Tacc3 inhibitors and uses thereof

Abstract

The application belongs to the technical field of small-molecule chemical drugs, and particularly relates to a TACC3 inhibitor, a preparation method thereof and application thereof in medicine. The application provides a TACC3 inhibitor described in formula (I) and a composition and use thereof, and the compound can be used for treating or preventing a TACC3-mediated disease or disorder and a related disease or disorder.

Description

Technical Field

[0001] This invention belongs to the field of small molecule chemical drug technology, specifically relating to a heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, and its application in the preparation of drugs for treating related diseases. Background Technology

[0002] TACC3 belongs to the TACC (Transforming acidic coiled-coil) family and is a class of highly acidic structural proteins present in multiple locations within the cell, such as the spindle, centromere, and nucleus, interacting with numerous protein complexes at different stages of the cell cycle. Its functions include typical regulation of microtubule stability and dynamics, as well as centromere integrity, and other atypical functions involved in chromatin remodeling and transcriptional regulation.

[0003] Members of the TACC family are frequently dysregulated in cancer. TACC3 is the most extensively studied and characterized member of this oncogenic family, overexpressed in various cancer types and possessing prognostic value, including breast, prostate, colorectal, and gastric cancers. In hepatocellular carcinoma, silencing the TACC3 gene inhibits proliferation, colony formation, and cancer stem cell-like phenotype. It also induces p21 expression, G1 arrest, and triggers HCT-116 hepatocellular carcinoma cell death in a p53- and p38-dependent manner. In cholangiocarcinoma, TACC3 knockdown induces G2 / M cell cycle arrest and inhibits invasion, metastasis, and proliferation in vivo and in vitro. In cervical cancer cells, TACC3 has been shown to promote proliferation, transformation capacity, migration, and the expression of EMT-related markers by activating the PI3K / AKT and ERK signaling pathways. TACC3 inhibition also effectively induces multipolar spindle formation, mitotic arrest, and apoptosis in Burkitt lymphoma and T-cell acute lymphoblastic leukemia (T-ALL), suggesting that TACC3 may also be a potential therapeutic target in hematologic malignancies. Furthermore, given the crucial role of TACC3 in regulating HIF-1 and GATA-1-dependent gene transcription, it may also have therapeutic potential in hypoxic tumors or GATA-altered tumors.

[0004] Furthermore, TACC3 is also a key driver of survival in highly aggressive cancer cells such as those with centromere expansion (CA). Inhibition of TACC3 in mitotic cells blocks the formation of the TACC3 / KIFC1 complex, leading to centromere deaggregation, multipolar spindle formation, and activation of the spindle assembly checkpoint (SAC), ultimately resulting in mitotic cell death. Conversely, inhibition of TACC3 in interphase cancer cells with CA blocks the TACC3 / HDAC2 / MBD2 complex, leading to enhanced transcription of cyclin-dependent kinase inhibitors (e.g., p21 and p16) and apoptosis regulators (e.g., APAF1), ultimately resulting in p53-independent G1 phase arrest and intense apoptosis.

[0005] KHS101 is the first TACC3 inhibitor, initially shown to selectively induce neuronal differentiation, and later demonstrated to inhibit cell growth, motility, epithelial-mesenchymal transition, and breast cancer cell stemness, while also inducing breast cancer cell apoptosis. KHS101 is also effective against hepatocellular carcinoma cells, inhibiting cell growth, spheroid formation, and the expression of stem cell transcription factors, but it is currently still in preclinical research. AO-252 is currently the only small-molecule TACC3 inhibitor in clinical trials, with investigational indications including ovarian cancer, triple-negative breast cancer (TNBC), and endometrial cancer.

[0006] Therefore, TACC3 inhibitors, which aim to disrupt key cellular mechanisms related to cancer cell proliferation, are very attractive targets in the field of cancer treatment. Summary of the Invention

[0007] The technical problem to be solved by this invention is to provide a novel heterocyclic compound that can be used as a TACC3 degrading agent for the preparation of drugs for treating TACC3-mediated diseases or symptoms and related diseases or symptoms. To solve the above technical problem, the technical solution provided by this invention is as follows:

[0008] On the one hand, the present invention provides heterocyclic compounds with the structure shown in formula (I) or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites:

[0009]

[0010] in,

[0011] It can be a single bond or a double bond;

[0012] X1 is selected from N or CR a X4 is selected from N or CR d X5 is selected from N or CR eX6 is selected from N or CR f ;

[0013] X2 is selected from N(R) b ) p or C(R) b ) q X3 is selected from N(R) c ) p or C(R) c ) q ;

[0014] p is selected from 0 or 1, and q is selected from 1 or 2;

[0015] R1, R2, and the N atom attached thereto form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is not a piperazine and may optionally be substituted by one or more atoms selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Substituents of haloalkyl groups;

[0016] R3, R4, R a R b R c R d R e R f Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Halogenated alkyl groups;

[0017] or,

[0018] The R b R c The C or N atom bonded to it can further form a 5-6 membered heteroaryl group, which may optionally be bonded by one or more atoms selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C1-6 Alkylthio, C 3-6 cycloalkyl or C 1-6 Substituents of haloalkyl groups;

[0019] R5 is selected from -SF5, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, -SC 3-6 Cycloalkyl, -NR6R7 or -NR8R9;

[0020] R6 is selected from C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0021] R7 is selected from C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0022] R8, the N atom bonded to R8, the C atom on the benzene ring bonded to the N atom, and the C atom on the adjacent benzene ring together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group. The 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be atomized by one or more elements selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C, etc. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 The alkyl halogroup is substituted; and the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group does not have the following structure: ;

[0023] R9 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-6 Halogenated alkyl groups;

[0024] R 10 Selected from hydrogen or C 1-6 alkyl;

[0025] m is selected from 0, 1, or 2, and n is selected from 0, 1, 2, 3, or 4.

[0026] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (II), (III) or (IV) as follows:

[0027]

[0028] Among them, X1, X2, X3, X4, R1, R2, R3, R4, R5, R 10 R e R f The definitions of , m, and n are as described in general formula (I).

[0029] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), (IVA), (IVB), (IVC), (IVD), (IVE), or (IVF):

[0030]

[0031]

[0032] Among them, R1, R2, R3, R4, R5, R 10 R a R b R c R d R e R f The definitions of , m, and n are as described in general formula (I).

[0033] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein the R... 10 Selected from hydrogen.

[0034] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein the... Selected from

[0035] In some embodiments, in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecule or metabolite thereof, R5 is selected from C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0036] In a further embodiment, R5 is selected from -OCH3 or -OCF2H.

[0037] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein the R... a Selected from hydrogen or halogen.

[0038] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein the R... f Selected from hydrogen or cyano groups.

[0039] In some embodiments, R3 is selected from hydrogen or halogen in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules or metabolites thereof.

[0040] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein R4, R b R c R d R e Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, or C. 1-6 alkyl.

[0041] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites are selected from the following structural compounds:

[0042] .

[0043] On the other hand, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compounds represented by the above general formulas or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0044] In another aspect, the present invention provides the use of compounds represented by the above general formulas or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions thereof in the preparation of medicaments for treating TACC3-related diseases or conditions and related diseases or conditions.

[0045] In another aspect, the present invention provides the use of compounds represented by the above general formulas or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions thereof for the treatment of TACC3-related diseases or conditions and related diseases or conditions.

[0046] The present invention also provides a method for treating and / or preventing diseases, comprising administering to a therapeutically effective amount of the compounds represented by the above general formulas or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules, metabolites, or the pharmaceutical compositions described above.

[0047] In some implementations, the disease being treated and / or prevented is a TACC3-related disease or condition or condition.

[0048] In some implementations, the TACC3-related disease or condition and related diseases or conditions are cancer.

[0049] In some implementations, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, melanoma, central nervous system cancer, leukemia, head and neck cancer, esophageal cancer, colorectal cancer, stomach cancer, lung cancer, liver cancer, pancreatic cancer, or kidney cancer.

[0050] The "compounds represented by the above general formulas" in this invention refer to compounds selected from any one or more of the general formulas (I), (II), (III), (IV), (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), (IVA), (IVB), (IVC), (IVD), (IVE), or (IVF).

[0051] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0052] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0053] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0054] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0055] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0056] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0057] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, wherein the "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0058] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0059] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0060] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C 1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0061] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0062] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0063] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-8 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azacyclic butyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazine, oxoperazine, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0064] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0065] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0066] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0067] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0068] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in water or an organic solvent, or a mixture thereof, with a stoichiometric amount of a suitable base or acid in the form of a free acid or base.

[0069] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0070] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0071] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0072] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0073] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0074] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0075] The so-called metabolites produced by the breakdown of the compounds of the present invention in the body are also included within the scope of the claims of this application. The "metabolites" of the compounds disclosed in this invention are derivatives formed during the metabolism of the compounds. The metabolites of the compounds disclosed in this invention may optionally be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0076] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0077] When the compounds represented by the above general formulas have tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0078] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0079] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0080] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0081] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties 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.

[0082] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0083] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0084] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0085] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure. Detailed Implementation

[0086] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0087] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0088] The following abbreviations were used in the examples:

[0089] LC-MS: Liquid Chromatography-Mass Spectrometry; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIPEA: N,N-diisopropylethylamine; MeCN: Acetonitrile; Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; n-BuOH: n-Butanol.

[0090] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0091] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or by self-production. The preparation process of raw materials and common intermediates that need to be self-produced is described in detail below.

[0092] Preparation Example 1: Preparation of Intermediate M1

[0093]

[0094] Step 1: Synthesis of intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidine-2-amine (M1)

[0095] 4-Chloropyrimidine-2-amine (M1-1, 100.00 mg, 0.77 mmol) and (4-(difluoromethoxy)phenyl)boronic acid (145.07 mg, 0.77 mmol) were dissolved in 1,4-dioxane (5.0 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (56.48 mg, 0.08 mmol), potassium phosphate (328.00 mg, 1.54 mmol), and water (1.0 mL) were added. The reaction was carried out under nitrogen protection and stirred at 90 °C for 16 hours. After the reaction was completed and the reaction solution was concentrated under reduced pressure, the residue was separated by silica gel column chromatography, eluted with a gradient of 0-60% ethyl acetate and petroleum ether, to give the intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (M1, 77.0 mg, yield 42.1%), LC-MS (m / z): 238.0 [M+H] + .

[0096] Preparation Example 2: Preparation of Intermediate M2

[0097]

[0098] Step 1: Synthesis of intermediate 4-(4-(difluoromethoxy)phenyl)pyridine-2-amine (M2)

[0099] 4-Chloropyridine-2-amine (M2-1, 100.00 mg, 0.78 mmol) and (4-(difluoromethoxy)phenyl)boronic acid (146.00 mg, 0.78 mmol) were dissolved in 1,4-dioxane (5.0 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (57.00 mg, 0.08 mmol), potassium phosphate (330.00 mg, 1.56 mmol) and water (0.5 mL) were added. The reaction was carried out under nitrogen protection and stirred at 100 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography using a gradient elution of a mixture of 0-70% ethyl acetate and petroleum ether to give the intermediate 4-(4-(difluoromethoxy)phenyl)pyridine-2-amine (M2, 20.0 mg, yield 10.8%), LC-MS (m / z): 237.0 [M+H] + .

[0100] Preparation Example 3: Preparation of Intermediate M3

[0101]

[0102] Step 1: Synthesis of intermediate 2-chloro-4-(4-(difluoromethoxy)phenyl)pyrimidine (M3)

[0103] 2,4-Dichloropyrimidine (M3-1, 50.00 mg, 0.34 mmol) and (4-(difluoromethoxy)phenyl)boronic acid (63.00 mg, 0.34 mmol) were dissolved in tetrahydrofuran (5.0 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25.00 mg, 0.03 mmol), sodium bicarbonate (56.00 mg, 0.67 mmol) and water (0.5 mL) were added. The reaction was carried out under nitrogen protection and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography using a gradient elution of a mixture of 0-30% ethyl acetate and petroleum ether to give the intermediate 2-chloro-4-(4-(difluoromethoxy)phenyl)pyrimidine (M3, 80.0 mg, yield 93.0%), LC-MS (m / z): 257.0 [M+H] + .

[0104] Example 1 Preparation of the target compound N-(4-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-5-((2R,6S)-2,6-dimethylmorpholino)pyridazine-3-amine (1)

[0105]

[0106] Step 1: Synthesis of intermediate (2R,6S)-4-(6-chloropyridazin-4-yl)-2,6-dimethylmorpholine (1-2)

[0107] 3,5-Dichloropyridazine (1-1, 300.00 mg, 2.01 mmol) was dissolved in acetonitrile (10 mL), and (2R,6S)-2,6-dimethylmorpholine hydrochloride (458.03 mg, 3.02 mmol) and N,N-diisopropylethylamine (520.55 mg, 4.03 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography with a gradient elution of 0-50% ethyl acetate and petroleum ether to give the intermediate (2R,6S)-4-(6-chloropyridazine-4-yl)-2,6-dimethylmorpholine (1-2, 180.0 mg, yield 43.7%), LC-MS (m / z): 228.0 [M+H] +.

[0108] Step 2: Synthesis of the target compound N-(4-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-5-((2R,6S)-2,6-dimethylmorpholino)pyridazine-3-amine (1)

[0109] Intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (M1, 77.00 mg, 0.32 mmol) and intermediate (2R,6S)-4-(6-chloropyridazin-4-yl)-2,6-dimethylmorpholine (1-2, 74.00 mg, 0.32 mmol) were dissolved in 1,4-dioxane (5.0 mL), and cesium carbonate (212.00 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (30.00 mg, 0.03 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (38.00 mg, 0.06 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 80 °C for 16 hours. After the reaction was completed and the reaction solution was concentrated under reduced pressure, the residue was separated by preparative liquid chromatography to obtain the target compound N-(4-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-5-((2R,6S)-2,6-dimethylmorpholino)pyridazine-3-amine (1, 10.0 mg, yield 7.2%).

[0110] 1 H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.74 (d, J = 3.0 Hz, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.49 (s, 0.25H), 7.37 (s, 0.5H), 7.34 (d, J = 8.4 Hz, 2H), 7.25 (s, 0.25H), 3.86 (d, J = 9.6 Hz, 2H), 3.74 – 3.65 (m, 2H), 2.58 – 2.51(m, 2H), 1.16 (d, J = 6.0 Hz, 6H); LC-MS(m / z): 429.0 [M+H] + .

[0111] Example 3 Preparation of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (3)

[0112]

[0113] Step 1: Synthesis of intermediate (2R,6S)-4-(2-chloropyrimidin-4-yl)-2,6-dimethylmorpholine (3-2)

[0114] 2,4-Dichloropyrimidine (3-1, 100.00 mg, 0.67 mmol) was dissolved in acetonitrile (5.0 mL), and (2R,6S)-2,6-dimethylmorpholine hydrochloride (102.00 mg, 0.67 mmol) and N,N-diisopropylethylamine (260.00 mg, 2.01 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was evaporated to dryness, and the residue was separated by preparative TLC (thin-layer chromatography) (ethyl acetate:petroleum ether = 2:1 as eluent) to give the intermediate (2R,6S)-4-(2-chloropyrimidin-4-yl)-2,6-dimethylmorpholine (3-2, 140.0 mg, yield 91.5%), LC-MS (m / z): 228.0 [M+H] + .

[0115] Step 2: Synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (3)

[0116] Intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (M1, 50.00 mg, 0.21 mmol) and intermediate (2R,6S)-4-(2-chloropyrimidin-4-yl)-2,6-dimethylmorpholine (3-2, 4800 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5.0 mL), and cesium carbonate (137.00 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (19.00 mg, 0.02 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (24.00 mg, 0.04 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 10 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to obtain the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (3, 5.0 mg, yield 5.6%).

[0117] 1H NMR (600 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.61 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H),7.49 (s, 0.25H), 7.37 (s, 0.5H), 7.33 (d, J = 8.4 Hz, 2H), 7.25 (s, 0.25 H),6.46 (d, J = 6.0 Hz, 1H), 4.30 (br s, 2H), 3.62 – 3.48 (m, 2H), 2.49 – 2.44(m, 2H), 1.02 (d, J = 6.6 Hz, 6H); LC-MS(m / z): 429.0 [M+H] + .

[0118] Example 4 Preparation of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyrazin-2-yl)pyrimidin-2-amine (4)

[0119]

[0120] Step 1: Synthesis of intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidine-2-amine (4-2)

[0121] 2,6-Dichloropyrazine (4-1, 200.00 mg, 1.34 mmol) was dissolved in acetonitrile (5.0 mL), and (2R,6S)-2,6-dimethylmorpholine hydrochloride (305.00 mg, 2.01 mmol) and N,N-diisopropylethylamine (521.00 mg, 4.03 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (4-2, 300.0 mg, yield 98.4%), LC-MS (m / z): 228.0 [M+H] + .

[0122] Step 2: Synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyrazin-2-yl)pyrimidin-2-amine (4)

[0123] Intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidine-2-amine (4-2, 30.00 mg, 0.13 mmol) and intermediate 4-(4-(difluoromethoxy)phenyl)pyrimidine-2-amine (M1, 31.00 mg, 0.13 mmol) were dissolved in 1,4-dioxane (5.0 mL), and cesium carbonate (86.00 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (12.00 mg, 0.01 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (15.00 mg, 0.03 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to obtain the target compound 4-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyrazin-2-yl)pyrimidine-2-amine (4, 25.0 mg, yield 46.5%).

[0124] 1 H NMR (600 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.83 (s, 1H), 8.64 (d, J =5.4 Hz, 1H), 8.31 – 8.24 (m, 2H), 7.93 (s, 1H), 7.55 (d, J = 5.4 Hz, 1H),7.51 (s, 0.25H), 7.39 (s, 0.5H), 7.38 (d, J = 9.0 Hz, 2H), 7.27 (s, 0.25H),4.24 (dd, J = 13.2, 2.4 Hz, 2H), 3.66 – 3.59 (m, 2H), 2.50 – 2.45 (m, 2H),1.16 (d, J = 6.0 Hz, 6H); LC-MS(m / z): 429.0 [M+H] + .

[0125] Example 9 Preparation of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (9)

[0126]

[0127] The preparation of compound 3-2 is described in step 1 of Example 3.

[0128] Step 1: Synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (9)

[0129] Intermediate 4-(4-(difluoromethoxy)phenyl)pyridine-2-amine (M2, 20.00 mg, 0.08 mmol) and intermediate (2R,6S)-4-(2-chloropyrimidin-4-yl)-2,6-dimethylmorpholine (3-2, 29.00 mg, 0.13 mmol) were dissolved in 1,4-dioxane (5.0 mL), and cesium carbonate (55.17 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (7.75 mg, 0.01 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (9.80 mg, 0.042 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative thin-layer chromatography (TLC) with dichloromethane:methanol = 10:1 to obtain the target compound 4-(4-(difluoromethoxy)phenyl)-N-(4-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-2-yl)pyrimidin-2-amine (9, 25.0 mg, yield 69.4%).

[0130] 1 H NMR (600 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.54 (s, 1H), 8.31 (d, J =4.8 Hz, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.45 (s,0.25H), 7.34 – 7.30 (m, 2.5H), 7.23 (d, J = 5.4 Hz, 1H), 7.20 (s, 0.25H), 6.40 (d, J = 6.0 Hz, 1H), 4.21 (s, 2H), 3.62 – 3.53 (m, 2H), 2.57 – 2.51 (m,2H), 1.06 (d, J = 6.0 Hz, 6H); LC-MS(m / z): 428.0 [M+H] + .

[0131] Example 11 Synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyrimidin-2-amine (11)

[0132]

[0133] Step 1: Synthesis of intermediate 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (11-2)

[0134] 2-Chloro-5-fluoropyrimidin-4-amine (11-1, 50.00 mg, 0.34 mmol) was dissolved in n-butanol (5.0 mL), and (2R,6S)-2,6-dimethylmorpholine hydrochloride (51.00 mg, 0.34 mmol) and N,N-diisopropylethylamine (131.00 mg, 1.02 mmol) were added. The reaction mixture was stirred at 120 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography using a gradient elution of 0-30% ethyl acetate in petroleum ether to give the intermediate 2-((2R,6S)-2,6-dimethylmorpholine)-5-fluoropyrimidin-4-amine (11-2, 44.0 mg, yield 57.1%), LC-MS (m / z): 227.0 [M+H] + .

[0135] Step 2: Synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyrimidin-2-amine (11)

[0136] Intermediate 2-chloro-4-(4-(difluoromethoxy)phenyl)pyrimidine (M3, 50.00 mg, 0.19 mmol) and intermediate 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (11-2, 44.00 mg, 0.19 mmol) were dissolved in 1,4-dioxane (5.0 mL), and cesium carbonate (137.00 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (18.00 mg, 0.02 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (24.00 mg, 0.04 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative thin-layer chromatography (TLC) with petroleum ether:ethyl acetate as the developing solvent at a ratio of 1:1, yielding the synthesis of the target compound 4-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyrimidin-2-amine (11, 15.0 mg, yield 17.2%).

[0137] 1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 5.4 Hz, 1H),7.49 (s, 0.25H), 7.37 (s, 0.5H), 7.33 (d, J = 8.4 Hz, 2H), 7.25 (s, 0.25H), 4.38 (dd, J = 13.2, 2.4 Hz, 2H), 3.58 – 3.50 (m, 2H), 2.49 – 2.44 (m, 2H),1.06 (d, J = 6.6 Hz, 6H); LC-MS(m / z): 447.0 [M+H] + .

[0138] Test Example 1: Assay of the Cell Inhibitory Activity of the Target Compound

[0139] 1. Preparation of compound solutions: First, dissolve the compound in DMSO, and then use culture medium to serially dilute the compound to be tested from 10 μM to obtain 8 concentrations of compound solutions.

[0140] 2. The inhibitory effect of the compounds on the activity of MDA-MB-231 cells was tested using the SRB method: MDA-MB-231 cells in the logarithmic growth phase were seeded at 1500 cells / well in 96-well cell culture plates and incubated at 37°C with 5% CO2 for 24 hours. Then, compound solutions of varying concentrations were added, and the cells were incubated at 37°C with 5% CO2 for another 5 days. After 5 days, 100 μL of SRB fixative was added to each well, and the cells were fixed at 4°C for 2-3 hours, after which the fixative was discarded. SRB washing solution B was added at 100 μL per well, and the cells were incubated at room temperature for 30 seconds, after which the washing solution B was discarded. The cells were then washed 3-5 times with pure water and air-dried at room temperature. 100 μL of SRB staining solution was added to each well, and the cells were incubated at room temperature in the dark for 15 minutes, after which the staining solution was discarded. 100 μL of SRB washing solution D was added to each well, and the washing solution D was discarded. This process was repeated rapidly 3-5 times until all unbound staining solution was washed away. Add 100 μL of SRB dissolving solution to each well and incubate at room temperature in the dark for 5 min. Then, measure the absorbance at 515 nm using a microplate reader and determine the inhibition rate of each compound. Calculate the cell inhibition rate using the following formula, with lgC as X and the corresponding inhibition rate as Y. The IC50 value was obtained by fitting the data using Graphpad Prism 8.0.2 software. 50Value. (Cell inhibition rate (%) = (Absorbance of control group - Absorbance of experimental group) / (Absorbance of control group - Absorbance of blank group) × 100%)

[0141] Table 1. Cell inhibitory activity of the compounds of the present invention

[0142] Compound numbering <![CDATA[IC of MDA-MB-231 cells 50 (µM)]]> Compound numbering <![CDATA[IC of MDA-MB-231 cells 50 (µM)]]> 1 ++++ 9 +++++ 3 ++++ 11 +++++ 4 +++++

[0143] [Note] "+++++" means ≤ 0.1 µM, "++++" means ≤ 0.5 µM but > 0.1 µM; "+++" means ≤ 2.5 µM but > 0.5 µM; "++" means ≤ 10 µM but > 2.5 µM; "+" means ≤ 25 µM but > 10 µM; "0" means > 25 µM.

Claims

1. The compound represented by formula (I) or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite: in, It can be a single bond or a double bond; X1 is selected from N or CR a X4 is selected from N or CR d X5 is selected from N or CR e X6 is selected from N or CR f ; X2 is selected from N(R) b ) p or C(R) b ) q X3 is selected from N(R) c ) p or C(R) c ) q ; p is selected from 0 or 1, and q is selected from 1 or 2; R1, R2, and the N atom attached thereto form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is not a piperazine and may optionally be substituted by one or more atoms selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Substituents of haloalkyl groups; R3, R4, R a R b R c R d R e R f Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Halogenated alkyl groups; or, The R b R c The C or N atom bonded to it can further form a 5-6 membered heteroaryl group, which may optionally be bonded by one or more atoms selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Alkylthio, C 3-6 cycloalkyl or C 1-6 Substituents of haloalkyl groups; R5 is selected from -SF5, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, -SC 3-6 Cycloalkyl, -NR6R7 or -NR8R9; R6 is selected from C 1-6 Alkyl or halogenated C 1-6 alkyl; R7 is selected from C 1-6 Alkyl or halogenated C 1-6 alkyl; R8, the N atom bonded to R8, the C atom on the benzene ring bonded to the N atom, and the C atom on the adjacent benzene ring together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group. The 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be atomized by one or more elements selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C, etc. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 The alkyl halogroup is substituted; and the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group does not have the following structure: ; R9 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-6 Halogenated alkyl groups; R 10 Selected from hydrogen or C 1-6 alkyl; m is selected from 0, 1, or 2, and n is selected from 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has the structure shown in formula (II), (III) or (IV): Among them, X1, X2, X3, X4, R1, R2, R3, R4, R5, R 10 R e R f The definitions of m and n are as described in claim 1.

3. The compound as described in claim 1 or 2, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has a structure as shown in formulas (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), (IVA), (IVB), (IVC), (IVD), (IVE), or (IVF): Among them, R1, R2, R3, R4, R5, R 10 R a R b R c R d R e R f The definitions of m and n are as described in claim 1.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R 10 Selected from hydrogen.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The Selected from 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, R5 is selected from C. 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R a Selected from hydrogen or halogen; R f R3 is selected from hydrogen or cyano; R4 and R5 are selected from hydrogen or halogen. b R c R d R e Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, or C. 1-6 alkyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The compound is selected from the following structural compounds: 。 9. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of the compounds of claims 1-8 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

10. Use of any compound of claims 1 to 8 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 9 in the preparation of a medicament for treating TACC3-related diseases or conditions and related diseases or conditions.

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