High homology of the gene encoding the protein of the present application with the gene encoding the protein of the patent application WO 2005 / 007

Abstract

The present invention relates to novel homoharringtonine derivatives, to processes for preparing these compounds, to compositions comprising these compounds and to their use in the manufacture of medicaments for the treatment of diseases.

Description

Technical Field

[0001] This invention belongs to the field of natural medicines and medicinal chemistry, and relates to homoharringtonine derivatives, methods for preparing these compounds, compositions containing these compounds, and their use in the preparation of medicaments for treating diseases. Background Technology

[0002] Homoharringtonine (HHT) exists in plants of the genus Cephalotaxus. In 1963, Paudler et al. first isolated cephaloyaxine from Cephalotaxus drupacea sieb. etc. Zucc and Cephalotaxus fortunei Hook.f. In 1969, Powell et al. first isolated homoharringtonine from Cephalotaxus columnaris, determined its structure to be (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinic acid (methyl)(homoharringtonine) ester, and found that it had significant activity against mouse lymphocytic leukemia P388.

[0003] Although homoharringtonine has achieved good results in the clinical treatment of leukemia, and preliminary studies on its bioactivity indicate that it also has high inhibitory activity against various solid tumors, it still has strong toxic side effects. The main toxic side effects are those affecting the cardiovascular system, digestive system, and hematopoietic cells; allergic reactions, hypersensitivity reactions, hypotension, and hypoglycemia are relatively common. Hypotension toxicity is the dose-limiting toxicity of homoharringtonine in clinical practice, and this toxicity issue needs to be addressed and resolved during the molecular structure modification of homoharringtonine. The toxic substance basis for the hypotension caused by homoharringtonine is its metabolite 4'-demethylhomoharringtonine (4'-DMHHT). Although 4'-DMHHT, formed after the hydrolysis of homoharringtonine, loses its antitumor activity, it exhibits hypotension toxicity, which should be the molecular basis for the hypotension caused by homoharringtonine in clinical practice.

[0004]

[0005] It is evident that existing technologies still require a homoharringtonine derivative that is highly effective in treating tumors while having fewer toxic side effects and better safety. Summary of the Invention

[0006] The purpose of this invention is to provide a homoharringtonine derivative that is effective in treating tumors, has better safety, fewer toxic side effects, better metabolic stability, and is more suitable for pharmaceutical preparation.

[0007] This invention is achieved through the following technical solution:

[0008] A homoharringtonine derivative of formula (Ⅰ):

[0009]

[0010] Or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein:

[0011] X is -O-, -CHR X -or-NR X -;

[0012] R X Is it H or C? 1-6 alkyl;

[0013] L may not exist, or L may be optionally represented by 0 to 3 identical or different R. L Replacement of H, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Alkyloxy;

[0014] R L Each is independently H, oxo, or C. 1-3 alkyl;

[0015] R 1 It is H or -C(O)-R 5 ;

[0016] R 2 Is it H or C? 1-6 Alkyl group;

[0017] R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted H, hydroxyl, amino, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkoxy acyl, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy group, C 1-10 Alkoxyamide group, C 1-10 Alkylamide group, 5-10 heteroaryl group or 5-10 heteroaryloxy group, wherein the heteroaryl group contains at least one nitrogen atom;

[0018] R 3a Each is independently H, halogen, C 1-10 Alkyl, C 1-10 Alkoxy acyl or C 1-10 Alkoxy;

[0019] by The key indicated is either a single bond or a double bond;

[0020] when When it is a single bond, R 4 Is it a hydroxyl group or a C? 1-10 Alkyloxy;

[0021] when When it is a double bond, R 4 It is oxygenation;

[0022] R 5 It can be optionally used by 0 to 3 identical or different Rs. 5a Replacement of H, C 1-20 Alkyl or 5-10-membered heteroaryl, wherein the heteroaryl contains at least one nitrogen atom;

[0023] R 5a Each is independently H, halogen, C 1-10 Alkyl, C 1-10 Alkyloxy, 5-10 heteroaryloxy or C 5-10 aryloxy group;

[0024] When R 1 H is H, L is C 1-10 Alkylene or C 2-10 When it is alkenyl, R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted amino groups, C 5-10 Aryl, C 5-10 aryloxy or C 1-10 Alkoxyamide group;

[0025] When R 5 When L is methyl or 5-10 heteroaryl, L is not methylene.

[0026] In some implementation schemes, R X It is H or methyl;

[0027] when When it is a single bond, R 4 It is a hydroxyl or acetoxy group;

[0028] when When it is a double bond, R 4 It is oxygenation;

[0029] R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted H, amino, C 1-10 Alkoxy acyl, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy or C 1-10Alkoxyamide group;

[0030] R 3a Each is independently H, halogen, C 1-10 Alkyl or C 1-10 Alkoxy acyl group;

[0031] R 5 It can be optionally used by 0 to 3 identical or different Rs. 5a Replacement of H, C 1-20 Alkyl or 5-10-membered heteroaryl, wherein the heterocyclic or heteroaryl group contains one nitrogen atom;

[0032] R 5a Each is independently H, halogen, or C. 5-10 Aryloxy group.

[0033] In some embodiments, the derivative has the chemical structure of formula (II):

[0034]

[0035] Among them, X, L, R 1 and R 3 As defined above.

[0036] In some implementations, X is -O- or -CHR X -;

[0037] R X It is H;

[0038] L may not exist, or L may be optionally represented by 0 to 3 identical or different R. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl;

[0039] R L Each is independently either H or methyl;

[0040] R 3 It is H, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy or C 1-10 Alkoxyamide group;

[0041] R 3a Is it H, halogen, or C? 1-10 alkyl;

[0042] R 5 It can be optionally used by 1 R 5a Replacement of H or C 1-20 alkyl;

[0043] R5a Is it H or C? 5-10 aryloxy group;

[0044] Preferably, R 5a It is H or phenoxy.

[0045] In some implementations, X is -O-;

[0046] L can optionally be any 0 to 3 identical or different Rs. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl;

[0047] R 5 It can be optionally used by 1 R 5a Substituted H or methyl;

[0048] R 5a It is H or phenoxy;

[0049] When L is C 1-3 When alkylene, R 3 Not H.

[0050] In some embodiments, the derivative has the chemical structure of formula (Ⅲ):

[0051]

[0052] Among them, X, L and R 3 As defined above.

[0053] In some implementations, L may be absent, or L may optionally be 0 to 3 identical or different Rs. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl;

[0054] R L Each is independently either H or methyl;

[0055] R 3 It is H, C 5-10 Aryl or C 5-10 aryloxy group;

[0056] R 3a Is it H, halogen, or C? 1-3 alkyl;

[0057] Preferably, R 3 It is H, phenyl, or phenoxy.

[0058] In some embodiments, the derivative has a chemical structure of formula (IIa), formula (IIb), formula (IIc), or formula (IId):

[0059]

[0060]

[0061] Among them, L and R 1 and R 3a As defined above.

[0062] On the other hand, the present invention provides a derivative having the structure described below, or a pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug thereof, wherein the derivative is selected from:

[0063]

[0064]

[0065]

[0066] On the other hand, this invention is intended to include all isotopes of atoms in all compounds. The isotope-labeled compounds of this invention can generally be prepared using conventional techniques known in the art or by methods similar to those described in this application, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0067] This invention is intended to include all stereoisomers of compounds. The compounds of this invention may contain one or more chiral centers, and therefore these compounds (and their intermediates) may exist as racemic mixtures, pure stereoisomers (i.e., enantiomers or diastereomers), mixtures of concentrated stereoisomers, etc. Unless otherwise indicated, chiral compounds shown or named herein with undefined stereochemistry of the chiral center are intended to include any or all possible stereoisomer variants of the undefined stereocenter. The description or naming of a particular stereoisomer indicates that the indicated stereocenter has the specified stereochemistry; it should be understood that, unless otherwise indicated, small amounts of other stereoisomers may also exist, provided that the efficacy of the described or named compound is not eliminated by the presence of another stereoisomer.

[0068] On the other hand, the present invention is intended to include tautomers of all compounds. A tautomer is a proton that has shifted from one atom of a molecule to another atom of the same molecule, and non-limiting examples include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, etc.

[0069] On the other hand, the present invention provides a method for preparing compound (I):

[0070] The compounds of the present invention can be synthesized by the following scheme:

[0071] Option 1:

[0072]

[0073] HHT feedstock is hydrolyzed with sodium hydroxide to obtain 4'-DMHHT, which is then esterified to generate intermediate IM-1. Alternatively, HHT can be directly converted to intermediate IM-1 via sodium-hydrogen catalytic transesterification, and then esterified with anhydride or carboxylic acid to generate S-1 and S-2 type compounds.

[0074] Option 2:

[0075]

[0076] 4'-DMHHT is reacted with Wiberamide to give S-3 type compounds, then reacted with Grignard reagent to give S-4 type compounds, and then condensed with anhydride or carboxylic acid to generate S-5 and S-6 type compounds.

[0077] Option 3:

[0078]

[0079] HHT is reduced to S-7 type compounds by sodium borohydride and sodium borohydride acetate, then esterified with carboxylic acids to form S-8 type compounds, and further esterified with acid anhydrides or carboxylic acids to form S-5 and S-6 type compounds.

[0080] Option 4:

[0081]

[0082] 4'-DMHHT is condensed and amidated with an amino compound to generate intermediate IM-2, which is then condensed and esterified with an anhydride or carboxylic acid to generate S-5 and S-6 type compounds.

[0083] On the other hand, the present invention provides a pharmaceutical composition comprising any of the derivatives described above or their pharmaceutical salts, isotope labels, solvates, stereoisomers or prodrugs, and one or more pharmaceutically acceptable carriers or excipients.

[0084] On the other hand, the pharmaceutical composition provided by the present invention is suitable for oral administration or parenteral administration.

[0085] On the other hand, the present invention provides the use of any of the above-described derivatives or their pharmaceutical salts, isotope labels, solvates, stereoisomers or prodrugs, or the above-described pharmaceutical compositions in the preparation of antitumor drugs.

[0086] On the other hand, the present invention provides a medicament for treating or preventing diseases, characterized in that it comprises any of the above-described derivatives or their pharmaceutical salts, isotope labels, solvates, stereoisomers or prodrugs as active ingredients.

[0087] In some implementations, the disease is a tumor.

[0088] In some preferred embodiments, the tumor is one or more of the following: melanoma, prostate cancer, pancreatic cancer, leukemia, esophageal cancer, multiple myeloma, lymphoma, nasopharyngeal carcinoma, clear cell renal cell carcinoma, glioma, osteosarcoma, liver cancer, endometrial cancer, basal carcinoma, cervical cancer, laryngeal cancer, colorectal cancer, gastric cancer, and ovarian cancer.

[0089] The homoharringtonine derivative provided by this invention has excellent therapeutic effects on tumors while also being safer and having fewer toxic side effects.

[0090] Terminology Explanation

[0091] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0092] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 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, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc.Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Non-limiting examples of the substituents include D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, etc., preferably independently selected independently from one or more substituents selected from D atoms, halogens, C1-6 alkoxy groups, C1-6 haloalkyl groups, C1-6 haloalkoxy groups, C1-6 cycloalkyloxy groups, 3-6 membered heterocyclic oxy groups, hydroxyl groups, C1-6 hydroxyalkyl groups, cyano groups, amino groups, C3-6 cycloalkyl groups, 3-6 membered heterocyclic groups.

[0093] The term "alkylene" refers to an alkyl linking group, where one hydrogen atom of an alkyl group is further substituted, wherein the alkyl group is as defined above.

[0094] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Non-limiting examples of substituents include alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, preferably independently selected from one or more substituents chosen from the D atom, halogen, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 cycloalkyloxy, 3-6 membered heterocyclic oxy, hydroxy, C1-6 hydroxyalkyl, cyano, amino, C3-6 cycloalkyl, and 3-6 membered heterocyclic.

[0095] The term "alkenyl" refers to an alkenyl linking group, in which one of the hydrogen atoms of the alkenyl group is further replaced, wherein the alkenyl group is as defined above.

[0096] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. Non-limiting examples of the substituent include alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, preferably independently selected from one or more substituents chosen from the D atom, halogen, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 cycloalkyloxy, 3-6 membered heterocyclic oxy, hydroxy, C1-6 hydroxyalkyl, cyano, amino, C3-6 cycloalkyl, and 3-6 membered heterocyclic groups.

[0097] The term "ethynyl" refers to an ethynyl linking group, in which one of the hydrogen atoms of the ethynyl group is further substituted, wherein the ethynyl group is as defined above.

[0098] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The term "spirocycloalkyl" refers to a 5 to 20-membered polycyclic group sharing a single carbon atom (called the spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, they are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, they are 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of rings, alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups, preferably bicyclic or tricyclic, and more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused-ring alkyl groups. The term "bridged alkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, and may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Based on the number of rings, alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged-ring alkyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... wait.

[0099] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0100] The term "cycloalkylene" refers to a cycloalkyl linking group, where one hydrogen atom of the cycloalkyl group is further substituted, wherein the cycloalkyl group is as defined above.

[0101] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0102] The term "alkoxy group" refers to an alkoxy linkage group, in which one of the hydrogen atoms of the alkoxy group is further substituted, wherein the alkoxy group is as defined above.

[0103] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic heterocyclic group. The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, they can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the sulfur may be optionally substituted with oxygen (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.Preferably, the value is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9, or 10 yuan). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. The heterocyclic group includes heterocyclic groups (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: The heterocyclic group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0104] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0105]

[0106] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. Non-limiting examples of the substituent include alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl, preferably independently selected independently from one or more substituents selected from D atom, halogen, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 cycloalkyloxy, 3-6 membered heterocyclic oxy, hydroxy, C1-6 hydroxyalkyl, cyano, amino, C3-6 cycloalkyl, and 3-6 membered heterocyclic.

[0107] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0108]

[0109] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable linker. Non-limiting examples of the substituent include alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl, preferably independently selected independently from one or more substituents selected from D atom, halogen, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 cycloalkyloxy, 3-6 membered heterocyclic oxy, hydroxy, C1-6 hydroxyalkyl, cyano, amino, C3-6 cycloalkyl, and 3-6 membered heterocyclic.

[0110] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0111] The term "cycloalkyloxy" refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0112] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0113] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0114] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0115] The term “cycloalkylalkyl” refers to cycloalkyl-alkyl-, where cycloalkyl and alkyl are as defined above.

[0116] The term “heterocyclic alkyl” refers to heterocyclic-alkyl-, where heterocyclic and alkyl are as defined above.

[0117] The term “arylalkyl” refers to aryl-alkyl-, where aryl and alkyl are as defined above.

[0118] The term “heteroarylalkyl” refers to heteroaryl-alkyl-, where heteroaryl and alkyl are as defined above.

[0119] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0120] The term "alkanoyl" refers to alkyl-C(O)-, where the alkyl group is as defined above.

[0121] The term "alkoxyacyl" refers to alkyl-OC(O)-, where the alkyl group is as defined above.

[0122] The term "alkanoyloxy" refers to an alkyl group -C(O)-O-, wherein the alkyl group is as defined above.

[0123] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0124] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0125] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0126] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0127] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0128] The term "hydroxyl group" refers to -OH.

[0129] The term "thiol" refers to -SH.

[0130] The term "amino" refers to -NH2.

[0131] The term "cyano" refers to -CN.

[0132] The term "nitro" refers to -NO2.

[0133] The term "oxo" or "oxo" refers to "=O".

[0134] The term "carbonyl" refers to C=O.

[0135] The term "amide group" refers to -NH-C(O)-.

[0136] The term "alkylamide group" refers to a group in which an alkyl group is linked to other structures via an amide group, wherein the alkyl and amide groups are as defined above.

[0137] The term "alkoxyamide group" refers to a group in which an alkoxy group is linked to other structures via an amide group, where the alkoxy group and the amide group are as defined above.

[0138] The term "carboxyl group" refers to -C(O)OH.

[0139] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0140] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0141] In this invention, "optional" or "optionally" means that the events or circumstances described below may, but do not necessarily, occur. For example, "optionally alkyl-substituted heterocyclic groups" means that alkyl groups may, but do not necessarily, be present, and this description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

[0142] In this invention, "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the 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 (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0143] In this invention, any substitution on the aliphatic ring, aliphatic heterocyclic ring, aromatic ring, or aromatic heterocyclic ring refers to one or more hydrogen atoms (preferably up to 5, more preferably 1 to 3 hydrogen atoms) at any substituted position on the aliphatic ring, aliphatic heterocyclic ring, aromatic ring, or aromatic heterocyclic ring being independently substituted by one or more substituents.

[0144] The compounds in this patent application include their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this patent application that use "deuterium" or "tritium" instead of hydrogen, or use 18F-fluorine labeling (18F isotope) instead of fluorine, or use 11C-, 13C-, or 14C-enriched carbon (11C-, 13C-, or 14C-carbon labeling; 11C-, 13C-, or 14C-isotope) instead of carbon atoms are within the scope of this patent application. Such compounds can be used as analytical tools or probes, for example, in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds in this patent application refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds typically retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thus providing certain therapeutic advantages.

[0145] The compounds of this patent application may exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, transisomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds of this patent application may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this patent application. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This patent application specifies an isomer of a compound that can be prepared by asymmetric synthesis or with chiral auxiliaries. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it can form a salt of the diastereomer with a suitable optically active acid or base, and then the diastereomer can be resolved by conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0146] In the chemical structure of the compound described in this patent application, the bond " / " indicates that the configuration is not specified. That is, if a chiral isomer exists in the chemical structure, the bond " / " can be or or simultaneously contain both configurations.

[0147] The compounds of this patent application may exist in various tautomer forms, and all such forms are included within the scope of this patent application. The term "tautomer" or "tautomer form" refers to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. It includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactamimide, etc. All tautomer forms are within the scope of this patent application, and the naming of the compounds does not exclude any tautomer.

[0148] In this invention, "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0149] In this invention, "medicinal salt" refers to the salt of the compound of this invention. Such salts are safe and effective when used in mammals and have the required biological activity.

[0150] In this invention, "solvent" refers to the physical combination of a compound disclosed herein with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical combination includes hydrogen bonds. In some cases, for example, when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0151] In this invention, "prodrug" refers to a compound that can be converted in vivo under physiological conditions, such as by hydrolysis in the blood, to produce an active drug compound.

[0152] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0153] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0154] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0155] In this invention, "multiple" refers to two or more, such as an integer number of 2, 3, 4, 5, 6, 7, 8, etc.

[0156] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations. Attached Figure Description

[0157] Figure 1 Mouse safety test: Body weight change curves of mice in each group after continuous administration of HHT derivatives

[0158] Figure 2 Mean tumor growth curves for each experimental group in the RPMI 8226-Luc tibial orthotopic model pharmacodynamics trial. Detailed Implementation

[0159] The technical solution of the present invention will be further described in detail below with reference to specific implementation examples, but the implementation of the present invention is not limited thereto. Equivalent substitutions, combinations, improvements, or modifications made by those skilled in the art based on the description of the present invention should all be covered within the protection scope of the present invention.

[0160] Unless otherwise specified, the reagents, methods, and equipment used in this invention are commonly used in this technical field. Unless otherwise specified, the reagents and materials used in the following examples are commercially available products.

[0161] The chemical abbreviations used in this specification and examples generally follow the conventions used in the art and are defined as follows:

[0162] HHT represents homoharringtonine;

[0163] 4'-DMHHT represents 4'-demethylhomoharringtonine;

[0164] DMF stands for N,N-dimethylformamide;

[0165] DMSO stands for dimethyl sulfoxide;

[0166] 4-ppy represents 4-pyrrolidinylpyridine;

[0167] DCC stands for dicyclohexylcarbodiimide;

[0168] HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;

[0169] HPLC stands for High Performance Liquid Chromatography;

[0170] TLC stands for Thin Layer Chromatography;

[0171] LCMS stands for Liquid Chromatography-Polymerization.

[0172] Example 1: Synthesis of Derivative H3-4

[0173]

[0174] Compound H3-0 (150 mg, 0.24 mmol), lauric acid (95 mg, 0.48 mmol), 4-pyrrolylpyridine (71 mg, 0.48 mmol), and dicyclohexylcarbodiimide (99 mg, 0.48 mmol) were added to a 100 mL round-bottom flask. Then, 8 mL of dichloromethane was added, and the mixture was stirred at 50 °C for 8 hours. The reaction was then stopped, concentrated, and purified by preparative thin-layer chromatography. The purified compound was then obtained by rotary evaporation under reduced pressure to give compound H3-4. LCMS: m / z = 812.5 [M+H] +

[0175] Example 2: Synthesis of Derivative H3-5

[0176]

[0177] Compound H3-0 (200 mg, 0.32 mmol), n-heptanoic acid (83 mg, 0.64 mmol), 4-pyrrolylpyridine (94 mg, 0.64 mmol), and dicyclohexylcarbodiimide (131 mg, 0.64 mmol) were added to a 100 mL round-bottom flask. Then, 4 mL of dichloromethane was added, and the mixture was stirred at 45 °C for 6.5 hours. The reaction was then stopped, concentrated, and purified by preparative thin-layer chromatography. The purified compound was then obtained by rotary evaporation under reduced pressure to give compound H3-5. LCMS: m / z = 742.4 (M+1)

[0178] Example 3: Synthesis of Derivative H3-6

[0179]

[0180] Compound H3-0 (120 mg, 0.19 mmol), phenoxyacetic acid (58 mg, 0.38 mmol), 4-pyrrolylpyridine (56 mg, 0.38 mmol), and dicyclohexylcarbodiimide (78 mg, 0.38 mmol) were added to a 100 mL round-bottom flask. Then, 5 mL of dichloromethane was added, and the mixture was stirred at 50 °C for 12 hours. The reaction was then stopped, concentrated, and purified by preparative thin-layer chromatography. The crude product was further purified by high-performance liquid chromatography (HPLC) and lyophilized to give compound H3-6. LCMS: m / z = 764.2 [M+H] +

[0181] Example 4 Synthesis of Derivative H1-2

[0182]

[0183] Add homoharringtonine (200 mg, 0.37 mmol), n-heptanoic acid (95 mg, 0.73 mmol), 4-pyrrolylpyridine (108 mg, 0.73 mmol), and dicyclohexylcarbodiimide (151 mg, 0.73 mmol) to a 100 mL round-bottom flask, then add 5 mL of dichloromethane. Stir the mixture at room temperature for 12 hours, then stop the reaction. Concentrate the solution under reduced pressure by rotary evaporation and purify by preparative thin-layer chromatography to give compound H1-2. LCMS: m / z = 658.3 [M+H] +

[0184] Example 5: Synthesis of Derivative H2-1

[0185]

[0186] Add 4'-DMHHT (550 mg, 1.04 mmol), 4-pyrrolidinylpyridine (307 mg, 2.07 mmol), and dicyclohexylcarbodiimide (426 mg, 2.07 mmol) to a 100 mL round-bottom flask, then add 10 mL of ethanol. React at 80 °C for 10.5 hours, stop the reaction, concentrate, purify by silica gel column chromatography, and concentrate under reduced pressure to obtain compound H2-0.

[0187] H2-0 (200 mg, 0.36 mmol) was added to a 100 mL round-bottom flask, followed by 4 mL of acetic anhydride. The mixture was reacted at 90 °C for 21 hours. The solvent was concentrated to remove some of the solvent. Saturated sodium bicarbonate was added until alkaline, and ethyl acetate (20 mL * 3) was added for extraction. The mixture was separated, and the organic phase was collected. It was washed with saturated brine, collected again, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography. The crude product was then prepared by high-performance liquid chromatography and lyophilized to give compound H2-1. LCMS: m / z = 602.4 [M + H] +

[0188] Example 6 Synthesis of Derivative H2-2

[0189]

[0190] Add H2-O (100 mg, 0.18 mmol), nicotinic acid (56.7 mg, 0.36 mmol), 4-pyrrolylpyridine (53.28 mg, 0.36 mmol), and dicyclohexylcarbodiimide (74.16 mg, 0.36 mmol) to a 100 mL round-bottom flask, then add 4 mL of dichloromethane. Stir the mixture at 45 °C for 5 hours, then stop the reaction. Concentrate the mixture and purify it using preparative thin-layer chromatography. The crude product is then prepared by high-performance liquid chromatography and lyophilized to give compound H2-2. LCMS: m / z = 699.4 [M+H] +

[0191] Example 7 Synthesis of Derivative H4-1

[0192]

[0193] 4'-DMHHT (500 mg, 0.94 mmol) was added to a three-necked flask, followed by 4-pyrrolidinylpyridine (279 mg, 1.88 mmol) and dicyclohexylcarbodiimide (387 mg, 1.88 mmol). 8 mL of isopropanol was added, and the mixture was reacted at 80 °C for 5 hours. The reaction was then stopped, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give compound H4-0.

[0194] Crude H4-0 (120 mg, 0.21 mmol) was added to a three-necked flask, followed by 2 mL of acetic anhydride. The mixture was heated and stirred at 90 °C for 14.5 hours, after which the reaction was stopped. The solvent was removed by vacuum distillation, and saturated sodium bicarbonate was added to bring the solution to alkalinity. The solution was extracted three times with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography, and then prepared by high-performance liquid chromatography (HPLC). After lyophilization, compound H4-1 was obtained. LCMS: m / z 616.4 [M+H] +

[0195] Example 8 Synthesis of Derivative H6-1

[0196]

[0197] Homoharringtonine (200 mg, 0.37 mmol) was added to a 100 mL three-necked flask, followed by 60% NaH (5 mg, 0.11 mmol), and then 5 mL of phenoxyethanol. The mixture was stirred at room temperature for 1.5 hours, and the reaction was stopped. The pH was adjusted to 5 with 1 N dilute hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic phase was collected, and the aqueous phase was adjusted to pH 8 with ammonia. The mixture was extracted five times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain compound H6-0.

[0198] H6-0 (200 mg, 0.31 mmol) was added to a three-necked flask, followed by 2 mL of acetic anhydride. The mixture was heated and stirred at 90 °C for 8 hours, and the reaction was stopped. The solvent was removed by vacuum distillation, and saturated sodium bicarbonate was added to bring the solution to alkalinity. The mixture was extracted three times with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography, and then prepared by high-performance liquid chromatography (HPLC). After lyophilization, compound H6-1 was obtained. LCMS: m / z 694.2 [M+H] +

[0199] 1 HNMR (400MHz, CD3OD) δ7.31-7.23(m,2H),6.99-6.88(m,3H),6.68(d,J=12Hz,2H),5. 93-4.79(m,3H),5.23(s,1H),4.37-4.28(m,1H),4.27-4.07(m,3H),3.94-3.81(m,1H ),3.71(s,3H),3.24-3.77(m,4H),2.57-2.43(m,1H),2.16(d,J=16Hz,1H),2.08-1.8 9(m,7H),1.86-1.74(m,2H),1.72-1.55(m,2H),1.44-1.34(m,9H),1.31-1.24(m,1H).

[0200] Example 9: Synthesis of Derivative H7-1

[0201]

[0202] Homoharringtonine (200 mg, 0.37 mmol) was added to a 100 mL three-necked flask, followed by 60% NaH (5 mg, 0.11 mmol), and then 5 mL of 3-fluorophenylethanol. The mixture was stirred at room temperature for 3.5 hours, and the reaction was stopped. The pH was adjusted to 5 with 1 N dilute hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic phase was collected, and the aqueous phase was adjusted to pH 8 with ammonia. The mixture was extracted five times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain compound H7-0.

[0203] H7-0 (127 mg, 0.19 mmol) was added to a three-necked flask, followed by 2 mL of acetic anhydride. The mixture was heated and stirred at 90 °C for 4 hours, and the reaction was stopped. The solvent was removed by vacuum distillation, and the mixture was brought to alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared by high-performance liquid chromatography and lyophilized to give compound H7-1. LCMS: m / z 696.2 [M+H] +

[0204] Example 10 Synthesis of Derivative H9-1

[0205]

[0206] Add homoharringtonine (200 mg, 0.37 mmol) and NaH (4 mg, 0.11 mmol) to a 100 mL three-necked flask, then add 5 mL of 3-methylbenzyl alcohol. Stir at room temperature for 2 hours, then stop the reaction. Add 1 N hydrochloric acid to pH 5, extract with ethyl acetate (20 mL * 2), collect the organic phase, add ammonia to the aqueous phase to pH 8, extract with dichloromethane (20 mL), combine the organic phases, wash with water, collect the organic phase, dry to anhydrous sodium sulfate, concentrate, purify by preparative thin-layer chromatography, and rotary evaporate under reduced pressure to give compound H9-0.

[0207] Add H9-0 (100 mg, 0.16 mmol) to a 100 mL three-necked flask, then add 2 mL of acetic anhydride. Stir at 90 °C for 8 hours, then stop the reaction. Concentrate to remove some solvent, add saturated sodium bicarbonate to pH = 8, extract with dichloromethane (20 mL * 2), separate the layers, collect the organic phase, wash with saturated sodium chloride aqueous solution, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, prepare by high performance liquid chromatography, lyophilize to obtain compound H9-1. LCMS: m / z = 678.4 [M + H] +

[0208] Example 11 Synthesis of derivatives H10-0 and H10-1

[0209]

[0210] Add homoharringtonine (200 mg, 0.37 mmol) and NaH (4.4 mg, 0.18 mmol) to a 100 mL three-necked flask, then add 4 mL of cinnamyl alcohol. Stir at room temperature for 2.5 h, then stop the reaction. Add 1 N hydrochloric acid to pH 5, extract with ethyl acetate (20 mL * 2), collect the organic phase, add ammonia to the aqueous phase to pH 8, extract with dichloromethane (20 mL), combine the organic phases, wash with water, collect the organic phase, dry to anhydrous sodium sulfate, concentrate, purify by preparative thin-layer chromatography, and rotary evaporate under reduced pressure to give compound H10-0. LCMS: m / z = 648.3 [M + H] +

[0211] Add H10-0 (240 mg, 0.37 mmol) to a 100 mL three-necked flask, then add 2 mL of acetic anhydride. Stir at 90 °C for 10 hours, then stop the reaction. Concentrate to remove some solvent, add saturated sodium bicarbonate to pH = 8, extract with dichloromethane (20 mL * 2), separate the layers, collect the organic phase, wash with saturated sodium chloride aqueous solution, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, prepare by high performance liquid chromatography, lyophilize to obtain compound H10-1. LCMS: m / z = 690.2 [M + H] +

[0212] 1 HNMR(400MHz, CDCl3)δ7.40-7.35(m,2H),7.34-7.29(m,2H),7.28-7.23(m,1H),6.66-6.57(m,3H),6.2 4-6.14(m,1H),6.04-6.57(d,J=8HZ,1H),5.87(s,2H),5.00(s,1H),4.69-4.53(m,2H),3.92-3.86(m,1H ),3.78(s,3H),3.64-3.45(m,1H),3.28-3.19(m,1H),2.99-2.90(m,2H),2.56-2.51(m,1H),2.42-2.32 (m,2H),2.13-2.07(m,2H),2.03-1.89(m,6H),1.66-1.59(m,2H),1.41-1.27(m,9H),1.16-1.06(m,1H).

[0213] Example 12 Synthesis of Derivative H12-1

[0214]

[0215] Add homoharringtonine (300 mg, 0.55 mmol) and NaH (6.6 mg, 0.16 mmol) to a 100 mL three-necked flask, then add 5 mL of propylene glycol. Stir at room temperature for 4 h, then stop the reaction. Add 1 N hydrochloric acid to pH 5, extract with ethyl acetate (20 mL * 2), collect the organic phase, add ammonia to the aqueous phase to pH 8, extract with dichloromethane (20 mL), combine the organic phases, wash with water, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and give compound H12-0, which can be directly used for the next reaction.

[0216] Crude H12-0 (200 mg, 0.34 mmol) was added to a 100 mL three-necked flask, followed by 4 mL of acetic anhydride. The mixture was stirred at 90 °C for 15 hours, and the reaction was stopped. The solvent was concentrated to remove some of the solvent, and saturated sodium bicarbonate was added to adjust the pH to 8. Dichloromethane (20 mL x 2) was added for extraction. The mixture was separated, and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution, collected again, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography. The crude product was then prepared by high-performance liquid chromatography and lyophilized to give compound H12-1. LCMS: m / z = 674 [M+H] +

[0217] Example 13 Synthesis of derivatives H13-1, H13-2, H13-3 and H13-4

[0218]

[0219] Add homoharringtonine (400 mg, 0.73 mmol), 7 mL N-Boc aminoethanol, and 2 mL dichloromethane to a 100 mL round-bottom flask, then add NaH (15 mg, 0.38 mmol). React at room temperature for 5 hours, then stop the reaction. Add 1 N hydrochloric acid to the reaction solution until pH = 3, extract with ethyl acetate (50 mL), collect the organic phase, add ammonia to the aqueous phase until pH = 8, extract with dichloromethane (50 mL * 2), combine the organic phases, concentrate, and prepare by high-performance liquid chromatography (HPLC). Lyophilize to obtain compound H13-1. LCMS: m / z = 675.3 [M + H] +

[0220] Add H13-1 (50 mg, 0.07 mmol) to a 100 mL round-bottom flask, then add 2 mL of acetic anhydride. Heat and stir at 85 °C for 21 hours, then stop the reaction. Concentrate to remove some solvent, add saturated sodium bicarbonate to pH = 8, add ethyl acetate (15 mL) for extraction, separate the liquid and liquid phases, collect the organic phase, wash with water, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, prepare by high performance liquid chromatography, lyophilize, and obtain compound H13-2, LCMS: m / z = 717.3 [M+H].+ And compound H13-4, LCMS: m / z = 759.4 [M+H] +

[0221] Add H13-1 (50 mg, 0.07 mmol) to a 100 mL round-bottom flask, then add 1 mL of ethyl acetate to dissolve it, followed by 1 mL of ethyl hydrochloride solution. Stir at room temperature for 3 hours, then stop the reaction. Concentrate under reduced pressure to remove the solvent, giving compound H13-3. LCMS: m / z = 652 [M+H] +

[0222] Example 14 Synthesis of Derivative H13-5

[0223]

[0224] Add 4'-DMHHT (600 mg, 1.13 mmol), N-tert-butoxycarbonylaminopentanol (344.1 mg, 1.70 mmol), dicyclohexylcarbodiimide (466 mg, 2.26 mmol), and 4-pyrrolidinylpyridine (1003 mg, 6.78 mmol) to a 100 mL three-necked flask, then add 10 mL of dichloromethane. React at room temperature for 6 hours, then stop the reaction. Column chromatography yields a nearly colorless oily substance H13-IM-1.

[0225] H13-IM-1 (229 mg, 0.22 mmol) was added to a 100 mL three-necked flask, followed by 8 mL of acetic anhydride. The mixture was heated and stirred at 80 °C for 12 hours, and the reaction was stopped. The solvent was concentrated to remove some of the solvent, and saturated sodium bicarbonate was added to adjust the pH to 8. Ethyl acetate (15 mL * 3) was added for extraction. The mixture was separated, and the organic phase was collected. The organic phase was washed with water, collected again, dried over anhydrous sodium sulfate, concentrated, and prepared by high-performance liquid chromatography (HPLC). The resulting lyophilized compound was given as H13-5. LCMS: m / z = 759.4 [M+H] +

[0226] Example 15 Synthesis of Derivative H13-6

[0227]

[0228] Add 4'-DMHHT (400 mg, 0.75 mmol), N-Boc aminoheptanol (235 mg, 1.02 mmol), dicyclohexylcarbodiimide (931 mg, 4.58 mmol), and 4-pyrrolidinylpyridine (1.34 g, 9.04 mmol) to a 100 mL three-necked flask, then add 7 mL of dichloromethane. React at room temperature for 6 hours, then stop the reaction, dilute with water, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatography to obtain a nearly colorless oil H13-IM-2.

[0229] H13-IM-2 (108 mg, 0.10 mmol) was added to a 100 mL three-necked flask, followed by 4 mL of acetic anhydride. The mixture was heated and stirred at 80 °C for 22 hours, after which the reaction was stopped. The solvent was concentrated to remove some of the solvent, and saturated sodium bicarbonate was added to adjust the pH to 8. Ethyl acetate (15 mL * 3) was added for extraction. The mixture was separated, and the organic phase was collected. The organic phase was washed with water, collected again, dried over anhydrous sodium sulfate, concentrated, and prepared by high-performance liquid chromatography (HPLC). The resulting lyophilized compound was H13-6. LCMS: m / z = 787.3 [M+H] +

[0230] Example 16 Synthesis of derivatives H15-1, H15-2 and H17-2

[0231]

[0232] Add 4'-DMHHT (500 mg, 0.93 mmol) and HATU (393 mg, 1.03 mmol) to a 100 mL three-necked flask, then add 5 mL of N,N-dimethylformamide to dissolve it. Next, add a solution of dimethylhydroxylamine hydrochloride (137.5 mg, 1.41 mmol) and N,N-diisopropylethylamine (0.82 mL, 4.70 mmol) dissolved in 5 mL of N,N-dimethylformamide. React at room temperature for 0.5 hours. Extract with water (30 mL) and ethyl acetate (50 mL), collect the organic phase, wash the organic phase with saturated sodium chloride aqueous solution, collect the organic phase, concentrate, purify by silica gel column chromatography, and concentrate under reduced pressure to give compound H17-2. LCMS: m / z = 575.2 [M+H] +

[0233] Add 100 mg (0.34 mmol) of H17-2 to a 100 mL three-necked flask, add 4 mL of tetrahydrofuran at 0 °C, purge three times with nitrogen, then add 3.48 mL (3.48 mmol) of methyl magnesium bromide dropwise. Stir at 0 °C for 1 hour to stop the reaction. Quench with water, extract with ethyl acetate, separate the layers, collect the organic phase, wash with water, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, purify by preparative thin-layer chromatography, concentrate under reduced pressure to give compound H15-1. LCMS: m / z = 530.2 [M+H] +

[0234] H15-1 (60 mg, 0.11 mmol) was added to a 100 mL three-necked flask, followed by 3 mL of acetic anhydride. The mixture was heated and stirred at 85 °C for 19 hours, after which the reaction was stopped. Saturated sodium bicarbonate solution was added to bring the solution to alkalinity. The mixture was extracted with ethyl acetate, concentrated, and the crude product was prepared by high-performance liquid chromatography (HPLC). The product was then lyophilized to give compound H15-2. LCMS: m / z = 572.3 [M+H] +

[0235] Example 17 Synthesis of Derivative H16-1

[0236]

[0237] Add 4'-DMHHT (200 mg, 0.38 mmol), 4-pyrrolidinylpyridine (111 mg, 0.75 mmol), and dicyclohexylcarbodiimide (155 mg, 0.75 mmol) to a 100 mL three-necked flask, then add 3 mL of 2-octanol. Stir at 80 °C for 3 hours, stop the reaction, concentrate, purify by preparative thin-layer chromatography, and concentrate under reduced pressure to obtain crude product H16-0.

[0238] H16-0 (120 mg, 0.19 mmol) was added to a 100 mL three-necked flask, followed by 2 mL of acetic anhydride. The mixture was heated and stirred at 90 °C for 12 hours, and the reaction was stopped. Saturated sodium bicarbonate was added to bring the solution to alkalinity. The mixture was extracted with ethyl acetate (20 mL * 3), washed with water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was then subjected to high-performance liquid chromatography (HPLC) and lyophilized to obtain compound H16-1. LCMS: m / z = 686.4 [M + H] +

[0239] 1 HNMR(400MHz,CD3OD)δ6.79-6.74(m,2H),6.03-5.99(m,1H),5.95-5.90(m,2H),5.33(s,1H),4.89-4.8 2(m,2H),4.75-4.72(m,1H),4.15(d,J=8.0Hz,1H),3.81(s,3H),3.48-3.46(m,1H),3.33-3.32(m,2H),3 .18-3.13(m,1H),2.66-2.64(m,1H),2.23-2.12(m,4H),1.95-1.88(m,4H),1.64-1.62(m,2H),1.55-151 (m,1H),1.49-1.38(m,7H),1.35-1.33(m,3H),1.29-1.27(m,8H),1.16-1.14(m,4H),0.91-0.86(m,3H).

[0240] Example 18 Synthesis of Derivative H17-1

[0241]

[0242] Add 4'-DMHHT (200 mg, 0.38 mmol), N-methylheptylamine (73 mg, 0.56 mmol), N,N-diisopropylethylamine (97 mg, 0.75 mmol), and HATU (202 mg, 0.56 mmol) to a 100 mL three-necked flask, then add 4 mL of tetrahydrofuran. Stir at room temperature for 3 hours, stop the reaction, concentrate, purify by preparative thin-layer chromatography, and rotary evaporate under reduced pressure to obtain compound H17-0.

[0243] H17-0 (120 mg, 0.19 mmol) was added to a 100 mL three-necked flask, followed by 3 mL of acetic anhydride. The mixture was stirred at 90 °C for 17.5 hours, and the reaction was stopped. After concentration, the mixture was purified by preparative thin-layer chromatography. The crude product was then subjected to high-performance liquid chromatography (HPLC) and lyophilized to obtain compound H17-1. LCMS: m / z = 685.4 [M+H] +

[0244] Example 19 Synthesis of derivatives H18-1, H18-2 and H18-3

[0245]

[0246] Add H15-1 (33 mg, 0.06 mmol) to a 100 mL three-necked flask, then add 2 mL of methanol. Add sodium borohydride acetate (52.9 mg, 0.25 mmol) and sodium borohydride (59.26 mg, 1.56 mmol) at 0 °C. React at 0 °C for 10 min. Prepare by high-performance liquid chromatography (HPLC), and lyophilize to obtain compound H18-1. LCMS: m / z = 532.2 [M+H] +

[0247] H18-1 (90 mg, 0.17 mmol) dissolved in 7 mL of dichloromethane was added to a 100 mL three-necked flask containing acetic acid (51 mg, 0.85 mmol), 4-pyrrolylpyridine (126 mg, 0.85 mmol), and dicyclohexylcarbodiimide (175 mg, 0.85 mmol). The mixture was stirred at -10 °C for 30 min, then automatically warmed to room temperature and stirred for 8.5 h. The mixture was purified by preparative thin-layer chromatography, and the crude product was further purified by high-performance liquid chromatography (HPLC), lyophilized, and the compounds H18-2 (m / z = 616.3 [M+H]) were obtained. + And compound H18-3, m / z = 574.3 [M+H] +

[0248] BS-HH-002 Prepared according to Example 2 in the specification of patent CN103635476A.

[0249] H3-0 Prepared according to Example 66 in the specification of US20040006064A1.

[0250] Biological Test Example 1: Determination of Antitumor Activity

[0251] Biological Test Example 1-1: Assay for Anti-HepG-2 Liver Cancer Cell Activity

[0252] The inhibitory effect of the compound on tumor cell proliferation was detected using the CCK8 assay. A certain number of HepG2 cells in logarithmic growth phase were seeded in 96-well plates and cultured for 24 h. Different concentrations of drug-containing culture medium were then added. The compound concentration started at 1000 nM and was serially diluted 3-fold, resulting in 9 concentration points. Each concentration was tested in triplicate. Cell-free wells were included as a negative control. Tumor cells were cultured at 37℃ and 5% CO2 for 72 h, then CCK8 solution was added. After approximately 2 h of further culture, the OD450 value was measured using a microplate reader. Cell proliferation inhibition rate = (OD value of negative control group - OD value of experimental group) / (OD value of experimental group - OD value of blank group). The IC50 curve was fitted using GraphpadPrism software and a four-parameter logistic regression model was used to calculate the IC50 value. The experimental results are shown in Table 1-1. In Table 1-1, the IC50 values ​​of the compound are... 50 The classification is as follows: A represents IC. 50 ≤50nM; B indicates 50nM < IC 50 ≤100nM; C indicates 100nM < IC 50 ≤500nM; D indicates IC 50 >500nM.

[0253] Table 1-1

[0254] compound <![CDATA[IC 50 ]]> HHT B BS-HH-002 A H3-0 A H3-4 D H3-5 C H3-6 A H1-2 B H6-1 A H7-1 A H9-1 A H10-0 A H10-1 A H12-1 A H13-1 D H13-2 C H13-4 D H13-5 A H13-6 A H15-1 C H16-1 A H17-2 D H18-2 D H18-3 D

[0255] Biological Test Example 1-2: Assay for the Activity of Anti-Multiple Myeloma Cells RPMI 8226

[0256] The inhibitory effect of the compound on tumor cell proliferation was detected using the CCK8 assay. A certain number of RPMI 8226 cells in logarithmic growth phase were seeded in 96-well plates and cultured for 24 h. Different concentrations of drug-containing culture medium were then added. The compound concentration started at 1000 nM and was serially diluted 3-fold, resulting in 9 concentration points. Each concentration was tested in triplicate. Cell-free wells were included as a negative control. Tumor cells were cultured at 37℃ and 5% CO2 for 72 h, then CCK8 solution was added. After approximately 2 h of further culture, the OD450 value was measured using a microplate reader. Cell proliferation inhibition rate = (OD value of negative control group - OD value of experimental group) / (OD value of experimental group - OD value of blank group). The IC50 curve was fitted using GraphpadPrism software and a four-parameter logistic regression model was used to calculate the IC50 value. The experimental results are shown in Table 1-2. In Table 1-2, the IC50 values ​​of the compound are... 50 The classification is as follows: A represents IC. 50 ≤50nM; B indicates 50nM < IC 50 ≤100nM; C indicates 100nM < IC 50 ≤500nM; D indicates IC 50 >500nM.

[0257] Table 1-2

[0258]

[0259]

[0260] Biological Test Examples 1-3: K562 Activity Assay for Anti-Chronic Myeloid Leukemia Cells

[0261] The inhibitory effect of the compound on tumor cell proliferation was detected using the CCK8 assay. A certain number of K562 cells in logarithmic growth phase were seeded in 96-well plates and cultured for 24 h. Then, different concentrations of drug-containing culture medium were added. The compound concentration started at 1000 nM and was serially diluted 3-fold, resulting in 9 concentration points. Each concentration was tested in triplicate. Cell-free wells were included as a negative control. Tumor cells were cultured at 37℃ and 5% CO2 for 72 h, then CCK8 solution was added. After approximately 2 h of further culture, the OD450 value was measured using a microplate reader. Cell proliferation inhibition rate = (OD value of negative control group - OD value of experimental group) / (OD value of experimental group - OD value of blank group). The IC50 curve was fitted using GraphpadPrism software and a four-parameter logistic regression model was used to calculate the IC50 value. The experimental results are shown in Tables 1-3. In Tables 1-3, the IC50 values ​​of the compounds are... 50 The classification is as follows: A represents IC. 50 ≤50nM; B indicates 50nM < IC 50≤100nM; C indicates 100nM < IC 50 ≤500nM; D indicates IC 50 >500nM.

[0262] Table 1-3

[0263] compound <![CDATA[IC 50 ]]> HHT B BS-HH-002 A H3-0 A H3-6 A H1-2 C H6-1 A H7-1 A H9-1 A H10-0 A H10-1 A H12-1 C H13-1 C H13-5 A H13-6 A H15-1 C H16-1 A H17-2 D H18-2 D H18-3 D

[0264] Biological Test Example 2: In Vitro Plasma and Liver Microsomal Metabolic Stability Test

[0265] 1. In vitro plasma stability

[0266] 198 μL of plasma (human / KM mouse) was mixed with 2 μL of 200 μM H16-1 solution by vortexing and incubated at 37°C for 0 min, 5 min, 15 min, and 30 min. At each time point, 30 μL of plasma sample was collected, the residual concentration was measured, and the degradation rate of the compound was calculated. In vitro plasma stability can predict the metabolic degradation of compounds in human plasma. Generally, compounds with improved metabolic stability degrade more slowly in plasma. Slower degradation in plasma usually leads to a longer duration of action and / or higher blood drug concentrations, thereby reducing the frequency of dosing and / or the dosage, and thus exhibiting better drug development potential.

[0267] The degradation rate of homoharringtonine derivatives in mouse plasma is shown in Table 2-1.

[0268] Table 2-1

[0269]

[0270] 2. Hepatic microsomal metabolic stability

[0271] 182 μL PBS + 10 μL NADPHA solution + 2 μL NADPH B solution + 1 μL 200 μM H16-1 solution were mixed by vortexing and pre-incubated at 37°C for 5 min. Then, 5 μL of liver S9 / liver microsomes were added, mixed, and incubated at 37°C for 0 min, 5 min, 15 min, and 30 min. At each time point, 30 μL was taken to determine the remaining concentration and calculate the degradation rate of the compound. Hepatic microsomal metabolic stability can predict the metabolic degradation of compounds in the human liver. Generally, compounds with improved metabolic stability are degraded more slowly in liver microsomes. Slower degradation in liver microsomes usually leads to a longer duration of action and / or higher blood drug concentrations, thereby reducing the dosing frequency and / or dosage, and thus having better drug development potential.

[0272] The degradation rate of homoharringtonine derivatives in mouse liver microsomes is shown in Table 2-2.

[0273] Table 2-2

[0274]

[0275] Biological Test Example 3: Mouse Safety Test

[0276] 1. Test Methods

[0277] Female SPF-grade BALB / c-nu mice (provided by Chengdu Yaokang Biotechnology Co., Ltd.) aged 42-56 days were intravenously injected with BS-HH-002 at a dose of 6 mg / kg, HHT derivative H16-1 at a dose of 6 mg / kg, and HHT derivative H15-2 at a dose of 8 mg / kg, once daily for 10 consecutive days, with 3 animals in each dose group. Animal condition and weight changes were monitored during the administration period.

[0278] 2. Test Results

[0279] Table 4 shows the changes in body weight in mice after 10 days of continuous administration of homoharringtonine (HHT) derivatives. Among them, the animals in the H15-2 continuous administration group (8 mg / kg) showed a decrease in body temperature and reduced activity on the second day, and a significant decrease in body weight on the third day, so the administration was stopped; the animals in the BS-HH-002 continuous administration group (6 mg / kg) showed a significant trend of decreasing body weight, so the administration was stopped on the 7th day.

[0280] The weight change curves of mice after continuous administration of homoharringtonine (HHT) derivatives H16-1, H15-2, and BS-HH-002 are shown in the attached figure. Figure 1 As shown.

[0281] Biological Test Example 4: Canine Safety Test

[0282] 1. Test Methods

[0283] Adult male Beagle dogs were acclimatized for 5-7 days and then administered the drug via intravenous bolus injection over 1 hour using an infusion pump, after which the animals were observed. Blood pressure and heart rate were continuously measured and recorded for 6 hours after the start of administration. Plasma samples were collected at different time points to determine the concentration of the hypotensive toxicant 4'-DMHHT (the main metabolite of HHT in the body). The dosage was an equimolar dose of 0.4 mg / kg HHT, administered in 50 mL volumes.

[0284] 2. Test Results

[0285] The effects of intravenous injection of each compound in Beagle dogs are shown in Table 4-1.

[0286] Table 4-1

[0287]

[0288] The concentrations of the toxic substance 4'-DMHHT in plasma at each time point are shown in Table 4-2 (Note: BLOQ indicates below the lower limit of quantitation).

[0289] Table 4-2

[0290]

[0291] Biological Test Example 5: Pharmacodynamic Test of RPMI 8226-Luc Tibial Orthotopic Model

[0292] The in vivo efficacy of homoharringtonine (HHT) and its derivatives was evaluated using the RPMI 8226-Luc tibial inoculation orthotopic model (multiple myeloma).

[0293] 1. Cell Culture

[0294] RPMI 8226-Luc (KH-00091P6-190415) cells were cultured in IMDM (HyClone, Lot No. AJ30762634) medium containing 10% fetal bovine serum (Gibco, Lot No. 2544621CP). RPMI 8226-Luc cells in the exponential growth phase were collected and resuspended in PBS to a suitable concentration for inoculation into the right tibia of nude mice.

[0295] 2. Animal modeling and grouping

[0296] Female 6-9 week old SPF-grade NOG mice were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. (VRL).

[0297] Each mouse will be inoculated with RPMI8226-Luc cells (5 × 10⁶ cells) in 25 μL PBS via tibial injection (right tibia). 5 cell).

[0298] Imaging was performed 8 days after tumor cell inoculation. All mice underwent in vivo bioluminescence imaging. Eighteen mice were randomly assigned to three experimental groups of six mice each based on their signal strength (Total Flux, photosns / sec / cm2) and body weight. The day of group assignment was designated as Day 0.

[0299] 3. Animal administration

[0300] On Day 1, the drugs were administered according to the experimental design. Detailed administration methods, dosages, and routes of administration are shown in the table below.

[0301]

[0302] 4. Animal Imaging

[0303] In this experiment, tumor growth was monitored by in vivo bioluminescence imaging in mice. The imaging system used was the IVIS Lumina III mouse in vivo imaging system (PerkinElmer, USA).

[0304] 5. Experimental Results

[0305] Table 2 shows the changes in tumor volume in each group from the start of the experiment to the end of the experiment. The mean tumor growth curve is attached. Figure 2 As shown.

[0306] Table 5

[0307]

Claims

1. A homoharringtonine alkaloid derivative of formula (Ⅰ): Or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein: X is -O-, -CHR X -or-NR X -; R X Is it H or C? 1-6 alkyl; L may not exist, or L may be optionally represented by 0 to 3 identical or different R. L Replacement of H, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Alkyloxy; R L Each is independently H, oxo, or C. 1-3 alkyl; R 1 It is H or -C(O)-R 5 ; R 2 Is it H or C? 1-6 Alkyl group; R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted H, hydroxyl, amino, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkoxy acyl, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy group, C 1-10 Alkoxyamide group, C 1-10 Alkylamide group, 5-10 heteroaryl group or 5-10 heteroaryloxy group, wherein the heteroaryl group contains at least one nitrogen atom; R 3a Each is independently H, halogen, C 1-10 Alkyl, C 1-10 Alkoxy acyl or C 1-10 Alkoxy; by The key indicated is either a single bond or a double bond; when When it is a single bond, R 4 Is it a hydroxyl group or a C? 1-10 Alkyloxy; when When it is a double bond, R 4 It is oxygenation; R 5 It can be optionally used by 0 to 3 identical or different Rs. 5a Replacement of H, C 1-20 Alkyl or 5-10-membered heteroaryl, wherein the heteroaryl contains at least one nitrogen atom; R 5a Each is independently H, halogen, C 1-10 Alkyl, C 1-10 Alkyloxy, 5-10 heteroaryloxy or C 5-10 aryloxy group; When R 1 H is H, L is C 1-10 Alkylene or C 2-10 When it is alkenyl, R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted amino groups, C 5-10 Aryl, C 5-10 aryloxy or C 1-10 Alkoxyamide group; When R 5 When L is methyl or 5-10 heteroaryl, L is not methylene.

2. The derivative of claim 1 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein: R X It is H or methyl; when When it is a single bond, R 4 It is a hydroxyl or acetoxy group; when When it is a double bond, R 4 It is oxygenation; R 3 It can be optionally used by 0 to 3 identical or different Rs. 3a Substituted H, amino, C 1-10 Alkoxy acyl, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy or C 1-10 Alkoxyamide group; R 3a Each is independently H, halogen, C 1-10 Alkyl or C 1-10 Alkoxy acyl group; R 5 It can be optionally used by 0 to 3 identical or different Rs. 5a Replacement of H, C 1-20 Alkyl or 5-10-membered heteroaryl, wherein the heterocyclic or heteroaryl group contains one nitrogen atom; R 5a Each is independently H, halogen, or C. 5-10 Aryloxy group.

3. The derivative of claim 1 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein the derivative has the chemical structure of formula (II): in, X, L, R 1 and R 3 As defined in claim 1.

4. The derivative of claim 3 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein: X is -O- or -CHR X -; R X It is H; L may not exist, or L may be optionally represented by 0 to 3 identical or different R. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl; R L Each is independently either H or methyl; R 3 It is H, C 1-10 Alkyloxy, C 5-10 Aryl, C 5-10 aryloxy or C 1-10 Alkoxyamide group; R 3a Is it H, halogen, or C? 1-10 alkyl; R 5 It can be optionally used by 1 R 5a Replacement of H or C 1-20 alkyl; R 5a Is it H or C? 5-10 aryloxy group; Preferably, R 5a It is H or phenoxy.

5. The derivative of claim 4 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein: X is -O-; L can be optionally represented by 0 to 3 identical or different Rs. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl; R 5 It can be optionally used by 1 R 5a Substituted H or methyl; R 5a It is H or phenoxy; When L is C 1-3 When alkylene, R 3 Not H.

6. The derivative of claim 4 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein the derivative has the chemical structure of formula (III): in, X, L, and R 3 As defined in claim 4.

7. The derivative of claim 6 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein: L may not exist, or L may be optionally represented by 0 to 3 identical or different R. L Replacement of H, C 1-10 Alkylene or C 2-10 alkenyl; R L Each is independently either H or methyl; R 3 It is H, C 5-10 Aryl or C 5-10 aryloxy group; R 3a Is it H, halogen, or C? 1-3 alkyl; Preferably, R 3 It is H, phenyl, or phenoxy.

8. The derivative or pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug according to any of the preceding claims, wherein the derivative has a chemical structure of formula (IIa), (IIb), (IIc), or (IId): in, L, R 1 and R 3a As defined in claim 1.

9. The derivative of claim 1 or its pharmaceutical salt, isotope label, solvate, stereoisomer, or prodrug, wherein the derivative is selected from:

10. A pharmaceutical composition comprising a derivative as described in any of the preceding claims or a pharmaceutical salt thereof, an isotope label, a solvate, a stereoisomer or a prodrug, and one or more pharmaceutically acceptable carriers or excipients.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutical composition is suitable for oral or parenteral administration.

12. Use of the derivatives of any one of claims 1-9 or their pharmaceutical salts, isotope labels, solvates, stereoisomers or prodrugs, or the pharmaceutical composition of claim 10 in the preparation of an antitumor drug.

13. The use according to claim 12, characterized in that, The tumor is one or more of the following: melanoma, prostate cancer, pancreatic cancer, leukemia, esophageal cancer, multiple myeloma, lymphoma, nasopharyngeal carcinoma, clear cell renal cell carcinoma, glioma, osteosarcoma, liver cancer, endometrial cancer, basal carcinoma, cervical cancer, laryngeal cancer, colorectal cancer, gastric cancer, and ovarian cancer.

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