are each independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 4 to 8 membered aryl or -NR a R b , the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 4 to 8 membered aryl or -NR aR b is optionally selected from halogen, hydroxy, amino, carboxyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, -O-(C1-C3 alkyl)-NR a R b or substituted by a 4- to 8-membered heterocycloalkyl group, provided that R1 and R2 are not hydrogen or methyl at the same time; or

[0009] R1, R2 and the nitrogen atom to which they are attached together form a 4- to 8-membered cycloalkyl, a 4- to 8-membered heterocycloalkyl, a 4- to 8-membered aryl or a 9- to 12-membered azaspiroalkyl group, wherein the 4- to 8-membered cycloalkyl, the 4- to 8-membered heterocycloalkyl, the 4- to 8-membered aryl or the 9- to 12-membered azaspiroalkyl group is optionally selected from hydroxy, amino, carboxyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2, -NR a R b or -C(O)R c or

[0010] R, its adjacent hydroxyl group and the C atom on the benzene ring to which it is connected together form a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is optionally selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, -NR a R b or substituted by a 4- to 8-membered heterocycloalkyl group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, -NR a R b or the 4- to 8-membered heterocycloalkyl group is optionally substituted by a substituent selected from halogen, hydroxy, amino, carboxyl, C1-C6 alkoxy or C1-C6 alkoxycarbonyl, provided that at least one of R1 and R2 is H.

[0011] R a and R b Each is independently selected from H, C1-C6 alkyl or C1-C6 alkoxycarbonyl.

[0012] R c Selected from amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0013] In one embodiment, in the compound of formula (I), R is -CH2NR1R2, wherein R1 and R2 are each independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl or -NR a R bThe C1-C6 alkyl group is optionally selected from halogen, hydroxy, amino, carboxyl, C1-C6 alkoxycarbonyl, -O-(C1-C3 alkyl)-NR a R b or substituted by a substituent of a 4- to 8-membered heterocycloalkyl; wherein the C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted by a substituent selected from hydroxy, C1-C3 alkoxy or C1-C6 alkoxycarbonyl, provided that R1 and R2 are not hydrogen or methyl at the same time; or,

[0014] R1, R2 and the nitrogen atom to which they are attached together form a 4- to 8-membered heterocycloalkyl group or a 9- to 12-membered azaspirocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is optionally selected from hydroxyl, amino, carboxyl, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2 or -C(O)R c or

[0015] R, its ortho hydroxyl group and the C atom on the benzene ring to which it is connected together form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally substituted by a substituent selected from a halogen-substituted C1-C6 alkyl group, a C3-C6 cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that at least one of R1 and R2 is H.

[0016] In one embodiment, R a and R b Each is independently selected from H, methyl or tert-butyloxycarbonyl.

[0017] In one embodiment, R c Selected from amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0018] In one embodiment, in the compound of formula (I), R is -CH2NHR1, R1 is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl or -NR a R b , the C1-C6 alkyl group is optionally selected from halogen, hydroxy, amino, carboxyl, C1-C6 alkoxycarbonyl, -O-(C1-C3 alkyl)-NR a R b or substituted by a substituent of a 4- to 8-membered heterocycloalkyl, wherein the C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted by a substituent selected from hydroxy, C1-C3 alkoxy or C1-C6 alkoxycarbonyl, provided that R1 is not hydrogen; or

[0019] R, its ortho hydroxyl group and the C atom on the adjacent benzene ring together form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally substituted by a substituent selected from a halogen-substituted C1-C6 alkyl group, a C3-C6 cycloalkyl group or a 4- to 8-membered heterocycloalkyl group.

[0020] In one embodiment, R a and R b Each is independently selected from H, methyl or tert-butyloxycarbonyl.

[0021] In one embodiment, R1 and R2 are each independently selected from hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclopentyl, cyclohexyl, a 5- or 6-membered heterocycloalkyl containing 1 to 2 N atoms as ring atoms, a 5- or 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N or O as ring atoms, or -NR a R b , wherein the methyl, ethyl, propyl or isopropyl group is optionally selected from halogen, hydroxy, amino, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butylalkoxycarbonyl, methoxy-NR a R b , ethoxy-NR a R b , pyrrolidinyl, piperidinyl or piperazinyl substituents; the cyclopropane, cyclopentane, cyclohexane, 5- or 6-membered heterocycloalkyl containing 1 to two N atoms as ring atoms, or 5- or 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N or O as ring atoms are optionally substituted by substituents selected from hydroxy, methoxy, ethoxy, propoxy or methoxycarbonyl, ethoxycarbonyl or tert-butylalkoxycarbonyl, provided that R1 and R2 are not hydrogen or methyl at the same time.

[0022] In one embodiment, R1, R2 and the N atom to which they are attached together form a pyrrolidinyl, piperidinyl, piperazinyl or 11-membered azaspiroalkyl group, wherein the pyrrolidinyl, piperidinyl or piperazinyl or 11-membered azaspiroalkyl group is optionally selected from hydroxy, amino, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butylalkoxycarbonyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -O-NH2 or -C(O)R c substituted by a substituent.

[0023] In one embodiment, R, its ortho hydroxyl group and the C atom on the adjacent phenyl ring together form a pyrrolidinyl, piperidinyl or piperazinyl or oxazinyl group, and the pyrrolidinyl, piperidinyl, piperazinyl or oxazinyl group is optionally substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropanyl, cyclopentanyl, cyclohexanyl, pyrrolidinyl, piperidinyl, piperazinyl or oxazinyl.

[0024] In one embodiment, in the compound of formula (I), R1 and R2 are each independently selected from hydrogen, hydroxy, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoroethyl, cyclopropyl, -(CH2)2OH, -(CH2) 2-4 NH2, -CH(CH3)COOH, -CH(CH3)CH2OCH3, -CH(CH3)CH2OH, -(CH2)2CH3, -NHBoc, N(CH3)Boc, -CH(CH3)Boc, -(CH2)2O(CH2)2NHBoc, Provided that R1 and R2 are not hydrogen or methyl at the same time; or,

[0025] R1, R2 and the nitrogen atom to which they are connected together form pyrrolidine, piperidine, piperazine or 3,9-diazaspironadecane (for example ), wherein the pyrrolidine, piperidine, piperazine or 3,9-diazaspirocycloundecane is optionally selected from hydroxy, amino, methyl, methoxy, carboxyl, tert-butyloxycarbonyl, -O-NH2 or -C(O)R c or

[0026] R, its ortho-hydroxyl group and the C atom on the adjacent benzene ring together form 1,3-oxazinane, and the 1,3-oxazinane is optionally substituted by a substituent selected from trifluoromethyl, cyclopropyl or morpholin-4, provided that at least one of R1 and R2 is H. c is selected from amino, methyl, methoxy, hydroxyethyl or cyclopropyl.

[0027] In one embodiment, R, its adjacent hydroxyl group and the C atom on the adjacent benzene ring together form described Optionally substituted with a substituent selected from C1-C6 alkyl or 4- to 8-membered heterocycloalkyl.

[0028] In one embodiment, R, its adjacent hydroxyl group and the C atom on the adjacent benzene ring together form described Optionally substituted by a substituent selected from trifluoromethyl, cyclopropyl or morpholin-4-yl, provided that at least one of R1 and R2 is H.

[0029] In one embodiment, R1, R2 and the N atom to which they are attached together form pyrrolidine, piperidine, piperazine or 3,9-diazaspirocycloundecane, and the pyrrolidine, piperidine, piperazine or 3,9-diazaspirocycloundecane is optionally substituted with a substituent selected from amino, methoxy, -O-NH2, carboxyl, tert-butyloxycarbonyl, -C(O)-NH2, -C(O)OCH3, -C(O)CH3, -C(O)-cyclopropyl, -C(O)CH2OH.

[0030] In one embodiment, R is -CH2NHR1, and R1 is selected from hydrogen, hydroxy, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoroethyl, cyclopropyl, -(CH2)2OH, -(CH2) 2-4 NH2, -CH(CH3)COOH, -CH(CH3)CH2OCH3, -CH(CH3)CH2OH, -(CH2)2CH3, -NHBoc, N(CH3)Boc, -CH(CH3)Boc, -(CH2)2O(CH2)2NHBoc, Provided that R1 is not hydrogen; or,

[0031] R, its adjacent hydroxyl group and the C atom on the adjacent benzene ring together form described Optionally substituted with a substituent selected from trifluoromethyl, cyclopropyl or morpholin-4yl.

[0032] In one embodiment, R, its adjacent hydroxyl group and the C atom on the adjacent benzene ring together form described Optionally substituted with a trifluoromethyl or morpholin-4-yl substituent.

[0033] In one embodiment, R is selected from the following structures:

[0034]

[0035] In one embodiment, R is selected from the following structures:

[0036]

[0037] In one embodiment, R is selected from the following structures:

[0038]

[0039] In the present invention, in the above compounds, R does not include the following structures: -CH2NHCH2CH2OH, -CH2NHCH2CH2N(CH3)2,

[0040] Furthermore, the compounds of formula (I) do not include the following compounds:

[0041]

[0042] In one embodiment, the compound of formula (I) is a compound of formula (II):

[0043]

[0044] Where,

[0045] The Y ring is selected from a 4- to 8-membered nitrogen-containing saturated heterocyclic ring, a 4- to 8-membered nitrogen-containing aromatic ring, or a 9- to 12-membered nitrogen-containing saturated spirocyclic ring, wherein the 4- to 8-membered nitrogen-containing saturated ring, the 4- to 8-membered nitrogen-containing aromatic ring, or the 9- to 12-membered nitrogen-containing saturated spirocyclic ring is optionally further selected from hydroxyl, amino, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2, or -C(O)R c substituted by a substituent; preferably, the C1-C6 alkoxycarbonyl group is a tert-butyloxycarbonyl group.

[0046] Preferably, the Y ring is selected from a 4- to 8-membered nitrogen-containing saturated ring or a 9- to 12-membered nitrogen-containing saturated spiro ring, wherein the 4- to 8-membered nitrogen-containing saturated ring is optionally selected from hydroxyl, amino, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2 or -C(O)R c substituted by a substituent; preferably, the C1-C6 alkoxycarbonyl group is a tert-butyloxycarbonyl group.

[0047] R c Selected from hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0048] Preferably, Rc is selected from hydroxy, amino, methyl, methoxy, hydroxymethyl, tert-butyloxy or cyclopropyl.

[0049] In one embodiment, the compound of formula (II) is a compound of formula (IIa), formula (IIb) or formula (IIc):

[0050]

[0051] Among them, R c Selected from hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0052] Preferably, Rc is selected from hydroxy, amino, methyl, methoxy, hydroxymethyl, tert-butyloxy or cyclopropyl.

[0053]

[0054] Where,

[0055] The Y ring is selected from a 4- to 8-membered nitrogen-containing saturated heterocyclic ring, a 4- to 8-membered nitrogen-containing aromatic ring, or a 9- to 12-membered nitrogen-containing saturated spirocyclic ring, wherein the 4- to 8-membered nitrogen-containing saturated ring, the 4- to 8-membered nitrogen-containing aromatic ring, or the 9- to 12-membered nitrogen-containing saturated spirocyclic ring is optionally further selected from hydroxyl, amino, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2, or -C(O)Rc substituted by a substituent; preferably, the C1-C6 alkoxycarbonyl group is a tert-butyloxycarbonyl group.

[0056] Among them, R c The same definitions as for the compounds of formula (I).

[0057] Preferably, the Y ring is selected from a 4- to 8-membered nitrogen-containing saturated ring or a 9- to 12-membered nitrogen-containing saturated spiro ring, wherein the 4- to 8-membered nitrogen-containing saturated ring is optionally selected from hydroxyl, amino, C1-C6 alkoxycarbonyl, C1-C3 alkyl, C1-C3 alkoxy, -O-NH2 or -C(O)R c substituted by a substituent; preferably, the C1-C6 alkoxycarbonyl group is a tert-butyloxycarbonyl group.

[0058] R c ' is selected from hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0059] Preferably, Rc' is selected from hydroxy, amino, methyl, methoxy, hydroxymethyl, tert-butyloxy or cyclopropyl.

[0060] In one embodiment, the compound of formula (II) is a compound of formula (IIa), formula (IIb) or formula (IIc):

[0061]

[0062] Among them, R c ' is selected from hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or hydroxy-substituted C1-C3 alkyl.

[0063] Preferably, R c ' is selected from hydroxy, amino, methyl, methoxy, hydroxymethyl, tert-butyloxy or cyclopropyl.

[0064] The present invention provides the following compounds:

[0065]

[0066]

[0067]

[0068]

[0069] Another aspect of the present invention provides a method for preparing the above compound, which comprises steps selected from the following reaction scheme:

[0070] Reaction Scheme 1:

[0071]

[0072] 10-hydroxycamptothecin, formaldehyde or paraformaldehyde and an amine compound are subjected to a Mannich reaction at position 9 to obtain a compound of formula (I);

[0073] Wherein, the amine compound is NHR1R2, and R, R1 and R2 are respectively defined as above.

[0074] Reaction Scheme 2:

[0075]

[0076] 9-formyl-10-hydroxycamptothecin, an amine compound and sodium cyanoborohydride are subjected to a reductive amination reaction to obtain a compound of formula (I);

[0077] Wherein, the amine compound is NHR1R2, and R, R1 and R2 are respectively defined as above.

[0078] In one embodiment, the 9-formyl-10-hydroxycamptothecin is obtained by reacting 10-hydroxycamptothecin with hexamethylenetetramine.

[0079] In one embodiment, in the Mannich reaction described in Reaction Scheme 1, the amount of paraformaldehyde or formaldehyde used is 1.0-5.0 molar equivalents; preferably, 1.0-3.0 molar equivalents; more preferably, 1.2-2.2 molar equivalents.

[0080] Preferably, the amount of the amine compound in Reaction Scheme 1 is 1.0-5.0 molar equivalents; more preferably, 1.0-2.0 molar equivalents; more preferably, 1.2-1.6 molar equivalents.

[0081] In one embodiment, in the reductive amination reaction described in Reaction Scheme 2, the reducing agent is sodium cyanoborohydride.

[0082] Preferably, in Reaction Scheme 2, the amount of the amine compound used is 1.0-3.0 molar equivalents; more preferably, 1.0-1.2 molar equivalents.

[0083] Preferably, the amount of sodium cyanoborohydride used is 1.0-3.0 molar equivalents; more preferably, 1.0-2.0 molar equivalents; more preferably, 1.2-1.5 molar equivalents.

[0084] Another aspect of the present invention provides an antibody-drug conjugate comprising a small molecule drug and a linker antibody, wherein the small molecule drug is the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0085] Another aspect of the present invention provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, prodrug or the above antibody-drug conjugate thereof.

[0086] The pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0087] Another aspect of the present invention provides a use of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate or pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0088] In one embodiment, the cancer includes gastric cancer, esophageal cancer, cardia cancer, breast cancer, ovarian cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic myeloid leukemia, choriocarcinoma, lung cancer, bladder cancer, intestinal cancer and small cell lung cancer; preferably, the cancer is esophageal cancer, breast cancer and gastric cancer.

[0089] Another aspect of the present invention provides a method for treating cancer, comprising the step of administering the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate or pharmaceutical composition thereof to a patient in need thereof.

[0090] In one embodiment, the amount of the compound or its pharmaceutically acceptable salt, stereoisomer, prodrug, antibody drug conjugate or pharmaceutical composition administered is a therapeutically effective amount.

[0091] The camptothecin derivative compound provided by the present invention has significant inhibitory activity on cancer cells such as esophageal cancer cell OE33, breast adenocarcinoma cell SK-BR-3 and gastric cancer cell NCI-N87.

[0092] It is noteworthy that the present invention also provides methods for preparing the aforementioned compounds, which have surprisingly high yields. DETAILED DESCRIPTION

[0093] I. Definition

[0094] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0095] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0096] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The stereoisomers include geometric isomers (such as cis, trans structures) and optical isomers (such as enantiomers), and therapeutic substances composed of monomers, racemates, racemic mixtures and pharmaceutically acceptable salts thereof. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0097] The compounds of the present disclosure also include tautomeric forms.Tautomeric forms arise from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0098] As used herein, numerical ranges refer to the individual integers within the given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C3-C6" means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0099] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom or group with a substituent, provided that the valence of the particular atom or group is normal and the substituted compound is stable. Unless otherwise specified, the type and number of substituents may be any chemically feasible.

[0100] When any variable (e.g., Rn) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-5 Rn, the group may be optionally substituted with up to 5 Rn, with each occurrence of Rn being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0101] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, with methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred in the present disclosure.

[0102] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclyl, optionally substituted by 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiroheterocyclyl, or nitrogen-containing fused heterocyclyl.

[0103] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.

[0104] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0105] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0106] The hydrogen atoms described in the present disclosure may all be replaced by their isotope deuterium.

[0107] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0108] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0109] Refers to the chemical bond connection.

[0110] Drug or pharmaceutical composition

[0111] As used herein, "pharmaceutically acceptable salts" refer to salts formed between the corresponding amine compounds and inorganic or organic acids, or between the corresponding carboxylic acid compounds and alkali metals or alkaline earth metals, or between the corresponding carboxylic acid compounds and organic amines. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, and the like; alkali metal or alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, and magnesium salts; and organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, and amino acids.

[0112] As used herein, "precursor" refers to a compound that, after entering the human body via an appropriate administration route, undergoes metabolism or simple chemical changes within the patient's body to transform into the compound of Formula 1 of the present invention and its corresponding salt. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonates, phosphates, sulfates, sulfonates, amino acid esters, gluconates, and various amides, acetals, hemiacetals, and carbonate amides.

[0113] The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. The oral route is generally desirable. The active agent can be administered orally in the form of capsules, tablets, and the like (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0114] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0115] Tablets comprising the active compound can be coated by methods well known in the art. The compositions of the present disclosure comprising the compound of formula I as the active compound can also be introduced into beads, microspheres or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

[0116] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0117] The term "inhibit" is used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0118] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0119] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that can achieve the desired effect. In embodiments of the present invention, when a patient is treated according to the present invention, the amount of a given drug depends on many factors, such as a specific dosage regimen, the type of disease or condition and its severity, the uniqueness (e.g., body weight) of the patient or host in need of treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, the condition to be treated, and the patient or host to be treated, the dosage can be conventionally determined by methods known in the art. Typically, with respect to the dosage used for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. The desired dosage can be conveniently expressed as a single dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0120] The term "antibody-drug conjugate (ADC)" refers to a small molecule drug with biological activity connected to a monoclonal antibody through a chemical link. The monoclonal antibody acts as a carrier to transport the small molecule drug into the target cells.

[0121] As used herein, the terms "reduce," "inhibit," "mitigate," or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0122] Unless otherwise specified, the raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0123] Preparation Example 1:

[0124] General Synthesis Method A: Add formaldehyde (1-3 eq), an amine compound (1-2 eq), and dioxane to a reaction flask, heat to 50-70°C with stirring for 1 h, cool to room temperature, add 10-hydroxycamptothecin (1 eq), raise the temperature to 70-90°C, and continue stirring for 4 h. Cool, filter, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (DCM:MeOH = 90:1-10:1) to obtain the target compound. Removal of the Boc-protecting group: Add the compound with the Boc-protecting group obtained above to a reaction flask, dissolve the product in ethyl acetate, stir at 0°C, add 4M HCl in ethyl acetate, stir at room temperature for 2 h, concentrate, and recrystallize to obtain the final compound.

[0125] General synthetic method B: 10-hydroxycamptothecin (1 eq) and hexamethylenetetramine (1.2-2.0 eq) were stirred and heated at 50 to 70°C under argon for 12 hours. The reaction mixture was concentrated, H2O was added, stirred for 1 hour, and the pH was adjusted to 8-9 with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate, and the aqueous phase was acidified to pH 4-5 with 2N HCl, extracted with ethyl acetate, dried with Na2SO4, purified by silica gel column chromatography, washed with MeOH / DCM (1:50), and concentrated to obtain the 9-formylated camptothecin product.

[0126] 9-Formyl-10-hydroxycamptothecin (1 eq), an amine compound (2 eq), and methanol / dichloromethane were added to a reaction flask and reacted at room temperature for 30 minutes. Sodium cyanoborohydride was added and the reaction was continued with stirring at room temperature for 6 hours. The mixture was filtered, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography with DCM:MeOH = 90:1-10:1 to obtain the target compound.

[0127] Removal of the Boc-protecting group: Same as above method A, recrystallization to obtain the final compound.

[0128] Example 1: 9-(1-(4-aminopiperidine))methyl-10-hydroxycamptothecin (1)

[0129]

[0130] Method A: Paraformaldehyde (8.3 mg, 0.274 mmol), 4-Bocaminopiperidine (27 mg, 0.137 mmol), and dioxane (10 mL) were heated to 70°C with stirring for 2 h. After cooling to room temperature, 10-hydroxycamptothecin (25 mg, 0.07 mmol) was added, and the temperature was raised to 110°C with continued stirring for 6 h. The mixture was cooled, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to column chromatography using DCM:MeOH = 90:1-10:1 as the eluent to afford the target compound 9-(4-Bocaminopiperidine)methyl-10-hydroxycamptothecin (37.1 mg, 93.7% yield); LC / MS (M+H): 577.11 (calcd: 576.26).

[0131] Dissolve the above-mentioned 9-(4-Boc-aminopiperidinyl)methyl-10-hydroxycamptothecin (37.1 mg) in ethyl acetate (2 mL), stir at 0°C, add 4M HCl in ethyl acetate (0.5 mL), and stir at room temperature for 2 h. Concentrate the solvent and recrystallize from ethyl acetate / petroleum ether to obtain the product compound 9-(1-(4-aminopiperidinyl)methyl-10-hydroxycamptothecin (30.1 mg, 90.9% yield) as a red solid. 1 H NMR (500MHz, DMSO-d6) δ8.84 (s, 1H), 8.37-8.15 (m, 3H), 8.10 (d, J = 9.2Hz, 1H), 7.61 (d,J=9.2Hz,1H),7.28(s,1H),6.35(s,3H),5.42(s,2H),5.26(s,2H),4.48(s,2H), 3.28 (d, J = 11.4 Hz, 1H), 2.95 (s, 2H), 2.03 (d, J = 12.9 Hz, 2H), 1.87 (dt, J = 16.2, 7.1 Hz, 2H), 1.83-1.68 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 476.99 (calculated value: 476.21).

[0132] Example 2: 9-(1-piperazine)methyl-10-hydroxycamptothecin (2)

[0133]

[0134] Paraformaldehyde, 1-Boc piperazine, dioxane and 10-hydroxycamptothecin were prepared according to method A to give the compound 9-(4-Boc-piperazine-1-)methyl-10-hydroxycamptothecin (yield: 92.2%); LC / MS (M+H): 563.05 (calculated value: 562.24).

[0135] The above 9-(4-Boc-piperazine-1-)methyl-10-hydroxycamptothecin (35.6 mg) was dissolved in ethyl acetate (2 mL), stirred at 0°C, 4M HCl in ethyl acetate (0.5 mL) was added, and stirred at room temperature for 2 h. The mixture was concentrated and recrystallized from ethyl acetate / petroleum ether to obtain a solid product compound 9-(1-piperazine)methyl-10-hydroxycamptothecin (26.8 mg, yield 91.2%). 1 HNMR (500 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.93 (s, 2H), 9.10 (s, 1H), 8.13 (dt, J = 9.2, 3.0 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.26 (t, J = 1.8 Hz, 1H), 5.39 (s, 2H), 5.19-5.15 (m, 2H), 4.80 (s, 2H), 3.73 (s, 2H), 1.97 (s, 1H), 1.90 (s, 2H), 1.86 (dd, J = 10.7, 7.1 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 462.97 (calculated value: 462.19).

[0136] Example 3: 9-(1-(4-aminooxypiperidine))methyl-10-hydroxycamptothecin (3)

[0137]

[0138] Preparation of 2-(piperidin-4-oxy)isoindoline-1,3-dione: Dissolve triphenylphosphine (1.93 g, 7.34 mmol) and N-hydroxyphthalimide (1.20 g, 7.34 mmol) in THF (10 mL). Stir at 0°C. Add 1-Boc-4-hydroxypiperidine (0.500 g, 4.90 mmol) and diethyl azodicarboxylate (3.34 mL, 7.34 mmol). Slowly warm to room temperature and stir overnight. Concentrate the solvent under reduced pressure. Purify by silica gel column chromatography eluting with petroleum ether / ethyl acetate (90 / 10 to 50 / 50) to give the product, 2-(1-Boc-piperidin-4-oxy)isoindoline-1,3-dione (1.8 g, 72% yield); LC / MS (M+H): 347.02 (calcd: 346.15).

[0139] 2-(1-Boc-piperidin-4-oxy)isoindoline-1,3-dione (1.8 g, 5.2 mmol) was dissolved in ethyl acetate (5 mL), and 4 M HCl in ethyl acetate (2 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to give 2-(piperidin-4-oxy)isoindoline-1,3-dione hydrochloride (1.31 g, 89% yield); LC / MS (M+H): 247.07 (calculated: 246.10).

[0140] Paraformaldehyde, 2-(piperidin-4-oxy)isoindoline-1,3-dione hydrochloride, dioxane, and 10-hydroxycamptothecin were synthesized according to Method A to give compound 9-(2-(piperidin-4-oxy)isoindoline-1,3-dione-1-)methyl-10-hydroxycamptothecin (yield 66.5%); LC / MS (M+H): 623.05 (calculated value: 622.21).

[0141] 9-(2-(piperidin-4-oxy)isoindoline-1,3-dione-1-)methyl-10-hydroxycamptothecin was added to a reaction flask, and ethanol and 85% hydrazine hydrate (1.5 eq) were added. The mixture was stirred at room temperature for 1 hour, concentrated, and converted into hydrochloride with ethyl acetate containing 4M HCl. The mixture was recrystallized from ethyl acetate / petroleum ether to obtain a red solid compound 9-(1-(4-aminooxypiperidinyl))methyl-10-hydroxycamptothecin (yield: 85.6%). 1 H NMR (600MHz, DMSO-d6) δ11.50(s,1H),11.01(s,2H),10.19(s,1H),9.07(s,1H),8.16(d,J=9.2 Hz,1H),7.74(dd,J=9.2,6.3Hz,1H),7.28(s,1H),6.55(s,1H),5.42(s,2H),5.24(s,2H),4.74 (s, 2H), 4.41 (d, J = 43.2 Hz, 1H), 3.30 (s, 2H), 3.06 (dd, J = 7.3, 4.8 Hz, 1H), 2.19 (s, 3H), 1.88 (dp, J = 21.6, 7.2 Hz, 2H), 1.55 (s, 1H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 493.00 (calculated value: 492.20).

[0142] Example 4: 9-(O-ethylhydroxylamine)methyl-10-hydroxycamptothecin (4)

[0143]

[0144] 9-Formyl-10-hydroxycamptothecin, O-ethylhydroxylamine hydrochloride, methanol and cyano group were synthesized according to method B to obtain the compound 9-(o-ethylhydroxylamine)methyl-10-hydroxycamptothecin (yield 56.3%); 1 H NMR (600 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.87 (s, 1H), 8.69 (s, 2H), 8.15 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 4.57 (s, 2H), 3.13 (q, J = 7.6, 7.1 Hz, 2H), 1.87 (ddt, J = 21.2, 14.5, 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 438.08 (calculated: 437.16).

[0145] Example 5: 9-(1-(4-methoxypiperidine))methyl-10-hydroxycamptothecin (5)

[0146]

[0147] Paraformaldehyde, 4-hydroxymethylpiperidine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(4-methoxypiperidin-1-)methyl-10-hydroxycamptothecin (yield 81.5%); 1 H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.30 (s, 1H), 8.94 (s, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 4.72 (s, 2H), 3.36 (s, 5H), 2.13 (s, 1H), 2.04-1.81 (m, 4H), 1.60 (s, 1H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 492.06 (calculated: 491.21).

[0148] Example 6: 9-(1-(4-cyclopropylcarbonylpiperazine))methyl-10-hydroxycamptothecin (6)

[0149]

[0150] Paraformaldehyde, 1-cyclopropylcarbonylpiperazine, dioxane and 10-hydroxycamptothecin were prepared according to the synthesis method A to obtain the compound 9-(4-cyclopropylcarbonylpiperazine-1-)methyl-10-hydroxycamptothecin (yield 91.1%); 1 H NMR (500MHz, DMSO-d6) δ8.74(d,J=9.0Hz,1H),7.96(t,J=8.9Hz,1H),7.45(dd,J=9.5,4.6Hz,1H),7.25(d, J=3.3Hz,1H),5.41(s,2H),5.20(d,J=11.3Hz,2H),4.02(d,J=3.8Hz,2H),3.53-3.45(m,4H),3.43-3.39(m, 1H), 3.37 (t, J = 6.5 Hz, 1H), 2.58 (s, 2H), 2.02-1.92 (m, 1H), 1.87 (dt, J = 16.5, 7.2 Hz, 2H), 1.46 (dd, J = 8.5, 6.0 Hz, 1H), 1.35-1.27 (m, 1H), 0.89 (t, J = 7.5 Hz, 3H), 0.82-0.60 (m, 4H); LC / MS (M+H): 531.04 (calculated value: 530.22).

[0151] Example 7: 9-(1-(4-acetylpiperazine))methyl-10-hydroxycamptothecin (7)

[0152]

[0153] Paraformaldehyde, 1-acetylpiperazine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(4-acetylpiperazine-1-)methyl-10-hydroxycamptothecin (yield 79.6%); 1 H NMR (500 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.86 (s, 1H), 8.93 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 4.73 (s, 2H), 3.47 (s, 7H), 2.05 (s, 3H), 1.96-1.78 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 505.07 (calculated: 504.20).

[0154] Example 8: 9-(1-(4-carbamoylpiperazine))methyl-10-hydroxycamptothecin (8)

[0155]

[0156] Paraformaldehyde, piperidine-1-carboxamide, dioxane and 10-hydroxycamptothecin were prepared according to synthesis method A to obtain the compound 9-(4-carbamoylpiperazine-1-)methyl-10-hydroxycamptothecin (yield 84.2%); 1 H NMR(500MHz,DMSO-d6)δ8.71-8.61(m,1H),7.98-7.88(m,1H),7.41-7.33(m,1H),7.31-7.25(m,1H),7.25-7.21(m,1H) ,6.77(s,1H),5.49-5.32(m,2H),5.27-5.13(m,2H),3.47(tdd,J=9.7,6.4,4.2Hz,3H),3.40(t,J=5.3Hz,1H),3.36(td , J=6.6,1.9Hz,1H),3.06-2.93(m,2H),2.29-2.13(m,2H),1.86(dt, J=15.0,7.2Hz,2H),1.76-1.70(m,1H),1.59(td, J=12.7,12.3,3.6Hz,2H),1.51-1.40(m,1H),1.32-1.26(m,1H),0.89-0.85(m,3H); LC / MS(M+H): 505.01(calculated value: 504.20).

[0157] Example 9: 9-(1-(4-methoxycarbonylpiperazine))methyl-10-hydroxycamptothecin (9)

[0158]

[0159] Paraformaldehyde, piperazine-1-carboxylic acid methyl ester, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(4-methoxycarbonylpiperazine-1-)methyl-10-hydroxycamptothecin (yield 87.5%); 1 H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.73 (s, 1H), 8.92 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 4.71 (s, 2H), 4.03 (s, 2H), 3.64 (s, 3H), 3.27 (s, 5H), 1.87 (m, J = 18.2, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 521.07 (calculated: 520.20).

[0160] Example 10: 9-(N-methyl-N-isopropylamino)methyl-10-hydroxycamptothecin (10)

[0161]

[0162] Paraformaldehyde, N-methylpropan-2-amine, dioxane and 10-hydroxycamptothecin were prepared according to method A to obtain the compound 9-(N-methylisopropylamino)methyl-10-hydroxycamptothecin (yield 87.5%); 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.23 (s, 1H), 5.40 (d, J = 2.2 Hz, 2H), 5.17 (s, 2H), 4.19 (s, 2H), 3.08 (q, J = 6.6 Hz, 1H), 2.24 (s, 3H), 1.87 (dq, J = 14.8, 7.2 Hz, 2H), 1.14 (d, J = 6.6 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 450.04 (calculated: 449.20).

[0163] Example 11: 9-(N-4-aminobutyl-N-methylamino)methyl-10-hydroxycamptothecin (11)

[0164]

[0165] Paraformaldehyde, tert-butyl (4-(methylamino)butyl)-1-carbamate, dioxane and 10-hydroxycamptothecin were synthesized according to method A to give the compound 9-(N-4-Bocaminobutyl-N-methylamino)methyl-10-hydroxycamptothecin (yield 82.7%); LC / MS (M+H): 579.07 (calculated value: 578.27).

[0166] 9-(N-4-Bocaminobutyl-N-methylamino)methyl-10-hydroxycamptothecin was dissolved in ethyl acetate and stirred at 0°C. A 4M HCl solution in ethyl acetate was added and stirred at room temperature for 2 h. The mixture was concentrated and recrystallized to obtain a red solid compound 9-(N-4-aminobutyl-N-methylamino)methyl-10-hydroxycamptothecin (yield 88.3%). 1H NMR (600MHz, DMSO-d6)8.93-8.84(m,1H),8.73(s,1H),8.19(ddd,J=19.2,9.2,3.4Hz,1H),7.90- 7.71(m,2H),7.64(td,J=8.9,8.5,3.7Hz,1H),7.30(s,1H),6.53(s,1H),5.43(s,2H),5.29(s,2H ),4.86-4.63(m,1H),2.90-2.79(m,1H),2.71(d,J=32.2Hz,2H),1.87(m,J=21.4,14.3,7.2Hz,2H),1.59(d,J=7.9Hz,1H),1.23(s,1H),0.88(t,J=7.3Hz,3H); LC / MS(M+H):479.04(calculated value: 478.22).

[0167] Example 12: 9-(N-methylhydroxyethylamino)methyl-10-hydroxycamptothecin (12)

[0168]

[0169] Paraformaldehyde, N-methylethanolamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methylhydroxyethylamino)methyl-10-hydroxycamptothecin (yield 90.7%); 1 H NMR (500 MHz, DMSO-d6) δ 11.44 (s, 1H), 9.20 (s, 1H), 8.88 (s, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 9.2, 1.9 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.43 (s, 3H), 5.28 (s, 2H), 4.87 (s, 1H), 4.74 (s, 1H), 3.86 (s, 2H), 2.80 (s, 3H), 1.87 (dp, J = 21.4, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 452.00 (calculated: 451.17).

[0170] Example 13: 9-(N-methyl-N-aminoethylamino)methyl-10-hydroxycamptothecin (13)

[0171]

[0172] Method B: 9-Formyl-10-hydroxycamptothecin (25 mg, 0.064 mmol), tert-butyl (2-(methylamino)ethyl)carbamate (10.2 mg, 0.07 mmol), and methanol (3 mL) were added to a reaction flask, stirred and reacted at 20°C for 1 h, cooled to 0°C, added with sodium cyanoborohydride (4.4 mg, 0.07 mmol), and continued to stir and react at 20°C for 2 h. The product was concentrated and purified by silica gel column chromatography (DCM / MeOH: 90:1-10:1) to give compound 9-(N-methyl-N-Bocaminoethylamino)methyl-10-hydroxycamptothecin (34.1 mg, yield 95.7%); LC / MS (M+H): 551.21 (calculated value: 550.24).

[0173] 9-(N-methyl-N-Bocaminoethylamino)methyl-10-hydroxycamptothecin (34.1 mg) was dissolved in ethyl acetate (2 mL), stirred at 0°C, 4M HCl in ethyl acetate (0.5 mL) was added, and stirred at room temperature for 2 h. The mixture was concentrated and recrystallized from ethyl acetate / petroleum ether to obtain a light red solid compound 9-(N-methyl-N-aminoethylamino)methyl-10-hydroxycamptothecin (27.6 mg, yield 87.7%). 1 H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.77 (s, 1H), 8.89 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.14-7.78 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.30 (s, 1H), 5.43 (s, 2H), 5.28 (s, 2H), 4.68 (s, 2H), 3.24 (s, 5H), 2.77 (s, 2H), 1.88 (dp, J = 14.3, 7.1 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H); LC / MS (M+H): 451.19 (calculated value: 450.19).

[0174] Example 14: 9-(N-methyltetrahydropyran-4-amine)methyl-10-hydroxycamptothecin (14)

[0175]

[0176] Paraformaldehyde, N-methyltetrahydro-2H-pyran-4-amine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methyltetrahydropyran-4-amino)methyl-10-hydroxycamptothecin (yield 88.7%); 1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),9.22(s,1H),8.87(s,1H),8.20(dd,J=9.2,2.3Hz,1H),7 .66(dd,J=9.2,2.0Hz,1H),7.29(d,J=1.1Hz,1H),6.53(s,1H),5.43(s,2H),5.35-5.19(m,2H), 4.73 (d, J = 120.2 Hz, 2H), 4.15-3.98 (m, 2H), 3.71 (s, 1H), 2.67 (s, 3H), 2.19-2.06 (m, 2H), 1.88 (ddq, J = 21.3, 14.1, 7.1, 6.5 Hz, 4H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 492.12 (calculated value: 491.21).

[0177] Example 15: 9-(trans-4-hydroxycyclohexylamino)methyl-10-hydroxycamptothecin (15)

[0178]

[0179] Paraformaldehyde, trans-4-aminocyclohexan-1-ol, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(4-hydroxycyclohexylamino)methyl-10-hydroxycamptothecin (yield 76.9%); 1 H NMR (500 MHz, DMSO-d6) δ 8.64-8.54 (m, 1H), 7.94-7.82 (m, 1H), 7.34-7.10 (m, 2H), 5.39 (s, 2H), 5.27-5.11 (m, 2H), 4.36 (s, 2H), 4.30-4.12 (m, 4H), 3.41 (dp, J = 8.5, 4.2 Hz, 2H), 1.98 (d, J = 10.0 Hz, 2H), 1.85 (tq, J = 14.5, 8.4, 7.8 Hz, 4H), 1.19 (q, J = 12.5 Hz, 4H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 492.09 (calculated: 491.21).

[0180] Example 16: 9-(N-methyl-trans-4-hydroxycyclohexylamino)methyl-10-hydroxycamptothecin (16)

[0181]

[0182] Paraformaldehyde, trans-4-(methylamino)cyclohexan-1-ol, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methyl-4-hydroxycyclohexylamino)methyl-10-hydroxycamptothecin (yield 82%); 1 H NMR (600MHz, DMSO-d6) δ11.63(s,1H),9.15(s,1H),8.86(s,1H),8.19(d,J=9.1Hz,1H),7.66(d ,J=9.2Hz,1H),7.28(s,1H),6.55(s,1H),5.43(s,2H),5.26(s,2H),4.77(d,J=12.7Hz,1H),4. 72-4.51 (m, 1H), 3.50-3.39 (m, 2H), 2.65 (s, 3H), 2.26-2.08 (m, 2H), 2.00 (s, 2H), 1.93-1.62 (m, 4H), 1.29 (td, J = 13.2, 6.6 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H); LC / MS (M+H): 506.02 (calculated value: 505.22).

[0183] Example 17: 9-(N-methyl-N-cyclopropylamino)methyl-10-hydroxycamptothecin (17)

[0184]

[0185] Paraformaldehyde, N-methylcyclopropylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methyl-N-cyclopropylamino)methyl-10-hydroxycamptothecin (yield 83.9%); 1 H NMR(500MHz,DMSO-d6)δ8.55(s,1H),7.87(d,J=9.1Hz,1H),7.35(d,J=9.2Hz,1H),7.17(s,1H),5.3 4(d,J=2.7Hz,2H),5.13(s,2H),4.09(s,2H),3.42(tdd,J=9.9,6.5,4.2Hz,3H),3.35(t,J=5.3Hz,1 H), 3.30 (t, J = 6.6 Hz, 1H), 2.19 (s, 3H), 1.86 (ddt, J = 9.8, 7.1, 3.1 Hz, 1H), 1.79 (p, J = 7.1 Hz, 2H), 1.39 (dd, J = 8.4, 6.2 Hz, 1H), 1.29-1.19 (m, 1H), 0.87-0.81 (m, 3H); LC / MS (M+H): 448.02 (calculated value: 447.18).

[0186] Example 18: 9-(Morpholin-4-amine)methyl-10-hydroxycamptothecin (18)

[0187]

[0188] 9-Formyl-10-hydroxycamptothecin, 4-aminomorpholine, methanol and sodium cyanoborohydride were synthesized according to Method B to give the compound 9-(morpholin-4-amino)methyl-10-hydroxycamptothecin (yield 81.0%); LC / MS (M+H): 479.08 (calculated value: 478.19).

[0189] Example 19: 9-(N-methylethylamino)methyl-10-hydroxycamptothecin (19)

[0190]

[0191] Paraformaldehyde, N-methylethylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methyl-N-ethylamino)methyl-10-hydroxycamptothecin (yield 77.3%); 1 H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.88 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 4.70 (s, 2H), 3.28 (m, J = 7.0 Hz, 2H), 2.73 (s, 3H), 1.87 (d, J = 21.5, 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 436.02 (calculated: 435.18).

[0192] Example 20: 9-(Ethylamino)methyl-10-hydroxycamptothecin (20)

[0193]

[0194] Paraformaldehyde, ethylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-ethylamino)methyl-10-hydroxycamptothecin (yield 84.0%); 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.25 (s, 1H), 5.41 (s, 2H), 5.23 (s, 2H), 4.42 (s, 2H), 2.85 (dq, J = 27.0, 7.3 Hz, 4H), 1.87 (dt, J = 15.5, 8.2 Hz, 3H), 1.18 (d, J = 7.5 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H; LC / MS (M+H): 422.06 (calculated: 421.16).

[0195] Example 21: 9-(Isopropylamino)methyl-10-hydroxycamptothecin (21)

[0196]

[0197] Paraformaldehyde, isopropylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(isopropylamino)methyl-10-hydroxycamptothecin (yield 79.7%); 1 H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.83 (s, 1H), 8.60 (s, 2H), 8.14 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.28 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.25 (s, 2H), 4.55 (d, J = 6.2 Hz, 2H), 1.87 (dp, J = 18.1, 7.1 Hz, 2H), 1.38 (d, J = 6.5 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 436.02 (calculated: 435.18).

[0198] Example 22: 3-(N-morpholino)-1,3-oxazine[5,6][9,10]camptothecin (22)

[0199]

[0200] 40% formaldehyde aqueous solution, morpholin-4-amine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to give the compound 3-(N-morpholino)-1,3-oxazino[5,6][9,10]camptothecin (yield 64.3%); LC / MS (M+H): 491.07 (calculated value: 490.19).

[0201] Example 23: 9-(1-Methyl-2-Bochydrazine)methyl-10-hydroxycamptothecin (23)

[0202]

[0203] Paraformaldehyde, 2-methylhydrazine-1-carboxylic acid tert-butyl ester, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 1-methyl-2-Bochydrazinemethyl-10-hydroxycamptothecin (yield 90.7%); 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.26 (s, 1H), 6.44 (d, J = 56.6 Hz, 2H), 5.41 (s, 3H), 5.24 (s, 2H), 4.93 (s, 2H), 2.41 (s, 3H), 1.93-1.84 (m, 2H), 1.48 (s, 9H), 0.89 (d, J = 7.3 Hz, 3H); LC / MS (M+H): 523.08 (calculated: 522.21).

[0204] Example 24: 9-(1-methylhydrazine)methyl-10-hydroxycamptothecin (24)

[0205]

[0206] 1-Methyl-2-Boc hydrazinemethyl-10-hydroxycamptothecin (Compound 23) was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated, and recrystallized from petroleum ether / ethyl acetate to obtain a solid product, 1-methylhydrazinemethyl-10-hydroxycamptothecin (yield 89.5%). 1 H NMR (600 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.97 (s, 2H), 8.72 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 6.51 (s, 1H), 5.86 (s, 1H), 5.42 (s, 2H), 5.26 (s, 2H), 4.49 (s, 2H), 2.75 (d, J = 26.1 Hz, 3H), 1.87 (dq, J = 10.7, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 423.08 (calculated: 422.16).

[0207] Example 25: 9-(1-methyl-3-aminopropylamino)methyl-10-hydroxycamptothecin (25)

[0208]

[0209] 9-Formyl-10-hydroxycamptothecin, tert-butyl (3-(methylamino)propyl)carbamate and sodium cyanoborohydride were synthesized according to method B to give the compound 9-(1-methyl-3-Bocaminopropylamino)methyl-10-hydroxycamptothecin (yield 90.6%); LC / MS (M+H): 565.17 (calculated value: 564.26).

[0210] The Boc-group protected product was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4 M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, and the solvent was concentrated. The mixture was recrystallized from ethyl acetate / petroleum ether to obtain a solid product, 9-(1-methyl-3-aminopropylamino)methyl-10-hydroxycamptothecin (yield 85.5%). 1 H NMR (500MHz, DMSO-d6) δ8.55(s,1H),7.87(d,J=9.1Hz,1H),7.35(d,J=9.2Hz,1H),7.17(s,1H),5. 34(d,J=2.7Hz,2H),5.13(s,2H),4.09(s,2H),3.42(m,J=9.9,6.5,4.2Hz,3H),3.35(t,J=5.3Hz,1 H), 3.30 (t, J = 6.6 Hz, 1H), 2.19 (s, 3H), 1.86 (m, J = 9.8, 7.1, 3.1 Hz, 1H), 1.79 (p, J = 7.1 Hz, 2H), 1.39 (dd, J = 8.4, 6.2 Hz, 1H), 1.29-1.07 (m, 2H), 0.87-0.81 (m, 3H); LC / MS (M+H): 465.09 (calculated value: 464.21).

[0211] Example 26: 9-(Piperidin-1-amine)methyl-10-hydroxycamptothecin (26)

[0212]

[0213] 9-Formyl-10-hydroxycamptothecin, 1-aminopiperidine, methanol and sodium cyanoborohydride were synthesized according to Method B to give the compound 9-(piperidin-1-amino)methyl-10-hydroxycamptothecin (yield 87.6%); LC / MS (M+H): 477.20 (calculated value: 476.21).

[0214] Example 27: 9-(N-methyl(tetrahydropyranylmethyl)amine)methyl-10-hydroxycamptothecin (27)

[0215]

[0216] Paraformaldehyde, N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine, dioxane and 10-hydroxycamptothecin (synthesized according to method A) gave the compound 9-(N-methyl(tetrahydropyranylmethyl)amine)methyl-10-hydroxycamptothecin (yield 87%); 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),8.88(d,J=3.3Hz,1H),8.18(dd,J=9.3,3.0Hz,1H),7.65(dd,J=9.4,3.6Hz,1H), 7.29(d,J=2.9Hz,1H),6.54(s,1H),5.42(d,J=3.1Hz,2H),5.26(s,2H),4.76(s,2H),3.88(d,J=11.3Hz,2H),3.34(d,J =11.6 Hz, 2H), 3.20 (s, 2H), 2.73 (d, J=3.5 Hz, 3H), 2.25 (ddd, J=11.4, 7.6, 3.9 Hz, 1H), 1.88 (ddd, J=16.5, 11.9, 7.2 Hz, 2H), 1.76 (d, J=12.8 Hz, 2H), 1.26 (q, J=12.3 Hz, 2H), 1.08-0.78 (d, J=12.8 Hz, 3H); LC / MS (M+H): 506.09 (calculated value: 505.22).

[0217] Example 28: 9-(N-methyl(piperidin-4-methyl)amine)methyl-10-hydroxycamptothecin (28)

[0218]

[0219] Paraformaldehyde, tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate, dioxane, and 10-hydroxycamptothecin were synthesized according to Method A to obtain the compound 9-(N-methyl(1-Boc-piperidin-4-methyl)amine)methyl-10-hydroxycamptothecin (yield 93.3%): LC / MS (M+H): 605.14 (calculated value: 604.29). The Boc-protected intermediate was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated, and recrystallized to obtain a solid product, 9-(N-methyl(piperidin-4-methyl)amine)methyl-10-hydroxycamptothecin (yield 88.5%). 1H NMR (500MHz, DMSO-d6) δ11.65(s,1H),8.89(s,1H),8.19(dd,J=9.7,3.8Hz,1H),7.64(dd,J=9.2,1.7Hz,1H),7.29(d,J=2 .1Hz,1H),6.52(s,1H),5.42(s,2H),5.28(d,J=5.8Hz,2H),4.76(s,2H),3.87(dt,J=10.9,3.4Hz,2H),3.34((td,J=11.8 2.1 Hz, 2H), 3.19 (s, 2H), 2.73 (s, 3H), 2.24 (ddd, J = 11.4, 7.6, 4.1 Hz, 1H), 1.94-1.82 (m, 2H), 1.75 (s, 2H), 1.26 (d, J = 14.3 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 505.14 (calculated value: 504.24).

[0220] Example 29: 9-(3-(Undec-5,5-spirocyclo-3,9-diazane))methyl-10-hydroxycamptothecin (29)

[0221]

[0222] Paraformaldehyde, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, dioxane, and 10-hydroxycamptothecin were synthesized according to Method A to give compound 9-(3-(9-Boc-undec-5,5-spirocyclo-3,9-diazane))methyl-10-hydroxycamptothecin (yield 92.9%); LC / MS (M+H): 631.18 (calculated: 630.31).

[0223] The above Boc-intermediate was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4 M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain a solid product - (3-(undeca-5,5-spirocyclo-3,9-diazane))methyl-10-hydroxycamptothecin (yield 91.1%); 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.59 (s, 1H), 8.92 (s, 1H), 8.73 (s, 2H), 8.15 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 9.3 Hz, 1H), 7.28 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.23 (s, 2H), 4.75 (s, 2H), 3.69-3.25 (m, 8H), 1.87 (dq, J = 14.3, 7.5 Hz, 4H), 1.58 (d, J = 82.2 Hz, 4H), 0.90 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 531.18 (calculated value: 530.25).

[0224] Example 30: 9-(Piperidin-4-ethylamino)methyl-10-hydroxycamptothecin (30)

[0225]

[0226] Paraformaldehyde, tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, dioxane and 10-hydroxycamptothecin were synthesized according to method A to give the compound 9-(1-Boc-piperidine-4-ethylamino)methyl-10-hydroxycamptothecin (yield 91.1%); LC / MS (M+H): 605.27 (calculated value: 604.29).

[0227] The above Boc-intermediate was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain a solid compound 9-(piperidin-4-ethylamino)methyl-10-hydroxycamptothecin (yield 94.5%). 1 H NMR (600 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.86 (d, J = 17.7 Hz, 3H), 8.85-8.43 (m, 2H), 8.16 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 4.65 (s, 2H), 3.20 (t, J = 6.2 Hz, 6H), 2.80-2.57 (m, 6H), 1.88 (dhept, J = 21.4, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 504.87 (calculated: 504.24).

[0228] Example 31: 9-(L-Proline tert-butyl ester)methyl-10-hydroxycamptothecin (31)

[0229]

[0230] Paraformaldehyde, L-proline tert-butyl ester, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(L-proline tert-butyl ester)methyl-10-hydroxycamptothecin (yield 90.2%); 1 H NMR (600MHz, DMSO-d6) δ11.55(s,1H),10.08(s,1H),8.89(s,1H),8.15(d,J=9.0Hz,1H),7.6 2(d,J=9.2Hz,1H),7.29(s,1H),6.54(s,1H),5.43(s,2H),5.29(s,2H),4.87(s,2H),4.49(d , J = 43.8 Hz, 1H), 3.19 (s, 2H), 2.46 (s, 1H), 2.04 (d, J = 10.0 Hz, 1H), 1.88 (ddt, J = 27.3, 14.2, 7.4 Hz, 4H), 1.35 (d, J = 4.2 Hz, 9H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 548.17 (calculated value: 547.23).

[0231] Example 32: 9-(L-Proline)methyl-10-hydroxycamptothecin (32)

[0232]

[0233] 9-(L-proline tert-butyl ester)methyl-10-hydroxycamptothecin (Example 31 compound) was dissolved in dichloromethane (2 mL), stirred at 0°C, trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 h. The mixture was concentrated and recrystallized from ethyl acetate / petroleum ether to obtain a solid product, 9-(L-proline)methyl-10-hydroxycamptothecin (yield 81.4%). 1H NMR (500MHz, DMSO-d6) δ8.92(s,1H),8.17(d,J=9.2Hz,1H),7.62(d,J=9.3Hz,1H),7.30(d,J=1 .5Hz,1H),6.52(s,1H),5.43(s,2H),5.36-5.20(m,2H),4.92(d,J=13.6Hz,1H),4.82(d,J=13.7 Hz, 1H), 4.49 (t, J = 8.8 Hz, 1H), 3.33 (q, J = 10.0, 9.4 Hz, 3H), 2.02 (tq, J = 12.6, 4.3, 3.2 Hz, 2H), 1.87 (ddd, J = 16.6, 14.1, 7.5 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 491.99 (calculated value: 491.17).

[0234] Example 33: 9-(1-piperidine-4-carboxylic acid methyl ester)methyl-10-hydroxycamptothecin (33)

[0235]

[0236] Paraformaldehyde, piperidine-4-carboxylic acid methyl ester, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(1-piperidine-4-carboxylic acid methyl ester)methyl-10-hydroxycamptothecin (yield 91.3%); 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),9.56(s,1H),8.92(d,J=3.7Hz,1H),8.17(t,J=8.5Hz,1H),7 .65(d,J=9.2Hz,1H),7.33-7.26(m,1H),5.43(s,2H),5.26(d,J=11.0Hz,2H),4.72(d,J=13.5Hz,2H ), 3.72(s, 2H), 3.62(s, 3H), 3.24(d, J=17.2Hz, 2H), 2.70(ddd, J=12.3,8.6,3.7Hz, 1H), 2.09-1.96(m, 2H), 1.86(qt, J=18.5,10.0Hz, 4H), 0.89(t, J=7.3Hz, 3H); LC / MS(M+H): 520.05 (calculated value: 519.20).

[0237] Example 34: 9-(1-piperidine-4-carboxylic acid)methyl-10-hydroxycamptothecin (34)

[0238]

[0239] Paraformaldehyde, piperidine-4-carboxylic acid, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(1-piperidine-4-carboxylic acid)methyl-10-hydroxycamptothecin (yield 87.5%); 1 H NMR(500MHz,DMSO-d6)δ12.53(s,1H),11.40(s,1H),9.34(s,1H),8.92(s,1H),8.18(d, J=9.2Hz,1H),7.64(d,J=9.2Hz,1H),7.29(s,1H),6.52(s,1H),5.43(s,2H),5.28(s,2H ),4.70(s,2H),3.55(s,2H),3.23(s,2H),2.56(s,1H),2.07-1.98(m,2H),1.87(dp,J=18.3,7.1Hz,2H),1.78(s,1H),0.89(t,J=7.3Hz,3H); LC / MS(M+H):506.02(calculated value: 505.18).

[0240] Example 35: 9-(L-Alanine tert-butyl ester)methyl-10-hydroxycamptothecin (35)

[0241]

[0242] Paraformaldehyde, tert-butylmethyl-L-alanine hydrochloride, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(tert-butyl L-alanine)methyl-10-hydroxycamptothecin (yield 74.8%); 1 H NMR (600 MHz, DMSO-d6) δ8.85 (s, 1H), 8.15 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.26 (d, J = 3.6 Hz, 2H), 4.69 (d, J = 36.8 Hz, 2H), 4.27 (s, 1H), 2.69 (s, 3H), 1.87 (dq, J = 11.2, 7.0 Hz, 2H), 1.57 (d, J = 7.0 Hz, 2H), 1.49 (d, J = 20.5 Hz, 9H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 522.07 (calculated value: 521.22).

[0243] Example 36: 9-(N-methyl-L-alanine)methyl-10-hydroxycamptothecin (36)

[0244]

[0245] Paraformaldehyde, N-methyl-L-alanine hydrochloride, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(N-methyl-L-alanine)methyl-10-hydroxycamptothecin (yield 81.4%); 1 H NMR (600 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.26 (d, J = 4.4 Hz, 2H), 4.83-4.66 (m, 2H), 4.35 (d, J = 9.1 Hz, 1H), 2.72 (s, 2H), 1.87 (dp, J = 21.1, 7.1 Hz, 2H), 1.63 (d, J = 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 479.92 (calculated: 479.17).

[0246] Example 37: 9-(Tetrahydropyran-4-amine)methyl-10-hydroxycamptothecin (37)

[0247]

[0248] Paraformaldehyde, 4-aminotetrahydropyran, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(tetrahydropyran-4-amine)methyl-10-hydroxycamptothecin (yield 90.8%); 1 H NMR(500MHz,DMSO-d6)δ11.31(s,1H),8.85(s,1H),8.72(s,2H),8.17(dt,J=9.3,2.4Hz,1H), 7.64(dt,J=9.2,1.8Hz,1H),7.29(d,J=1.4Hz,1H),6.52(s,1H),5.43(s,2H),5.29(d,J=2.7H z, 2H), 4.61 (s, 2H), 3.98 (dd, J = 10.9, 4.4 Hz, 2H), 2.13 (dd, J = 11.5, 3.4 Hz, 2H), 1.87 (dq, J = 18.3, 7.0 Hz, 2H), 1.76-1.62 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 478.03 (calculated value: 477.19).

[0249] Example 38: 9-(4-Boc-piperazin-1-amine)methyl-10-hydroxycamptothecin (38)

[0250]

[0251] 9-Formyl-10-hydroxycamptothecin, tert-butyl 4-aminopiperazine-1-carboxylate, methanol and sodium cyanoborohydride were synthesized according to method B to give compound 9-(4-Boc-piperazin-1-amine)methyl-10-hydroxycamptothecin (yield 87.8%); LC / MS (M+H): 578.26 (calculated value: 577.25).

[0252] Example 39: 9-((2-(2-Boc-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (39)

[0253]

[0254] Paraformaldehyde, tert-butyl (2-(2-aminoethoxy)ethyl)carbamate, dioxane and 10-hydroxycamptothecin were synthesized according to method A to give the compound 9-((2-(2-Boc-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (yield 81.8%); LC / MS (M+H): 581.23 (calculated value: 580.25).

[0255] Example 40: 3-(N-trifluoroethyl)-1,3-oxazine[5,6][9,10]camptothecin (40)

[0256]

[0257] 40% formaldehyde aqueous solution, trifluoroethylamine hydrochloride, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain compound 3-(N-trifluoroethyl)-

[0258] 1.3-oxazine[5,6][9,10]camptothecin (yield 75.1%); 1 H NMR (500MHz, DMSO-d6) δ8.84 (s, 1H), 8.15 (dd, J = 9.1, 4.7Hz, 1H), 7.63 (dd, J=9.1,1.5Hz,1H),6.56(s,1H),5.52(s,1H),4.62(s,1H),3.75(dd,J=11.6, 4.5Hz, 1H), 3.64 (dd, J=11.9, 5.9Hz, 1H), 1.87 (dt, J=16.2, 7.2Hz, 2H), 1.34 (d, J=6.6Hz, 2H), 0.89 (t, J=7.3Hz, 3H); LC / MS (M+H): 488.01 (calculated: 487.14).

[0259] Example 41: 9-(Trifluoroethylamino)methyl-10-hydroxycamptothecin (41)

[0260]

[0261] 9-(trifluoroethylamino)methyl-10-hydroxycamptothecin was synthesized from 9-formyl-10-hydroxycamptothecin, trifluoroethylamine, methanol and sodium cyanoborohydride according to method B (yield 71.3%). 1 H NMR (600 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.07 (d, J = 10.3 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.33–7.24 (m, 3H), 6.50 (s, 2H), 5.42 (s, 2H), 5.27 (s, 2H), 4.47 (s, 1H), 1.86 (dq, J = 14.2, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 476.01 (calculated: 475.14).

[0262] Example 42: 9-(trans-4-methoxycyclohexylamino)methyl-10-hydroxycamptothecin (42)

[0263]

[0264] Paraformaldehyde, trans-4-methoxycyclohexyl-1-amine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(trans-4-methoxycyclohexylamino)methyl-10-hydroxycamptothecin (yield 82.6%); 1 H NMR (500MHz, DMSO-d6) δ11.37(s,1H),8.83(s,1H),8.63(s,2H),8.15(d,J=9.1Hz,1H),7.64(d,J= 9.2Hz,1H),7.29(s,1H),6.52(s,1H),5.76(s,1H),5.43(s,2H),5.27(s,2H),4.58(s,2H),3.26(s , 3H), 3.17-3.10 (m, 1H), 2.24 (d, J = 11.0 Hz, 2H), 2.12 (d, J = 9.5 Hz, 2H), 1.87 (d, J = 7.8 Hz, 2H), 1.51 (qd, J = 12.7, 3.3 Hz, 2H), 1.23 (s, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 506.09 (calculated value: 505.22).

[0265] Example 43: 9-(Tetrahydropyranyl 4-methylamine)methyl-10-hydroxycamptothecin (43)

[0266]

[0267] Paraformaldehyde, (tetrahydro-2H-pyran-4-yl)methylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(tetrahydropyran-4-methylamino)methyl-10-hydroxycamptothecin (yield 87.2%). 1 H NMR (500MHz, DMSO-d6) δ11.44(s,1H),8.85(s,1H),8.71(s,2H),8.15(d,J=9.1Hz,1H),7.64(d,J=9.2Hz,1H ),7.29(s,1H),6.52(s,1H),5.42(s,2H),5.27(s,2H),4.60(s,2H),3.87(ddd,J=11.5,4.6,2.0Hz,2H),3.2 9 (td, J = 11.8, 2.1 Hz, 2H), 3.01 (d, J = 7.1 Hz, 2H), 2.05 (dt, J = 7.4, 3.6 Hz, 1H), 1.87 (dt, J = 15.1, 7.1 Hz, 2H), 1.75-1.66 (m, 2H), 1.25 (qd, J = 12.1, 4.5 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 492.06 (calculated value: 491.21).

[0268] Example 44: 9-(N-methylhydroxylamine)methyl-10-hydroxycamptothecin (44)

[0269]

[0270] 9-Formyl-10-hydroxycamptothecin, N-methylhydroxylamine, methanol and sodium cyanoborohydride were synthesized according to method B to obtain compound 9-(N-methylhydroxylamine)methyl-10-hydroxycamptothecin (yield 44.1%); 1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.98 (s, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H), 6.46 (s, 1H), 5.38 (s, 2H), 5.13 (s, 2H), 4.71 (s, 1H), 2.51 (s, 3H), 1.83 (hept, J = 6.7, 6.1 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 424.08 (calculated value: 423.14).

[0271] Example 45: 9-(2'-N-Boc-2'-N-methylhydrazine)methyl-10-hydroxycamptothecin (45)

[0272]

[0273] 9-Formyl-10-hydroxycamptothecin, tert-butyl 1-methylhydrazine-1-carboxylate, methanol and sodium cyanoborohydride were synthesized according to method B to give the compound 9-(2'-N-Boc-2'-N-methylhydrazine)methyl-10-hydroxycamptothecin (yield 74.1%); 1 HNMR (600 MHz, DMSO-d6) δ9.36 (s, 1H), 8.71 (s, 1H), 8.10 (d, J = 10.1 Hz, 2H), 8.04 (s, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.28 (s, 1H), 6.51 (s, 1H), 5.42 (s, 2H), 5.27 (s, 2H), 4.24 (t, J = 5.4 Hz, 1H), 3.47 (s, 3H), 1.87 (dq, J = 14.2, 7.0 Hz, 2H), 1.56 (s, 9H), 0.91-0.87 (m, 3H); LC / MS (M+H): 523.15 (calculated value: 522.21).

[0274] Example 46: 9-(1-(4-hydroxyacetylpiperazine))methyl-10-hydroxycamptothecin (46)

[0275]

[0276] Compound 2 (15 mg, 3.2 mmol) was dissolved in THF (5 mL), and glycolic acid (5.0 mg, 6.4 mmol) was added. Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 2.9 mg, 6.4 mmol) was added with stirring. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain 9-(1-(4-hydroxyacetylpiperazine))methyl-10-hydroxycamptothecin (11.5 mg, yield 69.3%). 1 H NMR (500MHz, DMSO-d6) δ8.86(s,1H),8.09(d,J=9.2Hz,1H),7.58(d,J=9.2Hz,1H),7.27(s,1H),6.52(s,3H),5.42(s,2H),5.26( s,2H),4.43(s,2H),4.11(s,2H),3.56(d,J=43.9Hz,4H),3.15-2.89(m,4H),1.87(dt,J=16.5,7.2Hz,2H),0.89(t,J=7.3Hz,3H);

[0277] LC / MS (M+H): 520.99 (calculated: 520.20).

[0278] Example 47: 9-(N,O-dimethylhydroxylamine)methyl-10-hydroxycamptothecin (47)

[0279]

[0280] 9-Formyl-10-hydroxycamptothecin, N,O-dimethylhydroxylamine hydrochloride, methanol and sodium cyanoborohydride were synthesized according to method B to obtain the compound 9-(N,O-dimethylhydroxylamine)methyl-10-hydroxycamptothecin (yield 65.3%); 1 H NMR (600MHz, DMSO-d6) δ10.44(s,1H),10.33(s,1H),8.82(s,1H),8.66(s,1H),8.01(dd,J= 15.4,9.2Hz,1H),7.52(t,J=8.5Hz,1H),7.26(d,J=2.2Hz,1H),6.49(s,1H),5.42(s,2H),5. 27 (d, J = 4.5 Hz, 2H), 4.87 (s, 1H), 4.28 (s, 1H), 3.33 (d, J = 3.4 Hz, 3H), 2.55 (s, 1H), 1.86 (dh, J = 21.3, 7.2 Hz, 2H), 1.24 (s, 1H), 0.88 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 438.11 (calculated value: 437.16).

[0281] Example 48: 9-((1-methoxypropan-2-yl)amino)methyl-10-hydroxycamptothecin (48)

[0282]

[0283] Paraformaldehyde, 1-methoxypropan-2-amine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-((1-methoxypropan-2-yl)amino)methyl-10-hydroxycamptothecin (yield 93.2%); 1H NMR (500MHz, DMSO-d6) δ8.57(s,1H),7.98(t,J=6.8Hz,1H),7.38(d,J=8.8Hz,1H),7. 37-7.29(m,1H),5.48(d,J=7.4Hz,2H),5.27(s,2H),5.12(q,J=4.4,3.9Hz,2H),4.47( s, 2H), 3.32 (ddd, J = 40.3, 11.5, 6.3 Hz, 4H), 3.22 (d, J = 8.4 Hz, 3H), 1.93 (q, J = 8.2, 7.6 Hz, 2H), 1.22-1.12 (m, 3H), 0.95 (q, J = 7.6 Hz, 3H); LC / MS (M+H): 466.09 (calculated value: 465.51).

[0284] Example 49: 9-((1-Hydroxyprop-2-yl)amino)methyl-10-hydroxycamptothecin (49)

[0285]

[0286] Paraformaldehyde, 1-hydroxypropan-2-amine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-((1-hydroxypropan-2-yl)amino)methyl-10-hydroxycamptothecin (yield 84.7%); 1 H NMR (600MHz, DMSO-d6) δ11.42(s,1H),8.83(s,1H),8.71(s,1H),8.43(s,1H),8.15(d,J=9.2 Hz,1H),7.63(d,J=9.1Hz,1H),7.29(s,1H),6.54(s,1H),5.50(s,1H),5.43(s,2H),5.27(s,2 H), 4.61 (s, 2H), 3.75 (dd, J = 11.7, 4.5 Hz, 1H), 3.63 (dd, J = 12.0, 5.8 Hz, 1H), 1.87 (m, J = 21.4, 7.2 Hz, 2H), 1.34 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 462.13 (calculated value: 461.48).

[0287] Example 50: 9-(Propylamino)methyl-10-hydroxycamptothecin (50)

[0288]

[0289] Paraformaldehyde, n-propylamine, dioxane and 10-hydroxycamptothecin were synthesized according to method A to obtain the compound 9-(propylamino)methyl-10-hydroxycamptothecin (yield 82.6%); 1 H NMR (500MHz, DMSO-d6) δ11.29(s,1H),8.87(s,1H),8.63(s,2H),8.17(dd,J=9.2,1.7 Hz,1H),7.63(dd,J=9.2,2.1Hz,1H),7.29(s,1H),6.52(s,1H),5.43(s,2H),5.29(d,J =2.8 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 3.03 (s, 2H), 1.93-1.80 (m, 2H), 1.71 (q, J = 7.7 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 436.45 (calculated value: 435.48).

[0290] Example 51: 9-((2-(2-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (51)

[0291]

[0292] The above 9-((2-(2-Boc-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (39) was dissolved in ethyl acetate (2 mL), stirred at 0°C, and a 4M HCl solution in ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain a solid compound 9-((2-(2-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (yield 96.5%). 1 H NMR(500MHz,DMSO-d6)δ11.48(s,1H),9.18(dq,J=12.1,6.0Hz,2H),9.00(s,1H),8.29(d, J=6.1Hz,2H),8.24(s,1H),7.76(d,J=9.2Hz,1H),7.27(s,1H),5.41(s,2H),5.21(s,2H),4 .62 (t, J = 5.6 Hz, 2H), 3.85-3.65 (m, 6H), 3.25 (p, J = 5.3 Hz, 2H), 3.03 (tq, J = 10.7, 5.4 Hz, 2H), 1.88 (dp, J = 21.2, 7.2 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H); LC / MS (M+H): 481.50 (calculated value: 480.52).

[0293] Test Example 1: Inhibitory activity of compounds on cancer cell growth

[0294] Human esophageal cancer cells OE33, human breast adenocarcinoma cells SK-BR-3, and human gastric cancer cells NCI-N87 were cultured in RPMI1640 (Cellmax) containing 10% fetal bovine serum (Cellmax). Tumor cells in the exponential growth phase were diluted to 1×10 5 cells / mL, 100 μL was added to each well of a 96-well cell culture plate and returned to a 37°C, 5% CO2 incubator for overnight incubation. The next day, test and control compounds were diluted to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM in culture medium. 2 μL of the diluted compounds were added to each well of the 96-well cell culture plate, with three replicates for each concentration. For the negative control and blank control, 2 μL of the dilution was added to each well. After addition, the plates were returned to a 37°C, 5% CO2 incubator for an additional 72 hours. After incubation, the plates were removed, the culture medium was aspirated, and 100 μL of culture medium containing 10% CCK-8 was added to each well. The plates were incubated at 37°C for 3 hours. After incubation, remove the culture plate, protect from light, and place it in an ELISA plate. Select 630 nm as the reference wavelength and 450 nm as the measurement wavelength to measure the absorbance. According to the absorbance value, use the four-parameter regression method in GraphPad to calculate the IC 50 SN38 (7-ethyl-10-hydroxycamptothecin) and 10CPT (10-hydroxycamptothecin) were used as control compounds. 50 Value, where "++++" indicates IC 50 <50nM; “+++” indicates IC 50 Between 50nM-100nM; “++” indicates IC 50 Between 100-500nM; “+” indicates IC 50 >500nM.

[0295] Table 1 Inhibitory activity of compounds against OE33 cell growth

[0296] Compound number <![CDATA[IC 50 / nM]]> Compound number <![CDATA[IC 50 / nM]]> Compound number <![CDATA[IC 50 / nM]]> 1 ++ 16 0.221 31 ++ 2 +++ 17 +++ 33 ++ 3 ++ 18 ++ 34 + 5 +++ 19 +++ 35 +++ 6 ++ 20 ++ 36 ++ 7 +++ 21 ++ 37 ++ 8 ++ 22 ++ 40 ++ 9 ++ 23 ++++ 42 ++ 10 +++ 25 ++ 43 ++ 11 ++ 26 ++ 46 ++ 12 ++ 28 ++ 10CPT ++++ 13 ++ 29 ++ SN38 ++++ 14 ++ 30 ++

[0297] Table 2 Inhibitory activity of compounds against SK-BR-3 cell growth

[0298] Compound number <![CDATA[IC 50 / nM]]> Compound number <![CDATA[IC 50 / nM]]> Compound number <![CDATA[IC 50 / nM]]> 1 +++ 9 +++ 19 +++ 2 +++ 10 +++ 21 ++ 5 + 11 ++ 10CPT ++++ 6 +++ 12 ++ SN38 ++++ 7 +++ 17 +++ 8 ++ 18 +++

[0299] Table 3 Inhibitory activity of compounds against NCI-N87 cell growth

[0300] Compound number <![CDATA[IC 50 / nM]]> 9 ++++ 10 ++++ 17 ++++ 19 ++++

[0301] Results: The example compounds provided by the present invention have good inhibitory effects on the growth of esophageal cancer cells OE33, breast cancer cells SK-BR-3 and gastric cancer cells NCI-N87. Some compounds, such as compounds 10, 17 and 19, have an IC2 inhibitory effect on the growth of these three cancer cells. 50 The values ​​were all less than 100 nM, indicating a broad-spectrum anticancer activity.

Claims

1. The following compound or a pharmaceutically acceptable salt thereof: in, The compound was named 9-(N-methyl-trans-4-hydroxycyclohexylamino)methyl-10-hydroxycamptothecin.

2. The method for preparing the compound according to claim 1, wherein The steps of the following reaction scheme are included: 10-Hydroxycamptothecin, paraformaldehyde and trans-4-(methylamino)cyclohexan-1-ol were subjected to a Mannich reaction at position 9 to obtain compound 16.

3. The preparation method according to claim 2, characterized in that The amount of the paraformaldehyde used is 1.0-5.0 molar equivalents.

4. The preparation method according to claim 2 or 3, characterized in that The amount of the paraformaldehyde used is 1.0-3.0 molar equivalents.

5. The preparation method according to claim 4, characterized in that The amount of the paraformaldehyde used is 1.2-2.2 molar equivalents.

6. The preparation method according to claim 2, characterized in that The amount of trans-4-(methylamino)cyclohexan-1-ol used is 1.0-5.0 molar equivalents.

7. The preparation method according to any one of claim 6, characterized in that The amount of trans-4-(methylamino)cyclohexan-1-ol used is 1.0-2.0 molar equivalents.

8. The preparation method according to any one of claim 7, characterized in that The amount of trans-4-(methylamino)cyclohexan-1-ol used is 1.2-1.6 molar equivalents.

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating cancer.

11. The use according to claim 10, characterized in that The cancer is selected from gastric cancer, esophageal cancer, cardiac cancer, breast cancer, ovarian cancer, primary liver cancer, acute and chronic myeloid leukemia, choriocarcinoma, lung cancer, bladder cancer or intestinal cancer.

12. The use according to claim 10 or 11, characterized in that The cancer is selected from esophageal cancer, breast cancer or gastric cancer.

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