Camptothecin derivatives, their preparation methods and uses

Abstract

The present invention provides a novel camptothecin-derived compound, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, and methods for their preparation and use. The compound has a structure represented by formula (I) and has good anti-cancer activity. [Chemical Formula 1] TIFF2025524170000094.tif44170

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically to camptothecin derivatives having a series of novel structures, a preparation method thereof, and uses thereof.

Background Art

[0002] Camptothecin (CPT) is a natural product first extracted from the Chinese plant Camptotheca acuminata by American scientists Wall and Wani. It is a water-insoluble and cytotoxic quinoline alkaloid with broad antitumor activity. As its mechanism of action, it is thought to bind to topoisomerase Top1 and DNA to form a complex, inhibit the activity of Top1, block DNA replication and protein synthesis, and lead to apoptosis. Camptothecin has significant therapeutic effects on gastric cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic granulocytic leukemia, choriocarcinoma, lung cancer, bladder cancer, etc. Despite its excellent antitumor activity, only two camptothecin compounds, irinotecan (useful for colorectal cancer and small cell lung cancer (SCLC)) and topotecan (useful for lung cancer and ovarian cancer), have been globally developed as antitumor agents so far. Another camptothecin derivative, beletecan, is only approved in Korea as a therapeutic agent for SCLC and ovarian cancer. Camptothecin is hindered from wider application in tumor treatment due to its cytotoxicity, poor solubility, and drug resistance.

[0003] Therefore, there is a need to develop camptothecin derivative-based drugs with low toxicity, water solubility, and drug resistance, which have broad application value.

Summary of the Invention

Problems to be Solved by the Invention

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

Means for Solving the Problem

[0005] One aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

Chemical formula

[0006] Wherein, R is -CH2NR1R2, where R1 and R2 are each independently hydrogen, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 4-8 membered heterocycloalkyl group, a 4-8 membered aryl group or -NR a R b selected from, and the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 4-8 membered heterocycloalkyl group, 4-8 membered aryl group or -NR a R b is optionally substituted with a substituent selected from halogen, hydroxy group, amino group, carboxyl group, C1-C6 alkoxy group, C1-C6 alkoxycarbonyl group, -O-(C1-C3 alkyl)-NR a R b group, or a 4-8 membered heterocycloalkyl group, provided that R1 and R2 are not both hydrogen or methyl at the same time, or R1 and R2, together with the N atom to which they are attached, form a 4-8 membered cycloalkyl group, a 4-8 membered heterocycloalkyl group, a 4-8 membered aryl group or a 9-12 membered azaspiroalkyl group, and the 4-8 membered cycloalkyl group, 4-8 membered heterocycloalkyl group, 4-8 membered aryl group or 9-12 membered azaspiroalkyl group is optionally hydroxy group, amino group, carboxyl group, C1-C6 alkoxy group, C1-C6 alkoxycarbonyl group, C1-C3 alkyl group, C1-C3 alkoxy group, -O-NH2, -NR a R b or -C(O)R c selected from the substituents, or R and the hydroxy group at the ortho position thereof together with the C atom on the benzene ring to which they are attached form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, -NR a R b or is substituted with a substituent selected from a 4- to 8-membered heterocycloalkyl group, and the C1-C6 alkyl group, the C1-C6 alkoxy group, the C3-C6 cycloalkyl group, the 4- to 8-membered heterocycloalkyl group, -NR a R b or the 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from halogen, a hydroxy group, an amino group, a carboxy group, a C1-C6 alkoxy group or a C1-C6 alkoxycarbonyl group, provided that at least one of R1 and R2 is H.

[0007] R a and R b are each independently selected from H, a C1-C6 alkyl group or a C1-C6 alkoxycarbonyl group.

[0008] R c is selected from an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, or a C1-C3 alkyl group substituted with a hydroxy group.

[0009] In one embodiment, in the compound of formula (I), R is -CH2NR1R2, where R1 and R2 are each independently hydrogen, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, or -NR a R b selected from, and the C1-C6 alkyl is optionally halogen, a hydroxy group, an amino group, a carboxyl group, a C1-C6 alkoxycarbonyl group, -O-(C1-C3 alkyl)-NR a R b、 or substituted with a substituent selected from a 4- to 8-membered heterocycloalkyl group, wherein the C3-C6 cycloalkyl group or 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from a hydroxy group, a C1-C3 alkoxy group, or a C1-C6 alkoxycarbonyl group, provided that R1 and R2 are not simultaneously hydrogen or a methyl group, or R1 and R2, together with the N atom to which they are attached, form a 4- to 8-membered heterocycloalkyl group or a 9- to 12-membered azaspiroalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally a hydroxy group, an amino group, a carboxyl group, a C1-C6 alkoxycarbonyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, an -O-NH2 group, or -C(O)R c selected from the group consisting of substituents, or R and the hydroxy group at the ortho position thereof, together with the C atom on the benzene ring to which they are attached, form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally substituted with 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.

[0010] In one embodiment, R a and R b are each independently selected from H, a methyl group, or a tert-butoxycarbonyl group.

[0011] In one embodiment, R c is selected from an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, or a hydroxy-substituted C1-C3 alkyl group.

[0012] In one embodiment, in the compound of formula (I), R is -CH2NHR1, and R1 is hydrogen, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, or -NR a R bselected from, and the C1-C6 alkyl group is optionally substituted with a substituent selected from halogen, hydroxy group, amino group, carboxy group, C1-C6 alkoxycarbonyl group, -O-(C1-C3 alkyl)-NR a R b , or a 4- to 8-membered heterocycloalkyl group, and the C3-C6 cycloalkyl group or 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from hydroxy group, C1-C3 alkoxy group, or C1-C6 alkoxycarbonyl group, provided that R1 is not hydrogen, or R and the hydroxy group at the ortho position thereof form a 4- to 8-membered heterocycloalkyl group together with the C atom on the benzene ring to which they are attached, and the 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from halogen-substituted C1-C6 alkyl group, C3-C6 cycloalkyl group or 4- to 8-membered heterocycloalkyl group.

[0013] In one embodiment, R a and R b are each independently selected from H, methyl group, or tert-butoxycarbonyl group.

[0014] In one embodiment, R1 and R2 are each independently selected from hydrogen, hydroxy group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, cyclopropyl group, cyclopentyl group, cyclohexyl group, 5- or 6-membered heterocycloalkyl group containing 1 to 2 N atoms as ring atoms, 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N or O as ring atoms, or -NR a R b wherein the methyl group, ethyl group, propyl group or isopropyl group is optionally substituted with halogen, hydroxy group, amino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, tert-butylalkoxycarbonyl group, methoxy-NR a R b , ethoxy-NR a R bsubstituted with a substituent selected from a pyrrolidinyl group, a piperidinyl group, or a piperazinyl group, provided that the cyclopropyl group, cyclopentyl group, cyclohexyl group, 5- or 6-membered heterocycloalkyl group containing 1 to 2 N atoms as ring atoms, or 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N or O as ring atoms is optionally substituted with a substituent selected from a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, or a methoxycarbonyl group, an ethoxycarbonyl group, or a tert-butylalkoxycarbonyl group, provided that R1 and R2 are not simultaneously hydrogen or a methyl group.

[0015] In one embodiment, R1 and R2, together with the N atom to which they are attached, form a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, or an 11-membered azaspiroalkyl group, and the pyrrolidinyl group, piperidinyl group, piperazinyl group, or 11-membered azaspiroalkyl group is optionally substituted with a substituent selected from a hydroxy group, an amino group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butylalkoxycarbonyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, -O-NH2 or -C(O)R c selected from the substituents.

[0016] In one embodiment, R and the hydroxy group at the ortho position thereof, together with the C atom on the benzene ring adjacent thereto, form a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, or an oxazinyl group, and the pyrrolidinyl group, piperidinyl group, piperazinyl group, or oxazinyl group is optionally substituted with a substituent selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, or an oxazinyl group.

[0017] In one embodiment, in the compound of formula (I), R1 and R2 are each independently hydrogen, a hydroxy group, an amino group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a trifluoroethyl group, a cyclopropyl group, -(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, and are selected from the groups represented by the following formulae,

Chemical formula

Chemical formula

[0018] In one embodiment, R and the hydroxy group at its ortho position together with the C atom on the benzene ring adjacent to them form a group represented by the following formula, [Chemical formula] The group represented by the above formula is optionally substituted with a substituent selected from a C1-C6 alkyl group or a 4- to 8-membered heterocycloalkyl group.

[0019] In one embodiment, R and the hydroxy group at the ortho position thereof, together with the C atom on the benzene ring adjacent thereto, form a group represented by the following formula: [Chemical formula] The group represented by the above formula is optionally substituted with a substituent selected from a trifluoromethyl group, a cyclopropyl group, or a morpholin-4-yl group, provided that at least one of R1 and R2 is H.

[0020] In one embodiment, R1 and R2, together with the N atom to which they are attached, form pyrrolidine, piperidine, piperazine, or 3,9-diazaspiro[5.5]undecane, and the pyrrolidine, piperidine, piperazine, or 3,9-diazaspiro[5.5]undecane is optionally substituted with a substituent selected from an amino group, a methoxy group, -O-NH2, a carboxy group, a tert-butoxycarbonyl group, -C(O)-NH2, -C(O)OCH3, -C(O)CH3, -C(O)-cyclopropyl group, -C(O)CH2OH.

[0021] In one embodiment, R is -CH2NHR1, and R1 is hydrogen, a hydroxy group, an amino group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a trifluoroethyl group, a cyclopropyl group, -(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, a group represented by the following formula: [Chemical formula] However, on the condition that R1 is not hydrogen, or R and the hydroxy group at the ortho position thereof, together with the C atom on the benzene ring adjacent thereto, form a group represented by the following formula:

Chemical formula

[0022] In one embodiment, R and the hydroxy group at the ortho position thereof, together with the C atom on the benzene ring adjacent thereto, form a group represented by the following formula:

Chemical formula

[0023] In one embodiment, R is selected from the following structures.

Chemical formula

[0024] In one embodiment, R is selected from the following structures.

Chemical formula

[0025] In one embodiment, R is selected from the following structures.

Chemical formula

[0026] In the present invention, in the above compound, R does not include structures such as -CH2NHCH2CH2OH, -CH2NHCH2CH2N(CH3)2, and the group represented by the following formula:

Chemical formula

Chemical formula

[0027] In one embodiment, the compound of formula (I) is a compound having the structure of formula (II).

Chemical formula

[0028] Wherein 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 spiro ring, and the 4- to 8-membered nitrogen-containing saturated heterocyclic ring, 4- to 8-membered nitrogen-containing aromatic ring, or 9- to 12-membered nitrogen-containing saturated spiro ring is optionally substituted with a hydroxy group, an amino group, a C1-C6 alkoxycarbonyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, -O-NH2, or -C(O)R c and is further substituted with a substituent selected from, preferably, the C1-C6 alkoxycarbonyl group is a tert-butoxycarbonyl group.

[0029] 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, and the 4- to 8-membered nitrogen-containing saturated ring is optionally substituted with a hydroxy group, an amino group, a C1-C6 alkoxycarbonyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, -O-NH2, or -C(O)R c and is substituted with a substituent selected from, preferably, the C1-C6 alkoxycarbonyl group is a tert-butoxycarbonyl group.

[0030] R c is selected from a hydroxy group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, or a hydroxy-substituted C1-C3 alkyl group.

[0031] Preferably, Rc is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group or a cyclopropyl group.

[0032] In one embodiment, the compound of formula (II) is a compound having a structure of formula (IIa), formula (IIb) or formula (IIc).

Chemical formula

[0033] Here, R c is selected from a hydroxy group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group or a hydroxy-substituted C1-C3 alkyl group.

[0034] Preferably, R c is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group or a cyclopropyl group.

Chemical formula

[0035] In the formula, 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 spiro ring, and the 4- to 8-membered nitrogen-containing saturated heterocyclic ring, the 4- to 8-membered nitrogen-containing aromatic ring or the 9- to 12-membered nitrogen-containing saturated spiro ring is optionally substituted with a substituent selected from a hydroxy group, an amino group, a C1-C6 alkoxycarbonyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, -O-NH2 or -C(O)R c and is further substituted with a substituent selected therefrom, and preferably, the C1-C6 alkoxycarbonyl group is a tert-butoxycarbonyl group.

[0036] Here, R c is defined in the same manner as the compound of formula (I).

[0037] 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, and the 4- to 8-membered nitrogen-containing saturated ring is optionally a hydroxy group, an amino group, a C1-C6 alkoxycarbonyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, -O-NH2, or -C(O)R c and is substituted with a substituent selected from, preferably, the C1-C6 alkoxycarbonyl group is a tert-butoxycarbonyl group.

[0038] R c ’ is selected from a hydroxy group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, or a hydroxy-substituted C1-C3 alkyl group.

[0039] Preferably, R c ’ is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group, or a cyclopropyl group.

[0040] In one embodiment, the compound of formula (II) is a compound having the structure of formula (IIa), formula (IIb), or formula (IIc),

Chemical formula

[0041] Preferably, R c ’ is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group, or a cyclopropyl group.

[0042] The present invention provides the following compounds.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0043] Another aspect of the present invention provides a method for preparing the above compound, comprising steps selected from the following reaction routes.

[0044] Reaction Route 1:

Chemical formula

[0045] Here, the amine compound is NHR1R2, and R, R1, and R2 are each defined as described above.

[0046] Reaction Route 2:

Chemical formula

[0047] Here, the amine compound is NHR1R2, and R, R1, and R2 are each defined as described above.

[0048] In one embodiment, the 9-formyl-10-hydroxycamptothecin is obtained by reacting 10-hydroxycamptothecin with hexamethylenetetramine.

[0049] In one embodiment, in the Mannich reaction described in Reaction Route 1, the amount of paraformaldehyde or formaldehyde used is 1.0 to 5.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, and more preferably 1.2 to 2.2 molar equivalents.

[0050] Preferably, in Reaction Route 1, the amount of the amine compound used is 1.0 to 5.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, and even more preferably 1.2 to 1.6 molar equivalents.

[0051] In one embodiment, in the reductive amination reaction described in Reaction Route 2, the reducing agent is sodium cyanoborohydride.

[0052] Preferably, in Reaction Route 2, the amount of the amine compound used is 1.0 to 3.0 molar equivalents, more preferably 1.0 to 1.2 molar equivalents.

[0053] Preferably, the amount of sodium cyanoborohydride used is 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, and even more preferably 1.2 to 1.5 molar equivalents.

[0054] Another aspect of the present invention provides an antibody-drug conjugate compound comprising a small molecule drug and a linker antibody, wherein the small molecule drug is the above compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0055] 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.

[0056] The pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

[0057] Another aspect of the present invention provides the use of the above compound or its pharmaceutically acceptable salt, stereoisomer or prodrug, antibody-drug conjugate, or pharmaceutical composition in the preparation of a medicament for treating cancer.

[0058] In one embodiment, the cancer includes gastric cancer, esophageal cancer, cardiac cancer, breast cancer, ovarian cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic granulocytic leukemia, choriocarcinoma, lung cancer, bladder cancer, intestinal cancer, and small cell lung cancer, and preferably, the cancer is esophageal cancer, breast cancer, and gastric cancer.

[0059] Another aspect of the present invention provides a method for treating cancer, including administering the above compound or its pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition to a patient in need thereof.

[0060] In one embodiment, the dosage of the above compound or its pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition is an amount effective for treatment.

[0061] The camptothecin derivative compound provided by the present invention exhibits significant inhibitory activity against cancer cells such as esophageal cancer cell OE33, breast cancer cell SK-BR-3, and gastric cancer cell NCI-N87.

[0062] Notably, the present invention also provides a method for preparing the above compound with a surprisingly high yield.

Embodiments for Carrying Out the Invention

[0063] I. Definitions In the present invention, scientific and technical terms used herein have the meanings generally understood by those skilled in the art, unless otherwise specified. Further, the related terms and experimental procedures used herein are terms widely used in their respective fields and normal steps. In addition, to better understand the present invention, the definitions and explanations of related terms are provided below.

[0064] As used herein and unless otherwise specified, the terms "comprising," "including," "having," and "containing" should generally be understood as open-ended and non-limiting, including their grammatically equivalent forms, and do not exclude other elements or steps not recited, for example.

[0065] The compounds according to the present invention may be asymmetric and may have, for example, one or more stereoisomers. Unless otherwise specified, all stereoisomers such as enantiomers and diastereomers are included. The stereoisomers include geometric isomers (e.g., cis and trans structures) and optical isomers (e.g., enantiomers), and are therapeutic agents consisting of single entities, racemates, racemic mixtures, and pharmaceutically acceptable salts thereof. Compounds containing an asymmetric carbon atom according to the present invention can be isolated in optically pure form or in racemic form. The optically pure form can be isolated from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are included within the scope of the present invention.

[0066] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and involve the movement of one proton together.

[0067] The numerical ranges herein refer to individual integers within the specified range. For example, "C1~C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and "C3~C6" means that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0068] The term "substituted" means that any one or more hydrogen atoms on a particular atom or group are replaced by a substituent, provided that the valence of the particular atom or group is normal and the resulting compound is stable. Unless otherwise specified, the type and number of substituents are arbitrary as long as they are chemically feasible.

[0069] When any variable (e.g., Rn) appears one or more times within the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted with 1 to 5 Rs, the group may be optionally substituted with up to 5 Rs, and in each case the R has an independent choice. Further, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

[0070] The term "alkyl group" means a saturated aliphatic hydrocarbon group, which is a straight-chain 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 group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 2,2-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof, etc. are included.More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available bonding point, and the substituent is preferably independently one or more groups selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxy group or a carboxylic acid ester group. In the present invention, preferably, it is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a haloalkyl group, a deuterated alkyl group, an alkoxy group-substituted alkyl group, and a hydroxy group-substituted alkyl group.

[0071] The term "heterocyclyl group" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but not containing ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, 1 to 4 of which are heteroatoms, more preferably, it contains 3 to 8 ring atoms, most preferably, it contains 3 to 8 ring atoms, and still more preferably, it is a 3- to 8-membered heterocyclyl containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing fused heterocyclyl groups.

[0072] The term "heterocycloalkyl group" refers to a saturated ring substituent containing a heteroatom on the ring skeleton, where one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) of the ring atoms are heteroatoms selected from N, O, S.

[0073] The term "aryl group" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6 to 12 members such as, for example, phenyl group and naphthyl group.

[0074] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably, independently, one or more groups selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, sulfhydryl group, hydrogen group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carboxy group or carboxylic acid ester group.

[0075] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), and the definition of the alkyl group is as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group. The alkoxy group may be optionally substituted or unsubstituted. When it is substituted, the substituents are preferably independently one or more groups selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, sulfhydryl group, hydrogen group, nitro group, chloro group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carboxylic acid group or carboxylic acid ester group.

[0076] In the present invention, all of the hydrogen atoms described can be substituted with deuterium, which is an isotope thereof.

[0077] "Optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.

[0078] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are each independently substituted with the corresponding number of substituents. The substituents are present only at chemically possible positions, and it is obvious that those skilled in the art can determine (by experiment or theory) possible substitutions or impossible substitutions without undue effort. For example, an amino group or a hydroxy group having a free hydrogen may become unstable when bonded to a carbon atom having an unsaturated (e.g., alkene-like) bond.

[0079] The following symbols represent chemical bonding sites.

Chem.

[0080] Drug or pharmaceutical composition As used herein, the term "pharmaceutically acceptable salt" means a salt formed by reacting the corresponding amine compound with an inorganic or organic acid, or a salt formed by reacting the corresponding carboxylic acid compound with an alkali metal or alkaline earth metal, or a salt formed by reacting the corresponding carboxylic acid compound with an organic amine. Here, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. 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, etc. Alkali metal or alkaline earth metal salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, etc. Organic amine salts include salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, etc., but are not limited thereto.

[0081] As used herein, the term "precursor" refers to a compound that, after being taken into the human body by an appropriate administration method, is metabolized or undergoes a simple chemical change in the patient's body and is converted into the form of the compound included in General Formula 1 of the present invention and its corresponding salt. Precursors of compounds include, but are not limited to, various carboxylic acid esters, carbonic acid esters, phosphate esters, sulfate esters, sulfonic acid esters, amino acid esters, gluconic acid esters, and various amides, acetals, hemiacetals, carbonic acid amide esters, etc.

[0082] The drug or pharmaceutical composition according to the present invention can be administered orally, topically, parenterally, or mucosally (e.g., sublingually, by inhalation, or rectally) in dosage unit formulations containing a conventional non-toxic pharmaceutically acceptable carrier. Usually, oral administration is preferred. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0083] When administered orally in tablet or capsule form, the active pharmaceutical ingredient can be combined with non-toxic pharmaceutically acceptable adjuvants such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate), coloring agents and flavoring agents, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth gum or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. When administered orally in liquid form, the drug ingredient can be combined with non-toxic pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible oils), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, ester oil, ethanol, or fractionated vegetable oil), preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, citronellyl propionate, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0084] Tablets containing the active compound can be coated by methods well known in the art. The composition according to the invention containing a compound of formula I as the active compound can also be introduced, for example, into beads, microspheres or microcapsules constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions, suspensions, etc., or can be dry formulations reconstituted with water or other suitable adjuvants before use. Formulations for oral administration can be appropriately formulated to provide controlled or delayed release of the active compound.

[0085] The term "treatment" includes the inhibition, alleviation, prevention or elimination of one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0086] The use of the term "inhibition" is in contrast to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, the reduction in response in a subject or cell treated with a compound is compared to the response in a subject or cell not treated with the compound.

[0087] The term "pharmaceutical composition" means a composition containing at least one selected from pharmaceutically acceptable components 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, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending aids, etc., depending on the compound or its pharmaceutically acceptable salt according to the invention and the nature of the administration method and dosage form.

[0088] The term "effective amount" or "therapeutically effective amount" means an amount of a drug or agent that is non-toxic but sufficient to achieve the desired effect. In embodiments of the present invention, when treating a patient in accordance with the present invention, the amount of a given drug to be administered depends on many factors such as the specific administration protocol, the type and severity of the disease or medical condition, and the specificity of the subject or host in need of treatment (e.g., body weight). However, the dosage can be routinely determined by methods known in the art depending on, for example, the specific drug employed, the route of administration, the medical condition being treated, and the particular circumstances surrounding the subject or host being treated. Generally, when used for the treatment of adults, the dosage typically ranges from 0.02 to 5000 mg / day, for example, about 1 to 1500 mg / day. This required dosage can be conveniently expressed as a single dose or as divided doses administered simultaneously (or over a short period) or at appropriate intervals, for example, 2, 3, 4 or more divided doses per day. Although the above dosage ranges are indicated, it will be understood by those skilled in the art that the specific effective amount can be appropriately adjusted according to the condition of the patient and in conjunction with the diagnosis of the physician.

[0089] The term "antibody-drug conjugate (ADC)" refers to a conjugate in which a biologically active small molecule drug is linked to a monoclonal antibody via a chemical bond, and the monoclonal antibody functions as a carrier for transporting the small molecule drug to target cells.

[0090] As used herein, the terms "decrease", "inhibit", "alleviate" or "reduce" are in reference to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, the decrease in response in a subject or cell treated with a compound is compared to the response in a subject or cell not treated with the compound.

[0091] Unless otherwise specified, the raw materials and devices used in the specific embodiments of the present invention are known products and can be obtained by purchasing commercially available products.

[0092] Preparation Example 1: General synthesis method A: Formaldehyde (1 - 3 eq), amine - based compound (1 - 2 eq), and dioxane were added to a reaction flask. While stirring, the mixture was heated to 50 - 70 °C and reacted for 1 hour. After cooling to room temperature, 10 - hydroxycamptothecin (1 eq) was added. The temperature was raised to 70 - 90 °C, and the reaction was continued with stirring for 4 hours. After cooling, filtration was carried out, extraction was performed with ethyl acetate, washing was done with saturated brine, drying was carried out with anhydrous sodium sulfate, and purification was carried out by silica gel column chromatography (DCM:MeOH = 90:1 - 10:1) to obtain the target compound. Removal of the Boc protecting group: The Boc - protected compound obtained above was added to a reaction flask, ethyl acetate was added to dissolve the product, and the mixture was stirred at 0 °C. A solution of 4M HCl in ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours, concentrated, and recrystallized to obtain the final compound.

[0093] General synthesis method B: 10 - hydroxycamptothecin (1 eq) and hexamethylenetetramine (1.2 - 2.0 eq) were heated to 50 - 70 °C and reacted for 12 hours while stirring in TFA under an argon gas atmosphere. The reaction mixture was concentrated, H2O was added and stirred for 1 hour, adjusted to pH = 8 - 9 with saturated aqueous NaHCO3 solution, extracted with ethyl acetate, 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.

[0094] 9 - Formyl - 10 - hydroxycamptothecin (1 eq), amine - based compound (2 eq), methanol / dichloromethane were added to a reaction flask and reacted at room temperature for 30 minutes. Sodium cyanoborohydride was added, and the reaction was carried out with stirring at room temperature for 6 hours. Filtration was carried out, extraction was performed with ethyl acetate, washing was done with saturated brine, drying was carried out with anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography, and eluted with DCM:MeOH = 90:1 - 10:1 to obtain the target compound.

[0095] Removal of the Boc protecting group: The same as method A above, and recrystallization was carried out to obtain the final compound.

[0096] Example 1: 9-(1-(4-Aminopiperidine))methyl-10-hydroxycamptothecin (1) [Chemical formula] Method A: Paraformaldehyde (8.3 mg, 0.274 mmol), 4-Boc aminopiperidine (27 mg, 0.137 mmol) and dioxane (10 mL) were heated to 70 °C with stirring and reacted for 2 hours. After cooling to room temperature, 10-hydroxycamptothecin (25 mg, 0.07 mmol) was added, the temperature was raised to 110 °C, and the reaction was continued with stirring for 6 hours. After cooling, filtration was carried out, extraction was performed with ethyl acetate, drying was carried out with anhydrous sodium sulfate, concentration was carried out, filtration was carried out through a column, and the target compound 9-(4-Boc aminopiperidine)methyl-10-hydroxycamptothecin was obtained with an eluent of DCM:MeOH = 90:1 to 10:1 (37.1 mg, yield 93.7%). LC / MS (M+H): 577.11 (calculated value: 576.26).

[0097] The above 9-(4-Boc-aminopiperidine)methyl-10-hydroxycamptothecin (37.1 mg) was dissolved in ethyl acetate (2 mL), stirred at 0 °C, and a 4M HCl ethyl acetate solution (0.5 mL) was added, followed by stirring at room temperature for 2 hours. The solvent was concentrated, and recrystallization was carried out from ethyl acetate / petroleum ether to obtain the product as a red solid compound 9-(1-(4-aminopiperidine))methyl-10-hydroxycamptothecin (30.1 mg, yield 90.9%). 1 H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.37 - 8.15 (m, 3H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 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).

[0098] Example 2: 9-(1-Piperazinyl)methyl-10-hydroxycamptothecin (2)

Chem.

[0099] The above 9-(4-Boc-piperazin-1-yl)methyl-10-hydroxycamptothecin (35.6 mg) was dissolved in ethyl acetate (2 mL), and while stirring at 0 °C, a 4M HCl ethyl acetate solution (0.5 mL) was added. It was stirred at room temperature for 2 hours, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain the solid compound 9-(1-piperazinyl)methyl-10-hydroxycamptothecin as a product (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).

[0100] Example 3: 9-(1-(4-Aminoxypiperidine))methyl-10-hydroxycamptothecin (3)

Chem.

[0101] 2-(1-Boc-piperidin-4-yloxy)isoindoline-1,3-dione (1.8 g, 5.2 mmol) was dissolved in ethyl acetate (5 mL), a 4M HCl ethyl acetate solution (2 mL) was added, stirred at room temperature for 1 hour, then concentrated to obtain 2-(piperidin-4-yloxy)isoindoline-1,3-dione hydrochloride (1.31 g, yield 89%). LC / MS (M+H): 247.07 (calculated: 246.10).

[0102] Paraformaldehyde, 2-(piperidin-4-yloxy)isoindoline-1,3-dione hydrochloride, dioxane and 10-hydroxycamptothecin were synthesized according to Method A to obtain the compound 9-(2-(piperidin-4-yloxy)isoindoline-1,3-dione-1-)methyl-10-hydroxycamptothecin (yield 66.5%). LC / MS (M+H): 623.05 (calculated: 622.21).

[0103] 9-(2-(Piperidin-4-yloxy)isoindoline-1,3-dione-1-)methyl-10-hydroxycamptothecin was added to a reaction flask, ethanol and 85% hydrazine hydrate (1.5 eq) were added, stirred at room temperature for 1 hour, concentrated, converted to the hydrochloride salt with ethyl acetate containing 4M HCl, and recrystallized from ethyl acetate / petroleum ether to obtain the red solid compound 9-(1-(4-aminooxypiperidine))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=9.2Hz,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=43.2Hz,1H),3.30(s,2H),3.06(dd,J=7.3,4.8Hz,1H),2.19(s,3H),1.88(dp,J=21.6,7.2Hz,2H),1.55(s,1H),0.89(t,J=7.3Hz,3H).LC / MS(M+H):493.00(calculated:492.20).

[0104] Example 4: 9-(O-Ethylhydroxyamine)methyl-10-hydroxycamptothecin (4)

Chemical formula

[0105] Example 5: 9-(1-(4-Methoxypiperidine))methyl-10-hydroxycamptothecin (5)

Chemical Structure

[0106] Example 6: 9-(1-(4-Cyclopropylcarbonylpiperazine))methyl-10-hydroxycamptothecin (6)

Chemical Structure

[0107] Example 7: 9-(1-(4-acetylpiperazine))methyl-10-hydroxycamptothecin (7)

Chemical Structure

[0108] Example 8: 9-(1-(4-Carbamoylpiperazine))methyl-10-hydroxycamptothecin (8)

Chemical Structure

[0109] Example 9: 9-(1-(4-Methoxycarbonylpiperazine))methyl-10-hydroxycamptothecin (9)

Chem.

[0110] Example 10: 9-(N-Methyl-N-isopropylamino)methyl-10-hydroxycamptothecin (10)

Chem.

[0111] Example 11: 9-(N-4-Aminobutyl-N-methylamino)methyl-10-hydroxycamptothecin (11)

Chemical Structure

[0112] 9-(N-4-Boc aminobutyl-N-methylamino)methyl-10-hydroxycamptothecin was dissolved in ethyl acetate, stirred at 0 °C, a solution of 4M HCl in ethyl acetate was added, stirred at room temperature for 2 hours, concentrated, and recrystallized to obtain the red solid compound 9-(N-4-aminobutyl-N-methylamino)methyl-10-hydroxycamptothecin (yield 88.3%). 11H NMR (600 MHz, DMSO-d6) δ 8.93 - 8.84 (m, 1H), 8.73 (s, 1H), 8.19 (ddd, J = 19.2, 9.2, 3.4 Hz, 1H), 7.90 - 7.71 (m, 2H), 7.64 (td, J = 8.9, 8.5, 3.7 Hz, 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 = 32.2 Hz, 2H), 1.87 (m, J = 21.4, 14.3, 7.2 Hz, 2H), 1.59 (d, J = 7.9 Hz, 1H), 1.23 (s, 1H), 0.88 (t, J = 7.3 Hz, 3H). LC / MS (M + H): 479.04 (calculated: 478.22).

[0113] Example 12: 9-(N-Methylhydroxyethylamino)methyl-10-hydroxycamptothecin (12)

Chemical Structure

[0114] Example 13: 9-(N-Methyl-N-aminoethylamino)methyl-10-hydroxycamptothecin (13)

Chemical Structure

[0115] 9-(N-methyl-N-Boc-aminoethylamino)methyl-10-hydroxycamptothecin (34.1 mg) was dissolved in ethyl acetate (2 mL), stirred at 0 °C, and a solution of 4M HCl (0.5 mL) in ethyl acetate was added. The mixture was stirred at room temperature for 2 hours, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain compound 9-(N-methyl-N-aminoethylamino)methyl-10-hydroxycamptothecin as a light red solid (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).

[0116] Example 14: 9-(N-methyltetrahydropyran-4-amine)methyl-10-hydroxycamptothecin (14)

Chemical formula

[0117] Example 15: 9-(trans-4-Hydroxycyclohexylamine)methyl-10-hydroxycamptothecin (15)

Chemical formula

[0118] Example 16: 9-(N-Methyl-trans-4-hydroxycyclohexylamine)methyl-10-hydroxycamptothecin (16)

Chemical Structure

[0119] Example 17: 9-(N-Methyl-N-cyclopropylamine)methyl-10-hydroxycamptothecin (17) [Chemistry] Using paraformaldehyde, N-methylcyclopropylamine, dioxane and 10-hydroxycamptothecin, compound 9-(N-methyl-N-cyclopropylamine)methyl-10-hydroxycamptothecin was obtained according to Method A (yield 83.9%). 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 5.34 (d, J = 2.7 Hz, 2H), 5.13 (s, 2H), 4.09 (s, 2H), 3.42 (tdd, J = 9.9, 6.5, 4.2 Hz, 3H), 3.35 (t, J = 5.3 Hz, 1H), 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).

[0120] Example 18: 9-(Morpholin-4-amine)methyl-10-hydroxycamptothecin (18) [Chemistry] 9-Formyl-10-hydroxycamptothecin, 4-aminomorpholine, methanol and sodium cyanoborohydride were synthesized according to Method B to obtain compound 9-(morpholin-4-amine)methyl-10-hydroxycamptothecin (yield 81.0%). LC / MS (M+H): 479.08 (calculated value: 478.19).

[0121] Example 19: 9-(N-methylethylamine)methyl-10-hydroxycamptothecin (19) [Chemistry] Paraformaldehyde, N-methylethylamine, dioxane and 10-hydroxycamptothecin were synthesized according to Method A to obtain the compound 9-(N-methyl-N-ethylamine)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).

[0122] Example 20: 9-(Ethylamine)methyl-10-hydroxycamptothecin (20)

Chemical formula

[0123] Example 21: 9-(Isopropylamine)methyl-10-hydroxycamptothecin (21)

Chemical formula

[0124] Example 22: 3-(N-morpholine)-1,3-oxazine[5,6],[9,10]camptothecin (22)

Chemical formula

[0125] Example 23: 9-(1-methyl-2-Boc hydrazine)methyl-10-hydroxycamptothecin (23)

Chemical formula

[0126] Example 24: 9-(1-Methylhydrazino)methyl-10-hydroxycamptothecin (24)

Chemical Structure

[0127] Example 25: 9-(1-Methyl-3-aminopropylamino)methyl-10-hydroxycamptothecin (25)

Chemical Structure

[0128] The above Boc group-protected product was dissolved in ethyl acetate (2 mL), stirred at 0 °C, a 4M HCl solution in ethyl acetate (0.5 mL) was added, stirred at room temperature for 2 hours, the solvent was concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain the solid product 9-(1-methyl-3-aminopropylamine)methyl-10-hydroxycamptothecin (yield 85.5%). 1 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 5.34 (d, J = 2.7 Hz, 2H), 5.13 (s, 2H), 4.09 (s, 2H), 3.42 (m, J = 9.9, 6.5, 4.2 Hz, 3H), 3.35 (t, J = 5.3 Hz, 1H), 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: 464.21).

[0129] Example 26: 9-(Piperidin-1-amine)methyl-10-hydroxycamptothecin (26)

Chemical Structure

[0130] Example 27: 9-(N-Methyl(tetrahydropyranmethyl)amine)methyl-10-hydroxycamptothecin (27)

Chemical Structure

[0131] Example 28: 9-(N-Methyl(piperidin-4-yl)methyl)amine)methyl-10-hydroxycamptothecin (28)

Chemical Structure

[0132] Example 29: 9-(3-(Undeca-5,5-spirocyclo-3,9-diazane))methyl-10-hydroxycamptothecin (29)

Chemical Structure

[0133] The above Boc-intermediate was dissolved in ethyl acetate (2 mL), stirred at 0 °C, a solution of 4M HCl in ethyl acetate (0.5 mL) was added, stirred at room temperature for 2 hours, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain the solid product 9-(3-(undecane-5,5-spiro-3,9-diazane))methyl-10-hydroxycamptothecin (yield 91.1%). 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: 530.25).

[0134] Example 30: 9-(Piperidin-4-ethylamine)methyl-10-hydroxycamptothecin (30)

Chemical Structure

[0135] The above-mentioned Boc-intermediate was dissolved in ethyl acetate (2 mL), stirred at 0 °C, a 4M HCl solution in ethyl acetate (0.5 mL) was added, stirred at room temperature for 2 hours, concentrated, and recrystallized from ethyl acetate / petroleum ether to obtain the solid compound 9-(piperidin-4-ethylamine)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 value: 504.24).

[0136] Example 31: 9-(L-proline tert-butyl ester)methyl-10-hydroxycamptothecin (31)

Chemical Structure

[0137] Example 32: 9-(L-proline)methyl-10-hydroxycamptothecin (32)

Chemical Structure

[0138] Example 33: 9-(1-Piperidine-4-carboxylic acid methyl ester)methyl-10-hydroxycamptothecin (33)

Chem.

[0139] Example 34: 9-(1-Piperidine-4-carboxylic acid)methyl-10-hydroxycamptothecin (34)

Chem.

[0140] Example 35: 9-(L-Alanine tert-butyl ester)methyl-10-hydroxycamptothecin (35)

Chemical Structure

[0141] Example 36: 9-(N-Methyl-L-alanine)methyl-10-hydroxycamptothecin (36)

Chemical Structure

[0142] Example 37: 9-(Tetrahydropyran-4-amine)methyl-10-hydroxycamptothecin (37)

Chemical formula

[0143] Example 38: 9-(4-Boc-piperazin-1-ylamine)methyl-10-hydroxycamptothecin (38)

Chem.

[0144] Example 39: 9-((2-(2-Boc-aminoethoxy)ethyl)amine)methyl-10-hydroxycamptothecin (39)

Chem.

[0145] Example 40: 3-(N-Trifluoroethyl)-1,3-oxazine[5,6],[9,10]camptothecin (40)

Chem.

[0146] Example 41: 9-(Trifluoroethylamine)methyl-10-hydroxycamptothecin (41)

Chem.

[0147] Example 42: 9-(trans-4-Methoxycyclohexylamine)methyl-10-hydroxycamptothecin (42)

Chem.

[0148] Example 43: 9-(Tetrahydropyran-4-ylmethylamine)methyl-10-hydroxycamptothecin (43)

Chem.

[0149] Example 44: 9-(N-methylhydroxyamine)methyl-10-hydroxycamptothecin (44)

Chemical Structure

[0150] Example 45: 9-(2’-N-Boc-2’-N-methylhydrazine)methyl-10-hydroxycamptothecin (45)

Chemical Structure

[0151] Example 46: 9-(1-(4-hydroxyacetylpiperazine))methyl-10-hydroxycamptothecin (46)

Chemical Structure

[0152] Example 47: 9-(N,O-Dimethylhydroxyamine)methyl-10-hydroxycamptothecin (47)

Chem.

[0153] Example 48: 9-((1-Methoxypropan-2-yl)amino)methyl-10-hydroxycamptothecin (48)

Chemical Structure

[0154] Example 49: 9-((1-Hydroxypropan-2-yl)amino)methyl-10-hydroxycamptothecin (49) [Chemistry] 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 1H NMR (600 MHz, DMSO-d6) δ 11.42 (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 = 9.1 Hz, 1H), 7.29 (s, 1H), 6.54 (s, 1H), 5.50 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 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).

[0155] Example 50: 9-(propylamino)methyl-10-hydroxycamptothecin (50) [Chemistry] 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%). 11H NMR (500 MHz, DMSO-d6) δ 11.29 (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, 2.1 Hz, 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: 435.48).

[0156] Example 51: 9 - ((2-(2-Aminoethoxy)ethyl)amino)methyl-10-hydroxycamptothecin (51)

Chemical Structure

[0157] Test Example 1: Inhibitory Activity of Compounds against Cancer Cell Proliferation Human esophageal cancer cell line OE33, human breast cancer cell line SK-BR-3, and human gastric cancer cell line NCI-N87 were cultured in RPMI 1640 (Cellmax) containing 10% fetal bovine serum (Cellmax), respectively. Tumor cells in the exponential growth phase were diluted with the medium to 1×10 5 cells / mL, and 100 μL per well was added to a 96-well cell culture plate, and then returned to an incubator at 37°C and 5% CO2 for overnight culture. The next day, the test compound and the control compound were diluted with the medium to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM, respectively. After dilution, 2 μL of the diluted compound was added to each well of the 96-well cell culture plate, and three replicate wells were set up for each concentration. For the negative control group and the blank control group without the added compound, 2 μL of the diluent was added per well. After the addition was completed, it was returned to an incubator at 37°C and 5% CO2 and continuously incubated for 72 hours. After the incubation was completed, the cell culture plate was taken out, and the medium in the plate was aspirated and removed with a pipette. Then, 100 μL of the medium containing 10% CCK-8 was added to each well and incubated at 37°C for 3 hours. After the incubation was completed, the culture plate was taken out, shielded from light, placed on an ELISA plate, and the absorbance was measured with 630 nm as the reference wavelength and 450 nm as the measurement wavelength. The IC 50 value was calculated from the absorbance value using the four-parameter regression method of GraphPad (Tables 1 - 3). SN38 (7-ethyl-10-hydroxycamptothecin) and 10CPT (10-hydroxycamptothecin) were used as the control compounds. For the IC 50 value, "++++" indicates that the IC 50 <50 nM, "+++" indicates that the IC 50 is 10 - 100 nM, "++" indicates that the IC 50 is 100 - 500 nM, and "+" indicates that the IC 50 >500 nM. [Table 2]

Table 3

Table 4

[0158] Results: The compounds of the examples provided by the present invention have a good inhibitory effect on the proliferation of cancer cells such as esophageal cancer cell OE33, breast cancer cell SK-BR-3, and gastric cancer cell NCI-N87. Some compounds such as compound 10, compound 17, and compound 19 have an IC 50 value of all less than 100 nM and have broad anti-cancer activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, 【Chemical 1】 wherein, R is -CH ２ NR １ R ２ wherein R １ and R ２ are each independently hydrogen, a hydroxy group, a C １ -C ６ alkyl group, a C １ -C ６ alkoxy group, a C ３ -C ６ cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, a 4- to 8-membered aryl group or -NR ａ R ｂ selected from the group consisting of, provided that the C １ -C ６ alkyl group, a C １ -C ６ alkoxy group, a C ３ -C ６ cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, a 4- to 8-membered aryl group or -NR ａ R ｂ is optionally substituted with a substituent selected from halogen, a hydroxy group, an amino group, a carboxyl group, a C １ -C ６ alkoxy group, a C １ -C ６ alkoxycarbonyl group, -O-(C １ -C ３ alkyl)-NR ａ R ｂ group, or a 4- to 8-membered heterocycloalkyl group, provided that R １ and R ２ are not simultaneously hydrogen or methyl, or R １ and R ２ together with the N atom to which they are attached form a 4- to 8-membered cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, a 4- to 8-membered aryl group or a 9- to 12-membered azaspiroalkyl group, and the 4- to 8-membered cycloalkyl group, 4- to 8-membered heterocycloalkyl group, 4- to 8-membered aryl group or 9- to 12-membered azaspiroalkyl group is optionally substituted with a substituent selected from a hydroxy group, an amino group, a carboxyl group, C １ -C ６ alkoxy group, C １ -C ６ alkoxycarbonyl group, C １ -C ３ alkyl group, C １ -C ３ alkoxy group, -O-NH ２ , -NR ａ R ｂ or -C(O)R ｃ and is optionally substituted, or R and the hydroxy group ortho thereto together with the C atom on the benzene ring to which they are attached form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C ３ -C ６ cycloalkyl group, 4- to 8-membered heterocycloalkyl group, -NR ａ R ｂ or a 4- to 8-membered heterocycloalkyl group, and is substituted with a substituent selected from the group consisting of, and the C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C ３ -C ６ cycloalkyl group, 4- to 8-membered heterocycloalkyl group, -NR ａ R ｂ , or a 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from halogen, hydroxy group, amino group, carboxy group, C １ -C ６ alkoxy group or C １ -C ６ alkoxycarbonyl group, provided that at least one of R １ , R ２ is H, R ａ and R ｂ are each independently selected from H, C １ to C ６ alkyl group or C １ to C ６ alkoxycarbonyl group, R ｃ is selected from an amino group, a C １ -C ３ alkyl group, a C １ -C ３ alkoxy group, a C ３ -C ６ cycloalkyl group or a hydroxy group-substituted C １ -C ３ alkyl group. the compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

2. R is -CH ２ NR １ R ２ wherein R １ and R ２ are each independently hydrogen, a hydroxy group, a C １ -C ６ alkyl group, a C １ -C ６ alkoxy group, a C ３ -C ６ cycloalkyl group, a 4- to 8-membered heterocycloalkyl group or -NR ａ R ｂ selected from the group consisting of, provided that the C １ -C ６ alkyl group is optionally substituted with a substituent selected from halogen, a hydroxy group, an amino group, a carboxyl group, a C １ -C ６ alkoxycarbonyl group, -O-(C １ -C ３ alkyl)-NR ａ R ｂ or a 4- to 8-membered heterocycloalkyl group, and the C ３ -C ６ cycloalkyl group or 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from a hydroxy group, a C １ -C ３ alkoxy group or a C １ -C ６ alkoxycarbonyl group, provided that R １ and R ２ are not simultaneously hydrogen or a methyl group, or R １ and R ２ together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group or a 9- to 12-membered azaspiroalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally substituted with a hydroxy group, an amino group, a carboxyl group, C １ -C ６ alkoxycarbonyl group, C １ -C ３ alkyl group, C １ -C ３ alkoxy group, -O-NH ２ group or -C(O)R ｃ selected from the substituents, or R and the hydroxy group at the ortho position thereof together with the C atom on the benzene ring to which they are attached form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally halogen-substituted C １ -C ６ alkyl group, C ３ -C ６ cycloalkyl group or a substituent selected from a 4- to 8-membered heterocycloalkyl group, provided that at least one of R １ , R ２ is H Preferably, R ａ and R ｂ are each independently selected from H, a methyl group or a tert-butoxycarbonyl group, Preferably, R ｃ is an amino group, C １ to C ３ alkyl group, C １ to C ３ alkoxy group, C ３ to C ６ cycloalkyl group or hydroxy group-substituted C １ to C ３ selected from alkyl groups, The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

3. R is -CH ２ NHR １ wherein R １ is hydrogen, a hydroxy group, a C １ -C ６ alkyl group, a C １ -C ６ alkoxy group, a C ３ -C ６ cycloalkyl group, a 4- to 8-membered heterocycloalkyl group or -NR ａ R ｂ selected from the group consisting of, provided that the C １ -C ６ alkyl group is optionally substituted with a substituent selected from halogen, hydroxy group, amino group, carboxy group, a C １ -C ６ alkoxycarbonyl group, -O-(C １ -C ３ alkyl)-NR ａ R ｂ or a 4- to 8-membered heterocycloalkyl group, and the C ３ -C ６ cycloalkyl group or 4- to 8-membered heterocycloalkyl group is optionally substituted with a substituent selected from hydroxy group, a C １ -C ３ alkoxy group or a C １ -C ６ alkoxycarbonyl group, provided that R １ is not hydrogen, or R and the hydroxy group at the ortho position thereof together with the C atom on the benzene ring adjacent thereto form a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is optionally substituted with a halogen-substituted C １ -C ６ alkyl group, C ３ -C ６ substituted with a substituent selected from a cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, Preferably, R ａ and R ｂ are each independently selected from H, a methyl group or a tert-butoxycarbonyl group, The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

4. R １ and R ２ are each independently selected from hydrogen, a hydroxy group, an amino group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a trifluoroethyl group, a cyclopropyl group, -(CH ２ ) ２ OH, -(CH ２ ) ２－４ NH ２ , -CH(CH ３ )C(O)OH, -CH(CH ３ )CH ２ OCH ３ , -CH(CH ３ )CH ２ OH, -(CH ２ ) ２ CH ３ , -NHBoc, -N(CH ３ )Boc, -CH(CH ３ )Boc, -(CH ２ ) ２ O(CH ２ ) ２ NH ２ , -(CH ２ ) ２ O(CH ２ ) ２ NHBoc, and are selected from the groups represented by the following formulae: [Chemical 2] However, R １ and R ２ are not simultaneously hydrogen or a methyl group, or R １ and R ２ together with the N atom to which they are attached form pyrrolidine, piperidine, piperazine or 3,9-diazaspiro[5.5]undecane, and the pyrrolidine, piperidine, piperazine or 3,9-diazaspiro[5.5]undecane is optionally substituted with a substituent selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a carboxyl group, a tert-butoxycarbonyl group, -O-NH ２ or -C(O)R ｃ and is optionally substituted with a substituent selected therefrom, or R and the hydroxy group at the ortho position thereof form a group represented by the following formula together with the C atom on the benzene ring adjacent thereto, [Chemical 3] The group represented by the formula is optionally substituted with a substituent selected from a trifluoromethyl group, a cyclopropyl group or a morpholin-4-yl group, provided that R １ , R ２ is at least one of H, R ｃ is selected from an amino group, a methyl group, a methoxy group, a hydroxyethyl group or a cyclopropyl group, Preferably, R is -CH ２ NHR １ wherein R １ is selected from hydrogen, a hydroxy group, an amino group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a trifluoroethyl group, a cyclopropyl group, -(CH ２ ) ２ OH, -(CH ２ ) ２－４ NH ２ , -CH(CH ３ )COOH, -CH(CH ３ )CH ２ OCH ３ , -CH(CH ３ )CH ２ OH, -(CH ２ ) ２ CH ３ , -NHBoc, N(CH ３ )Boc, -CH(CH ３ )Boc, -(CH ２ ) ２ O(CH ２ ) ２ NHBoc, and a group represented by the following formula, 【Chemical 4】 However, provided that R １ is not hydrogen, or R and the hydroxy group at the ortho position thereof form a group represented by the following formula together with the C atom on the benzene ring adjacent thereto, 【Chemical Formula 5】 the group represented by the above formula is optionally substituted with a substituent selected from a trifluoromethyl group, a cyclopropyl group or a morpholin-4-yl group, preferably, R is selected from the following structures, 【Chemical Formula 6】 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

5. The compound is a compound of formula (II), 【Chemical Formula 7】 wherein, The Y ring is selected from a 4- to 8-membered nitrogen-containing saturated ring, a 4- to 8-membered nitrogen-containing aromatic ring, or a 9- to 12-membered nitrogen-containing saturated spiro ring, and 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 spiro ring is optionally a hydroxy group, an amino group, C １ -C ６ alkoxycarbonyl group, C １ -C ３ alkyl group, C １ -C ３ alkoxy group, -O-NH ２ or -C(O)R ｃ and is further substituted with a substituent selected from, preferably, the C １ -C ６ alkoxycarbonyl group is a tert-butoxycarbonyl group, 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, and the 4- to 8-membered nitrogen-containing saturated ring is optionally a hydroxy group, an amino group, C １ to C ６ alkoxycarbonyl group, C １ to C ３ alkyl group, C １ to C ３ alkoxy group, -O-NH ２ or -C(O)R ｃ substituted with a substituent selected from, preferably, the C １ to C ６ alkoxycarbonyl group is a tert-butoxycarbonyl group, R ｃ ' is selected from a hydroxy group, an amino group, a C １ -C ３ alkyl group, a C １ -C ３ alkoxy group, a C ３ -C ６ cycloalkyl group or a hydroxy group-substituted C １ -C ３ alkyl group, and Preferably, R ｃ ’ is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group or a cyclopropyl group, preferably, the compound of formula (II) is a compound of formula (IIa), formula (IIb) or formula (IIc), 【Chemical 8】 Here, R ｃ ’ is selected from a hydroxy group, an amino group, a C １ -C ３ alkyl group, a C １ -C ３ alkoxy group, a C ３ -C ６ cycloalkyl group or a hydroxy group-substituted C １ -C ３ alkyl group, and Preferably, R ｃ ’ is selected from a hydroxy group, an amino group, a methyl group, a methoxy group, a hydroxymethyl group, a tert-butyloxy group or a cyclopropyl group, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

6. The compound is selected from the following compounds, the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】

7. A method for preparing the compound according to any one of claims 1 to 6, comprising the following reaction routes, Reaction route 1: 【Chemical Formula 9】 10-Hydroxycamptothecin is subjected to a Mannich reaction at the 9-position with formaldehyde or paraformaldehyde and an amine compound to obtain a compound of formula (I), where the amine compound is NHR １ R ２ and R, R １ and R ２ are the same as those defined in any one of claims 1 to 4, respectively. Reaction route 2: 【Chemical Formula 10】 9-Formyl-10-hydroxycamptothecin is subjected to a reductive amination reaction with an amine compound and sodium cyanoborohydride to obtain a compound of formula (I), wherein the amine compound is NHR １ R ２ wherein R, R １ and R ２ are the same as those defined in any one of claims 1 to 4, respectively. including steps selected from, preferably, the 9-formyl-10-hydroxycamptothecin is obtained by reacting 10-hydroxycamptothecin with hexamethylenetetramine, preferably, the usage amount of paraformaldehyde or formaldehyde in the Mannich reaction described in reaction route 1 is 1.0 to 5.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, more preferably 1.2 to 2.2 molar equivalents, preferably, the usage amount of the amine compound in reaction route 1 is 1.0 to 5.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, more preferably 1.2 to 1.6 molar equivalents, Preferably, in the reductive amination reaction described in Reaction Path 2, the reducing agent is sodium cyanoborohydride, Preferably, the amount of the amine compound used in Reaction Path 2 is 1.0 to 3.0 molar equivalents, more preferably 1.0 to 1.2 molar equivalents, Preferably, the amount of sodium cyanoborohydride used is 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, and even more preferably 1.2 to 1.5 molar equivalents, A preparation method characterized by the above.

8. An antibody-drug conjugate comprising a small molecule drug and a linker antibody, wherein the small molecule drug is the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof. An antibody-drug conjugate characterized by using.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, or the antibody-drug conjugate according to claim 8.

10. In the preparation of a drug for treating cancer, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, the antibody-drug conjugate according to claim 8 or the pharmaceutical composition according to claim 9 Use, The cancer includes gastric cancer, esophageal cancer, cardiac cancer, breast cancer, ovarian cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic granulocytic leukemia, choriocarcinoma, lung cancer, bladder cancer, intestinal cancer, and small cell lung cancer. More preferably, the cancer is esophageal cancer, breast cancer, and gastric cancer.

11. A method for treating cancer, comprising administering to a patient in need thereof the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, the antibody-drug conjugate according to claim 8 or the pharmaceutical composition according to claim 9.

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