Camptothecin-7-ethylamine derivatives, their preparation method and use

Abstract

The present invention provides a camptothecin-7-ethylamine derivative or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, and methods for preparing and using the same, wherein the camptothecin-7-ethylamine derivative has a structure represented by formula (1): [Formula 1] JPEG2025530932000072.jpg57170

Description

[Technical Field]

[0001] The present invention relates to the medical field. Specifically, the present invention provides the preparation of a series of camptothecin-7-ethylamine derivatives and their use in the treatment of tumors. [Background technology]

[0002] Camptothecin, a natural product extracted from the Chinese plant, Camptothecin, exhibits inhibitory activity against topoisomerase Top1, particularly against the Top1-DNA complex. Camptothecin is a broad-spectrum antitumor drug with significant therapeutic effects against gastric, esophageal, lung, and bladder cancers. Irinotecan and topotecan, among others, have been approved in many countries for the treatment of various cancers. Another camptothecin derivative, belotecan, has been approved in South Korea for the treatment of SCLC and ovarian cancer. The main drawbacks of camptothecin-based antitumor agents are their toxicity, insolubility, and tumor cell resistance.

[0003] The present invention provides a series of camptothecin-7-ethylamine derivatives characterized by improved solubility and enhanced antitumor activity, which have potential application value in tumor treatment. Summary of the Invention

[0004] The present invention provides a series of camptothecin-7-ethylamine derivatives or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof, as well as processes for their preparation and use in the field of antitumor.

[0005] One aspect of the present invention provides compounds of Formula 1, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof: [ka]

[0006] wherein R1 and R2 each independently represent a halogen, a hydroxyl group, an alkyl group, or an alkoxy group, or R1 and R2 together form a methylenedioxy bridge or an ethylenedioxy bridge; R3 and R4 each independently represent a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a sulfonyl group, or R3 and R4 together with the nitrogen atom connected thereto form a heterocycloalkyl group or a heteroaryl group, and the alkyl group, alkoxy group, cycloalkyl group, alkylacyl group, sulfonyl group, heterocycloalkyl group, aryl group, or heteroaryl group is optionally substituted with R; R is selected from halogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, an azide, or a 5- to 7-membered heteroaryl.

[0007] In one embodiment, R1 and R2 each independently represent a halogen, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or R1 and R2 together form a methylenedioxy bridge or an ethylenedioxy bridge.

[0008] In one embodiment, R1 and R2 each independently represent a halogen or a methyl group.

[0009] In one embodiment, R1 and R2 each independently represent a methyl group, F, Cl, Br, or I.

[0010] In one embodiment, R1 and R2 each independently represent a methyl group, F.

[0011] In one embodiment, R1 and R2 together comprise a methylenedioxy bridge or an ethylenedioxy bridge.

[0012] In one embodiment, R3 and R4 each independently represent a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a 4-8-membered heterocycloalkyl group, a 5-12-membered aryl group, a 5-12-membered heteroaryl group, a C1-C6 alkyl-acyl group, a C1-C6 alkyl-sulfonyl group, or a C3-C6 cycloalkyl-sulfonyl group; or R3 and R4 together with the nitrogen atom linked thereto form a 4-8-membered heterocycloalkyl group, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 4-8-membered heterocycloalkyl group, 5-12-membered aryl group, 5-12-membered heteroaryl group, C1-C6 alkyl-acyl group, C1-C6 alkyl-sulfonyl group, or C3-C6 cycloalkyl-sulfonyl group is optionally substituted with R.

[0013] In one embodiment, R3 and R4 each independently represent a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group, a C1-C3 alkyl-acyl group, a C1-C3 alkyl-sulfonyl group, or a C3-C6 cycloalkyl-sulfonyl group; or R3 and R4 together with the nitrogen atom linked thereto form a 5- to 6-membered heterocycloalkyl group, wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, 5- to 6-membered heterocycloalkyl group, 5- to 6-membered heteroaryl group, C1-C3 alkyl-acyl group, C1-C3 alkyl-sulfonyl group, or C3-C6 cycloalkyl-sulfonyl group is optionally substituted with R.

[0014] In one embodiment, R3 and R4 each independently represent a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group, a C1-C3 alkyl-acyl group, a C1-C3 alkyl-sulfonyl group, or a C3-C6 cycloalkyl-sulfonyl group; or R3 and R4 together with the nitrogen atom linked thereto form a 5- to 6-membered heterocycloalkyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, 5- to 6-membered heterocycloalkyl group, 5- to 6-membered heteroaryl group, C1-C3 alkyl-acyl group, C1-C3 alkyl-sulfonyl group, or C3-C6 cycloalkyl-sulfonyl group is optionally substituted with R; or R3 and R4 together with the nitrogen atom linked thereto form a 5- to 6-membered heterocycloalkyl group, and the heterocycloalkyl group and heteroaryl group independently contain 1 to 3 heteroatoms selected from N and O.

[0015] In one embodiment, R is selected from a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, or an azide.

[0016] In one embodiment, R is selected from F, Cl, Br, I, a hydroxy group, a methyl group, a methoxy group, a cyclopropyl group, or an azide.

[0017] In one embodiment, R is selected from F, a hydroxy group, a methyl group, a methoxy group, a cyclopropyl group, or an azide.

[0018] In one embodiment, R3 and R4 are each independently selected from the following groups: [ka]

[0019] In one embodiment, R3 and R4 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, or piperazine.

[0020] In one embodiment, R3, R4 together with the nitrogen atom to which they are attached are [ka] Form.

[0021] In one embodiment, R1 and R2, each independently or together, are the following structures: [ka]

[0022] In one embodiment, each of said -NR3R4 independently or together has the following structure: [ka]

[0023] The present invention provides the following compounds or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0024] Another aspect of the present invention provides a method for preparing a compound according to any one of the preceding claims, said method comprising steps selected from any one of the following synthetic routes:

[0025] Synthetic Route 1, comprising the following steps: (1) reacting a 3,4-substituted aniline with a halopropionitrile to obtain a 3',4'-disubstituted-3-halo-6'-aminopropiophenone; (2) displacing the 3',4'-disubstituted-3-halo-6'-aminopropiophenone with an amine to obtain a 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone; (3) condensing 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative.

[0026] Synthetic Route 2, comprising the following steps: (1) reacting 3',4'-disubstituted-3-halopropiophenone with nitric acid to obtain 6'-nitro-3',4'-disubstituted-3-halopropiophenone; (2) a substitution reaction of the 6'-nitro-3',4'-disubstituted-3-halopropiophenone with an amine to obtain a 6'-nitro-3',4'-disubstituted-3-alkylaminopropiophenone; (3) reducing the 6'-nitro-3',4'-disubstituted-3-alkylaminopropiophenone to obtain 6'-amino-3',4'-disubstituted-3-alkylaminopropiophenone; (4) condensing 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative.

[0027] Synthetic Route 3, comprising the following steps: (1) subjecting 3',4'-disubstituted acetophenone to a nitro reaction to obtain 6'-nitro-3',4'-disubstituted acetophenone; (2) condensing the 6'-nitro-3',4'-disubstituted acetophenone with formaldehyde and acidifying to give the 6'-nitro-3',4'-disubstituted acrylophenone; (3) Michael addition reaction of 6'-nitro-3',4'-disubstituted acrylophenone with amine to obtain 6'-nitro-3',4'-disubstituted phenylacetone-3-amine; (4) reducing 6'-nitro-3',4'-disubstituted phenylacetone-3-amine to obtain 6'-amino-3',4'-disubstituted phenylacetone-3-amine; (5) condensation reaction of 6'-amino-3',4'-disubstituted phenylacetone-3-amine with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative.

[0028] Synthetic Route 4, comprising the following steps: (1) condensation of a substituted 2-acetylaniline with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain 7-methylcamptothecin; (2) Mannich reaction of 7-methylcamptothecin with an amine in DMSO to obtain camptothecin-7-ethylamine derivative.

[0029] Preferably, the synthetic route of the present invention is as follows: [ka]

[0030] Synthetic Route 1. Using 3,4-disubstituted anilines as starting materials, the desired products are obtained by Friedel-Crafts reaction, nitration, amine substitution, nitro reduction, and ring closure. JPEG2025530932000012.jpg37170

[0031] Synthetic Route 2. Using 3,4-disubstituted 3'-chloropropiophenone as a starting material, the target product is obtained by amine substitution, nitration, reduction, and ring closure. JPEG2025530932000013.jpg38170

[0032] Synthetic Route 3. Using 3,4-disubstituted acrylophenone as a starting material, the target product is obtained by Michael addition of amine, nitration, reduction, and ring closure. JPEG2025530932000014.jpg39170

[0033] Synthetic Route 4. 7-Methylcamptothecin (Intermediate 5) is used as a substrate, and the Mannich reaction is carried out using an amine and DMSO to obtain 7-aminoethyl-substituted camptothecin.

[0034] In one embodiment, the preparation method of the present invention includes synthetic routes 1 to 4. Step 1) involves reacting a 3,4-substituted aniline with the corresponding halopropionitrile to obtain intermediate 3',4'-disubstituted-3-chloro-6'-aminopropiophenone (intermediate 1), step 2) involves replacing intermediate 1 with the corresponding amine to obtain 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone (intermediate 2), and step 3) involves converting intermediate 2 into (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f] Step 3) is a condensation reaction of 3',4'-disubstituted-3-chloropropiophenone with various amines, substituted amines, protected amines, protected aminohydroxy groups, methoxyhydroxyamines, etc. to obtain intermediate 3; Step 5) is nitration and reduction of intermediate 3 to obtain intermediate 4; and Step 6) is condensation of intermediate 4 with a tricyclic ketone. Step 6) condensing 6'-nitro-3',4'-disubstituted acrylophenone with an amine to give the corresponding product; Step 7) Michael addition reaction of 6'-nitro-3',4'-disubstituted phenylacetone-3-amine (intermediate 3); Step 8) reducing 6'-nitro-3',4'-disubstituted phenylacetone-3-amine to give 6'-amino-3',4'-disubstituted phenylacetone-3-amine (intermediate 4); Step 9) condensing 6'-amino-3',4'-disubstituted phenylacetone-3-amine with a "tricyclic ketone" to give the corresponding camptothecin-7-ethylamine derivative; Step 10) condensing substituted 2-acetylaniline with the "tricyclic ketone" to give 7-methylcamptothecin; and Step 11) Mannich reaction of 7-methylcamptothecin with the corresponding amine in DMSO to give the corresponding product.

[0035] In one embodiment, the halopropionitrile used in step (1) of synthetic pathway 1 is chloropropionitrile or bromopropionitrile, and the amount thereof is 1 to 2 molar equivalents, preferably 1.0 to 1.5 molar equivalents, more preferably 1.1 to 1.2 molar equivalents.

[0036] In one embodiment, step (1) of synthetic route 1 is catalyzed using AlCl3 or BCl3 in an amount of 1 to 3 molar equivalents, preferably 1.0 to 1.5 molar equivalents.

[0037] In one embodiment, step (2) of synthetic route 1 is catalyzed using PPTS in an amount of 1 to 2 molar equivalents, preferably 1.0 to 1.2 equivalents.

[0038] In one embodiment, the amount of amine in step (3) of synthetic route 1 is 1 to 20 molar equivalents, preferably 3 to 10 molar equivalents.

[0039] In one embodiment, step (2) of synthetic pathway 2 is nitration using nitric acid / acetic anhydride, and the reaction temperature is -10 to 10°C, preferably -5 to 0°C.

[0040] In one embodiment, the amount of amine in step (2) of synthetic route 4 is 1 to 20 molar equivalents, preferably 3 to 6 molar equivalents.

[0041] In one embodiment, step (2) of synthesis method 3 uses an aqueous formaldehyde solution or paraformaldehyde in an amount of 5 to 100 molar equivalents, preferably 30 to 40 molar equivalents.

[0042] In one embodiment, the Michael addition reaction in step (3) of synthesis method 3 is carried out at 0 to 100°C, preferably 50 to 70°C.

[0043] In one embodiment, the Mannich reaction in step (2) of synthesis method 4 is carried out by heating a hydrochloride of a primary or secondary amine in DMSO to 80 to 160°C, preferably 100 to 145°C, more preferably 110 to 140°C.

[0044] Another aspect of the present invention provides an antibody-drug conjugate using the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as a small molecule drug.

[0045] Another aspect of the present invention provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, or an antibody-drug conjugate, and a pharmaceutically acceptable adjuvant.

[0046] Another aspect of the present invention provides use of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, antibody-drug conjugate, or pharmaceutical composition in the preparation of a medicament for treating a tumor disease.

[0047] Another aspect of the present invention provides a method for treating a tumor disease, comprising administering to a patient in need thereof the compound described above, or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition thereof.

[0048] In one embodiment, the amount of the compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, antibody-drug conjugate, or pharmaceutical composition administered is a therapeutically effective amount.

[0049] In one embodiment, the tumor diseases include gastric cancer, esophageal cancer, cardia cancer, breast cancer, ovarian cancer, colorectal cancer, primary liver cancer, acute and chronic granulocytic leukemia, chorioepithelial carcinoma, lung cancer, bladder cancer, intestinal cancer, and small cell lung cancer, preferably, the cancers are esophageal cancer, breast cancer, and gastric cancer. DETAILED DESCRIPTION OF THE INVENTION

[0050] I. Definition In the present invention, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art unless otherwise specified. Furthermore, the relevant terms and experimental steps used herein are terms and common steps widely used in their respective fields. In addition, definitions and explanations of relevant terms are provided below to better understand the present invention.

[0051] As used herein, and unless otherwise specified, the terms "comprise," "include," "have," and "contain," including their grammatical equivalents, are to be generally understood as open-ended and non-limiting, e.g., not excluding other unrecited elements or steps.

[0052] The compounds of the present disclosure may be asymmetric, e.g., may have 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 configurations) and optical isomers (e.g., enantiomers), and are therapeutic agents consisting of individual compounds, racemates, racemic mixtures, and pharmaceutically acceptable salts thereof. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be isolated from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are within the scope of the present invention.

[0053] The compounds of the present invention also include tautomeric forms, which result from the swapping of a single bond with an adjacent double bond, both involving the migration of one proton.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a corresponding amine compound and an inorganic or organic acid, a salt formed between a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed between a corresponding carboxylic acid compound and an organic amine. 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, and the like; organic amine salts include, but are not limited to, salts of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, and the like.

[0055] As used herein, the term "precursor" refers to a compound that, after being taken into the human body by an appropriate administration method, undergoes metabolism or simple chemical changes in the patient's body and is converted into the compound included in the general formula 1 of the present invention and its corresponding salt form. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonate esters, phosphate esters, sulfate esters, sulfonate esters, amino acid esters, gluconate esters, and various amides, acetals, hemiacetals, carbonate amide esters, and other forms.

[0056] 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.

[0057] Any variable (e.g., R n When any element (R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 1 to 5 R, then that group may also be optionally substituted with up to 5 R, where R is an independent option at each occurrence. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0058] 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, 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, and 5-methylhexyl. groups, 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.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, and carboxylic acid ester groups. In the present disclosure, preferred are methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, haloalkyl groups, deuterated alkyl groups, alkoxy-substituted alkyl groups, and hydroxy-substituted alkyl groups.

[0059] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic 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 excluding the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. Preferably, it is a 3- to 8-membered heterocyclyl containing 3 to 12 ring atoms, one to four of which are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes a nitrogen-containing monocyclic heterocyclyl group, a nitrogen-containing spiroheterocyclyl group, or a nitrogen-containing fused heterocyclyl group.

[0060] The term "aryl group" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as, for example, phenyl and naphthyl groups.

[0061] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen, sulfhydryl groups, hydrogen groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or carboxylic acid ester groups.

[0062] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydrogen groups, nitro groups, chloro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxylic acid groups, and carboxylic acid ester groups.

[0063] All hydrogen atoms described in the present invention can be substituted with their isotope, deuterium.

[0064] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are each independently substituted with the corresponding number of substituents. Substituents are present only at chemically feasible positions, and it is obvious that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., alkene) bond.

[0065] [ka] denotes a chemical binding site.

[0066] Drug or pharmaceutical composition As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a corresponding amine compound and an inorganic or organic acid, a salt formed between a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed between a corresponding carboxylic acid compound and an organic amine. 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, and the like; organic amine salts include, but are not limited to, salts of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, and the like.

[0067] As used herein, the term "precursor" refers to a compound that, after being taken into the human body by an appropriate administration method, undergoes metabolism or simple chemical changes in the patient's body and is converted into the compound included in the general formula 1 of the present invention and its corresponding salt form. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonate esters, phosphate esters, sulfate esters, sulfonate esters, amino acid esters, gluconate esters, and various amides, acetals, hemiacetals, carbonate amide esters, and other forms.

[0068] The drugs or pharmaceutical compositions of the present invention can be administered orally, topically, parenterally, or mucosally (e.g., sublingually, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. Oral administration is usually preferred. The active agents can be administered orally in the form of capsules, tablets, etc. (See Remington: The Science and Practice of Pharmacy, 20th Edition).

[0069] When administered orally in tablet or capsule form, the active drug component may be combined 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, 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, and the like), disintegrants (e.g., potato starch or sodium hydroxyacetate starch), or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, gum tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. When administered orally in liquid form, the drug component may 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 and oils), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, ester oils, 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 gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0070] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present invention containing a compound of Formula I as an active compound can also be incorporated into beads, microspheres, or microcapsules, for example, constructed of polyglycolic / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions, suspensions, etc., or can be dry preparations that are reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to provide controlled or delayed release of the active compound.

[0071] The term "treatment" includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0072] The use of the term "inhibition" is relative to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, a reduction in a response in subjects or cells treated with a compound is compared to a response in subjects or cells not treated with the compound.

[0073] The term "pharmaceutical composition" means a composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one selected from pharmaceutically acceptable ingredients 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, dispersing agents, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspension aids, etc., depending on the nature of the administration method and dosage form.

[0074] The term "effective amount" or "therapeutically effective amount" refers to a nontoxic but sufficient amount of a drug or agent to achieve a desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug to be administered will depend on many factors, such as the specific administration protocol, the type and severity of the disease or condition, and the specific characteristics (e.g., body weight) of the subject or host requiring treatment. However, dosages can be routinely determined by methods known in the art depending on the specific circumstances, including, for example, the specific drug employed, the route of administration, the condition being treated, and the subject or host being treated. Generally, dosages used in adult treatment typically range from 0.02 to 5000 mg / day, e.g., about 1 to 1500 mg / day. This required dose can conveniently be expressed as a single dose or as divided doses administered simultaneously (or shortly thereafter) or at appropriate intervals, e.g., two, three, four, or more divided doses per day. Although the above dosage ranges are given, it will be understood by those skilled in the art that the specific effective amount may be appropriately adjusted depending on the condition of the patient and in conjunction with the diagnosis of a physician.

[0075] The term "antibody-drug conjugate (ADC)" refers to a monoclonal antibody that is chemically linked to a biologically active small molecule drug, with the monoclonal antibody acting as a carrier for the delivery of the small molecule drug to target cells.

[0076] As used herein, the use of the terms "reduce," "inhibit," "attenuate," or "reduce" is relative to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, the reduction in a response in subjects or cells treated with a compound is compared to the response in subjects or cells not treated with the compound.

[0077] Unless otherwise specified, the materials and equipment used in specific embodiments of the present invention are known products and can be obtained commercially.

[0078] II. Specific Examples The screening method of the present invention includes the growth inhibitory activity of compounds against tumor cells such as OE33 cells (human esophageal adenocarcinoma cells) and SKBR3 cells (human breast adenocarcinoma cells).

[0079] Example 1: 7-(2-acetylamino)ethyl-10-methyl-11-fluorocamptothecin (1) [ka] A 1M solution of BCl3 in dichloromethane (32 mL, 0.032 mol) was added to a single-neck flask containing 160 mL of anhydrous 1,2-dichloroethane. The mixture was cooled to 0 °C, and 3-fluoro-4-methylaniline (5.0 g, 0.04 mmol) was added. The mixture was then allowed to react at 0 °C for 10 minutes. Acetonitrile (16.40 g, 0.4 mol) and aluminum trichloride (7 g, 0.05 mol) were added, and the mixture was slowly warmed to room temperature and stirred for 10 minutes. The mixture was then heated to 80 °C and stirred for 12 hours. After cooling, the reaction mixture was poured into ice water and adjusted to pH 2 with 1M HCl solution. The mixture was extracted with dichloromethane, dried over Na2SO4, and purified by silica gel chromatography to give the intermediate 6-amino-4-fluoro-3-methylacetophenone (2.5 g, 37.4% yield, 94% HPLC yield). LC-MS (M+H) + 168.02 (theoretical value 167.07).

[0080] 6-Amino-4-fluoro-3-methylacetophenone (1.5 g, 9.0 mmol) was dissolved in anhydrous toluene, and "tricyclic ketone" (2.36 g, 9.0 mmol) and PPTS (0.6 g, 2.4 mmol) were added. The reaction was heated to 115°C and stirred for 12 hours. The solvent was concentrated under reduced pressure, 10 mL of methanol was added, filtered, and the filter cake was dried to give 7,10-dimethyl-11-fluoro-camptothecin (3.2 g, 90.4% yield, 96% HPLC yield). LC-MS (M+H) + 395.26 (theoretical value 394.13).

[0081] 127.1 mg of amine hydrochloride and 148 μl of hydrochloric acid were added to 1.5 ml of DMSO, and the reaction mixture was heated to 110°C in an oil bath. 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, and the reaction mixture was heated to 130-140°C and reacted for 50 minutes. After cooling to room temperature, methanol was added, filtered, and purified by silica gel chromatography to give the demethoxylated product 7-(2-amino)ethyl-10-methyl-11-fluorocamptothecin (41 mg, 38.7% yield, 94% HPLC yield). 1 H NMR(500MHz,DMSO-d6)δ8.02-7.92(m,3H),7.35(d,J=2.6Hz,1H),6.61-6.53(m,1H),5.43(d,J=33.0Hz ,4H),3.59-3.47(m,2H),3.22(s,2H),1.89(dt,J=14.5,6.9Hz,2H),0.89(q,J=5.3Hz,3H);LC-MS(M+H) + 424.02 (theoretical value 423.16).

[0082] 7-(2-amino)ethyl-10-methyl-11-fluorocamptothecin (10 mg, 0.023 mmol) was added to a 25 mL single-neck flask, followed by DMF (5 mL), acetic acid (2.8 mg, 0.046 mmol), HATU (18 mg, 0.046 mmol), and DIPEA (6 mg, 0.046 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched by adding 0.5 mL of water dropwise, and the reaction solution was adjusted to 0.1% TFA (A) and acetonitrile (B). The reaction mixture was purified by the following procedure: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The product, 7-(2-acetylamino)ethyl-10-methyl-11-fluorocamptothecin (4.78 mg, 45.5% yield, HPLC 97.5%), was obtained. 1H NMR(500MHz,DMSO-d6)δ8.32(d,J=8.0Hz,1H),7.90(d,J=10.5Hz,1H),7.30(s,1H),5.44(s,3H),5.41(s,2H),5.31(s, 2H),2.47(s,2H),2.30(s,2H),1.90(d,J=7.1Hz,3H),1.85(dt,J=14.1,7.5Hz,2H),0.89(d,J=7.1Hz,3H);LC / MS(M+H) + 466.41 (theoretical value 465.17).

[0083] Example 2: 7-(2-difluoroacetamino)ethyl-10-methyl-11-fluorocamptothecin (2) [ka] 7-(2-amino)ethyl-10-methyl-11-fluorocamptothecin (15 mg, 0.035 mmol) was added to a reaction flask, followed by DMF (5 mL), difluoroacetic acid (8.8 mg, 0.092 mmol), followed by HATU (18 mg, 0.046 mmol), DIPEA (6 mg, 0.046 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched by adding 0.5 mL of water dropwise, and the reaction mixture was adjusted to 0.1% TFA (A) and acetonitrile (B). The reaction mixture was run as follows: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The product, 7-(2-difluoroacetamino)ethyl-10-methyl-11-fluorocamptothecin, was obtained (7.29 mg, 41.1% yield, HPLC 96%). 1 H NMR(500MHz,DMSO-d6)δ8.34(d,J=8.1Hz,1H),7.93(d,J=10.6Hz,1H),7.31(s,1H),6.53(d,J=4.9Hz,1H),5.4 4(s,3H),5.42(s,2H),5.34(s,2H),2.53(s,2H),2.30(s,1H),1.88(s,2H),0.89(d,J=7.3Hz,3H);LC / MS(M+H) +502.28 (theoretical value 501.46).

[0084] Example 3: 7-(2-methanesulfonylamino)ethyl-10-methyl-11-fluorocamptothecin (3) [ka] 7-(2-amino)ethyl-10-methyl-11-fluorocamptothecin (10 mg, 0.023 mmol, Example 1) was added to a reaction flask, and DMF (5 mL), methanesulfonyl chloride (4 mg, 0.035 mmol), and DIPEA (6 mg, 0.046 mmol) were added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was quenched by the dropwise addition of 0.5 mL of water. The reaction mixture was adjusted to 0.1% TFA (A) and acetonitrile (B). The reaction mixture was adjusted as follows: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The product 7-(2-methanesulfonylamino)ethyl-10-methyl-11-fluorocamptothecin was obtained (6.22 mg, 54% yield, HPLC 97%). LC / MS (M+H) + 502.23 (theoretical value 501.53).

[0085] Example 4: 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (4) [ka] 4-Aminotetrahydropyran (154 mg, 1.52 mmol), 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol), hydrochloric acid (0.138 mL, 1.65 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring and reacted for 40 minutes. After cooling, isopropanol was added, the mixture was filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (49.3 mg, yield 39%, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ8.01(d,J=8.6Hz,1H),7.83(s,1H),7.35(s,1H),6.61(s,1H),5.77(s,3H),5.45(d,J=22.3Hz,4H),3.98-3.89(m,2H),3.5 7-3.52(m,2H),3.34-3.27(m,5H),1.96(d,J=10.6Hz,2H),1.88(dd,J=12.1,7.3Hz,2H),1.56(d,J=9.7Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 508.33 (theoretical value 507.22).

[0086] Example 5: 7-(2-(piperazin-4-yl))ethyl-10-methyl-11-fluorocamptothecin (5) [ka] Piperazine (86.14 mg, 1 mmol), hydrochloric acid (0.085 mL, 1.02 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 110°C with stirring. 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, and the mixture was reacted at 120-135°C for 1 hour with continued stirring. The mixture was then cooled, isopropanol was added, filtered, and purified by silica gel chromatography to obtain the compound 7-(2-(piperazin-4-yl)ethyl-10-methyl-11-fluorocamptothecin) (43.75 mg, yield 35.5%, HPLC 98%). 1H NMR(500MHz,DMSO-d6)δ8.21(d,J=8.1Hz,1H),7.89(d,J=10.7Hz,1H),7.31(s,1H),6.55(s,1H),5.44(s,2H),5.36(s,2) H),3.62(s,6H),3.44(s,3H),3.24(s,4H),2.52(s,2H),1.87(dp,J=21.6,7.1Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 493.15 (theoretical value 492.22).

[0087] Example 6: 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (6) [ka] (trans)-4-aminocyclohexanol (175.22 mg, 1.52 mmol), hydrochloric acid (0.138 mL, 1.65 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 110°C with stirring. 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, and the mixture was heated to 120-130°C. The mixture was allowed to react for 45 minutes with continued stirring, cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered and purified by silica gel column chromatography to obtain the compound 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (54.8 mg, yield 42.0%, HPLC 97%). 1H NMR(500MHz,DMSO-d6)δ8.85(d,J=63.5Hz,2H),8.15(dd,J=117.3,8.3Hz,1H),7.98-7.79(m,1H),7 .38(d,J=6.1Hz,1H),6.62(s,1H),5.51(d,J=3.9Hz,2H),5.41(d,J=8.8Hz,2H),3.64-3.41(m,7H), 3.26-3.09(m,1H),2.54-2.51(m,1H),2.10(d,J=10.0Hz,1H),2.00-1.87(m,3H),1.85-1.73(m,2H) ,1.47(dq,J=24.7,12.9Hz,2H),1.25(td,J=13.2,12.8,6.9Hz,1H),1.01-0.87(m,3H);LC-MS(M+H) + 522.15 (theoretical value 521.23).

[0088] Example 7: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (7) [ka] (trans)-4-Methoxycyclohexylamine (196.56 mg, 1.52 mmol), hydrochloric acid (0.138 mL, 1.65 mmol), 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring and reacted for 45 minutes. The mixture was then cooled, isopropanol was added, filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(4-methoxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (49.6 mg, yield 37.0%, HPLC 97%). 1H NMR(500MHz,DMSO-d6)δ8.71(s,2H),8.23-8.14(m,1H),8.00(d,J=8.6Hz,1H),7.82(s,1H),7.35(s,1H),5.46(s,2H),5.41(s,2H),3.81-3.73(m, 1H),3.24(s,3H),3.12(q,J=10.4Hz,3H),2.63(s,2H),2.28(s,2H),1.95 -1.81(m,4H),1.37(d,J=11.0Hz,4H),0.88(t,J=7.4Hz,3H);LC-MS(M+H) + 536.41 (theoretical value 535.25).

[0089] Example 8: 7-(2-(2-azidoethyl)amino)ethyl-10-methyl-11-fluorocamptothecin (8) [ka] 2-Azidoethylamine hydrochloride (218.30 mg, 2.54 mmol), 7,10-dimethyl-11-fluorocamptothecin (500 mg, 1.27 mmol), and DMSO (10 mL) were added to a reaction flask, and the mixture was heated to 120-135°C with stirring and reacted for 50 minutes. After cooling to room temperature, methyl tert-butyl ether was added, filtered, and purified by silica gel chromatography to obtain the compound 7-(2-(2-azidoethyl)amino)ethyl-10-methyl-11-fluorocamptothecin (294 mg, yield 47%, HPLC 95%). 1 H NMR(600MHz,DMSO-d6)δ8.33(d,J=8.1Hz,1H),8.24(s,2H),7.90(d,J=10. 6Hz,1H),7.30(s,1H),6.55(s,1H),5.41(s,2H),5.31(s,2H),3.66(dd,J=1 2.9,4.7Hz,2H),3.54(dd,J=12.9,6.6Hz,2H),2.47(d,J=2.2Hz,2H),2.30 (s,2H),1.90-1.86(m,2H),1.20(d,J=6.7Hz,3H),0.88(s,3H);LC-MS(M+H) + 493.21 (492.19).

[0090] Example 9: 7-(2-((S)-4-hydroxybutan-2-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (9) [ka] (R)-3-aminobutanol (135.60 mg, 1.52 mmol), hydrochloric acid (0.138 mL, 1.65 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 110°C with stirring. 7,10-dimethyl-11-fluoro-camptothecin (100 mg, 0.25 mmol) was added, and the mixture was heated to 130-140°C. The mixture was allowed to react for 50 minutes with stirring, cooled, isopropanol was added, the mixture was filtered, and the mixture was purified by silica gel column chromatography to obtain the compound 7-(2-((S)-4-hydroxybutan-2-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (53.4 mg, yield 43.1%, HPLC 99%). 1 H NMR(500MHz,DMSO-d6)δ8.77(d,J=68.4Hz,1H),8.25(d,J=8.0Hz,1H),7.91(d,J=10.7 Hz,1H),7.32(s,1H),6.55(s,1H),5.40(d,J=51.6Hz,4H),3.84-3.70(m,2H),3.54-3. 50(m,2H),3.27(s,2H),3.14-3.07(m,2H),2.53(s,3H),1.87(dq,J=21.6,7.2Hz,2H), 1.64(dt,J=13.6,6.7Hz,1H),1.26(d,J=6.4Hz,3H),0.88(t,J=7.2Hz,3H);LC-MS(M+H) + 496.36 (theoretical value 495.22).

[0091] Example 10: 7-(2-hydroxyethylamino)ethyl-10,11-difluorocamptothecin (10) [ka] A single-neck flask containing anhydrous 1,2-dichloroethane (80 mL) was charged with 1 M BCl3 in dichloromethane (16 mL, 0.016 mol). The reaction flask was cooled to 0 °C, and 3,4-difluoroaniline (2.5 g, 0.019 mol) was added. The mixture was then incubated at 0 °C for 10 min. Acetonitrile (8.2 g, 0.2 mol) and aluminum trichloride (3.5 g, 0.025 mol) were added, and the mixture was slowly warmed to room temperature and stirred for 10 min. After stirring, the mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was poured into ice water, adjusted to pH 2 with 1 M aqueous HCl, extracted with dichloromethane, dried over Na2SO4, added silica gel powder, and purified by column chromatography (PE:EA = 100% to 80%) to give 6-amino-3,4-difluoroacetophenone (1.0 g, 30.2% yield, HPLC 94%). LC-MS (M+H) + 172.21 (theoretical value 171.05).

[0092] 6-Amino-3,4-difluoroacetophenone (0.50 g, 2.9 mmol) was dissolved in anhydrous toluene (5 mL), "tricyclic ketone" (769.07 mg, 2.9 mmol) and PPTS (73 mg, 0.29 mmol) were added, and the reaction mixture was heated to 115°C and stirred for 12 hours. After cooling, the solvent was removed under reduced pressure, and 5 mL of methanol was added. The mixture was filtered and dried to give 7-methyl-10,11-difluorocamptothecin (0.82 g, 70.69% yield, 96% HPLC yield). LC-MS (M+H) + 399.23 (theoretical value 398.11).

[0093] Ethanolamine (46 mg, 0.75 mmol), hydrochloric acid (0.07 mL, 0.8 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 120°C with stirring. 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added, and the mixture was reacted at 120°C to 140°C for 30 minutes. The mixture was then cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered and purified by silica gel column chromatography to obtain the product 7-(2-hydroxyethylamino)ethyl-10,11-difluorocamptothecin (31 mg, yield 525%, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ8.64(s,2H),8.39(dd,J=11.9,8.6Hz,1H),8.29(dd,J=11.3,8.1Hz,1H),7.35(s,1H),6.58(s,1H),5.46(s,2H),5.41 (s,3H),3.69(s,2H),3.58-3.49(m,2H),3.30(d,J=5.4Hz,2H),3.10(s,2H),1.88(dt,J=18.5,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 472.09 (theoretical value 471.16).

[0094] Example 11: 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-difluorocamptothecin (11) [ka] (S)-1-Methoxy-2-propylamine (100 mg, 1.02 mmol), hydrochloric acid (0.09 mL, 1.08 mmol), and DMSO (1.5 mL) were added to a reaction flask, and the mixture was heated to 120°C with stirring. 7-methyl-10,11-difluoro-camptothecin (50 mg, 0.125 mmol) was added, and the mixture was reacted at 120°C to 140°C for 35 minutes. The mixture was then cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered and purified by silica gel column chromatography to obtain the compound 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-difluoro-camptothecin (42 mg, yield 67%, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.37(dd,J=11.9,8.6Hz,1H),8.30(dd,J=11.3,8.1Hz,1H),7.36(s,1H),6.58(s,1H),5.46(s,2H),5.41( d,J=4.5Hz,2H),3.84-3.44(m,6H),3.32-3.25(m,4H),1.88(dd,J=11.6,7.3Hz,2H),1.24(d,J=6.4Hz,3H),0.88(t,J=7.2Hz,3H);LC-MS(M+H) + 500.39 (theoretical value 499.19).

[0095] Example 12: 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (12) [ka] 4-Aminocyclohexanol (87 mg, 0.75 mmol) and hydrochloric acid (0.07 mL, 0.84 mmol) were added to a reaction flask containing DMSO (1 mL), and the mixture was heated to 110°C with stirring. 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added and the mixture was reacted at 120-140°C for 40 minutes. After cooling to room temperature, isopropanol was added, and the mixture was purified by silica gel column chromatography to obtain the compound 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (33 mg, yield 50%, HPLC 97%). 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.63(s,1H),8.34(dd,J=11.6,8.9Hz,1H),8.27(dd,J=11.2,8.1Hz ,1H),7.34(s,1H),6.57(s,1H),5.46(s,2H),5.40(s,2H),3.81(s,1H),3.52-3.48(m,2H),3.29(d,J=4. 4Hz,2H),3.19-3.09(m,1H),1.89(ddq,J=21.4,14.1,7.1Hz,2H),1.73(dd,J=18.8,9.0Hz,4H),1.45(t, LC-MS(M+H) + 526.15 (theoretical value 525.21).

[0096] Example 13: 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-difluorocamptothecin (13) [ka] A reaction flask was charged with 4-aminotetrahydropyran (88 mg, 0.86 mmol), hydrochloric acid (0.072 mL, 0.86 mmol), 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol), and DMSO (1.5 mL). The mixture was heated to 135-145°C over 30 minutes with stirring, and methyl tert-butyl ether was added. The mixture was filtered and purified by silica gel column chromatography to give 7-(2(tetrahydropyran-4-yl)amino)ethyl-10,11-difluorocamptothecin (43 mg, 0.125 mmol) (43 mg, 67% yield, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ8.68(s,2H),8.32(ddd,J=19.2,11.4,8.4Hz,2H),7. 35(s,1H),6.57(s,1H),5.44(d,J=18.6Hz,4H),3.93(dd,J=11.2,3.5Hz,2H), 3.503.47(m,3H),3.31(t,J=11.6Hz,4H),1.94(d,J=11.7Hz,2H),1.87(dd,J =15.5,7.5Hz,2H),1.56(d,J=12.0Hz,2H),0.87(t,J=7.3Hz,3H);LC-MS(M+H) + 512.09 (theoretical value 511.19).

[0097] Example 14: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (14) [ka] 4-Methoxycyclohexylamine (0.12 g, 0.9 mmol), hydrochloric acid (0.075 mL, 0.9 mmol), and DMSO (1 mL) were added to a reaction flask and heated to 120°C with stirring. 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added, and the mixture was heated to 130°C, followed by reaction for 30 minutes. The mixture was cooled to room temperature, added with methanol, filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (35.2 mg, yield 55.8%, HPLC 99%). 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.32(ddd,J=21.8,11.6,8.3Hz,1H),7.36(s,1H) ),6.58(s,1H),5.44(d,J=19.1Hz,4H),3.48(s,2H),3.28(d,J=4.7Hz,2H),3.24(s,3H ),3.14-3.05(m,2H),2.07(d,J=10.5Hz,4H),1.88(dt,J=18.8,7.0Hz,2H),1.37(dd,J =23.3,11.8Hz,2H),1.16(dd,J=23.0,10.6Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 540.30 (theoretical value 539.22).

[0098] Example 15: 7-(2-(2-azidoethyl)amino)ethyl-10,11-difluorocamptothecin (15) [ka] 2-Azidoethylamine hydrochloride (80 mg, 0.93 mmol), 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol), and DMSO (1 mL) were added to a reaction flask, and the mixture was heated to 120-140°C with stirring. After reacting for 30 minutes, the mixture was cooled to room temperature, isopropanol was added, the mixture was filtered, and purified by silica gel chromatography to obtain 7-(2-(2-azidoethyl)amino)ethyl-10,11-difluorocamptothecin (39 mg, yield 63%, HPLC 94%).1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.37(dd,J=11.9,8.6Hz,1H),8.30(dd,J=11.4,8.1Hz,1H),7.36(s,1H),6.58(s,1H),5.46(s,2H),5.41(s ,2H),3.97-3.71(m,2H),3.53(d,J=4.2Hz,2H),3.37-3.26(m,2H),3.21 (s,2H),1.88(dt,J=18.5,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 497.13 (theoretical value 496.17).

[0099] Example 16: 7-(2-(2-azidoethyl)amino)ethyl-10,11-methylenedioxycamptothecin (16) [ka] 3,4-Methylenedioxy-6-aminoacetophenone (5 g, 0.028 mol) was dissolved in anhydrous toluene (10 mL), and "tricyclic ketone" (7.35 g, 0.028 mol) and PPTS (0.7 g, 0.0028 mol) were added. The reaction mixture was heated to 115°C and stirred for 12 hours. After cooling, the solvent was concentrated under reduced pressure, and 20 mL of methanol was added. The mixture was filtered and dried to give 7-methyl-10,11-methylenedioxycamptothecin (11.0 g, 97% yield). LC-MS (M+H) analysis revealed that the 7-methyl-10,11-methylenedioxycamptothecin was obtained. + 407.15 (theoretical value 406.12).

[0100] 2-Azidoethylamine hydrochloride (63.56 mg, 0.74 mmol), DMSO (1 mL), and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol) were added to a stirred reaction solution, which was heated to 110-130°C and reacted for 1 hour. Isopropanol was then added, and the solid was filtered and purified by silica gel chromatography to obtain the product 7-(2-(2-azidoethyl)amino)ethyl-10,11-methylenedioxycamptothecin (29 mg, yield 47.9%, HPLC 99%). 1H NMR(500MHz,DMSO-d6)δ8.91(s,2H),7.61(s,1H),7.48(s,1H),7.20(s,1H),6.26(d,J=2.4Hz,1H),5.39(s,1H),5.22(s ,1H),3.75-3.69(m,2H),3.18(d,J=26.4Hz,4H),2.47-2.44(m,2H),1.83(dt,J=14.3,6.9Hz,2H),0.83(t,J=7.3Hz,3H); 13 CNMR(126MHz,DMSO)δ163.00,147.31,141.50,140.63,140.00,137.65,136.58,127.48,118.93,118.93,108 .67,96.12,93.28,89.64,86.54,62.88,55.70,40.28,37.46,36.36,36.36,30.86,20.71,16.74;LC-MS(M+H) + 505.17 (theoretical value 504.18).

[0101] Example 17: 7-(2-(2-methoxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (17) [ka] 2-Methoxyethylamine (2.5 g, 0.03 mol) and hydrochloric acid (4 mL, 0.05 mol) were dissolved in DMSO (10 mL), heated to 110°C with stirring, 7-methyl-10,11-methylenedioxycamptothecin (1.8 g, 4.4 mmol) was added, and the temperature was subsequently raised to 120-130°C and reacted for 1 hour. The mixture was then cooled to room temperature, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(2-methoxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (739 mg, yield 34%, HPLC 97%). 1H NMR(500MHz,DMSO-d6)δ7.55(s,1H),7.44(s,1H),7.20(s,1H),6.51(s,1H),6.27(d,J=3.6Hz,2H),5.41(d,J=4.6Hz,2H),5.13(q,J=18.6 Hz,2H),3.31-3.18(m,7H),2.94(t,J=7.5Hz,2H),2.85(d,J=4.9Hz,2H),1.86(dt,J=19.4,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 494.12 (theoretical value 493.18).

[0102] Example 18: 7-(2-((S)-4-hydroxybutyl-2-)amino)ethyl-10,11-methylenedioxycamptothecin (18) [ka] (S)-3-aminobutanol (146.7 mg, 1.65 mmol), concentrated hydrochloric acid (0.14 mL, 1.68 mmol), DMSO (5 mL), and 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.24 mmol) were added with stirring, and the reaction mixture was heated to 110-125°C and reacted for 50 minutes. The mixture was then cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered to precipitate a solid. The resulting mixture was purified by silica gel column chromatography to obtain the compound 7-(2-((S)-4-hydroxybutyl-2-)amino)ethyl-10,11-methylenedioxycamptothecin (62 mg, 51% yield, 93% by HPLC). 1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),8.45(d,J=7.7Hz,1H),7.57(s,1H),7.46(s,1H) ),7.31(d,J=7.7Hz,2H),6.93(s,2H),6.28(s,2H),5.31(s,2H),4.03(s,2H),3.56-3 .48(m,3H),3.43(d,J=4.5Hz,3H),1.87-1.71(m,2H),1.66(dd,J=13.4,6.7Hz,1H),1 .52(dd,J=13.4,6.4Hz,1H),1.10(d,J=6.5Hz,3H),0.84(t,J=7.3Hz,3H);LC-MS(M+H) + 508.33 (theoretical value 507.20).

[0103] Example 19: 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (19) [ka] A reaction flask was charged with (S)-1-methoxy-2-propylamine (100 mg, 1.12 mmol), hydrochloric acid (0.7 mL, 0.8 mmol), DMSO (3 mL), and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol). The mixture was heated to 120°C with stirring and reacted for 50 minutes. After cooling to room temperature, methyl tert-butyl ether was added, and the mixture was filtered to precipitate a solid. The precipitate was purified by silica gel column chromatography to give the product 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (36 mg, yield 61%, HPLC 99%). 1H NMR(500MHz,DMSO-d6)δ8.64(s,2H),7.69(s,1H),7.57(s,1H),7.27(s,1H) ,6.53(s,1H),6.33(s,2H),5.44(s,1H),5.33(d,J=4.7Hz,2H),3.71-3.54(m ,2H),3.47(dd,J=10.1,5.8Hz,6H),3.25(d,J=13.6Hz,2H),1.88(dt,J=14.2 ,9.2Hz,2H),1.24(d,J=6.4Hz,3H),0.88(dd,J=9.4,5.3Hz,3H);LC-MS(M+H) + 508.37 (theoretical value 507.20).

[0104] Example 20: 7-(2-(3-oxetanyl)amino)ethyl-10,11-methylenedioxycamptothecin (20) [ka] 3-Oxetanamine (84 mg, 1.14 mmol) and hydrochloric acid (0.1 ml, 1.2 mmol) were dissolved in DMSO (2 mL), heated to 120°C with stirring, 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.24 mmol) was added, and the temperature was raised to 130°C and reacted for 50 minutes. After cooling, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(3-oxetanyl)amino)ethyl-10,11-methylenedioxycamptothecin (49 mg, yield 41.5%, HPLC 94%). 1 H NMR(500MHz,DMSO-d6)δ7.72(s,1H),7.51(s,1H),7.24(s,1H),6.48(s,1H),6.30(s,2H),5.42(s,2H),5.27(d,J=3.4Hz,2H),4.28(d,J=8.4Hz, 1H),4.13-4.00(m,1H),3.93(s,1H),3.61(d,J=11.7Hz,1H),3.553.40(m,5H),1.87(td,J=14.2,6.8Hz,2H),0.88(t,J=7.2Hz,3H);LC-MS(M+H) + 492.01 (theoretical value 491.17).

[0105] Example 21: 7-(2-(1,3-dimethoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (21) [ka] 2-Amino-1,3-dimethoxypropane (100 mg, 0.84 mmol), hydrochloric acid (0.072 mL, 0.86 mmol), 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol), and DMSO (1.5 mL) were added to a reaction flask, heated to 120°C with stirring, and reacted for 1 hour. Methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(1,3-dimethoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (35 mg, yield 54.3%, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ8.88(s,2H),7.64(s,1H),7.54(s,1H),7.24(s,1H),6.50(s,1H),6.30(s,2H),5.41(s,2H),5.27(s,2H),3.60 (dt,J=10.7,6.7Hz,5H),3.41(s,2H),3.32(s,5H),3.283.21(m,3H),1.85(dt,J=14.3,6.9Hz,2H),0.85(t,J=7.3Hz,3H);LC-MS(M+H) + 538.18 (theoretical value 537.21).

[0106] Example 22: 7-(2-(2-hydroxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (22) [ka] Ethanolamine (0.5 mL, 8.2 mmol), concentrated hydrochloric acid (0.7 mL, 8.4 mmol), DMSO (10 mL), and 7-methyl-10,11-methylenedioxycamptothecin (0.5 g, 1.2 mmol) were added to a reaction flask, and the mixture was rapidly heated to 110-120°C. The mixture was stirred for 0.5 hours, cooled to room temperature, and methyl tert-butyl ether was added. The solid was filtered and purified by silica gel column chromatography to obtain the compound 7-(2-(2-hydroxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (0.38 g, yield 66%, HPLC 97%). 1 H NMR(500MHz,DMSO-d6)δ8.70(s,2H),7.66(s,1H),7.53(s,1H),7.23(s,1H),6.50(s,1H),6.30(d,J=1.6Hz,2H),5.42(s,2H),5.27(s,2 LC-MC(M+H) + 480.05 (theoretical value 479.17).

[0107] Example 23: 7-(2-(2-trifluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (23) [ka] Trifluoroethylamine hydrochloride (100 mg, 0.74 mmol) and 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) were dissolved in DMSO (3 mL), heated to 120°C with stirring, and reacted for 1 hour. After cooling, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain the product 7-(2-(2-trifluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (49 mg, yield 38%, HPLC 99%). 1H NMR(500MHz,DMSO-d6)δ7.71(s,1H),7.54(s,1H),7.29(s,1H),6.55(s,1H),6.34(d,J=2.0Hz,2H),5.48(d,J=3.0Hz,2H) ),5.30(s,2H),3.42(s,2H),3.42(s,2H),3.29(s,2H),1.92(dd,J=14.4,7.3Hz,2H),0.94(t,J=7.3Hz,4H);LC-MS(M+H) + 518.34 (theoretical value 517.15).

[0108] Example 24: 7-(2-(2-difluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (24) [ka] Difluoroethylamine (1.0 g, 12 mmol), hydrochloric acid (1.4 mL, 16 mmol), and 7-methyl-10,11-methylenedioxycamptothecin (1.0 g, 2.46 mmol) were placed in a reaction flask and heated to 120°C with stirring to react for 1 hour. The mixture was then cooled, isopropanol was added, the mixture was filtered, and the mixture was purified by silica gel column chromatography to obtain the product 7-(2-(2-difluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (393 mg, yield 32%, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ7.68(s,1H),7.52(s,1H),7.28(s,1H),6.58(s,1H),6.33(s,2H),6.02( t,J=56.6Hz,1H),5.47(s,2H),5.26(s,2H),3.26(s,3H),2.94(s,4H),1.92(s,2H),0.93(s,3H); 13CNMR(126MHz,DMSO)δ173.06,157.32,151.28,150.60,149.74,149.35,147.57,146.86,141.32,128.53,124.98,119 .15,118.45,117.25,115.35,105.91,105.81,103.06,100.05,96.39,72.88,65.73,49.25,44.94,30.79;LC-MS(M+H) + 500.13 (theoretical value 499.16).

[0109] Example 25: 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-methylenedioxycamptothecin (25) [ka] 4-Aminotetrahydropyran (0.75 g, 7.4 mmol), concentrated hydrochloric acid (0.7 mL, 7.5 mmol), and DMSO (15 mL) were heated to 120°C in an oil bath, and 7-methyl-10,11-methylenedioxycamptothecin (0.5 g, 1.2 mmol) was added. The temperature was raised to 130-140°C and the mixture was allowed to react for 1 hour. After that, methanol was added, and the mixture was suction filtered. The filtrate was concentrated and then purified by silica gel column chromatography to give 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-methylenedioxycamptothecin as a gray solid (0.41 g, 63% yield, 96% HPLC). 1 H NMR(500MHz,DMSO-d6)δ7.59(s,1H),7.47-7.41(m,1H),7.25-7.14(m,1H),6.54(s,1H),6.27(t,J=9.9Hz,2H),5.77(s,1H),5.44(d,J=16.5Hz,2 H),5.23-5.11(m,2H),3.83(d,J=9.5Hz,2H),3.23(t,J=24.9Hz,4H),2. 93(d,J=32.7Hz,3H),1.99-1.72(m,4H),1.33(s,2H),0.96-0.81(m,3H); 13CNMR(126MHz,DMSO)δ173.04,157.26,151.30,150.58,149.68,149.42,147.49,146.73,146.68,128.52,124. 79,118.49,105.90,103.14,99.83,96.39,72.82,66.05,65.69,55.41,53.65,50.31,30.66,8.27;LC-MS(M+H) + 520.11 (theoretical value 519.20).

[0110] Example 26: 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (26) [ka] A reaction flask was charged with 4-aminocyclohexanol (107.05 mg, 0.93 mmol), concentrated hydrochloric acid (0.1 mL, 1.2 mmol), and DMSO (4 mL), and the mixture was heated to 100°C in an oil bath. 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) was added, and the mixture was heated to 140°C and reacted for 0.5 hours. Water was then added, and the solid was filtered and purified by silica gel column chromatography to obtain the product 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (33 mg, yield 28%, HPLC 91%). 1 H NMR(500MHz,DMSO-d6)δ8.47(s,1H),7.67(s,1H),7.57(s,1H),7.27(s,1H),6.33(s,2H),5.44(s,2H),5.35(s,2H),3.81(s,2H),3.25(s,2H), 3.13(d,J=4.6Hz,2H),1.87(ddd,J=21.5,12.6,5.8Hz,2H),1.72(d,J=20.0Hz,6H),1.46(d,J=10.8Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 534.08 (theoretical value 533.22).

[0111] Example 27: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (27) [ka] 4-Methoxycyclohexylamine (117.7 mg, 0.91 mmol), hydrochloric acid (0.08 mL, 0.96 mmol), DMSO (2 mL), and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol) were added, and the mixture was heated to 115-125°C with stirring. After reacting for 1 hour, the mixture was cooled, and methyl tert-butyl ether was added. The solid was filtered and purified by silica gel column chromatography to obtain the compound 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (37 mg, yield 56%, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ8.76(s,1H),7.64(s,1H),7.53(s,1H),7.24(s,1H ),6.31(d,J=3.2Hz,2H),5.43(s,2H),5.29(s,2H),3.443.36(m,2H),3.22 (dd,J=11.4,4.0Hz,5H),3.12(d,J=3.9Hz,2H),1.93-1.80(m,2H),1.39(d ,J=11.4Hz,4H),1.15(d,J=13.0Hz,4H),0.88(t,J=7.2Hz,3H);LC-MS(M+H) + 548.35 (theoretical value 547.23).

[0112] Example 28: 7-(2-((S)-hydroxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (28) [ka] (S)-2-amino-1-propanol (110.89 mg, 1.48 mmol), concentrated hydrochloric acid (0.14 mL, 1.68 mmol), DMSO (3 mL), and 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring. After reacting for 1 hour, the mixture was cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered to precipitate a solid, which was then purified by silica gel column chromatography to obtain the product 7-(2-((S)-hydroxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (84.94 mg, 69% yield, 99% HPLC). 1 H NMR(500MHz,DMSO-d6)δ8.57(s,2H),7.70(s,IH),7.57(s,1H),7.27(s,1H) ,6.53(s,1H),6.33(d,J=2.0Hz,2H),5.50(s,1H),5.44(s,2H),5.34(d,J=4 .6Hz,2H),3.70(d,J=8.5Hz,1H),3.57-3.45(m,4H),3.23(d,J=6.5Hz,2H), 1.96-177(m,2H),1.21(d,J=6.6Hz,3H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 494.08 (theoretical value 493.18).

[0113] Example 29: 7-(2-((S)-azidoisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (29) [ka] In a 100 ml three-neck flask, compound (S)-2-N-Boc aminopropanol (1 g, 0.57 mmol) was added under Ar2 protection, and dry DCM (10 ml) was added and stirred to dissolve. The reaction solution was cooled to 0 °C, and TEA (0.87 g, 0.86 mmol) was added, followed by dropwise addition of MsCl (0.78 g, 0.68 mmol). The mixture was stirred at 0 °C for 2 hours, and water (10 ml) was added to the reaction solution. The mixture was extracted with DCM, dried, and the organic phase was concentrated to give compound (S)-2-N-Boc aminopropanol methanesulfonate (1.4 g, 97.2% yield), which was used directly in the next step without further purification.

[0114] (S)-2-N-Boc aminopropanol methanesulfonate (1.4 g, 0.55 mmol) was dissolved in DMF (10 ml), NaN3 (0.36 g, 0.55 mmol) was added, and the reaction solution was stirred at 40°C overnight. Water (20 ml) was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined and washed three times with water. The organic phase was concentrated and purified by silica gel column chromatography to give 1-azido-2-(S)-N-Boc propylamine (0.8 g, yield 72%).

[0115] 1-Azido-2-(S)-N-Boc propylamine (0.8 g, 4 mmol) was dissolved in ethyl acetate (2 ml), and a 4N solution of hydrogen chloride in ethyl acetate (5 ml, 20 mmol) was added dropwise. The mixture was stirred for 2 hours and concentrated to give 1-azido-2-(S)-isopropylamine (0.5 g, 92% yield). 1 H NMR (500MHz, CDCl3) δ4.72(s,1H),3.85(s,1H),3.39(s,1H),3.32(dd,J=12.0,4.6Hz,1H),1.45(s,9H),1.27-1.04(m,3H).

[0116] The 1-azido-2-(S)-isopropylamine hydrochloride (147.8 mg, 1.08 mmol) prepared above and 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) were dissolved in DMSO (1.5 mL), heated to 115-125°C with stirring, and reacted for 1 hour. After addition of isopropanol, the mixture was filtered and purified by silica gel column chromatography to obtain the product 7-(2-((S)-azidoisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (57 mg, 44% yield, 93% HPLC). 1 H NMR(600MHz,DMSO-d6)δ7.68(s,1H),7.55(m,1H),7.26(s,1H),6.52(s,1H),6.46(s,2H),5.45(d,J=16.7Hz,2H),5.36-5.25(m,2H),4.80- 4.60(m,1H),3.85-3.8(m,z,2H)3.52-3.38(m,4H),1.86(m,J=28.9,14.5,7.3Hz,2H),1.57-1.46(m,3H),0.87(t,J=7.3Hz,3H);LC-MS(M+H) + 519.02 (theoretical value 518.19).

[0117] Example 30: 7-(2-(N-hydroxyacetyl((S)-methoxyisopropyl))amino)ethyl-10,11-methylenedioxycamptothecin (30) [ka] Glycolic acid (7 mg, 0.09 mmol) was added to DMF (1 mL), and HATU (25 mg, 0.065 mmol) and DIPEA (7.0 μL) were added successively under ice bath conditions. After stirring for 30 minutes under ice bath conditions, 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (10 mg, 0.02 mmol, Example 1 The mixture was added with 9), slowly warmed to room temperature, and stirred for 18 hours. The mixture was then reconstituted with 0.1% TFA (A) and acetonitrile (B). The results were as follows: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The product, 7-(2-(N-hydroxyacetyl((S)-methoxyisopropyl))amino)ethyl-10,11-methylenedioxycamptothecin, was obtained (6 mg, 54% yield, HPLC 95%). LC-MS (M+H) analysis revealed the following: + 566.58 (theoretical value 565.21).

[0118] Example 31: 7-(2-(N-hydroxyacetyl(2-azidoethyl))amino)ethyl-10,11-methylenedioxycamptothecin (31) [ka] Glycolic acid (7 mg, 0.09 mmol) was added to DMF (1 mL), and HATU (25 mg, 0.065 mmol) and DIPEA (7.0 μL) were added successively under ice bath conditions. After stirring for 30 minutes under ice bath conditions, 7-(2-(2-azidoethyl)amino)ethyl-10,11-methylenedioxycamptothecin (10 mg, 0.02 mmol, Example 16) was added. The mixture was slowly warmed to room temperature, stirred for 18 hours, and then reconstituted with 0.1% TFA (A) and acetonitrile (B). The results were as follows: 0–4 min: A: 90%–75%, B: 10%–25%; 4–25 min: A: 75%–60%, B: 25%–40%; 25–35 min: A: 60%–50%, B: 40%–50%; 35–60 min: A: 50%–10%, B: 50%–90%. The product, 7-(2-(N-hydroxyacetyl(2-azidoethyl))amino)ethyl-10,11-methylenedioxycamptothecin, was obtained (6 mg, 58% yield, HPLC 95%). LC-MS (M+H) = 563.54 (theoretical value 562.18). 1 H NMR(500MHz,DMSO-d6)δ7.67(s,1H),7.55(s,1H),7.25(s,1H),6.51(s,1H),6.32(s,2H),5.43(s,2H),5.30(s,2H),3.91(s,2H),3.793.68(m,2H) ),3.26(s,2H),3.20(s,2H),2.62(d,J=4.6Hz,1H),2.54(d,J=7.6Hz,1H),1.86(ddd,J=21.5,14.2,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 563.54 (theoretical value 562.18).

[0119] Example 32: 7-(2-(N-hydroxyacetyl(2-methoxyethyl))amino)ethyl-10,11-methylenedioxycamptothecin (32) [ka] Glycolic acid (7 mg, 0.09 mmol) was added to DMF (1 mL), and HATU (25 mg, 0.065 mmol) and DIPEA (7.0 μL) were added successively under ice bath conditions. After stirring for 30 minutes under ice bath conditions, 7-(2-(2-methoxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (10 mg, 0.02 mmol, Example 17) was added. The mixture was slowly warmed to room temperature, stirred for 18 hours, and then reconstituted with 0.1% TFA (A) and acetonitrile (B). The results were as follows: 0–4 min: A: 90%–75%, B: 10%–25%; 4–25 min: A: 75%–60%, B: 25%–40%; 25–35 min: A: 60%–50%, B: 40%–50%; 35–60 min: A: 50%–10%, B: 50%–90%. The product, 7-(2-(N-hydroxyacetyl(2-methoxyethyl))amino)ethyl-10,11-methylenedioxycamptothecin, was obtained (6 mg, 60% yield, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.48(s,1H),7.22-7.16(m,1H),6.29(d,J=2.8Hz,2H),5.42(s,2H), 5.24(s,3H),3.56-3.45(m,8H),3.37-3.21(m,5H),1.99-1.77(m,2H),0.88(t,J=7.2Hz,3H);LC-MS(M+H) + 552.55 (theoretical value 551.19).

[0120] Example 33: 7-(2-(N-hydroxyacetyl(2-difluoroethyl))amino)ethyl-10,11-methylenedioxycamptothecin (33) [ka] Glycolic acid (7 mg, 0.09 mmol) was added to DMF (1 mL), and HATU (23 mg, 0.06 mmol) and DIPEA (7.0 μL) were added successively under ice bath conditions. After stirring for 30 minutes under ice bath conditions, 7-(2-(2-difluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (10 mg, 0.019 mmol, Example 24) was added. The mixture was slowly warmed to room temperature and stirred for 18 hours. The resulting mixture was then diluted with 0.1% TFA (A) and acetonitrile (B). From 0 to 4 min, A: 90% to 75%, B: 10% to 25%; from 4 to 25 min, A: 75% to 60%, B: 25% to 40%; from 25 to 35 min, A: 60% to 50%, B: 40% to 50%; from 35 to 60 min, A: 50% to 10%, B: 50% to 90%. The compound 7-(2-(N-hydroxyacetyl(2-difluoroethyl))amino)ethyl-10,11-methylenedioxycamptothecin was obtained (6 mg, 54% yield, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.51(d,J=5.2Hz,1H),7.24(d,J=3.2Hz,1H),6.30(s,2H),5.42(s,2H),5.30(d,J=6.1Hz,2H),4.16(d,J=31.8 Hz,2H),3.92(t,J=12.6Hz,2H),3.66-3.54(m,2H),3.44(s,1H),3.38-3.2 4(m,2H),1.87(dt,J=14.2,6.9Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 557.55 (theoretical value 557.16).

[0121] Example 34: 7-(2-(N—(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (34) [ka] (R)-3-aminotetrahydrofuran (64.31 mg, 0.738 mmol), concentrated hydrochloric acid (0.05 mL, 0.6 mmol), DMSO (1.5 mL), and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring and reacted for 1 hour. The mixture was then cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered to precipitate a solid, which was then purified by silica gel column chromatography to give the product 7-(2-(N-(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (16.2 mg, 32.3% yield, 96.2% by HPLC). 1 H NMR(500MHz,DMSO-d6)δ7.61(s,1H),7.47(s,1H),7.22(s,1H),6.50(s,1H),6.28(s,2H),5.42(s,2H),5.21(s,2H),4.21-3.53(m,4H),3. 21(t,J=7.6Hz,2H),2.84(q,J=8.7,8.1Hz,2H),1.90(ddt,J=31.9,16.2,7.1Hz,3H),1.63(dd,J=12.3,6.1Hz,1H),0.88(t,J=7.3Hz,3H); 13 CNMR(126MHz,DMSO)δ173.0,157.3,151.3,150.6,149.7,149.4,147.5,146.8,141.2,128.6,124.9,118. 4,105.9,103.1,99.9,96.4,72.9,66.9,65.7,58.4,55.4,50.4,47.6,32.6,30.7,30.6,8.3;LC-MS(M+H) + 506.34 (theoretical value 505.18).

[0122] Example 35: 7-(2-(N-(S)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (35) [ka] (S)-3-aminotetrahydrofuran (64.31 mg, 0.738 mmol), concentrated hydrochloric acid (0.05 mL, 0.6 mmol), DMSO (1.5 mL), and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring and reacted for 1 hour. After cooling to room temperature, methyl tert-butyl ether was added, and the mixture was filtered to precipitate a solid. The precipitate was purified by silica gel column chromatography to obtain the product 7-(2-(N-(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (18 mg, 33% yield, 95.9% HPLC). 1 H NMR(500MHz,DMSO-d6)δ7.61(d,J=3.4Hz,1H),7.47(d,J=3.9Hz,1H),7.22(d,J =4.2Hz,1H),6.50(s,1H),6.29(d,J=4.0Hz,2H),5.42(d,J=4.0Hz,2H),5.21(d ,J=3.2Hz,2H),3.87-3.58(m,4H),3.21(s,2H),2.85(td,J=11.2,10.7,5.8Hz, 2H),1.90(ddt,J=29.9,10.7,6.2Hz,3H),1.68-1.60(m,1H),1.08-0.76(m,3H); 13 CNMR(126MHz,DMSO)δ173.0,157.3,151.3,150.6,149.7,149.4,147.6,146.9,141.2,128.6,124.9,118. 5,105.9,103.1,100.0,96.4,72.9,72.7,66.9,65.7,58.4,50.4,47.6,32.6,30.7,30.6,8.2;LC-MS(M+H) + 506.31 (theoretical value 505.18).

[0123] Example 36: 7-(2-difluoroacetylamino)ethyl-10,11-methylenedioxycamptothecin (36) [ka] 160 mg of ammonium chloride and 6 drops of hydrochloric acid were added to 9 mL of DMSO, and the reaction mixture was heated to 120 °C in an oil bath. 200 mg of 7-methyl-10,11-methylenedioxycamptothecin (0.49 mmol) was added, and the temperature was raised to 130 °C for 1 hour. The mixture was then cooled to room temperature, slurried with methanol, and filtered under vacuum. After removing part of the DMSO by concentration, the mixture was reconstituted with 0.1% TFA (A) and acetonitrile (B). The following mixtures were prepared: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; and 35-60 min: A: 50%-10%, B: 50%-90%. The product 7-aminoethyl-10,11-methylenedioxycamptothecin was obtained (99 mg, 46% yield, HPLC 96%). 1 H NMR(500MHz,DMSO-d6)δ7.99(s,2H),7.70(s,1H),7.59(s,1H),7.30(s,1H),6.37(s,2H),5.49(s,2H) ),5.32(s,2H),3.67-3.49(m,2H),3.18(s,2H),1.93(dd,J=10.5,7.3Hz,2H),0.94(t,J=7.3Hz,3H); 13 CNMR(126MHz,DMSO)δ173.01,157.29,151.46,150.63,150.01,149.76,147.65,146.66,137.76,129.10,1 24.77,118.63,106.14,103.25,99.61,96.48,72.88,65.69,50.31,38.50,30.70,27.97,8.23;LC-MS(M+H) + 436.41 (theoretical value 435.14).

[0124] 7-Aminoethyl-10,11-methylenedioxycamptothecin (20 mg, 0.046 mmol) was added to a reaction flask, followed by DMF (5 mL), difluoroacetic acid (8.8 mg, 0.092 mmol), followed by HATU (35 mg, 0.092 mmol), DIPEA (12 mg, 0.092 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched by dropwise addition of 0.5 mL of ethanol. The reaction mixture was adjusted to 0.1% TFA (A) and acetonitrile (B). The reaction mixture was: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The desired product, 7-(2-difluoroacetylamino)ethyl-10,11-methylenedioxycamptothecin, was obtained (14.6 mg, 62% yield, 98% HPLC). 1 H NMR(500MHz,DMSO-d6)δ9.00(s,1H),7.67(s,1H),7.51(s,1H),7.24(s,1H),6.30(s,2H),5.43(s,2H) ,5.24(s,2H),3.51(dd,J=13.6,6.8Hz,2H),3.31-3.23(m,2H),2.07-1.75(m,2H),0.90-0.80(m,3H); 13 CNMR(126MHz,DMSO)δ173.02,157.30,151.39,150.61,149.83,149.55,147.63,146.77,139.56,128.71,125.06,1 18.54,109.02,106.04,103.14,99.81,96.42,72.88,65.71,53.93,50.23,42.21,38.28,30.67,13.04;LC-MS(M+H) + 514.25 (theoretical value 513.13).

[0125] Example 37: 7-(2-azidoacetylamino)ethyl-10,11-methylenedioxycamptothecin (37) [ka] 7-Aminoethyl-10,11-methylenedioxycamptothecin (15 mg, 0.035 mmol) was added to a reaction flask, followed by DMF (5 mL), azidoacetic acid (7.2 mg, 0.071 mmol), followed by HATU (35 mg, 0.092 mmol), DIPEA (12 mg, 0.092 mmol), and the mixture was allowed to react at room temperature for 1 hour to give a 0.5 The reaction was quenched by adding 1 ml of water dropwise, and the reaction mixture was adjusted to 0.1% TFA (A) and acetonitrile (B). The reaction mixture was: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The desired product, 7-(2-azidoacetylamino)ethyl-10,11-methylenedioxycamptothecin (13.1 mg, 71% yield, 95% HPLC analysis). 1 H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.69(s,1H),7.51(s,1H),7.23(s,1H),6.49(s,1H),6.30(s,2H),5.42(s,2H),5.24 (s,2H),3.80(s,2H),3.46(d,J=6.3Hz,2H),3.25(s,2H),1.86(dt,J=18.9,6.9Hz,2H),0.87(d,J=7.3Hz,3H);LC-MS(M+H) + 519.29 (theoretical value 518.15).

[0126] Example 38: 7-(2-methanesulfonylamino)ethyl-10,11-methylenedioxycamptothecin (38) [ka] Add 7-aminoethyl-10,11-methylenedioxycamptothecin (15 mg, 0.034 mmol) to a reaction flask, add DMF (5 mL), add methanesulfonyl chloride (5 mg, 0.043 mmol), and then add DIPEA (47.5 mg, 0.368 mmol). Allow to react at room temperature for 1 hour. Quench the reaction by adding water (0.5 mL) dropwise. Prepare the reaction solution with 0.1% TFA (A) and acetonitrile (B). 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; 35-60 min: A: 50%-10%, B: 50%-90%. The product, 7-(2-methanesulfonylamino)ethyl-10,11-methylenedioxycamptothecin, was obtained (14.2 mg, 80% yield, HPLC 96%). 1 H NMR(500MHz,DMSO-d6)δ7.56(s,1H),7.48(s,1H),7.21(d,J=8.4Hz,2H),6.28(d,J=2.1Hz,3H),5.42(d,J=3.1H) z,2H),5.19(s,2H),3.27(s,4H),2.84(s,3H),1.87(dt,J=14.5,7.0Hz,2H),0.89(t,J=7.3Hz,3H);LC-MS(M+H) + 514.25 (theoretical value 513.12).

[0127] Example 39: 7-(2-cyclopropylsulfonylamino)ethyl-10,11-methylenedioxycamptothecin (39) [ka] Add 7-aminoethyl-10,11-methylenedioxycamptothecin (20 mg, 0.046 mmol) to a reaction flask, add DMF (5 mL), add cyclopropylsulfonyl chloride (12.9 mg, 0.092 mmol), followed by DIPEA (47.5 mg, 0.368 mmol), and react at room temperature for 1 h. Quench the reaction by adding 0.5 mL of water dropwise. Prepare the reaction solution in 0.1% TFA (A) and acetonitrile (B). 0–4 min: A: 90%–75%, B: 10%–25%; 4–25 min: A: 75%–60%, B: 25%–40%; 25–35 min: A: 60%–50%, B: 40%–50%; 35–60 min: A: 50%–10%, B: 50%–90%. The product, 7-(2-cyclopropylsulfonylamino)ethyl-10,11-methylenedioxycamptothecin, was obtained (19.4 mg, 78% yield, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ7.60(s,IH),7.50(s,IH),7.28(s,IH),7.23(s,IH),6.49(s,IH),6.29(s,2H),5.42(s,2H),5.25(s,2H), 3.35(s,2H),3.29-3.20(m,2H),1.87(td,J=I4.2,7.0Hz,2H),1.24(ddd,J=20.4,13.3,6.6Hz,2H),0.94-0.79(m,6H);LC-MS(M+H) + 540.26 (theoretical value 539.14).

[0128] Example 40: 7-(2-(pyrazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (40) [ka] 1H-3-Pyrazolemethanamine (71.69 mg, 0.74 mmol) and hydrochloric acid (72 μL) were added to DMSO (1.5 mL), and the reaction mixture was heated to 110 °C in an oil bath. 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, and the mixture was heated to 135 °C for 1 h. After cooling, the mixture was slurried with methanol and filtered under suction. The mixture was then adjusted with 0.1% TFA (A) and acetonitrile (B). The following solutions were prepared: 0-4 min: A: 90%-75%, B: 10%-25%; 4-25 min: A: 75%-60%, B: 25%-40%; 25-35 min: A: 60%-50%, B: 40%-50%; and 35-60 min: A: 50%-10%, B: 50%-90%. The desired product, 7-(2-(pyrazole-5-amino))ethyl-10,11-methylenedioxycamptothecin, was obtained (20.8 mg, yield 33.6%, HPLC 98%). LC-MS (M+H) + 516.35 (theoretical value 515.18).

[0129] Example 41: 7-(2-(1,2,4-triazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (41) [ka] 1H-1,2,4-Triazole-3-amine (62.07 mg, 0.74 mmol) and hydrochloric acid (72 µL) were added to DMSO (1.5 mL) and heated to 120 °C with stirring. 7-Methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, and the mixture was heated to 140 °C for 1 h. After cooling to room temperature, methanol was added, and the mixture was filtered with suction, concentrated, and reconstituted with 0.1% TFA (A and acetonitrile (B)). The mixture was diluted with acetonitrile (B) and reconstituted with 0.1% TFA (A and acetonitrile (B)). The following reaction mixtures were prepared: 0–4 min: A: 90%–75%, B: 10%–25%; 4–25 min: A: 75%–60%, B: 25%–40%; 25–35 min: A: 60%–50%, B: 40%–50%; and 35–60 min: A: 50%–10%, B: 50%–90%. The desired product, 7-(2-(1,2,4-triazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (31.4 mg, yield 52%, HPLC 96%), was obtained. LC-MS (M+H) + 503.30 (theoretical value 502.16).

[0130] Example 42: 7-(2-(2-methoxyethyl)amino)ethyl-10,11-ethylenedioxycamptothecin (42) [ka] A 1M solution of BCl3 in methylene chloride (32 mL, 32 mmol dissolved in methylene chloride) was added to a single-neck flask containing anhydrous 1,2-dichloroethane (160 mL). The reaction flask was cooled to 0 °C, and 3,4-ethylenedioxyaniline (5 g, 33.08 mmol) was added. The reaction was allowed to proceed at 0 °C for 10 min. Acetonitrile (16.40 g, 409.54 mmol) and aluminum trichloride (7 g, 52.5 mmol) were added. The mixture was slowly warmed to room temperature and stirred for 10 min. After that, the mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was poured into ice water, adjusted to pH 2 with 1M HCl solution, extracted with dichloromethane, dried over Na2SO4, and purified by silica gel column chromatography to give 6-amino-3,4-ethylenedioxyacetophenone (2 g, 31.3% yield, 95% HPLC). LC-MS (M+H) analysis revealed that the 6-amino-3,4-ethylenedioxyacetophenone was obtained. + 194.17 (theoretical value 193.07).

[0131] 6-Amino-3,4-ethylenedioxyacetophenone (0.5 g, 0.26 mmol) was dissolved in anhydrous toluene (30 mL), and "tricyclic ketone" (0.68 g, 0.26 mmol) and PPTS (0.065 g, 0.026 mmol) were added with stirring. The reaction mixture was heated to 115°C, stirred for 12 hours, cooled, and the solvent was concentrated under reduced pressure. 5 mL of methanol was added, filtered, and the filter cake was dried to give 7-methyl-10,11-ethylenedioxycamptothecin (1.0 g, 91% yield, HPLC 95%). 1 H NMR(500MHz,DMSO-d6)δ7.55(d,J=19.7Hz,2H),7.25(s,1H),6.48(s,1H),5.42(s, 2H),5.19(s,2H),4.44(s,4H),2.66(s,3H),1.86(s,2H),0.88(s,3H);LC-MS(M+H) + 421.15 (theoretical value 420.13).

[0132] 2-Methoxyethylamine (33 mg, 0.44 mmol), hydrochloric acid (0.035 mL, 0.42 mmol), DMSO (1 mL), and 7-methyl-10,11-ethylenedioxycamptothecin (25 mg, 0.06 mmol) were heated to 120-130°C with stirring and reacted for 30 minutes. After cooling to room temperature, isopropanol was added, the mixture was filtered, and purified by silica gel column chromatography to obtain the product 7-(2-(2-methoxyethyl)amino)ethyl-10,11-ethylenedioxycamptothecin (17 mg, yield 55.7%, HPLC 97%). 1 H NMR(500MHz,DMSO-d6)δ8.68(s,2H),7.73(s,1H),7.60(s,1H),7.26(s,1H),6.52(s,1H),5.44(s,2H),5.31(s,2H),4 .46(s,4H),3.67-3.55(m,2H),3.43(s,3H),3.27-3.15(m,5H),1.97-1.77(m,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 508.18 (theoretical value 507.20).

[0133] Example 43: 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-ethylenedioxycamptothecin (43) [ka] 4-Aminotetrahydropyran (72 mg, 0.71 mmol) and hydrochloric acid (0.06 mL, 0.72 mmol) were added to DMSO (1.5 mL), and the mixture was heated to 120°C with stirring. 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, and the mixture was heated to 130°C and reacted for 30 minutes. After cooling to room temperature, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to give the compound 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-ethylenedioxycamptothecin (37 mg, 57.8% yield, 95% HPLC). LC-MS (M+H) + 534.19 (theoretical value 533.22).

[0134] Example 44: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-ethylenedioxycamptothecin (44) [ka] 4-Methoxycyclohexylamine (52 mg, 0.45 mmol), hydrochloric acid (0.035 mL, 0.42 mmol), DMSO (1.5 mL), and 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) were added to a reaction flask, and the mixture was heated to 120-130°C with stirring and reacted for 45 minutes. After that, isopropanol was added, the mixture was filtered, and purified by silica gel column chromatography to obtain the compound 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-ethylenedioxycamptothecin (34 mg, yield 50.5%, HPLC 97%). 1H NMR(500MHz,DMSO-d6)δ8.56(s,2H),7.69(s,1H),7.60(s,1H),7.28(s,1H), 5.44(s,2H),5.32(s,2H),4.46(s,4H),3.31(s,2H),3.24(s,5H),3.12(d,J= 10.1Hz,2H),2.06(d,J=10.3Hz,4H),1.96-1.81(m,2H),1.37(dd,J=23.1,11 .7Hz,2H),1.16(dd,J=22.9,10.6Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H) + 562.24 (theoretical value 561.25).

[0135] Example 45: 7-(2-((S)-methoxyisopropyl)amino)ethyl-10,11-ethylenedioxycamptothecin (45) [ka] (S)-1-Methoxy-2-propylamine (47.5 mg, 0.53 mmol) and hydrochloric acid (0.04 mL, 0.48 mmol) were added to a reaction flask containing DMSO (1 mL), and the mixture was heated to 110°C with stirring. 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, and the mixture was heated to 130°C and reacted for 30 minutes. After cooling to room temperature, isopropanol was added, the mixture was filtered, and purified by silica gel column chromatography to obtain the product 7-(2-((S)-methoxyisopropyl)amino)ethyl-10,11-ethylenedioxycamptothecin (34.6 mg, yield 55.3%, HPLC 98%). 1 H NMR(500MHz,DMSO-d6)δ8.64(s,1H),7.70(s,1H),7.58(s,1H),7.25(s,1H),5.41(s,1H),5.29(d,J=4.7Hz,1H),4.44(s,4H),3.59-3.54( LC-MS(M+H)+ 522.16 (theoretical value 521.22).

[0136] Example 46: Inhibition of tumor cell proliferation activity Human esophageal cancer cells OE33 (human breast cancer cells SK-BR-3 or human gastric cancer cells NCI-N87) were cultured in RPMI1640 (Cellmax) containing 10% fetal bovine serum. Exponentially growing tumor cells were cultured at 1 × 10 5 The 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 a 96-well cell culture plate. Three replicate wells were set up for each concentration. 2 μL of the diluted compound was added to each well for negative and blank controls. After sample addition, the plate was returned to the incubator at 37°C and 5% CO2 for 72 hours. After incubation, the plate was removed, the medium was aspirated, and 100 μL of medium containing 10% CCK-8 was added to each well. The plate was then incubated at 37°C for 3 hours. After incubation, the culture plate was removed and placed on the enzyme plate in a dark place, and the absorbance was measured using a reference wavelength of 630 nm and a measurement wavelength of 450 nm. 50 Values ​​were calculated from absorbance values ​​using a four-parameter regression in GraphPad (Table 2). [Table 2-1] [Table 2-2]

[0137] The above is merely an embodiment of the present invention, and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof. 【Chemical 1】 (where R １ and R ２ each independently represents a halogen, a hydroxyl group, an alkyl group, or an alkoxy group, or R １ and R ２ together constitute a methylenedioxy bridge or an ethylenedioxy bridge, R ３ and R ４ each independently represents a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a sulfonyl group, or R ３ , R ４ together with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl group, wherein said alkyl, alkoxy, cycloalkyl, alkylacyl, sulfonyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with R; R is selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl, azide, or 5- to 7-membered heteroaryl.

2. R １ and R ２ are each independently a halogen, a hydroxy group, or C １ ~C ６ Alkyl group, C １ ~C ６ represents an alkoxy group, or R １ and R ２ together constitute a methylenedioxy bridge or an ethylenedioxy bridge, Preferably, R １ and R ２ each independently represents a halogen or a methyl group, or R １ and R ２ together constitute a methylenedioxy bridge or an ethylenedioxy bridge, Preferably, R １ and R ２ each independently represents a methyl group, F, Cl, Br, or I, or R １ and R ２ together constitute a methylenedioxy bridge or an ethylenedioxy bridge, Preferably, R １ and R ２ are each independently a methyl group, F, or R １ and R ２ and R 1 and R 2 together form a methylenedioxy bridge or an ethylenedioxy bridge, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

3. R ３ and R ４ are each independently hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, a 5- to 12-membered aryl group, a 5- to 12-membered heteroaryl group, C １ ~C ６ Alkyl-acyl group, C １ ~C ６ Alkyl-sulfonyl group, C ３ ~C ６ represents a cycloalkyl-sulfonyl group, or R ３ , R ４ together with the nitrogen atom to which they are bonded form a 4- to 8-membered heterocycloalkyl group, １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group, a 5- to 12-membered aryl group, a 5- to 12-membered heteroaryl group, C １ ~C ６ Alkyl-acyl group, C １ ~C ６ Alkyl-sulfonyl group, C ３ ~C ６ The cycloalkyl-sulfonyl group is optionally substituted with R, Preferably, R ３ and R ４ are each independently C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, 5- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C １ ~C ３ Alkyl-acyl group, C １ ~C ３ Alkyl-sulfonyl group, C ３ ~C ６ represents a cycloalkyl-sulfonyl group, or R ３ , R ４ together with the nitrogen atom to which they are linked form a 5- to 6-membered heterocycloalkyl group, １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, 5- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C １ ~C ３ Alkyl-acyl group, C １ ~C ３ Alkyl-sulfonyl group, C ３ ~C ６ The cycloalkyl-sulfonyl group is optionally substituted with R, Preferably, R ３ and R ４ are each independently C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, 5- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C １ ~C ３ Alkyl-acyl group, C １ ~C ３ Alkyl-sulfonyl group, C ３ ~C ６ represents a cycloalkyl-sulfonyl group, or R ３ , R ４ together with the nitrogen atom to which they are linked form a 5- to 6-membered heterocycloalkyl group, １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, 5- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C １ ~C ３ Alkyl-acyl group, C １ ~C ３ Alkyl-sulfonyl group, C ３ ~C ６ The cycloalkyl-sulfonyl group is optionally substituted with R or R ３ , R ４ together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl and heteroaryl groups contain 1 to 3 heteroatoms independently selected from N and O; Preferably, R ａ and R ｂ are each independently selected from the following groups: 【Chemistry 2】 Or, R ３ , R ４ together with the nitrogen atom to which they are attached form pyrrolidine, piperidine, piperazine, Preferably, the -NR ３ R ４ are each independently or together of the following structure: 【Chemistry 3】 More preferably, R ３ , R ４ together with the nitrogen atoms connected to them 【Chemistry 4】 Forming 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

4. R is a halogen, a hydroxyl group, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ selected from a cycloalkyl group or an azide; Preferably, R is selected from F, Cl, Br, I, a hydroxy group, a methyl group, a methoxy group, a cyclopropyl group or an azide; Preferably, R is selected from F, a hydroxy group, a methyl group, a methoxy group, a cyclopropyl group, or an azide, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

5. The R １ , R ２ and R 1 and R 2 are independently or together represented by the following structure: 【Chemistry 5】

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

7. A method for preparing a compound according to any one of claims 1 to 6, said method comprising: (1) reacting a 3,4-substituted aniline with a halopropionitrile to obtain a 3',4'-disubstituted-3-halo-6'-aminopropiophenone; (2) displacing the 3',4'-disubstituted-3-halo-6'-aminopropiophenone with an amine to obtain a 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone; (3) condensing 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative; or (1) reacting a 3',4'-disubstituted-3-halopropiophenone with nitric acid to obtain a 6'-nitro-3',4'-disubstituted-3-halopropiophenone; Step (2) of subjecting 6'-nitro-3',4'-disubstituted-3-halopropiophenone to a substitution reaction with an amine to obtain 6'-nitro-3',4'-disubstituted-3-alkylaminopropiophenone; (3) reducing the 6'-nitro-3',4'-disubstituted-3-alkylaminopropiophenone to obtain a 6'-amino-3',4'-disubstituted-3-alkylaminopropiophenone; (4) condensing 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative; or Step (1) of subjecting 3',4'-disubstituted acetophenone to a nitro reaction to obtain 6'-nitro-3',4'-disubstituted acetophenone; (2) condensing the 6'-nitro-3',4'-disubstituted acetophenone with formaldehyde and acidifying to give the 6'-nitro-3',4'-disubstituted acrylophenone; Step (3) of subjecting 6'-nitro-3',4'-disubstituted acrylophenone to a Michael addition reaction with an amine to obtain 6'-nitro-3',4'-disubstituted phenylacetone-3-amine; (4) reducing the 6'-nitro-3',4'-disubstituted phenylacetone-3-amine to obtain 6'-amino-3',4'-disubstituted phenylacetone-3-amine; and step (5) condensation of 6'-amino-3',4'-disubstituted phenylaceton-3-amine with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain camptothecin-7-ethylamine derivative; or (1) condensing a substituted 2-acetylaniline with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranone-[3,4-f]indolizine-3,6,10(4H)-trione to give 7-methylcamptothecin; and (2) reacting 7-methylcamptothecin with an amine in DMSO for a Mannic time to obtain a camptothecin-7-ethylamine derivative.

8. An antibody-drug conjugate, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as a low molecular weight drug.

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, and a pharmaceutically acceptable adjuvant.

10. Use of 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 in the preparation of a medicament for treating a tumor disease, Preferably, the tumor diseases include gastric cancer, esophageal cancer, cardia cancer, breast cancer, ovarian cancer, colorectal cancer, primary liver cancer, acute and chronic granulocytic leukemia, chorioepithelial carcinoma, lung cancer, bladder cancer, intestinal cancer, and small cell lung cancer, more preferably, the tumor diseases are esophageal cancer, breast cancer, and gastric cancer.

11. 10. A method for treating a tumor, comprising the step of 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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