Camptothecin derivative

Abstract

The invention provides a compound as shown in a formula (I) or pharmaceutically acceptable salt, a pharmaceutical composition, a preparation method of the compound, and application of the compound in the anti-tumor aspect. # imgabs0 #

Description

[0001] The present invention claims priority to and the benefit of Chinese patent application No. 202310802669.1, filed with the State Intellectual Property Office of China on June 30, 2023, entitled “Camptothecin Derivatives”. The entire text of the above-mentioned prior application is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a novel camptothecin compound or a pharmaceutically acceptable salt thereof, and use of a pharmaceutical composition containing the same as an anti-tumor drug. Background Art

[0003] Camptothecin is a quinoline alkaloid extracted from Camptotheca acuminata, a plant of the Chinese blueberry family. Due to its significant cytotoxic activity, it is often used in cancer treatment-related research. Subsequent related mechanism studies have shown that camptothecin has the activity of inhibiting topoisomerase I. It can bind to the complex of topoisomerase I and DNA to form a stable ternary complex, thereby hindering DNA breakage mediated by topoisomerase I, and then blocking DNA replication, transcription and repair processes, ultimately leading to cell cycle arrest and cell apoptosis.

[0004] Early clinical studies have shown that camptothecin has problems such as low solubility, poor chemical stability, and significant toxic side effects, which ultimately hinder its clinical application. Subsequently, camptothecin derivatives such as topotecan and irinotecan obtained by modifying camptothecin have been successfully used to treat malignant tumors such as ovarian cancer, lung cancer, and colorectal cancer. Despite this, these clinical drugs still have problems such as low solubility and poor chemical stability leading to low oral bioavailability, as well as the occurrence of serious clinical adverse reactions such as vomiting and bone marrow suppression. Therefore, improving the physical and chemical properties of camptothecin drugs and increasing their activity and safety are still issues that need to be urgently addressed. Summary of the invention

[0005] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] R 1 Selected from N(R x )(R y ), OR z , halogen or CN, said R x , R y , R zEach independently selected from H or L 1 -R k , L 1 Selected from a bond or C=O, R k Selected from one or more R 1a Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2;

[0009] R 2 is selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2 is optionally replaced by one or more R 2a replace;

[0010] R 3 is selected from H, halogen, CN, or R 2 , R 3 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by one or more R 3a replace;

[0011] R 5 is selected from H, halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or C=NL 2 -R e , R 6 , R 7 Each is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, L 2 Select from bond or O, R e is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, each of which is a C1-C3 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 5a replace;

[0012] R 4 Selected from H, or R 4 , R 5Together with the atoms to which they are attached, they form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring, wherein the 5-6 membered carbocyclic ring or the 5-6 membered heterocyclic ring is optionally Replacement, R 8 , R 9 Each is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0013] Every R 1a , R 2a , R 3a , R 5a independently selected from D, halogen, CN, =O, OH, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R b replace;

[0014] Every R b Independently selected from halogen, CN, =O, C1-C3 alkyl, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl) or N(C1-C3 alkyl)2, wherein the C1-C3 alkyl, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl) or N(C1-C3 alkyl) is optionally substituted with one or more halogen, CN, =O, C1-C3 alkyl, OH or NH2.

[0015] In some embodiments, R 1 Selected from NH2, halogen or OH.

[0016] In some embodiments, R 2 Selected from C1-C6 alkyl or C3-C6 cycloalkyl.

[0017] In some embodiments, R 2 Selected from methyl or cyclopropyl.

[0018] In some embodiments, R 3 Selected from halogen, CN, or R 2 , R 3 The atoms to which they are attached together form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group contains 1 or 2 oxygen atoms as ring atoms, the 5-6 membered heterocyclic group is optionally substituted by one or more R 3a replace.

[0019] In some embodiments, R 3 is selected from halogen, or R2 , R 3 Together with the atoms they are connected to form

[0020] In some embodiments, R 3 Selected from F.

[0021] In some embodiments, R 4 Selected from H, R 5 Selected from H. or R 4 , R 5 Together with the atoms to which they are attached, they form a 5-6 membered carbon ring, which is optionally Replacement, R 8 , R 9 Each is independently selected from H or C3-C6 cycloalkyl.

[0022] In some embodiments, R 8 , R 9 Both are H.

[0023] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IA) or a pharmaceutically acceptable salt thereof:

[0024]

[0025] Among them, R d Select from H or R 1 , R 2 , R 3 , R 8 , R 9 As defined above.

[0026] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0027]

[0028]

[0029] The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0030] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating a topoisomerase I-related disease.

[0031] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating topoisomerase I related diseases.

[0032] Furthermore, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a topoisomerase I-related disease.

[0033] The present invention also relates to a method for treating topoisomerase I-related diseases, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention.

[0034] In a preferred embodiment of the present invention, the topoisomerase I-related diseases include but are not limited to cancer.

[0035] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of an anti-tumor drug.

[0036] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in anti-tumor aspects.

[0037] Furthermore, the present invention relates to an anti-tumor compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] The present invention also relates to a method for treating tumors, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention.

[0039] Definitions and explanations of terms

[0040] Unless otherwise specified, the terms used in the present invention have the following meanings. The groups and term definitions recorded in the present invention, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding product or its active ingredient.

[0041] In this article Indicates the connection site.

[0042] The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0043] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention includes all tautomeric forms of the compounds.

[0044] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0045] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also within the definition of the compounds of the present invention. The compounds of the present invention containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0046] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0047] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted by halogen, meaning that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F, CH2CH2Cl etc.), polysubstituted (such as CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2 etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3 etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any substitution or substitution pattern that may not exist and / or cannot be synthesized in space will not be introduced.

[0048] When any variable (such as R a , R b ) occurs more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by 2 R b is replaced, then each R b All have independent options.

[0049] When one of the variables is selected from a bond or is absent, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0050] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L 1 When selected from "C1-C3 alkylene-O", L 1 You can connect the rings Q and R in the same direction as reading from left to right. 1 The ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R in the opposite direction of the reading order from left to right 1 The ring QO-C1-C3 alkylene-R 1 ”.

[0051] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0052] In this article, C m -C n , refers to an integer number of carbon atoms in the range mn. For example, "C1-C 10” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0053] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.

[0054] The "C1-C6 alkyl group" described herein may further include a "C1-C3 alkyl group".

[0055] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C6 alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, and "C2-C6 alkenyl" may include "C2-C4 alkenyl", C2 or C3 alkenyl. It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated from each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl.

[0056] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group with at least one triple bond of a straight or branched chain consisting of a carbon atom and a hydrogen atom. For example, the term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon group comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. The example of "C2-C6 alkynyl" includes but is not limited to ethynyl (-C≡CH), prop-1-ynyl (1-propynyl,-C≡CCH3), prop-2-ynyl (-CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C6 alkynyl" may include "C2-C3 alkynyl", and "C2-C3 alkynyl" examples include ethynyl (-C≡CH), prop-1-ynyl (1-propynyl,-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0057] The term "cycloalkyl" refers to a fully saturated carbon ring in the form of a monocyclic, cyclic, bridged or spirocyclic ring. The term "C3-C6 cycloalkyl" refers to a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3 to 6 carbon atoms, and specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0058] The term "4-7 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6 or 7 ring atoms, and containing 1-3 heteroatoms or heteroatom groups independently selected from the above. Examples of 4-membered heterocyclyls include, but are not limited to, azetidinyl and oxetanyl; examples of 5-membered heterocyclyls include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazole or 2,5-dihydro-1H-pyrrolyl; examples of 6-membered heterocyclyls include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; examples of 7-membered heterocyclyls include, but are not limited to, diazepanyl. The "4-7 membered heterocyclic group" may include the range of "4-7 membered heterocyclic alkyl", "5-6 membered heterocyclic group", "5-6 membered heterocyclic alkyl" and the like.

[0059] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. 10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0060] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, such as 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, such as 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, for example 1-2, heteroatoms independently selected from N, O and S. The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0061] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0062] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0063] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0064] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.

[0065] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0066] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0067] The present invention also includes isotopically labeled compounds of the present invention that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0068] Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0069] The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0070] Typical routes of administration of the compounds of the invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0071] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0072] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0073] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0074] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0075] In all the methods of administration of the compounds of general formula (I) described herein, the dosage administered per day is 0.01 to 200 mg / kg body weight, in the form of single or divided doses. DETAILED DESCRIPTION

[0076] The invention is described in detail below by way of examples, but this is not intended to be any adverse limitation to the invention. The invention has been described in detail herein, and specific embodiments thereof are disclosed therein, and it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. All reagents used in the present invention are commercially available and can be used without further purification.

[0077] Unless otherwise specified, the ratios expressed for mixed solvents are volume mixing ratios.

[0078] Unless otherwise stated, % refers to wt %.

[0079] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0080] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0081] The eluent or mobile phase mentioned below can be a mixed eluent or mobile phase formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "0-10% methanol / dichloromethane" means that during the gradient elution process, the volume ratio of methanol to dichloromethane in the mixed eluent is 0:100 to 10:100.

[0082] Example 1: (S)-N-((5-amino-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyranyl[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 1)

[0083]

[0084] Step 1: Synthesis of 1-(2-amino-4-fluoro-5-methylphenyl)-2-chloroethane-1-one (Compound 001-1)

[0085] Boron trichloride (1M, 24.0mL) was dissolved in 1,2-dichloroethane (48.0mL), the reaction solution was cooled to 0°C, compound SM-1 (3.0g) and chloroacetonitrile (2.7g) were added thereto, the reaction was stirred at 0°C for 10 minutes, and aluminum chloride (4.2g) was added thereto. Then the reaction solution was heated to 25°C and stirred for 10 minutes under nitrogen protection. The reaction solution was stirred at 90°C for 18 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, ice water (50.0mL) and 5% hydrochloric acid (10.0mL) were slowly added in sequence, stirred at 25°C for 30 minutes, and then dichloromethane (50.0mL) was added. The organic phase was washed with water (5.0mL*2), and the washed organic phase was dried over anhydrous sodium sulfate. It was concentrated to dryness under reduced pressure, and the crude product was purified by preparative silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the title compound (2.3g).

[0086] MS m / z(ESI):202.0[M+H] +

[0087] Step 2: Synthesis of (S)-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 001-3)

[0088] Compound 001-1 (500.0 mg) and compound 001-2 (652.8 mg) were dissolved in acetic acid (3.0 mL) / toluene (3.0 mL), and p-toluenesulfonic acid pyridinium salt (124.6 mg) was added. The reaction solution was stirred at 100°C for 18 hours. After the reaction was completed, it was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol (4.0 mL*2) to obtain the title compound (420.0 mg).

[0089] MS m / z(ESI):429.0[M+H] +

[0090] Step 3: Synthesis of (S)-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 001-4)

[0091] At 0°C, nitric acid (105.2 mg, purity: 70%) was added dropwise to a solution of acetic anhydride (3.0 mL) containing compound 001-3 (250.0 mg), and the reaction was continued at this temperature for 12 hours after the addition was completed. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10.0 mL), concentrated to dryness under reduced pressure, and the crude product was slurried with dichloromethane (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with dichloromethanol to obtain the title compound (186.0 mg).

[0092] MS m / z(ESI):473.0[M+H] +

[0093] Step 4: Synthesis of (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 001-5)

[0094] Compound 001-4 (150.0 mg) was dissolved in tetrahydrofuran (2.0 mL) / methanol (2.0 mL), and hexamethylenetetramine (88.6 mg) was added thereto. The reaction solution was stirred at 50°C for 5 hours. After the reaction was completed, it was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (0.5 mL) / petroleum ether (7.0 mL), filtered, and the filter cake was washed with dichloromethane to obtain the title compound (120.0 mg). MS m / z (ESI): 455.0 [M+H] +

[0095] Step 5: Synthesis of (S)-N-((4-ethyl-8-fluoro-4-hydroxy-9-methyl-5-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyranyl[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 001-6)

[0096] Compound 001-5 (100.0 mg) and 2-hydroxyacetic acid (23.4 mg) were dissolved in anhydrous N,N-dimethylformamide (3.0 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (166.1 mg) and N,N-diisopropylethylamine (56.9 mg) were added thereto, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (0.5 mL) / petroleum ether (7.0 mL), filtered, and the filter cake was washed with dichloromethanol to obtain the title compound (78.0 mg).

[0097] MS m / z(ESI):513.0[M+H] +

[0098] Step 6: Synthesis of (S)-N-((5-amino-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyranyl[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 1)

[0099] Compound 001-6 (60.0 mg, 117.1 μmol) was dissolved in dry methanol (5.0 mL), palladium / carbon (5.7 mg, purity: 50%) was added and then replaced with hydrogen three times, and reacted at room temperature for 2 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, concentrated to dryness under reduced pressure, and the crude product was prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the product (5.0 mg).

[0100] MS m / z(ESI):483.2[M+H] +

[0101] 1 H NMR (400MHz, DMSO-d6) δ8.71-8.68(m,1H),8.34(d,J=8.3Hz,1H),7.75(d,J=10.9Hz,1H),7.02(s,1H),6.52(s,2H),5.59(s,1H),5.42 (d,J=6.4Hz,2H),5.37-5.29(m,2H),4.77(d,J=6.2Hz,2H),3.84(d,J=4.1Hz,2H),2.47(s,3H),2.10-2.02(m,2H),0.93-0.90(m,3H).

[0102] Example 2: (S)-5-amino-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 2)

[0103]

[0104] Step 1: Synthesis of methyl 5-bromo-2-((tert-butyloxycarbonyl)amino)-4-fluorobenzoate (Compound 002-1)

[0105] Di-tert-butyl dicarbonate (2.1 g) and 4-dimethylaminopyridine (98.5 mg) were added to a dichloromethane (10.0 mL) solution of compound SM-2 (2.0 g) and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the title compound (2.3 g).

[0106] MS m / z(ESI):349.0[M+H] +

[0107] Step 2: Synthesis of methyl 2-((tert-butyloxycarbonyl)amino)-5-cyclopropyl-4-fluorobenzoate (Compound 002-2)

[0108] Potassium phosphate (6.1 g) and tricyclohexylphosphine (321.7 mg) were added to a toluene (20.0 mL) / water (20.0 mL) solution of compound 002-1 (2.0 g) and cyclopropylboronic acid pinacol ester (965.3 mg) in sequence, and the atmosphere was replaced with nitrogen three times. Palladium acetate (128.7 mg) was then added to the reaction and heated to 95° C. for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the mixture was extracted with ethyl acetate, concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the title compound (1.3 g).

[0109] MS m / z(ESI):310.0[M+H] +

[0110] Step 3: Synthesis of 2-amino-5-cyclopropyl-4-fluorobenzaldehyde (Compound 002-3)

[0111] At 0°C, a solution of hydrochloric acid (1.0 M, 12.6 mL) in ethyl acetate was added dropwise to a solution of compound 002-2 (1.3 g) in dichloromethane (10.0 mL), and the mixture was warmed to room temperature and stirred for 12 hours. After the reaction is completed, the mixture is concentrated to dryness under reduced pressure to obtain a deprotected intermediate (1); under nitrogen protection, a tetrahydrofuran solution of lithium aluminum hydride (1.0 M, 7.5 mL) is added dropwise to a tetrahydrofuran (10.0 mL) solution containing the intermediate (1) at 0°C. After the addition is complete, the temperature is kept constant and the reaction is continued for 2 hours. After the reaction is completed, the reaction is quenched with methanol (5.0 mL), water (10.0 mL) is added, and the mixture is extracted with ethyl acetate (30.0 mL*2), and the mixture is concentrated to dryness under reduced pressure to obtain an ester group reduced intermediate (2); manganese dioxide (1.7 g) is added to a dichloromethane (10.0 mL) solution of the intermediate (2), and the reaction is carried out at room temperature for 2 hours. After the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed with dichloromethane (10.0 mL), and the filtrate is directly concentrated to dryness under reduced pressure to obtain the product title compound (365.0 mg).

[0112] MS m / z(ESI):180.0[M+H] +

[0113] Step 4: Synthesis of (S)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 002-4)

[0114] Compound 002-3 (260.0 mg) and compound 001-2 (382.0 mg) were dissolved in anhydrous acetic acid (4.0 mL) / toluene (4.0 mL), and p-toluenesulfonic acid pyridinium salt (72.9 mg) was added thereto. The reaction solution was stirred at 100°C for 18 hours. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol (4.0 mL*2) to obtain the title compound (210.0 mg).

[0115] MS m / z(ESI):407.0[M+H] +

[0116] Step 5: Synthesis of (S)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 002-5)

[0117] At 0°C, nitric acid (88.6 mg, purity: 70%) was added dropwise to a solution of acetic anhydride (3.0 mL) containing compound 002-4 (200.0 mg), and the temperature was maintained for 12 hours after the addition was complete. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10.0 mL*2), concentrated to dryness under reduced pressure, and the crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol to obtain the title compound (80.0 mg).

[0118] MS m / z(ESI):452.0[M+H] +

[0119] Step 6: Synthesis of (S)-5-amino-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 2)

[0120] Under nitrogen protection, iron powder (57.9 mg) and ammonium chloride (55.0 mg) were added to a mixed solution of water (1.0 mL) / ethanol (2.0 mL) containing compound 002-5 (78.0 mg) in sequence, and the reaction was heated to 80°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethanol (10 mL*2), and the filtrate was concentrated to dryness. The crude product was then prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the title compound (7.0 mg).

[0121] MS m / z(ESI):422.2[M+H] +

[0122] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.77-7.70(m,2H),7.03(s,1H),6.50(s,2H),5.44(d,J=17.1Hz,1H),5.32(d,J =17.0Hz,1H),5.19(s,2H),2.24-2.02(m,1H),2.10-2.00(m,2H),1.24(s,2H),1.17-1.03(m,2H),0.98-0.87(m,3H).

[0123] Example 3: N-((1S,9S)-8-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-1-yl)-2-hydroxyacetamide (Compound 3)

[0124]

[0125] Step 1: Synthesis of (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-8-nitro-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-10,13-dione (Compound 003-1)

[0126] At 0°C, nitric acid (62.0 mg, mass fraction: 70%) was added dropwise to a solution of isotecan (150.0 mg) in acetic anhydride (2.0 mL). After the addition was complete, the reaction was continued at the same temperature for 12 hours. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and then the mixture was extracted with dichloromethane (10.0 mL), concentrated to dryness under reduced pressure, and the crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol to obtain the title compound (120.0 mg).

[0127] MS m / z(ESI):481.0[M+H] +

[0128] Step 2: Synthesis of N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-8-nitro-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-1-yl)-2-hydroxyacetamide (Compound 003-2)

[0129] Compound 003-1 (85.0 mg) and 2-hydroxyacetic acid (20.2 mg) were dissolved in anhydrous N,N-dimethylformamide (4.0 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (133.5 mg) and N,N-diisopropylethylamine (114.3 mg, 154.1 μL) were added thereto. The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The crude product was dissolved in a small amount of methanol (0.5 mL) and then slurried with petroleum ether (7.0 mL) to obtain the title compound (82.0 mg). MS m / z (ESI): 539.2 [M+H] +

[0130] Step 3: Synthesis of N-((1S,9S)-8-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-1-yl)-2-hydroxyacetamide (Compound 3)

[0131] Compound 003-2 (70.0 mg) was dissolved in dry methanol (4.0 mL), palladium / carbon (31.6 mg, effective content: 10%) was added, and then replaced with hydrogen three times, and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the title product (7.5 mg).

[0132] MS m / z(ESI):509.2[M+H] +

[0133] 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=8.6Hz,1H),8.36(d,J=8.9Hz,1H),7.65(t,J=11.5Hz, 2H),7.01(d,J=6.5Hz,2H),6.50(s,4H),5.51(s,4H),5.46-5.40(m,2H),5.33-5.30(m,2H ),5.22-5.04(m,4H),4.82(s,1H),4.62(s,1H),4.11(s,2H),3.95(s,2H),3.12(d,J=10.3 Hz,2H),2.38-2.32(m,6H),2.17(d,J=15.4Hz,2H),2.08-2.02(m,4H),0.93-0.88(m,6H).

[0134] Example 4: (S)-8-amino-4-cyclopropyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-10,13-dione (Compound 4)

[0135]

[0136] Step 1: Synthesis of N-(3-bromo-5-fluorophenyl)acetamide (Compound 004-1)

[0137] Compound SM-4 (20.0 g) was dissolved in dichloromethane (200 mL), acetic anhydride (12.8 g) and triethylamine (32.0 g) were added thereto, and the reaction solution was reacted at 25°C for 2 hours. After the reaction was completed, water (300.0 mL) and dichloromethane (100.0 mL) were added thereto, and the organic phase was washed with saturated brine (100.0 mL*2) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by concentration under reduced pressure to obtain the title compound (23.2 g).

[0138] MS m / z(ESI):232.0 / 234.0[M+H] +

[0139] Step 2: Synthesis of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 004-2)

[0140] The intermediate 004-1 (13.0 g) and bis-pinacol borate (24.3 g) were dissolved in 1,4-dioxane (200.0 mL), potassium phosphate (10.9 g) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (4.1 g) were added thereto, and the mixture was heated to 90°C under nitrogen protection for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure. The title compound (9.1 g) was obtained by purification by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5).

[0141] MS m / z(ESI):280.1[M+H] +

[0142] Step 3: Synthesis of (E)-4-(3-acetylamino-5-fluorophenyl)but-2-enoic acid methyl ester (Compound 004-3)

[0143] Dissolve the intermediate 004-2 (6.0 g) and methyl 4-bromo-2-butenoate (4.6 mg) in 1,4-dioxane (60.0 mL) / water (15.0 mL), add potassium phosphate (9.1 g) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.6 g), and heat to 80°C under nitrogen protection for 4 hours. After the reaction is completed, cool to room temperature, add water to quench the reaction, extract with ethyl acetate, and concentrate the organic phase under reduced pressure to dryness. Purify by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the title compound (2.2 g). MS m / z (ESI): 252.0 [M+H] +

[0144] Step 4: Synthesis of methyl (4-(3-acetylamino-5-fluorophenyl)butyrate (Compound 004-4)

[0145] Intermediate 004-3 (2.2 g) was dissolved in methanol (40.0 mL), and palladium / carbon (220.0 mg, effective mass: 10%) was added, and the reaction solution was stirred at 25° C. for 2 hours under a hydrogen atmosphere. After the reaction was completed, the solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (2.0 g).

[0146] MS m / z(ESI):254.2[M+H] +

[0147] Step 5: Synthesis of methyl 4-(5-acetylamino-2-bromo-3-fluorophenyl)butyrate (Compound 004-5)

[0148] Intermediate 004-4 (1.7 g) was dissolved in acetic acid (30.0 mL), and liquid bromine (1.0 g) was added thereto and stirred at 25°C for 6 hours. After the reaction was completed, saturated sodium sulfite solution (30.0 mL) was added to quench the reaction, and the solvent was removed by concentration under reduced pressure, and water was added and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the title compound (1.8 g).

[0149] MS m / z(ESI):332.0 / 334.0[M+H] +

[0150] Step 6: Synthesis of 4-(5-acetylamino-2-bromo-3-fluorophenyl)butyric acid (Compound 004-6)

[0151] Intermediate 004-5 (1.8 g) was dissolved in tetrahydrofuran (30.0 mL) / water (5.0 mL), lithium hydroxide (649.0 mg) was added thereto and reacted at 25°C for 10 hours. After the reaction was completed, the pH was adjusted to 5.0 with dilute hydrochloric acid (2N), extracted with ethyl acetate (40.0 mL*2), and the organic phase was concentrated under reduced pressure to remove the solvent to obtain the title compound (1.7 g).

[0152] MS m / z(ESI):318.1 / 320.1[M+H] +

[0153] Step 7: Synthesis of N-(4-bromo-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (Compound 004-7)

[0154] The intermediate 004-6 (1.6 g) was dissolved in anhydrous 1,2-dichloroethane (20.0 mL), thionyl chloride (875.0 mg) was added, and the mixture was heated to 60°C for 2 hours. The reaction mixture was then cooled to room temperature, aluminum chloride (1.6 g) was added, and the mixture was reacted at 25°C for 40 minutes. After the reaction was completed, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to remove the solvent to obtain the title compound (1.3 g).

[0155] MS m / z(ESI):300.1 / 302.1[M+H] +

[0156] Step 8: Synthesis of N-(4-cyclopropyl-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (Compound 004-8)

[0157] Intermediate 004-7 (800.0 mg) and cyclopropylboronic acid (342.0 mg) were dissolved in 1,4-dioxane (8.0 mL), and cesium carbonate (1.7 mg) and [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (258.2 mg) were added, and heated to 80°C under nitrogen protection for 4 hours. After the reaction was completed, it was cooled to room temperature, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure. The title compound (612.0 mg) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5). MSm / z (ESI): 262.0 [M+H] +

[0158] Step 9: Synthesis of 8-amino-5-cyclopropyl-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Compound 004-9)

[0159] Dissolve the intermediate 004-8 (600.0 mg) in ethanol (3.0 mL), add hydrochloric acid (12 M, 0.5 mL), and heat the reaction solution to 50 ° C for 2 hours. Add water to quench the reaction, extract with ethyl acetate, and concentrate the organic phase to dryness under reduced pressure. Purify by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain the title compound (480.0 mg).

[0160] MS m / z(ESI):220.2[M+H] +

[0161] Step 10: Synthesis of (S)-4-cyclopropyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-10,13-dione (Compound 004-10)

[0162] Intermediate 004-9 (110.0 mg) and intermediate 001-2 (132.0 mg) were dissolved in toluene (4.0 mL), and p-toluenesulfonic acid pyridinium salt (126.0 mg) was added thereto. The reaction solution was stirred at 120°C for 36 hours. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with toluene (1.0 mL) / methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol (4.0 mL*2) to obtain the title compound (120.0 mg).

[0163] MS m / z(ESI):447.4[M+H] +

[0164] Step 11: Synthesis of (S)-4-cyclopropyl-9-ethyl-5-fluoro-9-hydroxy-8-nitro-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-10,13-dione (Compound 004-11)

[0165] At 0°C, nitric acid (88.6 mg, mass fraction: 70%) was added dropwise to a solution of acetic anhydride (3.0 mL) containing intermediate 004-10 (120.0 mg). After the addition was complete, the reaction was continued at this temperature for 12 hours. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10.0 mL*2), concentrated to dryness under reduced pressure, and the crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol to obtain the title compound (87.0 mg).

[0166] MS m / z(ESI):492.4[M+H] +

[0167] Step 12: Synthesis of (S)-8-amino-4-cyclopropyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-10,13-dione (Compound 4)

[0168] Under nitrogen protection, iron powder (57.9 mg) and ammonium chloride (55.0 mg) were added to a mixed solution of water (1.0 mL) / ethanol (2.0 mL) containing intermediate 004-11 (78.0 mg) in sequence, and the reaction was heated to 80°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethanol (10 mL*2), and the filtrate was concentrated to dryness. The crude product was then prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the title compound (5.2 mg).

[0169] MS m / z(ESI):462.2[M+H] +

[0170] 1 H NMR (400MHz, DMSO-d6) δ7.50 (d, J = 12.1Hz, 1H), 7.00 (s, 1H), 6.44 (s, 2H), 5.42-5.31 (m, 2H), 5.09 (s, 2H), 3.29-3.19 (m,2H),3.11-3.00(m,2H),2.13-2.01(m,2H),1.90-1.79(m,1H),1.12-1.01(m,2H),0.91(m,3H),0.75-0.66(m,2H).

[0171] Example 5: (S)-5-bromo-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 5)

[0172]

[0173] At room temperature and under nitrogen atmosphere, acetonitrile (10.0 mL) was added to a mixture of compound 002-5 (40.5 mg) and N-bromosuccinimide (35.6 mg), and the resulting mixture was stirred at 60° C. for 3 hours. After the reaction was completed, the solvent was removed from the mixture under reduced pressure, and the title compound 5 (35.0 mg) was purified by silica gel column chromatography (dichloromethane:methanol=0-20%).

[0174] LC-MS: m / z(ESI):485.4[M+H] + .

[0175] 1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.88–7.78(m,2H),6.39(s,1H),5.45(d,J=17.2Hz ,1H),5.32(d,J=17.2Hz,1H),5.22(s,2H),2.40–2.33(m,1H),2.28–2.21(m,1H),2.17–

[0176] 2.07(m,1H),1.17–1.10(m,2H),0.98–0.91(m,2H),0.84(t,J=7.5Hz,3H).

[0177] Example 6: (S)-N-(((S)-5-amino-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (Compound 6)

[0178]

[0179] Step 1: Synthesis of 4-cyclopropyl-3-fluoroaniline (Compound 006-1)

[0180] Potassium phosphate (27.3 g) and tricyclohexylphosphine (1.03 g) were added to the starting material SM-6 (7.0 g) and cyclopropylboronic acid pinacol ester (4.75 g) in toluene (40.0 mL) / water (6.0 mL) solution in sequence, and nitrogen was replaced three times. Then palladium acetate (412.0 mg) was added to the reaction and heated to 95° C. for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, water was added to quench the reaction, extracted with ethyl acetate, concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the title compound (5.1 g).

[0181] MS m / z(ESI):152.1[M+H] +

[0182] Step 2: Synthesis of 1-(2-amino-5-cyclopropyl-4-fluorophenyl)-2-chloroethane-1-one (Compound 006-2)

[0183] Under nitrogen protection, dissolve boron trichloride (1M, 23.2mL) in 1,2-dichloroethane (24mL), cool the reaction to 0℃, add intermediate 006-1 (3.5g) and chloroacetonitrile (2.64g), react at 0℃ for 10 minutes, and then add aluminum trichloride (4.0g). Heat the reaction to 25℃ for 10 minutes and then heat to 90℃ for 18 hours. After the reaction is completed, cool to room temperature, slowly add ice water (50.0mL) and hydrochloric acid (2N, 10mL) and stir at 25℃ for 30 minutes, extract with dichloromethane (20.0mL*2), and concentrate the organic phase to dryness under reduced pressure. Prepare by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60%~90%, 30mL / min) to obtain the title product (400mg).

[0184] MS m / z(ESI):228.6[M+H] + .

[0185] Step 3: Synthesis of (S)-11-(chloromethyl)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 006-3)

[0186] Intermediate 006-2 (200.0 mg) and compound 001-2 (231.0 mg) were dissolved in anhydrous acetic acid (1.5 mL) / toluene (1.5 mL), and p-toluenesulfonic acid pyridinium salt (44.2 mg) was added thereto. The reaction solution was stirred at 100°C for 18 hours. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol (4.0 mL*2) to obtain the title compound (125.0 mg).

[0187] MS m / z(ESI):455.2[M+H] +

[0188] Step 4: Synthesis of (S)-11-(chloromethyl)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolo[1,2-b]quinoline-3,14(4H)-dione (Compound 006-4)

[0189] At 0°C, nitric acid (42.0 mg, mass fraction: 70%) was added dropwise to a solution of acetic anhydride (3.0 mL) containing intermediate 006-3 (125.0 mg). After the addition was complete, the reaction was continued at this temperature for 12 hours. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10.0 mL*2), concentrated to dryness under reduced pressure, and the crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol to obtain the title compound (89.0 mg).

[0190] MS m / z(ESI):500.2[M+H] +

[0191] Step 5: Synthesis of (S)-11-(aminomethyl)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolo[1,2-b]quinoline-3,14(4H)-dione (Compound 006-5)

[0192] The intermediate 006-4 (80.0 mg) was dissolved in tetrahydrofuran (2.0 mL) / methanol (2.0 mL), and hexamethylenetetramine (67.2 mg) was added thereto. The reaction solution was stirred at 50°C for 5 hours. After the reaction was completed, it was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (0.5 mL) / petroleum ether (7.0 mL), filtered, and the filter cake was washed with dichloromethanol to obtain the title compound (66.0 mg). MSm / z(ESI):481.2[M+H] +

[0193] Step 6: Synthesis of (S)-2-cyclopropyl-N-(((S)-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-5-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 006-6)

[0194] Intermediate 006-6 (66.0 mg) and (S)-2-cyclopropyl-2-hydroxyacetic acid (19.2 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.3 mg), 1-hydroxybenzotriazole (38.0 mg) and N,N-diisopropylethylamine (53.0 mg) were dissolved in anhydrous N,N-dimethylformamide (4.0 mL), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The crude product was dissolved in a small amount of methanol (0.5 mL) and then slurried with petroleum ether (7.0 mL) to obtain the title compound (45.0 mg). MS m / z (ESI): 579.2 [M+H] +

[0195] Step 7: Synthesis of (S)-N-(((S)-5-amino-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinolin-11-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (Compound 6)

[0196] Under nitrogen protection, iron powder (26.0 mg) and ammonium chloride (25.0 mg) were added to a mixed solution of water (1.0 mL) / ethanol (3.0 mL) containing intermediate 006-6 (45.0 mg) in sequence, and the reaction was heated to 80°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethanol (10 mL*2), and the filtrate was concentrated to dryness. The crude product was then prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the title compound (1.0 mg).

[0197] MS m / z(ESI):549.2[M+H] +

[0198] Example 7: (S)-5-chloro-9-cyclopropyl-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizine[1,2-b]quinoline-3,14(4H)-dione (Compound 7)

[0199]

[0200] At room temperature and nitrogen atmosphere, acetonitrile (2.0 mL) was added to a mixture of compound 002-5 (8.1 mg) and N-chlorosuccinimide (5.3 mg). The resulting mixture was stirred at 60°C for 3 hours. After the reaction was completed, the solvent was removed from the mixture under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 0-20%) to obtain the title compound 7 (3.3 mg).

[0201] LC-MS: m / z(ESI):441.4[M+H] + .

[0202] Example 8: (S)-4-ethyl-8-fluoro-4,5-dihydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 8)

[0203]

[0204] Step 1: Synthesis of 2-amino-4-fluoro-5-methylbenzaldehyde (Compound 008-1)

[0205] Under nitrogen protection, a tetrahydrofuran solution of lithium aluminum hydride (1.0M, 34.0mL) was added dropwise to a tetrahydrofuran (30.0mL) solution of compound SM-7 (2.3g) at 0°C. After the addition was completed, the temperature was kept constant and the reaction was continued for 2 hours. After the reaction was completed, the reaction was quenched with methanol (10.0mL), water (20.0mL) was added and extracted with ethyl acetate (30.0mL*2), and concentrated to dryness under reduced pressure to obtain the reduced intermediate (1). Manganese dioxide (4.4g) was added to the dichloromethane (40.0mL) of the intermediate (1), and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, washed with dichloromethane (10.0mL), and the filtrate was directly concentrated to dryness under reduced pressure to obtain the product title compound (1.1g).

[0206] MS m / z(ESI):154.0[M+H] +

[0207] Step 2: Synthesis of (S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 008-2)

[0208] Compound 008-1 (400.0 mg) and compound 001-2 (687.0 mg) were dissolved in toluene (4.5 mL), and p-toluenesulfonic acid pyridinium salt (78.2 mg) was added thereto. The reaction solution was stirred at 100°C for 18 hours. The reaction was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol (4.0 mL*2) to obtain the title compound (590.0 mg).

[0209] MS m / z(ESI):380.2[M+H] +

[0210] Step 3: Synthesis of (S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-5-nitro-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 008-3)

[0211] At 0°C, nitric acid (76.0 mg, mass fraction: 70%) was added dropwise to a solution of acetic anhydride (4.0 mL) containing intermediate 008-2 (300.0 mg). After the addition was completed, the reaction was continued at this temperature for 12 hours. After the reaction was completed, water (2.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10.0 mL*2), concentrated to dryness under reduced pressure, and the crude product was slurried with methanol (1.0 mL) / petroleum ether (10.0 mL), filtered, and the filter cake was washed with methanol to obtain the title compound (289.0 mg).

[0212] MS m / z(ESI):426.2[M+H] +

[0213] Step 4: Synthesis of (S)-5-amino-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 008-4)

[0214] Intermediate 008-3 (120.0 mg) was dissolved in methanol (10.0 mL), and palladium / carbon (35.0 mg, effective mass: 10%) was added, and the reaction solution was stirred at 25°C for 2 hours under a hydrogen atmosphere. After the reaction was completed, the solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (92 mg).

[0215] MS m / z(ESI):396.2[M+H] +

[0216] Step 5: Synthesis of (S)-4-ethyl-8-fluoro-4,5-dihydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizinyl[1,2-b]quinoline-3,14(4H)-dione (Compound 8)

[0217] Under nitrogen protection, a round-bottom flask containing compound 008-4 (40.0 mg) was placed at 0°C, and sulfuric acid (0.2 mL) / water (1.8 mL) was added dropwise to the reaction flask, and the temperature was maintained for 20 minutes. A solution of sodium nitrite (11.0 mg) in water (1.0 mL) was then added dropwise to the reaction and the reaction continued for 30 minutes, and then heated to 100°C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and then extracted with dichloromethane. The organic phase was concentrated to dryness under reduced pressure, and the crude product was then prepared by reverse phase high performance liquid column chromatography (chromatographic column: YMC TA column; mobile phase A: 0.5‰ formic acid / water system; mobile phase B: acetonitrile. B%: 60% to 90%, 30 mL / min) to obtain the title compound 8 (5.0 mg).

[0218] MS m / z(ESI):397.2[M+H]+

[0219] Biological activity and related properties test examples

[0220] The compounds in the following test examples are all prepared according to the methods of the above embodiments of the present invention. The test example compounds can be in the form of free base or its formate salt, which is determined according to the specific form of the product prepared in the above embodiments.

[0221] Test Example 1: Tumor Cell Antiproliferative Activity Test

[0222] Cells and materials: Human colorectal cancer cell line HCT116 was purchased from Kangyuan Bochuang, human breast cancer cell line SKBR3 was purchased from ATCC, human ovarian cancer cell line OVCAR3 was purchased from ATCC, bovine serum (Gibco#10099-141C), McCoy's 5a medium (Gibco#16600-082), 1640 medium (Gibco#A10491-01), penicillin-streptomycin (Gibco#15140-122) and 0.25% Trypsin-EDTA (Gibco#25200-056) were purchased from Gibco (USA), bovine insulin (Solarbio#I8040) was purchased from Solarbio, 96-well plates (Greiner Bio-one#655098) were purchased from Corning (USA), Cell-Titer Glo reagent (Promega #G7568) was purchased from Promega (USA).

[0223] Cell culture: HCT116 cells and SKBR3 cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO2, while OVCAR3 cells were cultured in 1640 medium containing 20% ​​fetal bovine serum + 2 μg / mL bovine insulin + 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for the experiment.

[0224] Cell proliferation activity detection: Cell-Titer Glo reagent was used to detect the inhibitory activity of compounds on the proliferation of three cell lines HCT116, SKBR3 and OVCAR3. HCT116 cells (1500 per well), SKBR3 cells (3000 per well) and OVCAR3 cells (5000 per well) were inoculated in 96-well plates and cultured at 37°C and 5% CO2 for 24 hours. The test compound was dissolved in DMSO to a concentration of 1mM, and then the test compound was gradiently diluted with DMSO and the corresponding culture medium and transferred to a 96-well cell plate to a final concentration of 300nM, 3-fold dilution, and 9 concentration points. Continue to culture at 37°C and 5% CO2. HCT116 cells were cultured for 3 days, and SKBR3 cells and OVCAR3 cells were cultured for 5 days. Cell-Titer Glo reagent was added to detect cell activity.

[0225] A negative control group and a positive control group were set up as Bottom and Top, respectively. The negative control group did not add cells, but only added the same volume of culture medium, and other operations were consistent with the experimental group; the positive control group did not add the test compound, but only added the same volume of DMSO, and other operations were consistent with the experimental group.

[0226] Data analysis: Calculate % compound inhibition and fit to get the IC of the compound 50 .

[0227] % Compound inhibition = 1-100%*(Signal-Bottom) / (Top-Bottom). Signal refers to the signal value of the experimental group, Bottom refers to the average signal value of the negative control group, and Top refers to the average signal value of the positive control group.

[0228] Experimental results:

[0229] Under the experimental conditions, the compounds of the present invention showed strong proliferation inhibition activity on both HCT116 cells and OVCAR3 cells. The corresponding anti-cell proliferation activity of the compounds of the present invention is specifically shown in Table 1.

[0230] Table 1 Anti-cell proliferation activity of the compounds of the present invention

[0231]

[0232] In the above table, the symbols used to indicate binding activity mean the following:

[0233] “+++” indicates the IC value of the cell proliferation inhibition activity of the tested compound 50 The range is <10nM.

[0234] “++” indicates the inhibitory activity of the tested compound on cell proliferation IC 50 The range is 10~200nM.

[0235] "N / A" means not tested.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R 1 Selected from N(R x )(R y ), OR z , halogen or CN, said R x , R y , R z Each independently selected from H or L 1 -R k , L 1 Selected from a bond or C=O, R k Selected from one or more R 1a Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2; R 2 is selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, O(C1-C3 alkyl), NH(C1-C3 alkyl) or N(C1-C3 alkyl)2 is optionally replaced by one or more R 2a replace; R 3 is selected from H, halogen, CN, or R 2 , R 3 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by one or more R 3a replace; R 5 is selected from H, halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or C=NL 2 -R e , R 6 , R 7 Each is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, L 2 Selected from bond or O, R e is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, each of which is a C1-C3 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 5a replace; R 4 Selected from H, or R 4 , R 5 Together with the atoms to which they are attached, they form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring, wherein the 5-6 membered carbocyclic ring or the 5-6 membered heterocyclic ring is optionally Replacement, R 8 , R 9 Each is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl; Every R 1a , R 2a , R 3a , R 5a independently selected from D, halogen, CN, =O, OH, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R b replace; Every R b Independently selected from halogen, CN, =O, C1-C3 alkyl, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl) or N(C1-C3 alkyl)2, wherein the C1-C3 alkyl, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl) or N(C1-C3 alkyl) is optionally substituted with one or more halogen, CN, =O, C1-C3 alkyl, OH or NH2.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Selected from NH2, halogen or OH.

3. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from C1-C6 alkyl or C3-C6 cycloalkyl; or R 2 Selected from methyl or cyclopropyl.

4. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 3 is selected from halogen, CN, or R 2 , R 3 The atoms to which they are attached together form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group contains 1 or 2 oxygen atoms as ring atoms, the 5-6 membered heterocyclic group is optionally substituted by one or more R 3a replace; or R 3 is selected from halogen, or R 2 , R 3 Together with the atoms they are connected to form 5. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from H, R 5 Selected from H. or R 4 , R 5 Together with the atoms to which they are attached, they form a 5-6 membered carbon ring, which is optionally Replacement, R 8 , R 9 Each is independently selected from H or C3-C6 cycloalkyl.

6. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 8 , R 9 Both are H.

7. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IA) or a pharmaceutically acceptable salt thereof: Among them, R d Select from H or R 1 , R 2 , R 3 , R 8 , R 9 As defined in claim 1.

8. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of an anti-tumor drug.

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