Camptothecin-7-ethylamine derivatives and their preparation methods and applications

Abstract

The present invention provides a camptothecin-7-ethylamine derivative or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, as well as a preparation method and application thereof. The camptothecin-7-ethylamine derivative has a structure shown in formula (I).

Description

Technical Field

[0001] The present invention relates to the field of medicine and specifically provides a series of preparation methods of camptothecin-7-ethylamine derivatives and their application in the treatment of tumors. Background Art

[0002] Camptothecin is a natural product extracted from the Chinese plant Camptotheca acuminata. It inhibits topoisomerase Top1, particularly the Top1-DNA complex. Camptothecin has significant therapeutic effects on gastric, esophageal, lung, and bladder cancers, making it a broad-spectrum anti-tumor drug. Irinotecan and Topotecan have been approved in many countries for the treatment of various cancers. Belotecan, another camptothecin derivative, has been approved in South Korea for the treatment of SCLC and ovarian cancer. The main drawbacks of camptothecin anti-tumor drugs are their toxicity, poor solubility, and the development of drug resistance in tumor cells.

[0003] The present invention provides a series of camptothecin-7-ethylamine derivatives, which are characterized by improved solubility and enhanced anti-tumor activity and have potential application value in the treatment of tumors. 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 preparation methods and applications thereof in the anti-tumor field.

[0005] In one aspect of the present invention, there is provided a compound represented by Formula 1 or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,

[0006]

[0007] wherein R1 and R2 each independently represent a halogen, a hydroxyl group, an alkyl group, an alkoxy group, or R1 and R2 together form a methylenedioxy bridge or an ethyldioxy bridge;

[0008] R3 and R4 each independently represent hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl, or R3, R4 and the nitrogen atom to which they are attached together form a heterocycloalkyl or heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, alkylacyl, sulfonyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by R,

[0009] R is selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl, azide or 5- to 7-membered heteroaryl.

[0010] In one embodiment, R1 and R2 each independently represent halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or R1 and R2 together form a methylenedioxy bridge or an ethyldioxy bridge.

[0011] In one embodiment, R1 and R2 each independently represent halogen or methyl.

[0012] In one embodiment, R1 and R2 each independently represent methyl, F, Cl, Br, or I.

[0013] In one embodiment, R1 and R2 each independently represent methyl, F.

[0014] In one embodiment, R1 and R2 together form a methylenedioxy bridge or an ethyldioxy bridge.

[0015] In one embodiment, R3 and R4 each independently represent hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 5 to 12 membered aryl, 5 to 12 membered heteroaryl, C1-C6 alkyl-acyl, C1-C6 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl, or R3, R4 and the nitrogen atom to which they are attached together form a 4 to 8 membered heterocycloalkyl, and the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 5 to 12 membered aryl, 5 to 12 membered heteroaryl, C1-C6 alkyl-acyl, C1-C6 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl group is optionally substituted by R.

[0016] In one embodiment, R3 and R4 each independently represent C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C3 alkyl-acyl, C1-C3 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl, or R3, R4 and the nitrogen atom to which they are attached together form a 5- to 6-membered heterocycloalkyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C3 alkyl-acyl, C1-C3 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl are optionally substituted by R.

[0017] In one embodiment, R3 and R4 each independently represent C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C3 alkyl-acyl, C1-C3 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl, or R3, R4 and the nitrogen atom to which they are attached together form a 5- to 6-membered heterocycloalkyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C3 alkyl-acyl, C1-C3 alkyl-sulfonyl, C3-C6 cycloalkyl-sulfonyl are optionally substituted by R, or R3, R4 and the nitrogen atom to which they are attached together form a 5- to 6-membered heterocycloalkyl, and the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms independently selected from N and O.

[0018] In one embodiment, R is selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or azide.

[0019] In one embodiment, R is selected from F, Cl, Br, I, hydroxy, methyl, methoxy, cyclopropyl, or azide.

[0020] In one embodiment, R is selected from F, hydroxy, methyl, methoxy, cyclopropyl, or azide.

[0021] In one embodiment, R3 and R4 are each independently selected from the following groups:

[0022]

[0023] In one embodiment, R3, R4 and the nitrogen atom to which they are attached together form pyrrolidine, piperidine or piperazine.

[0024] In one embodiment, R3, R4 and the nitrogen atom to which they are attached together form

[0025] In one embodiment, R1 and R2 are each independently or collectively the following structures:

[0026]

[0027] In one embodiment, the -NR3R4 are each independently or collectively the following structures:

[0028]

[0029] The present invention provides the following compounds or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof:

[0030]

[0031]

[0032]

[0033] Another aspect of the present invention provides a method for preparing any of the above compounds, the method comprising steps selected from any one of the following collectively referred to routes:

[0034] Synthesis route 1, which includes the following steps:

[0035] (1) reacting 3,4-substituted aniline with halogenated propionitrile to obtain 3',4'-disubstituted-3-halogenated-6'-aminopropiophenone;

[0036] (2) substituting 3',4'-disubstituted-3-halogenated-6'-aminopropiophenone with an amine to obtain 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone;

[0037] (3) 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrone-[3,4-f]indolizine-3,6,10(4H)-trione are condensed to obtain a camptothecin-7-ethylamine derivative.

[0038] Synthesis route 2, which includes the following steps:

[0039] (1) reacting 3',4'-disubstituted-3-halogenated propiophenone with nitric acid to obtain 6'-nitro-3',4'-disubstituted-3-halogenated propiophenone;

[0040] (2) subjecting 6'-nitro-3',4'-disubstituted-3-halogenated propiophenone to a substitution reaction with an amine to obtain 6'-nitro-3',4'-disubstituted-3-alkylamino-propiophenone;

[0041] (3) Reducing 6'-nitro-3',4'-disubstituted-3-alkylamino-propiophenone to obtain 6'-amino-3',4'-disubstituted-3-alkylamino-propiophenone:

[0042] (4) 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrone-[3,4-f]indolizine-3,6,10(4H)-trione are condensed to obtain a camptothecin-7-ethylamine derivative.

[0043] Synthesis route 3, which includes the following steps:

[0044] (1) nitrating the 3',4'-disubstituted acetophenone to obtain 6'-nitro-3',4'-disubstituted acetophenone;

[0045] (2) condensing 6'-nitro-3',4'-disubstituted acetophenone with formaldehyde and acidifying to obtain 6'-nitro-3',4'-disubstituted phenyl ketone;

[0046] (3) subjecting 6'-nitro-3',4'-disubstituted propiophenone to a Michael addition reaction with an amine to obtain 6'-nitro-3',4'-disubstituted propiophenone-3-amine;

[0047] (4) reducing 6'-nitro-3',4'-disubstituted propiophenone-3-amine to obtain 6'-amino-3',4'-disubstituted propiophenone-3-amine;

[0048] (5) 6'-amino-3',4'-disubstituted propiophenone-3-amine and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrone-[3,4-f]indolizine-3,6,10(4H)-trione are subjected to a condensation reaction to obtain a camptothecin-7-ethylamine derivative.

[0049] Synthesis route 4, wherein, comprises the following steps:

[0050] (1) condensing a substituted 2-acetylaniline and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrone-[3,4-f]indolizine-3,6,10(4H)-trione to obtain 7-methylcamptothecin;

[0051] (2) 7-Methylcamptothecin and an amine are subjected to a Mannich reaction in DMSO to obtain a camptothecin-7-ethylamine derivative.

[0052] Preferably, the synthetic route of the present invention is as follows:

[0053]

[0054] Synthesis Route 1. Using 3,4-disubstituted aniline as the starting material, Friedel-Crafts acylation, nitration, amine substitution, nitro group reduction, and ring closure were performed to obtain the target product.

[0055]

[0056] Synthesis Route 2: Using 3,4-disubstituted 3'-chloropropiophenone as the starting material, amine substitution, nitration, reduction, and ring closure were performed to obtain the target product.

[0057]

[0058] Synthesis Route 3: Using 3,4-disubstituted phenyl ketone as raw material, Michael addition of amine, nitration, reduction, and ring closure were performed to obtain the target product.

[0059]

[0060] Synthesis Route 4: 7-Methylcamptothecin (intermediate 5) is used as a substrate to carry out a Mannich reaction with an amine and DMSO to obtain a 7-aminoethyl-substituted camptothecin product.

[0061] In one embodiment, the preparation method of the present invention includes synthetic routes 1 to 4. The method comprises: 1) reacting a 3,4-substituted aniline with a corresponding halogenated propionitrile to obtain an intermediate 3',4'-disubstituted-3-chloro-6'-aminopropiophenone (intermediate 1); 2) substituting intermediate 1 with a corresponding amine to obtain a 3',4'-disubstituted-3-alkylamino-6'-aminopropiophenone (intermediate 2); 3) condensing intermediate 2 with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrone-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter referred to as "tricyclic ketone") to obtain the corresponding product; 4) reacting 3',4'-disubstituted-3-chloropropiophenone with various amines, substituted amines, protected amines, protected aminohydroxyl groups, methoxyhydroxylamines, etc. to obtain intermediate 3; 5) nitrating and reducing intermediate 3 to obtain intermediate 4; 6) intermediate 4 and tricyclic ketone to obtain the corresponding product; 7) 6'-nitro-3',4'-disubstituted phenylpropenone and amine are subjected to Michael addition reaction to obtain 6'-nitro-3',4'-disubstituted phenylpropenone-3-amine (intermediate 3); 8) 6'-nitro-3',4'-disubstituted phenylpropenone-3-amine is reduced to obtain 6'-amino-3',4'-disubstituted phenylpropenone-3-amine (intermediate 4); 9) 6'-amino-3',4'-disubstituted phenylpropenone-3-amine is subjected to condensation reaction with "tricyclic ketone" to obtain the corresponding camptothecin-7-ethylamine derivative; 10) substituted 2-acetylaniline and "tricyclic ketone" are condensed to obtain 7-methylcamptothecin; 11) 7-methylcamptothecin and the corresponding amine are subjected to Mannich reaction in DMSO to obtain the corresponding product.

[0062] In one embodiment, the halogenated propionitrile used in step (1) of synthetic route 1 is chloropropionitrile or bromopropionitrile, and the amount used is 1-2 molar equivalents, preferably 1.0 to 1.5 molar equivalents, and more preferably 1.1 to 1.2 molar equivalents.

[0063] In one embodiment, AlCl3 or BCl3 is used as a catalyst in step (1) of synthetic route 1, and the amount used is 1-3 molar equivalents, preferably 1.0 to 1.5 molar equivalents.

[0064] In one embodiment, PPTS is used for catalysis in step (2) of synthetic route 1 in an amount of 1-2 molar equivalents, preferably 1.0-1.2 equivalents.

[0065] In one embodiment, the amount of amine used in step (3) of synthetic route 1 is 1-20 molar equivalents, preferably 3-10 molar equivalents.

[0066] In one embodiment, nitric acid / acetic anhydride is used for nitration in step (2) of synthetic route 2, and the reaction temperature is -10-10°C, preferably -5-0°C.

[0067] In one embodiment, the amount of amine used in step (2) of synthetic route 4 is 1-20 molar equivalents, preferably 3-6 molar equivalents.

[0068] In one embodiment, step (2) of synthesis method 3 uses aqueous formaldehyde solution or paraformaldehyde in an amount of 5-100 molar equivalents, preferably 30-40 molar equivalents.

[0069] In one embodiment, the Michael addition reaction in step (3) of synthesis method 3 is carried out at 0-100°C, preferably 50-70°C.

[0070] In one embodiment, the Mannich reaction in step (2) of synthesis method 4 is carried out using a hydrochloride of a primary or secondary amine in DMSO heated to 80-160°C, preferably 100-145°C, more preferably 110-140°C.

[0071] Another aspect of the present invention provides an antibody-drug conjugate, wherein the antibody-drug conjugate comprises the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as a small molecule drug.

[0072] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, prodrug or antibody-drug conjugate thereof and a pharmaceutically acceptable excipient.

[0073] Another aspect of the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer or prodrug, antibody-drug conjugate, or pharmaceutical composition in the preparation of a drug for treating tumor diseases.

[0074] Another aspect of the present invention provides a method for treating a tumor disease, comprising administering the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition thereof, to a patient in need thereof. In one embodiment, the amount of the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition administered is a therapeutically effective amount.

[0075] In one embodiment, the tumor diseases include gastric cancer, esophageal cancer, cardia cancer, breast cancer, ovarian cancer, colon cancer, rectal cancer, primary liver cancer, acute and chronic myeloid leukemia, choriocarcinoma, lung cancer, bladder cancer, intestinal cancer and small cell lung cancer; more preferably, the tumor diseases are esophageal cancer, breast cancer and gastric cancer. DETAILED DESCRIPTION

[0076] I. Definition

[0077] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0078] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0079] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The stereoisomers include geometric isomers (such as cis, trans structures) and optical isomers (such as enantiomers), and therapeutic substances composed of monomers, racemates, racemic mixtures and pharmaceutically acceptable salts thereof. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0080] The compounds of the present disclosure also include tautomeric forms.Tautomeric forms arise from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0081] As used herein, "pharmaceutically acceptable salts" refer to salts formed between the corresponding amine compounds and inorganic or organic acids, or between the corresponding carboxylic acid compounds and alkali metals or alkaline earth metals, or between the corresponding carboxylic acid compounds and organic amines. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, and the like; alkali metal or alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, and magnesium salts; and organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, and amino acids.

[0082] As used herein, "precursor" refers to a compound that, after entering the human body via an appropriate administration route, undergoes metabolism or simple chemical changes within the patient's body to transform into the compound of Formula 1 of the present invention and its corresponding salt. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonates, phosphates, sulfates, sulfonates, amino acid esters, gluconates, and various amides, acetals, hemiacetals, and carbonate amides.

[0083] As used herein, numerical ranges refer to the individual integers within the given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C3-C6" means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0084] When any variable (such as R n ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-5 R, the group may be optionally substituted with up to 5 R, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0085] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, with methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred in the present disclosure.

[0086] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclyl, optionally substituted by 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiroheterocyclyl, or nitrogen-containing fused heterocyclyl.

[0087] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.

[0088] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0089] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0090] The hydrogen atoms described in the present disclosure may all be replaced by their isotope deuterium.

[0091] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0092] Refers to the chemical bond connection.

[0093] Drug or pharmaceutical composition

[0094] As used herein, "pharmaceutically acceptable salts" refer to salts formed between the corresponding amine compounds and inorganic or organic acids, or between the corresponding carboxylic acid compounds and alkali metals or alkaline earth metals, or between the corresponding carboxylic acid compounds and organic amines. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, and the like; alkali metal or alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, and magnesium salts; and organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, and amino acids.

[0095] As used herein, "precursor" refers to a compound that, after entering the human body via an appropriate administration route, undergoes metabolism or simple chemical changes within the patient's body to transform into the compound of Formula 1 of the present invention and its corresponding salt. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonates, phosphates, sulfates, sulfonates, amino acid esters, gluconates, and various amides, acetals, hemiacetals, and carbonate amides.

[0096] The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. The oral route is generally desirable. The active agent can be administered orally in the form of capsules, tablets, and the like (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0097] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0098] Tablets comprising the active compound can be coated by methods well known in the art. The compositions of the present disclosure comprising the compound of formula I as the active compound can also be introduced into beads, microspheres or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

[0099] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0100] The term "inhibit" is used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0101] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0102] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that can achieve the desired effect. In embodiments of the present invention, when a patient is treated according to the present invention, the amount of a given drug depends on many factors, such as a specific dosage regimen, the type of disease or condition and its severity, the uniqueness (e.g., body weight) of the patient or host in need of treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, the condition to be treated, and the patient or host to be treated, the dosage can be conventionally determined by methods known in the art. Typically, with respect to the dosage used for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. The desired dosage can be conveniently expressed as a single dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0103] The term "antibody-drug conjugate (ADC)" refers to a small molecule drug with biological activity connected to a monoclonal antibody through a chemical link. The monoclonal antibody acts as a carrier to transport the small molecule drug into the target cells.

[0104] As used herein, the terms "reduce," "inhibit," "mitigate," or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0105] Unless otherwise specified, the raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0106] II. Specific Examples

[0107] The screening method of the present invention includes: the growth inhibitory activity of the compound against tumor cells OE33 cells (human esophageal adenocarcinoma cells), SKBR3 cells (human breast adenocarcinoma cells) and the like.

[0108] Example 1: 7-(2-Acetylamino)ethyl-10-methyl-11-fluorocamptothecin (1)

[0109]

[0110] To a single-necked flask containing 160 mL of anhydrous 1,2-dichloroethane was added a 1M BCl3 solution in dichloromethane (32 mL, 0.032 mol). The temperature was lowered to 0°C, and 3-fluoro-4-methylaniline (5.0 g, 0.04 mmol) was added. The mixture was reacted at 0°C for 10 min. Acetonitrile (16.40 g, 0.4 mol) and aluminum chloride (7 g, 0.05 mol) were added, and the temperature was slowly raised to room temperature and stirred for 10 min. The temperature was then raised to 80°C and stirred for 12 h. After cooling, the reaction solution was poured into ice water, and 1M HCl solution was added to adjust the pH to 2. The reaction solution was extracted with dichloromethane, dried over Na2SO4, and purified by silica gel column chromatography to give the intermediate 6-amino-4-fluoro-3-methylacetophenone (2.5 g, yield 37.4%, HPLC 94%); LC-MS (M+H) + 168.02 (theoretical value 167.07).

[0111] 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 h. The solvent was concentrated under reduced pressure, 10 mL of methanol was added, and the mixture was filtered and dried to obtain 7,10-dimethyl-11-fluorocamptothecin (3.2 g, yield 90.4%, HPLC 96%); LC-MS (M+H) + 395.26 (theoretical value 394.13).

[0112] Add 127.1 mg of amine hydrochloride and 148 μl of hydrochloric acid to 1.5 ml of DMSO, heat the reaction in an oil bath to 110°C, add 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol), heat the reaction to 130-140°C for 50 minutes, cool to room temperature, add methanol, filter, and purify by silica gel column chromatography to obtain the demethoxy product 7-(2-amino)ethyl-10-methyl-11-fluorocamptothecin (41 mg, yield 38.7%, HPLC 94%). 1H 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).

[0113] 7-(2-Amino)ethyl-10-methyl-11-fluorocamptotheca (10 mg, 0.023 mmol) was added to a 25 mL single-necked bottle, 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 reacted at room temperature for 1 hour. 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was prepared 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% to obtain the product 7-(2-acetylamino)ethyl-10-methyl-11-fluorocamptothecin (4.78 mg, yield 45.5%, HPLC 97.5%): 1 H 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).

[0114] Example 2: 7-(2-difluoroacetylamino)ethyl-10-methyl-11-fluorocamptothecin (2)

[0115]

[0116] 7-(2-Amino)ethyl-10-methyl-11-fluorocamptotheca (15 mg, 0.035 mmol) was added to a reaction flask, followed by DMF (5 mL), difluoroacetic acid (8.8 mg, 0.092 mmol), HATU (18 mg, 0.046 mmol), and DIPEA (6 mg, 0.046 mmol), and the mixture was reacted at room temperature for 1 hour. 0.5 ml of water was added dropwise to quench the reaction, and the reaction solution was prepared 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% to obtain the product 7-(2-difluoroacetylamino)ethyl-10-methyl-11-fluorocamptothecin (7.29 mg, yield 41.1%, 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).

[0117] Example 3: 7-(2-Methanesulfonylamino)ethyl-10-methyl-11-fluorocamptothecin (3)

[0118]

[0119] 7-(2-Amino)ethyl-10-methyl-11-fluorocamptotheca (10 mg, 0.023 mmol, Example 1) was added to a reaction flask, followed by DMF (5 mL), methanesulfonyl chloride (4 mg, 0.035 mmol), and DIPEA (6 mg, 0.046 mmol), and the mixture was reacted at room temperature for 1 hour. 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was prepared 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% to give the product 7-(2-methylsulfonylamino)ethyl-10-methyl-11-fluorocamptothecin (6.22 mg, yield 54%, HPLC 97%): LC / MS (M+H) + 502.23 (theoretical value 501.53).

[0120] Example 4: 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (4)

[0121]

[0122] To the reaction flask, 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 respectively, and the temperature was raised to 120-130 ° C. for 40 minutes. After cooling, isopropanol was added, filtered, and purified by silica gel column chromatography to obtain 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).

[0123] Example 5: 7-(2-(piperazin-4-yl))ethyl-10-methyl-11-fluorocamptothecin (5)

[0124]

[0125] To the reaction flask, piperazine (86.14 mg, 1 mmol), hydrochloric acid (0.085 mL, 1.02 mmol) and DMSO (1 mL) were added, and the temperature was raised to 110°C with stirring. 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, and the mixture was stirred and reacted at 120-135°C for 1 h. The mixture was cooled, isopropanol was added, and the mixture was filtered. The mixture was purified by silica gel column chromatography to obtain compound 7-(2-(piperazin-4-yl))ethyl-10-methyl-11-fluorocamptothecin (43.75 mg, yield 35.5%, HPLC 98%). 1 H 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).

[0126] Example 6: 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (6)

[0127]

[0128] (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, the temperature was raised to 110°C with stirring, 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, the temperature was raised to 120-130°C and the stirring was continued for 45 minutes, the mixture was cooled to room temperature, methyl tert-butyl ether was added, the mixture was filtered, and the mixture was purified by silica gel column chromatography to obtain 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).

[0129] Example 7: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (7)

[0130]

[0131] To the reaction flask, (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 respectively, and the temperature was raised to 120-130 ° C with stirring for 45 minutes. After cooling, isopropanol was added, filtered, and purified by silica gel column chromatography to obtain compound 7-(2-(4-methoxycyclohexyl)amino)ethyl-10-methyl-11-fluorocamptothecin (49.6 mg, yield 37.0%, HPLC 97%). 1 HNMR(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),1.9 5-1.81(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).

[0132] Example 8: 7-(2-(2-azidoethyl)amino)ethyl-10-methyl-11-fluorocamptothecin (8)

[0133]

[0134] To the reaction flask, 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. The mixture was heated to 120-135° C. with stirring for 50 minutes. The mixture was cooled to room temperature, methyl tert-butyl ether was added, and the mixture was filtered. The mixture was purified by silica gel column 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 = 8.1 Hz, 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).

[0135] Example 9: 7-(2-((S)-4-hydroxybutan-2-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (9)

[0136]

[0137] To the reaction flask, (R)-3-aminobutanol (135.60 mg, 1.52 mmol), hydrochloric acid (0.138 mL, 1.65 mmol) and DMSO (1 mL) were added, and the temperature was raised to 110°C with stirring. 7,10-dimethyl-11-fluorocamptothecin (100 mg, 0.25 mmol) was added, and the temperature was raised to 130-140°C and the reaction was continued with stirring for 50 minutes. The mixture was cooled, isopropanol was added, and the mixture was filtered. The mixture was purified by silica gel column chromatography to obtain compound 7-(2-((S)-4-hydroxybutan-2-)amino)ethyl-10-methyl-11-fluorocamptothecin (53.4 mg, yield 43.1%, HPLC 99%). 1H 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).

[0138] Example 10: 7-(2-Hydroxyethylamino)ethyl-10,11-difluorocamptothecin (10)

[0139]

[0140] To a single-necked flask containing anhydrous 1,2-dichloroethane (80 mL) was added a 1M BCl₃ solution 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 reacted at 0°C for 10 min. Acetonitrile (8.2 g, 0.2 mol) and aluminum chloride (3.5 g, 0.025 mol) were added and the temperature was slowly raised to room temperature and stirred for 10 min. The temperature was then raised to 80°C and stirred for 12 h. The reaction solution was poured into ice water and adjusted to pH 2 with 1M HCl solution. The product was extracted with dichloromethane, dried over Na₂SO₄, and silica gel powder was added. The product was purified by column chromatography (PE:EA = 100%-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).

[0141] 6-Amino-3,4-difluoroacetophenone (0.50 g, 2.9 mmol) was dissolved in anhydrous toluene (5 mL), and tricyclic ketone (769.07 mg, 2.9 mmol) and PPTS (73 mg, 0.29 mmol) were added. The reaction was heated to 115° and stirred for 12 h. The mixture was cooled and the solvent was removed under reduced pressure. 5 mL of methanol was added, the mixture was filtered, and the mixture was dried to obtain 7-methyl-10,11-difluorocamptothecin (0.82 g, yield 70.69%, HPLC 96%); LC-MS (M+H) +399.23 (theoretical value 398.11).

[0142] To the reaction flask, ethanolamine (46 mg, 0.75 mmol), hydrochloric acid (0.07 mL, 0.8 mmol) and DMSO (1 mL) were added, and the temperature was raised to 120°C with stirring. 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added, and the reaction was carried out at 120-140°C for 30 minutes. The mixture was cooled to room temperature, methyl tert-butyl ether was added, and the mixture was filtered. The product was purified by silica gel column chromatography to obtain 7-(2-hydroxyethylamino)ethyl-10,11-difluorocamptothecin (31 mg, yield 52.5%, 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).

[0143] Example 11: 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-difluorocamptothecin (11)

[0144]

[0145] (S)-1-methoxy-2-propylamine (100 mg, 1.02 mmol), hydrochloric acid (0.09 mL, 1.08 mmol) and DMSO (1.5

[0146] mL), heated to 120°C with stirring, added 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol), and reacted at 120-140°C for 35

[0147] The reaction mixture was stirred for 10 minutes, cooled to room temperature, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain compound 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-difluorocamptothecin (42 mg, yield 67%, HPLC 98%); 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.37

[0148] (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),

[0149] 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-

[0150] MS(M+H) + 500.39 (theoretical value 499.19).

[0151] Example 12. 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (12)

[0152]

[0153] 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). The temperature was raised to 110°C with stirring, and 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added. The mixture was reacted at 120-140°C for 40 minutes. The mixture was cooled to room temperature, and isopropanol was added. The compound was purified by silica gel column chromatography to obtain 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (33 mg, yield 50%, HPLC 97%). 1 HNMR(500MHz,DMSO-d6)δ8.71(s,1H),8.63(s,1H),8.34(dd,J=11.6,8.9Hz,1H),8.27(dd,J=11.2,8.1H z,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 ,J=14.5Hz,2H),1.37(d,J=12.3Hz,1H),1.21(dd,J=18.7,8.4Hz,1H),0.88(t,J=7.3Hz,3H); LC-MS(M+H)+ 526.15 (theoretical value 525.21).

[0154] Example 13: 7-(2-(Tetrahydropyran-4-yl)amino)ethyl-10,11-difluorocamptothecin (13)

[0155]

[0156] To the reaction flask were added 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 with stirring for 30 minutes. Methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain compound 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-difluorocamptothecin (43 mg, yield 67%, 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),3.50 3.47(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).

[0157] Example 14: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-difluorocamptothecin (14)

[0158]

[0159] To the reaction flask, 4-methoxycyclohexylamine (0.12 g, 0.9 mmol), hydrochloric acid (0.075 mL, 0.9 mmol) and DMSO (1 mL) were added, and the mixture was heated to 120° with stirring. 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) was added, and the temperature was raised to 130° and the reaction was carried out for 30 minutes. The mixture was cooled to room temperature, and methanol 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-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).

[0160] Example 15: 7-(2-(2-azidoethyl)amino)ethyl-10,11-difluorocamptothecin (15)

[0161]

[0162] To the reaction flask, 2-azidoethylamine hydrochloride (80 mg, 0.93 mmol), 7-methyl-10,11-difluorocamptothecin (50 mg, 0.125 mmol) and DMSO (1 mL) were added. The mixture was stirred and heated to 120-140°C for 30 minutes. The mixture was cooled to room temperature, and isopropanol was added. The mixture was filtered and purified by silica gel column chromatography to obtain the product 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).

[0163] Example 16: 7-(2-(2-azidoethyl)amino)ethyl-10,11-methylenedioxycamptothecin (16)

[0164]

[0165] 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 was heated to 115° and stirred for 12 h. After cooling, the solvent was concentrated under reduced pressure, 20 mL of methanol was added, and the mixture was filtered and dried to give 7-methyl-10,11-methylenedioxycamptothecin (11.0 g, 97% yield); LC-MS (M+H)+ 407.15 (theoretical value 406.12).

[0166] 2-Azidoethylamine hydrochloride (63.56 mg, 0.74 mmol), DMSO (1 mL) and 7-methyl-10,11-methylenedioxycamptothecin (50 mg, 0.12 mmol) were stirred and heated to 110-130°C for 1 h. Isopropanol was added, and the solid was filtered and purified by silica gel column chromatography to obtain the product 7-(2-(2-azidoethyl)amino)ethyl-10,11-methylenedioxycamptothecin (29 mg, yield 47.9%, HPLC 99%). 1 H 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 C NMR (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).

[0167] Example 17: 7-(2-(2-methoxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (17)

[0168]

[0169] 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, and 7-methyl-10,11-methylenedioxycamptothecin (1.8 g, 4.4 mmol) was added. The temperature was continued to rise to 120-130°C for 1 h, and then cooled to room temperature. Methyl tert-butyl ether was added, and the mixture was filtered. The mixture was 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%). 1 HNMR (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. 6Hz,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).

[0170] Example 18: 7-(2-((S)-4-hydroxybutyl-2-yl)amino)ethyl-10,11-methylenedioxycamptothecin (18)

[0171]

[0172] (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 to the reaction mixture under stirring at 110-125°C for 50 minutes. The mixture was cooled to room temperature and methyl tert-butyl ether was added. The precipitated solid was filtered and purified by silica gel column chromatography to obtain the compound 7-(2-((S)-4-hydroxybutyl-2-)amino)ethyl-10,11-methylenedioxycamptothecin (62 mg, yield 51%, HPLC 93%). 1 HNMR(500MHz,DMSO-d6)δ11.53(s,1H),8.45(d,J=7.7Hz,1H),7.57(s,

[0173] 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).

[0174] Example 19: 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (19)

[0175]

[0176] To the reaction flask, (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) were added. The mixture was heated to 120° with stirring for 50 minutes. The mixture was cooled to room temperature, methyl tert-butyl ether was added, and the precipitated solid was filtered and 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%). 1 H 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).

[0177] Example 20: 7-(2-(3-oxetanyl)amino)ethyl-10,11-methylenedioxycamptothecin (20)

[0178]

[0179] 3-Oxetanamine (84 mg, 1.14 mmol) and hydrochloric acid (0.1 ml, 1.2 mmol) were dissolved in DMSO (2 mL), stirred and heated to 120°C, 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.24 mmol) was added, and the temperature was raised to 130°C for reaction for 50 minutes. After cooling, methyl tert-butyl ether was added, and the mixture was filtered and purified by silica gel column chromatography to obtain 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).

[0180] Example 21: 7-(2-(1,3-dimethoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (21)

[0181]

[0182] 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, stirred and heated to 120°C for 1 h, methyl tert-butyl ether was added, filtered, and purified by silica gel column chromatography to obtain compound 7-(2-(1,3-dimethoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (35 mg, yield 54.3%, HPLC 98%). 1H 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),3.28 3.21(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).

[0183] Example 22: 7-(2-(2-hydroxyethyl)amino)ethyl-10,11-methylenedioxycamptothecin (22)

[0184]

[0185] Add 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) to the reaction flask, quickly heat to 110-120°C and stir to react for 0.5 hour, cool to room temperature, add methyl tert-butyl ether, filter the solid, and purify by silica gel column chromatography to obtain 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 H),3.82-3.56(m,2H),3.39(s,2H),3.23(d,J=4.9Hz,2H),3.08(s,2H),1.86(dt,J=14.3,6.9Hz,2H),0.86(t,J=7.3Hz,3H); LC-MC(M+H) + 480.05 (theoretical value 479.17).

[0186] Example 23: 7-(2-(2-trifluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (23)

[0187]

[0188] Trifluoroethylamine hydrochloride (100 mg, 0.74 mmol) and 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) were dissolved in DMSO (3 mL), stirred and heated to 120°C for 1 h. 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%). 1 H 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).

[0189] Example 24: 7-(2-(2-difluoroethyl)amino)ethyl-10,11-methylenedioxycamptothecin (24)

[0190]

[0191] To the reaction flask, difluoroethylamine (1.0 g, 12 mmol), hydrochloric acid (1.4 mL, 16 mmol), 7-methyl-10,11-methylenedioxycamptothecin (1.0 g, 2.46 mmol), and DMSO (5 mL) were added. The mixture was stirred and heated to 120°C for 1 h. After cooling, isopropanol was added, the mixture was filtered, and the product was purified by silica gel column chromatography to obtain 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); 13C NMR (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).

[0192] Example 25: 7-(2-(Tetrahydropyran-4-yl)amino)ethyl-10,11-methylenedioxycamptothecin (25)

[0193]

[0194] 4-Aminotetrahydropyran (0.75 g, 7.4 mmol), concentrated hydrochloric acid (0.7 mL, 7.5 mmol), and DMSO (15 mL) were reacted in an oil bath and heated to 120°C. 7-methyl-10,11-methylenedioxycamptothecin (0.5 g, 1.2 mmol) was added and the temperature was raised to 130-140°C for 1 h. Methanol was added and the mixture was filtered with suction. The filtrate was concentrated and purified by silica gel column chromatography to obtain a gray solid 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-methylenedioxycamptothecin (0.41 g, yield 63%, HPLC 96%). 1 HNMR(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, 2H),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); 13C NMR (126MHz, DMSO) δ173.04,157.26,151.30,150.58,149.68,149.42,147.49,146.73,146.68,128.52,124.7 9,118.49,105.90,103.14,99.83,96.39,72.82,66.05,65.69,55.41,53.65,50.31,30.66,8.27; LC-MS(M+H) + 520.11 (theoretical value 519.20).

[0195] Example 26: 7-(2-(4-hydroxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (26)

[0196]

[0197] 4-Aminocyclohexanol (107.05 mg, 0.93 mmol), concentrated hydrochloric acid (0.1 mL, 1.2 mmol), and DMSO (4 mL) were added to the reaction flask, and the temperature was raised to 100°C in an oil bath. 7-methyl-10,11-methylenedioxycamptothecin (100 mg, 0.25 mmol) was added, and the temperature was raised to 140°C and the reaction was carried out for 0.5 h. The mixture was poured into water, the solid was filtered, and the product was 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).

[0198] Example 27: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-methylenedioxycamptothecin (27)

[0199]

[0200] 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 heated to 115-125°C with stirring, reacted for 1 h, 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),3.44 3.36(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).

[0201] Example 28: 7-(2-((S)-hydroxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (28)

[0202]

[0203] To a reaction flask, (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, stirred, heated to 120-130°C for 1 h, cooled to room temperature, and methyl tert-butyl ether was added. The precipitated solid was filtered and purified by silica gel column chromatography to give the product 7-(2-((S)-hydroxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (84.94 mg, yield 69%, HPLC 99%). 1H 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).

[0204] Example 29: 7-(2-((S)-azidoisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (29)

[0205]

[0206] In a 100 ml three-necked flask under Ar2 protection, compound (S)-2-N-Boc aminopropanol (1 g, 0.57 mmol) was added, and 10 ml of dry DCM was added. After stirring and dissolving, the reaction solution was cooled to 0°C, TEA (0.87 g, 0.86 mmol) was added, and then MsCl (0.78 g, 0.68 mmol) was added dropwise. The mixture was kept stirring at 0°C for 2 hours. Water (10 ml) was added to the reaction solution, extracted with DCM, dried, and the organic phase was concentrated to obtain compound (S)-2-N-Boc aminopropanol methanesulfonate (1.4 g, yield 97.2%), which was used directly in the next step without further purification.

[0207] (S)-2-N-Boc aminopropanol methanesulfonate (1.4 g, 0.55 mmol) was dissolved in DMF (10 ml), and NaN3 (0.36 g, 0.55 mmol) was added. The reaction 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 phases were then concentrated and purified by silica gel column chromatography to obtain 1-azido-2-(S)-N-Boc propylamine (0.8 g, yield 72%).

[0208] 1-Azido-2-(S)-N-Bocpropylamine (0.8 g, 4 mmol) was dissolved in ethyl acetate (2 ml), and a 4N hydrogen chloride solution 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, yield 92%). 1H 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).

[0209] The above-prepared 1-azido-2-(S)-isopropylamine hydrochloride (147.8 mg, 1.08 mmol) 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 for 1 h, and then isopropanol was added. 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, yield 44%, HPLC 93%). 1 H NMR (600 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.55 (m, 1H), 7.26 (s, 1H), 6.52 (s, 1H), 6.46 (s, 2H), 5.45 (d, J = 16.7 Hz, 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, 7.3 Hz, 2H), 1.57-1.46 (m, 3H), 0.87 (t, J = 7.3 Hz, 3H); LC-MS (M+H) + 519.02 (theoretical value 518.19).

[0210] Example 30: 7-(2-(N-hydroxyacetyl((S)-methoxyisopropyl))amino)ethyl-10,11-methylenedioxycamptothecin (30)

[0211]

[0212] 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 in sequence under ice bath. After stirring for 30 min under ice bath, 7-(2-((S)-2-methoxyisopropyl)amino)ethyl-10,11-methylenedioxycamptothecin (10 mg, 0.02 mmol, Example 19) was added. The mixture was slowly warmed to room temperature and stirred for 18 h. The mixture was then quenched with 0.1% TFA (A) and acetonitrile (B). Preparation, 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%, to give the product 7-(2-(N-hydroxyacetyl((S)-methoxyisopropyl))amino)ethyl-10,11-methylenedioxycamptothecin (6 mg, yield 54%, HPLC 95%); LC-MS (M+H)+ 566.58 (theoretical value 565.21).

[0213] Example 31: 7-(2-(N-hydroxyacetyl(2-azidoethyl))amino)ethyl-10,11-methylenedioxycamptothecin (31)

[0214]

[0215] 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 in sequence under ice bath conditions. After stirring for 30 min 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 and stirred for 18 h. The mixture was prepared with 0.1% TFA (A) and acetonitrile (B). Preparation, 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%, to obtain the product 7-(2-(N-hydroxyacetyl(2-azidoethyl))amino)ethyl-10,11-methylenedioxycamptothecin (6 mg, yield 58%, HPLC 95%); 1H 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),3.79 3.68(m,2H),3.26(s,2H),3.20(s,2H),2.62(d,J=4.6Hz,1H),2.54(d,J=7.6H z,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).

[0216] Example 32: 7-(2-(N-hydroxyacetyl(2-methoxyethyl))amino)ethyl-10,11-methylenedioxycamptothecin (32)

[0217]

[0218] 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 in sequence under ice bath conditions. After stirring for 30 min 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 and stirred for 18 h. The mixture was prepared with 0.1% TFA (A) and acetonitrile (B). Preparation, 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%, to obtain the product 7-(2-(N-hydroxyacetyl(2-methoxyethyl))amino)ethyl-10,11-methylenedioxycamptothecin (6 mg, yield 60%, 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).

[0219] Example 33: 7-(2-(N-hydroxyacetyl(2-difluoroethyl))amino)ethyl-10,11-methylenedioxycamptothecin (33)

[0220]

[0221] 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 in sequence under ice bath conditions. After stirring for 30 min 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 h. The mixture was prepared using 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%, to obtain compound 7-(2-(N-hydroxyacetyl(2-difluoroethyl))amino)ethyl-10,11-methylenedioxycamptothecin (6 mg, yield 54%, 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).

[0222] Example 34: 7-(2-(N-(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (34)

[0223]

[0224] To a reaction flask, (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, stirred, heated to 120-130°C, and reacted for 1 h. The mixture was cooled to room temperature, and methyl tert-butyl ether was added. The precipitated solid was filtered and purified by silica gel column chromatography to give the product 7-(2-(N-(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (16.2 mg, yield 32.3%, HPLC 96.2%). 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 C NMR (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).

[0225] Example 35: 7-(2-(N-(S)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (35)

[0226]

[0227] To a reaction flask, (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, stirred, heated to 120-130°C, and reacted for 1 h. The mixture was cooled to room temperature, and methyl tert-butyl ether was added. The precipitated solid was filtered and purified by silica gel column chromatography to give the product 7-(2-(N-(R)-tetrahydrofuran-3-amino))ethyl-10,11-methylenedioxycamptothecin (18 mg, yield 33%, HPLC 95.9%). 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 C NMR (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).

[0228] Example 36: 7-(2-difluoroacetylamino)ethyl-10,11-methylenedioxycamptothecin (36)

[0229]

[0230] 160 mg of ammonium chloride and 6 drops of hydrochloric acid were added to DMSO (9 mL), and the reaction temperature was raised to 120°C in an oil bath. 7-methyl-10,11-methylenedioxycamptothecin (200 mg, 0.49 mmol) was added, and the temperature was raised to 130°C for 1 h. The mixture was cooled to room temperature, and methanol was added to make a pulp. The mixture was filtered and some DMSO was concentrated. The product was prepared 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%, to obtain the product 7-aminoethyl-10,11-methylenedioxycamptothecin (99 mg, yield 46%, 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 C NMR (126MHz, DMSO) δ173.01,157.29,151.46,150.63,150.01,149.76,147.65,146.66,137.76,129.10,12 4.77,118.63,106.14,103.25,99.61,96.48,72.88,65.69,50.31,38.50,30.70,27.97,8.23; LC-MS(M+H) + 436.41 (theoretical value 435.14).

[0231] 7-Aminoethyl-10,11-methylenedioxycamptothecin (20 mg, 0.046 mmol) was added to a reaction flask, and DMF (5 mL) was added, followed by difluoroacetic acid (8.8 mg, 0.092 mmol), HATU (35 mg, 0.092 mmol), and DIPEA (12 mg, 0.092 mmol). The mixture was reacted at room temperature for one hour, and 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was diluted with 0.1% TFA (A) and acetonitrile (B). Preparation, 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%, to obtain the target product 7-(2-difluoroacetylamino)ethyl-10,11-methylenedioxycamptothecin (14.6 mg, yield 62%, HPLC 98%); 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 C NMR (126MHz, DMSO) δ173.02,157.30,151.39,150.61,149.83,149.55,147.63,146.77,139.56,128.71,125.06,11 8.54,109.02,106.04,103.14,99.81,96.42,72.88,65.71,53.93,50.23,42.21,38.28,30.67,13.04; LC-MS(M+H) + 514.25 (theoretical value 513.13).

[0232] Example 37: 7-(2-Azidoacetamido)ethyl-10,11-methylenedioxycamptothecin (37)

[0233]

[0234] 7-Aminoethyl-10,11-methylenedioxycamptothecin (15 mg, 0.035 mmol) was added to a reaction flask, and DMF (5 mL) was added, followed by azidoacetic acid (7.2 mg, 0.071 mmol), HATU (35 mg, 0.092 mmol), and DIPEA (12 mg, 0.092 mmol). The mixture was reacted at room temperature for one hour, and 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was diluted with 0.1% TFA (A) and acetonitrile (B). Preparation, 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%, to obtain the target product 7-(2-azidoacetamido)ethyl-10,11-methylenedioxycamptothecin (13.1 mg, yield 71%, HPLC 95%); 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).

[0235] Example 38: 7-(2-Methanesulfonylamino)ethyl-10,11-methylenedioxycamptothecin (38)

[0236]

[0237] 7-Aminoethyl-10,11-methylenedioxycamptothecin (15 mg, 0.034 mmol) was added to the reaction flask, DMF (5 mL) was added, methanesulfonyl chloride (5 mg, 0.043 mmol) was added, and then DIPEA (47.5 mg, 0.368 mmol) was added. The reaction was allowed to react at room temperature for one hour, and 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was prepared with 0.1% TFA (A) and acetonitrile (B) for 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%, to obtain the product 7-(2-methylsulfonylamino)ethyl-10,11-methylenedioxycamptothecin (14.2 mg, yield 80%, 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).

[0238] Example 39: 7-(2-cyclopropylsulfonylamino)ethyl-10,11-methylenedioxycamptothecin (39)

[0239]

[0240] 7-Aminoethyl-10,11-methylenedioxycamptothecin (20 mg, 0.046 mmol) was added to a reaction flask, DMF (5 mL) was added, cyclopropylsulfonyl chloride (12.9 mg, 0.092 mmol) was added, and then DIPEA (47.5 mg, 0.368 mmol) was added. The reaction was allowed to react at room temperature for one hour, and 0.5 ml of water was added dropwise to quench the reaction. The reaction solution was prepared with 0.1% TFA (A) and acetonitrile (B), 0-4 m in: 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%, to obtain the product 7-(2-cyclopropylsulfonylamino)ethyl-10,11-methylenedioxycamptothecin (19.4 mg, yield 78%, 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).

[0241] Example 40: 7-(2-(Pyrazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (40)

[0242]

[0243] 1H-3-pyrazolemethylamine (71.69 mg, 0.74 mmol) and hydrochloric acid (72 μL) were added to DMSO (1.5 mL), and the reaction temperature was raised to 110°C in an oil bath. 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added and the temperature was raised to 135°C and the reaction was continued for 1 h. After cooling, methanol was added to make a pulp, and the mixture was filtered. The mixture was prepared with 0.1% TFA (A) and acetonitrile (B), and the reaction temperature was 90 °C for 0-4 min. %-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%, to obtain the target product 7-(2-(pyrazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (20.8 mg, yield 33.6%, HPLC 98%); LC-MS (M+H) + 516.35 (theoretical value 515.18).

[0244] Example 41: 7-(2-(1,2,4-triazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (41)

[0245]

[0246] 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), stirred and heated to 120°C, 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, the temperature was raised to 140°C and the reaction was continued for 1 h, cooled to room temperature, methanol was added, filtered, concentrated, and prepared with 0.1% TFA (A) and acetonitrile (B), 0-4 min: A: 9. 0%-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%, to obtain the target product 7-(2-(1,2,4-triazole-5-amino))ethyl-10,11-methylenedioxycamptothecin (31.4 mg, yield 52%, HPLC 96%); LC-MS (M+H) + 503.30 (theoretical value 502.16).

[0247] Example 42: 7-(2-(2-methoxyethyl)amino)ethyl-10,11-ethyldioxycamptothecin (42)

[0248]

[0249] To a one-necked flask containing anhydrous 1,2-dichloroethane (160 mL) was added a 1M BCl₃ solution in dichloromethane (32 mL, 32 mmol). The reaction flask was cooled to 0°C and 3,4-ethyldioxyaniline (5 g, 33.08 mmol) was added. The reaction was allowed to react at 0°C for 10 min. Acetonitrile (16.40 g, 409.54 mmol) and aluminum chloride (7 g, 52.5 mmol) were added and the mixture was slowly warmed to room temperature and stirred for 10 min. The temperature was then raised to 80°C and stirred for 12 h. The reaction solution was poured into ice water and adjusted to pH 2 with 1M HCl solution. The product was extracted with dichloromethane, dried over Na₂SO₄, and purified by silica gel column chromatography to afford 6-amino-3,4-ethyldioxyacetophenone (2 g, 31.3% yield, HPLC 95%). LC-MS (M+H) + 194.17 (theoretical value 193.07).

[0250] 6-Amino-3,4-ethyldioxyacetophenone (0.5 g, 0.26 mmol) was dissolved in anhydrous toluene (30 mL). Tricyclic ketone (0.68 g, 0.26 mmol) and PPTS (0.065 g, 0.026 mmol) were added with stirring. The reaction solution was heated to 115°C and stirred for 12 h. After cooling, the solvent was concentrated under reduced pressure, 5 mL of methanol was added, and the mixture was filtered and dried to obtain 7-methyl-10,11-ethyldioxycamptothecin (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).

[0251] 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 stirred and heated to 120-130°C for 30 minutes. The mixture was cooled to room temperature, and 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%). 1H 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).

[0252] Example 43: 7-(2-(Tetrahydropyran-4-yl)amino)ethyl-10,11-ethyldioxycamptothecin (43)

[0253]

[0254] 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 temperature was raised to 120°C with stirring. 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added, and the temperature was raised to 130°C and the reaction was continued for 30 minutes. The mixture was cooled to room temperature, and methyl tert-butyl ether was added. The mixture was filtered and purified by silica gel column chromatography to give compound 7-(2-(tetrahydropyran-4-yl)amino)ethyl-10,11-ethyldioxycamptothecin (37 mg, yield 57.8%, HPLC 95%); LC-MS (M+H)+ 534.19 (theoretical value 533.22).

[0255] Example 44: 7-(2-(4-methoxycyclohexyl)amino)ethyl-10,11-ethyldioxycamptothecin (44)

[0256]

[0257] To the reaction flask, 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, and the temperature was raised to 120-130°C with stirring for 45 minutes. Isopropanol was added, and 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).

[0258] Example 45: 7-(2-((S)-methoxyisopropyl)amino)ethyl-10,11-ethyldioxycamptothecin (45)

[0259]

[0260] (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). The temperature was raised to 110°C with stirring, and 7-methyl-10,11-ethylenedioxycamptothecin (50 mg, 0.12 mmol) was added. The temperature was raised to 130°C and the reaction was continued for 30 minutes. The mixture was cooled to room temperature, and 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-ethyldioxycamptothecin (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( m,2H),3.44(dd,J=10.3,5.7Hz,4H),3.23(d,J=19.3Hz,4H),1.92-1.79(m,2H),1.21(d,J=6.5Hz,3H),0.85(t,J=7.3Hz,3H); LC-MS(M+H) + 522.16 (theoretical value 521.22).

[0261] Example 46: Tumor Cell Growth Inhibition Activity

[0262] Human esophageal cancer cells OE33 (human breast adenocarcinoma cells SK-BR-3, or human gastric cancer cells NCI-N87) were cultured in RPMI1640 (Cellmax) supplemented with 10% fetal bovine serum (Cellmax). Tumor cells in the exponentially growing phase were diluted with culture medium to 1×105 cells / mL and 100 μL was added to each well of a 96-well cell culture plate. The plates were then returned to a 37°C, 5% CO2 incubator for overnight incubation. The next day, compounds were diluted with culture medium to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM, and 2 μL of the diluted compounds were added to each well of the 96-well cell culture plate. Three replicates were set for each concentration. For negative controls and blank controls without compound addition, 2 μL of the dilution was added to each well. After sample addition, the cells were returned to a 37°C, 5% CO2 incubator and incubated for 72 hours. After incubation, the cell culture plates were removed, the culture medium was aspirated and discarded with a pipette, and 100 μL of culture medium containing 10% CCK-8 was added to each well. The cells were incubated at 37°C for 3 hours. After incubation, the plates were removed, protected from light, and placed on an ELISA plate. The absorbance was measured at 630 nm as the reference wavelength and 450 nm as the measurement wavelength. Based on the absorbance values, IC50 values ​​were calculated using a four-parameter regression in GraphPad (Table 1).

[0263] Table 1. IC50 (nM) values ​​of compounds for inhibiting tumor cell growth

[0264]

[0265]

[0266] Note: “-” means not tested.

[0267] The above description 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 substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, in, R1 and R2 each independently represent halogen, C1-C6 alkyl, or R1 and R2 together form a methylenedioxy bridge or an ethylenedioxy bridge; R3 is hydrogen; R4 represents 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 each independently represent methyl, F, Cl, Br, I, or R1 and R2 together form a methylenedioxy bridge or an ethylenedioxy bridge.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 each independently represent a methyl group, F, or R1 and R2 together form a methylenedioxy bridge or an ethylenedioxy bridge.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The -NR3R4 is the following structure:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The R1, R2 and the carbon atoms at positions 10 and 11 to which they are connected together form the following structure:

6. The compound according to any one of claims 1-2, 4-5 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

7. A method for preparing the compound according to any one of claims 1 to 6, characterized in that: The preparation method is selected from the steps of the following synthetic route: (1) Make Reaction with tricyclic ketone to obtain intermediate 5; (2) Intermediate 5 and Mannich reaction was carried out in DMSO to obtain camptothecin-7-ethylamine derivative; Wherein, R1, R2, R3, and R4 are each defined as described in any one of claims 1-6.

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating tumor diseases.

10. The use according to claim 9, wherein: The tumor diseases are gastric cancer, esophageal cancer, cardia cancer, breast cancer, ovarian cancer, primary liver cancer, acute and chronic myeloid leukemia, choriocarcinoma, lung cancer, bladder cancer and intestinal cancer.

11. The use according to claim 9 or 10, wherein: The tumor diseases are esophageal cancer, breast cancer and gastric cancer.

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