Indazolyl-containing hydroxamic acid derivatives and uses thereof

Abstract

The application discloses a compound with a general formula (I), a pharmaceutically acceptable salt, a hydrate or a prodrug of the compound, and application of the compound in preparation of a medicine for preventing and / or treating diseases mediated by tyrosine kinase and / or histone deacetylase. The compound can simultaneously produce a good inhibiting effect on multiple targets (especially histone deacetylase 1, histone deacetylase 6 and two tyrosine kinases (vascular endothelial cell growth factor receptor and platelet-derived growth factor receptor)), and is expected to be used in treatment of malignant tumors.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, and particularly relates to a hydroxamic acid derivative containing indazolyl and application thereof. BACKGROUND

[0002] Tyrosine kinases are a class of proteins with tyrosine kinase activity, which can catalyze the transfer of phosphate groups on ATP to the tyrosine residues of many important proteins, causing phosphorylation, thereby activating the downstream signal transduction pathway. Protein tyrosine kinases play a very important role in the signal transduction pathway in cells, and regulate a series of physiological and biochemical processes such as cell growth, differentiation and death. The dysfunction of protein tyrosine kinases will cause a series of diseases in biological body, including tumors and other diseases. The occurrence, development and metastasis of many tumors and the generation of tumor neovascularization are closely related to the abnormal expression of tyrosine kinases. In particular, certain tyrosine kinase receptors are abnormally expressed in cells of solid tumors. For example, vascular endothelial cell growth factor receptor (VEGFR) is highly expressed in many tumor cells and tumor endothelial cells, and platelet-derived growth factor receptor (PDGFR) is abnormally expressed in fibroblasts in tumor stroma. The autocrine loop formed by the ligand and the receptor is directly involved in the occurrence and development of tumor cells, for example, vascular endothelial cell growth factor receptor (VEGFR) exists in melanoma; platelet-derived growth factor receptor (PDGFR) exists in glioma; stem cell growth factor receptor (KIT) exists in small cell lung cancer, etc. In addition, similar loops also exist in meningioma, neuroendocrine tumors, ovarian cancer, prostate cancer and pancreatic cancer. This loop is closely related to the occurrence and development of tumors.

[0003] In addition, the occurrence, development and metastasis of solid tumors depend on tumor angiogenesis, which provides essential nutrients and oxygen for tumor growth. Tumor angiogenesis is an important process of tumor cell infiltration, migration and proliferation. Among them, the vascular endothelial growth factor receptor family (VEGFR) and the platelet-derived growth factor receptor family (PDGFR) are directly related to the occurrence and development of tumors and tumor neovascularization. Vascular endothelial growth factor (VEGF) is the strongest known vascular permeability agent and endothelial cell-specific mitogen, which plays an important role in endothelial cell proliferation, migration and vascular construction. Its expression level and tumor tissue vascularization degree show a significant positive correlation. VEGF mainly exerts its biological effects by acting on the high-affinity receptors VEGFR-1 and KDR on endothelial cells to phosphorylate tyrosine kinase, and the two have different signal transduction pathways. Among them, KDR plays a key role in tumor growth, metastasis and tumor neovascularization. Platelet-derived growth factor (PDGF) and its receptor (PDGFR) are involved in the pathogenesis of various tumors and play an important role in angiogenesis. Platelet-derived growth factor (PDGF) exhibits its cellular biological effects through its receptor (PDGFR). PDGFR maintains the integrity of the vascular wall by regulating the proliferation and migration of pericytes and vascular smooth muscle cells in the vascular wall, and promotes tumor neovascularization. And by changing the microenvironment within the tumor, it promotes tumor growth.

[0004] Because the abnormal expression of tyrosine kinase is closely related to the occurrence, development and metastasis of tumors and tumor neovascularization, the development of drugs targeting tyrosine kinase has become a hot spot in international anti-tumor drug research. In particular, targeting neovascularization to inhibit tumor angiogenesis, block tumor nutrition supply and migration pathways, and prevent tumor growth and metastasis have become a new strategy for treating tumors.

[0005] Histone deacetylases (HDACs) are a class of intracellular metalloproteinases that play a crucial role in chromosome structural modification and gene expression regulation. In cancer cells, overexpression of HDACs leads to increased histone-DNA binding affinity, causing abnormal chromosomal conformational changes. Simultaneously, the expression of cell cycle repressors is suppressed, the stability and DNA-binding ability of the tumor suppressor p53 decrease, while the expression levels of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) increase. In mammalian cells, the balance between acetylation and deacetylation plays a critical role in gene transcription and the function of various cellular proteins. Histone acetylation status is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The dynamic balance between HATs and HDACs controls chromatin structure and gene expression; their dysfunction is one of the important molecular mechanisms of tumorigenesis and development. HDACs belong to the deacetylase superfamily. HDACs play important roles in chromatin remodeling, gene repression, cell cycle regulation, and differentiation. Abnormal function of histone deacetylases in tumor cells can lead to transcriptional repression of many genes and inhibit the expression of tumor suppressor genes. Data reports high expression of HDAC1 mRNA and protein levels in gastric, prostate, colon, and liver cancer tissues, which are associated with TNM stage and lymph node metastasis. Studies have found that inhibiting HDAC activity can effectively suppress cancer cell proliferation, induce cell cycle arrest, and promote apoptosis. Therefore, HDACs have become new targets for anticancer drug design, and the development of HDAC inhibitors (HDACi) is considered an effective strategy for cancer treatment. Hydroxamic acid-based small molecule HDACi are a class of HDACi that have received considerable attention in recent years, showing good antitumor activity both in vivo and in vitro. HDAC as an anticancer target drug has been relatively well-developed. Currently, HDAC inhibitors include vorinostat for the treatment of cutaneous T-cell lymphoma. Romidesin for treating T-cell lymphoma, belistat for treating relapsed or drug-resistant peripheral T-cell lymphoma, pabistamine for treating multiple myeloma, and chidamide for treating lymphoma are just some of the many HDACi that are increasingly being used in clinical practice for the treatment and adjuvant therapy of solid tumors such as colon cancer and lung cancer, as well as hematologic malignancies such as leukemia and lymphoma. Summary of the Invention

[0006] One of the objectives of this invention is to provide a novel indazole-containing hydroxamic acid derivative that can simultaneously exert good inhibitory effects on multiple targets (especially histone deacetylase 1, histone deacetylase 6, and two tyrosine kinases (vascular endothelial growth factor receptor and platelet-derived growth factor receptor)).

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described novel indazole-containing hydroxamic acid derivative.

[0008] Another object of the present invention is to provide the use of the above-mentioned novel indazole-containing hydroxamic acid derivative or the above-mentioned pharmaceutical composition comprising the above-mentioned novel indazole-containing hydroxamic acid derivative in the preparation of a medicament for treating diseases mediated by tyrosine kinases and / or histone deacetylases.

[0009] To achieve the above objectives, the present invention employs the following technical solution:

[0010] A compound having the general formula (I), which can be a pharmaceutical salt, hydrate, or prodrug.

[0011]

[0012] Where: R a R b Independently selected from hydrogen and C 1-20 Alkyl, 3-10-membered heterocyclic alkyl, 5-12-membered aromatic, 5-12-membered heteroaryl; wherein, the C 1-20 Alkyl, 3-10-membered heterocyclic alkyl, 5-12-membered aromatic, and 5-12-membered heteroaryl groups are each independently unsubstituted or substituted by one, two, three, or more of the following substituents: fluorine, chlorine, bromine, iodine, nitro, cyano, mercapto, hydroxyl, amino, C 1-6 Alkyl-substituted amino, C 1-10 Alkyl, halogenated C 1-6 Alkyl, nitro-substituted C 1-6 alkyl and cyano substituted C 1-6 alkyl and mercapto substituted C 1-6 alkyl and amino substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy- and nitro-substituted C 1-6 alkoxy- or cyano-substituted C 1-6 alkoxy- and mercapto-substituted C 1-6 alkoxy- and amino-substituted C 1-6 alkoxy- or hydroxy-substituted C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6Alkynyl, -C(=O)R1, -C(=O)NHR2, -C(=O)OR3, -NHC(=O)R4, -OC(=O)R5;

[0013] R1, R2, R3, R4, and R5 are independently selected from unsubstituted C. 1-20 Alkyl group, or a C group independently selected from those substituted by one or more substituents selected from fluorine, chlorine, bromine, iodine, nitro, cyano, mercapto, hydroxyl, and amino. 1-20 alkyl;

[0014] Each R c They may be the same or different, and each is independently selected from hydrogen and C. 1-20 Alkyl, C 1-20 Alkoxy, fluorine, chlorine, bromine, iodine, nitro, cyano, mercapto, hydroxyl, amino, C 1-6 Alkyl-substituted amino groups, halogenated C 1-6 Alkyl, nitro-substituted C 1-6 alkyl and cyano substituted C 1-6 alkyl and mercapto substituted C 1-6 alkyl and amino substituted C 1-6 alkyl;

[0015] R d R e Independently selected from hydrogen and C 1-20 Alkyl, nitro-substituted C 1-6 alkyl and cyano substituted C 1-6 alkyl and mercapto substituted C 1-6 alkyl and amino substituted C 1-6 alkyl;

[0016] R g It has a chain-like structure, wherein the main chain constituting the chain-like structure has 3-15 atoms and the number of heteroatoms does not exceed 2, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen;

[0017] x is 1, 2, 3 or 4.

[0018] In some implementations, C 1-20 Alkyl groups can be C 1-10 Alkyl or C 10-20 Alkyl groups; including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, heptyl, etc.

[0019] According to some preferred aspects of the invention, the number of heteroatoms in the main chain constituting the chain structure is one or two, and one of the heteroatoms is associated with an indazole ring. The benzene ring is linked in the middle.

[0020] According to some preferred aspects of the invention, the chain structure is a saturated straight chain or a saturated branched chain.

[0021] According to some preferred and specific aspects of the invention, the compound has the structure shown in general formula (II):

[0022]

[0023] Where: R a R b R c R d R e x and r are respectively related to R in general formula (Ⅰ) a R b R c R d R e The same for x, A and B are independently CH2, O, S or -N(R6)-, where R6 is hydrogen or C. 1-6 Alkyl groups, where m and n are independently selected from integers from 0 to 10, and 3 ≤ m + n ≤ 10.

[0024] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In some implementations, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0025] According to some preferred aspects of the invention, B is CH2 when any of the following conditions exist:

[0026] (1) A is CH2; (2) A is selected from O, S or -N(R6)-, and m is 0; (3) n is 0.

[0027] According to some preferred aspects of the invention, A is selected from CH2, O, S or -NH-, and B is selected from CH2, O, -N(CH3)-, -N(CH2CH3)- or -N(CH2 CH2CH3)-.

[0028] Furthermore, A is O, B is CH2, and m+n is 3, 4, or 5.

[0029] According to some preferred aspects of the invention, R a R b They are not both hydrogen.

[0030] Furthermore, R a R b In this composition, one group is selected from unsubstituted or substituted pyrimidinyl, pyrazolyl, pyridinyl, pyrazinyl, imidazolyl, pyridazinyl, thiazolyl, or phenyl groups; the other group is selected from hydrogen, or from unsubstituted or substituted C groups with 1-3 halogens. 1-6 alkyl.

[0031] In some embodiments, the compound has the structure shown in general formula (Ⅲ):

[0032]

[0033] Where: R c R d R e x, A, B, m, n are respectively related to R in general formula (II) c R d R e The following are the same: x, A, B, m, n; R b Selected from hydrogen, or from unsubstituted or substituted C atoms with 1-3 halogens. 1-6 Alkyl; R7 is selected from fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, cyano, amino, methylamino, ethylamino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxymethyl, mercaptomethyl, C(=O)CH3, C(=O)CH2CH3, C(=O)NHCH3, C(=O)NHCH2CH3, NHC(=O)CH3, NHC(=O)CH2CH3, NHCH3, N(CH3)2, NH CH2CH3, t is 0, 1, 2, 3, 4 or 5, and D and E are independently selected from CH or N.

[0034] In some implementations, when t is 4, at least one of D and E is CH, and when t is 5, both D and E are CH.

[0035] In some embodiments, the compound has the structure shown in general formula (Ⅳ):

[0036]

[0037] Where: R b R c R d R e x, A, B, m, n are respectively related to R in general formula (ⅠⅡ) b R c R d R e The following are the same: x, A, B, m, and n; R8 and R9 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, halon-n-butyl, haloisobutyl, methoxy, ethoxy, halomethoxy, and haloethoxy.

[0038] In some implementations, R b R d R e It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

[0039] In some implementations, each R c They may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, or ethoxy.

[0040] In some implementations, R b R c R d R e Both are hydrogen.

[0041] In some implementations, R g Selected from:

[0042] In some embodiments, the compound has the structure shown in general formula (V):

[0043]

[0044] Wherein: p is 2, 3, 4, 5, 6, 7, 8, 9 or 10, and R8 and R9 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, halon-n-butyl, haloisobutyl, methoxy, ethoxy, halomethoxy, haloethoxy.

[0045] In some embodiments of the present invention, the compound has the structural formula shown in any one of formulas (ST-01) to (ST-16):

[0046]

[0047] Another technical solution provided by the present invention is a pharmaceutical composition comprising the above-described compound, which may be a pharmaceutical salt, hydrate or prodrug, and a pharmaceutically acceptable carrier.

[0048] Furthermore, the pharmaceutical composition may also contain a diluent or excipient.

[0049] Furthermore, the pharmaceutical composition is a composition for the prevention and / or treatment of malignant tumors, including but not limited to renal cancer, liver cancer, colon cancer, gastrointestinal stromal tumors, lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, prostate cancer, leukemia, and lymphoma.

[0050] Another technical solution provided by the present invention is the use of the above-described compound as a pharmaceutical salt, hydrate, or prodrug, or the above-described pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases mediated by tyrosine kinases and / or histone deacetylases.

[0051] Furthermore, the disease mediated by tyrosine kinases and / or histone deacetylases is a malignant tumor, including but not limited to renal cancer, liver cancer, colon cancer, gastrointestinal stromal tumor, lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, prostate cancer, leukemia, and lymphoma.

[0052] According to the present invention, the compound includes not only a single compound form, but also a mixture of compounds whose structures satisfy the requirements of general formula (I), as well as different isomers of the same compound, such as racemates, enantiomers, diastereomers, etc.

[0053] The pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, acetate, trifluoroacetate, maleate, methanesulfonate, benzenesulfonate, benzoate, methylbenzenesulfonate, succinate, fumarate, fumarate, tartrate, gallate, citrate, etc.

[0054] Compounds having the general formula (I) or pharmaceutically acceptable salts thereof are typically administered orally in pharmaceutical formulations comprising the active ingredient or a pharmaceutically acceptable salt or solvation thereof, or a solvation of such salt, in a pharmaceutically acceptable dosage form. Depending on the disorder to be treated and the patient, the composition may be administered at different doses.

[0055] The pharmaceutical formulations having compounds of general formula (I) described above can be prepared for oral administration, specifically in the form of tablets or capsules, and particularly relate to techniques aimed at providing drug release targeting the colon.

[0056] The pharmaceutical formulations having the compounds shown in general formula (I) described above can be conveniently administered in unit dosage forms and can be prepared by any method known in the pharmaceutical field.

[0057] Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared using binders, fillers, lubricants, and / or surfactants (such as sodium lauryl sulfate). Liquid compositions may contain conventional additives such as suspending agents, emulsifiers, and / or preservatives. Liquid compositions may be encapsulated, for example, in gelatin to provide unit dosage forms.

[0058] Oral formulations are preferred, particularly tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose of the active compound in the range of 0.001 mg to 10,000 mg, for example, a dose of the active compound in the range of 0.01 mg to 5,000 mg, or a dose of the active compound in the range of 0.1 mg to 1,000 mg, etc.

[0059] In this invention, the prodrug of the compound represented by general formula (I) refers to a prodrug that, when administered by an appropriate method, can be metabolized or chemically reacted (e.g., enzymatically or hydrolyzed) in the body of a subject to be converted into at least one compound of general formula (I) or a salt thereof.

[0060] Another technical solution provided by the present invention: an intermediate for preparing the above-mentioned compound, which can be a pharmaceutical salt, hydrate, or prodrug, said intermediate having the structure shown in general formula (VI):

[0061]

[0062] Where: R a R b R c R d R e R g x and r are respectively related to R in the aforementioned general formula a R b R c R d R e R g x and r are the same, and R is C. 1-6 Alkyl group.

[0063] In some embodiments, R can be methoxy, ethoxy, propoxy, or tert-butoxy.

[0064] Another technical solution provided by the present invention is a method for preparing the above-described compound, which can be used as a pharmaceutical salt, hydrate, or prodrug, the method comprising the step of reacting the above-described intermediate with hydroxylamine.

[0065] In some embodiments, the hydroxylamine is prepared by adding an inorganic hydroxylamine acid salt, which includes, but is not limited to, hydroxylamine hydrochloride and / or hydroxylamine phosphate.

[0066] In some embodiments, the reaction between the aforementioned intermediate and hydroxylamine is carried out under alkaline conditions in an alcohol solvent. In some embodiments, the alkaline conditions are formed by adding an alkaline substance, including but not limited to sodium hydroxide, potassium hydroxide, etc.

[0067] In some embodiments, the alcohol solvent includes, but is not limited to, methanol.

[0068] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0069] The compound of this invention can target multiple important targets simultaneously, especially histone deacetylases 6 (HDAC6), histone deacetylases 1 (HDAC1), and two tyrosine kinases (vascular endothelial cell growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor β (PDGFR-β). This can effectively avoid the problems caused by different properties and metabolisms that may occur when multiple drugs are used in combination, and can give full play to the synergistic effect to increase biological activity, showing good application prospects. Detailed Implementation

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials to those described herein may be used in the implementation or testing of this invention, suitable methods and materials are described below.

[0071] Term "C" 1-20 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C20-alkyl"). In some embodiments, the alkyl group contains 1 to 10 carbon atoms, or 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Some non-limiting examples include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl.

[0072] The term "alkoxy group" refers to an alkyl group attached to a parent molecule via an oxygen atom. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms and can be represented as C0. 1-6 Alkoxy. Some non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0073] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" refers to fluorine (F), chlorine (Cl), or bromine (Br).

[0074] The term "amino-substituted alkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an amino group. For example, an amino-substituted C 1-6 Alkyl refers to C 1-6 At least one hydrogen atom of the alkyl group is replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by an amino group. Non-limiting examples of aminoalkyl groups include aminomethyl and 1-aminoethyl, etc.

[0075] The term "amino-substituted alkoxy group" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by an amino group. For example, an amino-substituted C 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms are replaced by an amino group. Non-limiting examples of aminoalkoxy groups are aminomethoxy and 1-aminoethoxy, etc.

[0076] The term "nitro-substituted alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a nitro group. For example, a nitro-substituted C 1-6 Alkyl refers to C 1-6 At least one hydrogen atom of the alkyl group is replaced by a nitro group.

[0077] The term "nitro-substituted alkoxy group" refers to an alkoxy group in which at least one hydrogen atom is replaced by a nitro group. For example, a nitro-substituted C 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by a nitro group.

[0078] The term "cyano-substituted alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a cyano group. For example, cyano-substituted C 1-6 Alkyl refers to C 1-6At least one hydrogen atom of the alkyl group is replaced by a cyano group.

[0079] The term "cyano-substituted alkoxy group" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cyano group. For example, cyano-substituted C 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by a cyano group.

[0080] The term "thiol-substituted alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a thiol group. For example, a thiol-substituted C 1-6 Alkyl refers to C 1-6 At least one hydrogen atom of the alkyl group is replaced by a thiol group.

[0081] The term "thiol-substituted alkoxy group" refers to an alkoxy group in which at least one hydrogen atom is replaced by a thiol group. For example, a thiol-substituted C 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by a mercapto group.

[0082] The term "hydroxyl-substituted alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group. For example, a hydroxyl-substituted C 1-6 Alkyl refers to C 1-6 At least one hydrogen atom of the alkyl group is replaced by a hydroxyl group.

[0083] The term "hydroxy-substituted alkoxy group" refers to an alkoxy group in which at least one hydrogen atom is replaced by a hydroxyl group. For example, a hydroxy-substituted C 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by a hydroxyl group.

[0084] The term "halogenated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). For example, halogenated C 1-6 Alkyl refers to C 1-6 At least one hydrogen atom of the alkyl group is replaced by a halogen.

[0085] The term "halogenated alkoxy group" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). For example, halogenated C... 1-6 Alkoxy, on the other hand, refers to C 1-6 At least one hydrogen atom of the alkoxy group is replaced by a halogen.

[0086] The term "heterocyclic alkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring with fused rings. For example, "3-10 membered heterocyclic alkyl" refers to a monocyclic, bicyclic, or polycyclic ring with fused rings of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Some non-limiting examples of heterocyclic alkyl groups include aziridine-3-yl, aziridine-2-yl, oxadiazine-3-yl, oxadiazine-2-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, pyrrolidine (e.g., pyrrolidine-2-yl), morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidine (e.g., pyrrolidine-3-yl), piperazine (e.g., piperazine-1-yl), 3-azabicyclo[3.1.0]hexane-6-yl, or 2,5-diazabicyclo[2.2.1]heptane-2-yl.

[0087] The term "aromatic group" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system. It is an aromatic cyclic group. When the aromatic group is preceded by a ring atom number limit, such as 5-12 membered aromatic groups, it means that the aromatic group has 5-12 ring atoms. Representative examples of aromatic groups include, but are not limited to: phenyl, naphthyl, or similar groups.

[0088] The term "heteroaryl" refers to an aromatic heterocyclic group having one to several (preferably 1, 2, 3, 4, or 5) heteroatoms, which can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) groups fused together or covalently linked. Each heterocyclic group containing a heteroatom may have one or more (e.g., 1, 2, 3, 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When a member is specified before "heteroaryl," it refers to the number of ring atoms in the heteroaryl group; for example, a 5-12 member heteroaryl refers to a heteroaryl group having 5-12 ring atoms. Representative examples of heteroaryl groups include, but are not limited to: pyrrole, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, 1H-pyrazolo[3,4-d]pyrimidin-6-yl, or similar groups.

[0089] The term "hydroxyl group" refers to the –OH group.

[0090] The term "amino" refers to the –NH2 group.

[0091] The term "cyano" refers to the –CN (nitrile) group.

[0092] The term "nitro" refers to the group -NO2.

[0093] The term "thiol" refers to the -SH group.

[0094] The term "medicinal salts" refers to those salts that retain the biological effects and properties of free bases or free acids, formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid) and organic acids (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc.). Alternatively, these salts can be prepared by adding inorganic or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following: primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimide resin, etc.).

[0095] The term "hydrate" refers to a compound formed by one, two, three or more water molecules with the compound of the present invention, where the solvent molecule is water.

[0096] As used herein, the term "treatment" includes: (1) a state, symptom, or condition that suppresses at least one clinical or subclinical symptom of a disease (e.g.,, in the case of maintenance therapy, preventing, alleviating, or delaying the progression of the disease or its recurrence); and / or (2) a condition that alleviates the symptoms (i.e., the state, symptom, or condition of the disease or at least one clinical or subclinical symptom). The benefit of treatment to a patient is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a patient is given medication to treat a disease, the outcome may not always be an effective treatment.

[0097] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the maximum number of possible substituents, that is, from substituents replacing one hydrogen to all hydrogens being replaced by substituents. For example, "one or more" can refer to one, two, three, four, five, or six, etc.

[0098] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which is administered to a mammal, such as a human being in need of it.

[0099] The terms “excipient,” “pharmaceutical carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that has no therapeutic activity and is non-toxic to the individual to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used to formulate pharmaceutical products.

[0100] The above-mentioned solution will be further described below with reference to specific embodiments; it should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments; the implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0101] Unless otherwise specified in the following examples, all raw materials are commercially available or prepared by conventional methods in the art.

[0102] Example 1: Synthesis of compound ST-01

[0103] Experimental procedure:

[0104] 1) Preparation of compound 2

[0105]

[0106] Compound 1 (11.6 g, 46.03 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran at -78 °C, followed by the addition of diisopropylaminolithium (30 mL, 59.83 mmol, 2 mol / L tetrahydrofuran solution). After stirring at -78 °C for 1 hour, carbon dioxide was bubbled into the reaction mixture and stirring was continued for another hour. The pH of the reaction mixture was then adjusted to 2 with 6 M hydrochloric acid, extracted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give 14.8 g of crude yellow solid, compound 2, which was used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ13.92(s,1H),7.62(dd,J=8.6,1.5Hz,1H),7.05(t,J=8.8Hz,1H),3.85(s,3H).

[0107] 2) Preparation of compound 3

[0108]

[0109] Compound 2 (16.6 g, 56.07 mmol) and dimethylformamide (0.3 mL) were added to 50 mL of thionyl chloride and heated at 80 °C for 3 hours. The reaction mixture was concentrated under vacuum to give the crude product 2-fluoro-6-iodo-3-methoxybenzoyl chloride. The crude product was then added to 50 mL of anhydrous tetrahydrofuran and 50 mL of ammonia at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was then concentrated under vacuum to give 10.0 g of a brown solid crude compound 3, which was used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.73(s,1H),7.57(dd,J=8.8,1.4Hz,1H),6.99(t,J=8.8Hz,1H),3.84(s,3H).

[0110] 3) Preparation of compound 4

[0111]

[0112] Compound 3 (10.7 g, 36.27 mmol) and thionyl chloride (22.0 g, 181.33 mmol) were added to 60 mL of dimethylformamide and heated to 115 °C overnight. The reaction mixture was poured into cooling water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 10:1) to give 4.4 g of red solid compound 4, yield 43.8%. 1 H NMR (400MHz, DMSO-d6) δ7.80 (dd, J=8.8, 1.3Hz, 1H), 7.36 (t, J=8.8Hz, 1H), 3.89 (s, 3H).

[0113] 4) Preparation of compound 5

[0114]

[0115] Compound 4 (1.0 g, 3.61 mmol) was dissolved in 10 mL of dichloromethane at -78 °C, and 22 mL of boron tribromide was added. The reaction mixture was placed at room temperature and stirred overnight. The reaction mixture was then poured into cold water and extracted with dimethylformamide. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 7:1) to give 850 mg of brown solid compound 5 in 89.5% yield. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.62(dd,J=8.8,1.2Hz,1H),7.09(t,J=8.8Hz,1H).

[0116] 5) Preparation of compound 7

[0117]

[0118] Compound 5 (1.0 g, 3.80 mmol) was dissolved in 10 mL of acetonitrile, and compound 6 (1.0 g, 4.56 mmol) and potassium carbonate (1.6 g, 11.41 mmol) were added. The reaction mixture was heated at 60 °C for 6 hours, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 5:1) to give 1.5 g of yellow solid compound 7 in 97.4% yield. 1 H NMR (400MHz, DMSO-d6) δ7.76(dd,J=8.8,1.3Hz,1H),7.36(t,J=8.8Hz,1H),4.09(t,J=6.4Hz,2H),3.58(s, 3H),2.30(t,J=7.2Hz,2H),1.76–1.67(m,2H),1.58–1.49(m,2H),1.44–1.28(m,4H).LC-MS:(ESI)m / z[M+H] + =406.0

[0119] 6) Preparation of compound 8

[0120]

[0121] Compound 7 (1.0 g, 2.47 mmol) and hydrazine hydrate (927 mg, 18.51 mmol) were added to 10 mL of n-butanol and heated at 110 °C for 1 hour. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 30:1) to give 508 mg of yellow solid compound 8, in 49.3% yield. 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),7.19(d,J=7.6Hz,1H),6.50(d,J=7.6Hz,1H),4.97(s,2H),4.06(t ,J=6.4Hz,2H),3.58(s,3H),2.31(t,J=7.2Hz,2H),1.80–1.70(m,2H),1.55(dt,J=15.2,7.2Hz,2H),1.46

[0122] (dd,J=15.2,7.2Hz,2H),1.38–1.29(m,2H).LC-MS:(ESI)m / z[M+H] + =418.0

[0123] 7) Preparation of compound 10

[0124]

[0125] Compound 8 (1.1 g, 2.64 mmol) was dissolved in a mixture of 12 mL dimethyl ether and 4 mL water. Compound 9 (1.2 g, 5.27 mmol), tetrakis(triphenylphosphine)palladium (305 mg, 0.26 mmol), and sodium carbonate (838 mg, 7.91 mmol) were added. The reaction mixture was purged with nitrogen and heated to 80 °C overnight. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 15:1) to give 868 mg of brown solid compound 10, in 86.1% yield. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),7.07(d,J=8.4Hz,2H),6.70(d,J=7.6Hz,1H),6. 65(d,J=8.4Hz,2H),6.57(d,J=7.6Hz,1H),5.19(s,2H),4.31(s,2H),4.09(t,J=6.4Hz ,2H),3.58(s,3H),2.33(t,J=7.2Hz,2H),1.82–1.73(m,2H),1.57(dt,J=14.8,7.2Hz, 2H),1.49(dd,J=15.2,7.6Hz,2H),1.36(dd,J=14.8,8.0Hz,2H).LC-MS:(ESI)m / z[M+H] + =383.2

[0126] 8) Preparation of compound 12

[0127]

[0128] Compound 10 (860 mg, 2.25 mmol) was dissolved in 8 mL of dimethylformamide at 0 °C, and compound 11 (299 mg, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 680 mg of yellow solid compound 12, in 58.7% yield. 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.75(s,1H),8.63(s,1H),7.55(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2 H),7.32(s,1H),7.25(d,J=8.4Hz,1H),7.16(t,J=7.6Hz,1H),6.80(d,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H) ,6.67(d,J=7.6Hz,1H),4.30(s,2H),4.12(t,J=6.4Hz,2H),3.58(s,3H),2.33(t,J=7.6Hz,2H),2.29(s,3H ),1.84–1.74(m,2H),1.59(dd,J=15.0,7.6Hz,2H),1.54–1.46(m,2H),1.40–1.31(m,2H).LC-MS:(ESI)m / z

[0129] [M+H] + =516.2

[0130] 9) Preparation of compound ST-01

[0131]

[0132] 4.2 g of hydroxylamine hydrochloride and 2.4 g of sodium hydroxide were added to 25 mL of methanol and stirred at 0 °C for half an hour. The reaction mixture was filtered to obtain a filtrate. Compound 12 (1.5 g, 2.91 mmol) and sodium hydroxide (465 mg, 11.64 mmol) were added to 15 mL of the above filtrate and stirred at room temperature for 2 hours. The pH of the reaction mixture was then adjusted to 7 with 1 mol / L hydrochloric acid. The reaction mixture was filtered to obtain a solid, which was washed with methanol and water to give 1.0 g of a white solid, compound ST-01, in 66.5% yield. 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),10.38(s,1H),8.80–8.62(m,3H),7.57(d,J=8.0Hz, 2H),7.39–7.31(m,3H),7.27(d,J=8.0Hz,1H),7.17(t,J=7.6Hz,1H),6.80(d,J=7.2Hz,1H ),6.75(d,J=7.6Hz,1H),6.68(d,J=7.6Hz,1H),4.32(s,2H),4.11(t,J=6.0Hz,2H),2.29( s,3H),1.99(t,J=7.2Hz,2H),1.83–1.75(m,2H),1.58–1.47(m,4H),1.34(d,J=6.8Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ169.7,153.0,148.9,143.9,140.1,139.3,138.5,134.2,133.2,129.7,129.1,127.9,12 3.1,120.0,119.2,118.5,115.9,112.3,106.4,68.2,32.7,29.1,28.9,25.6,25.6,21.7.LC-MS: (ESI)m / z[M+H] + =517.2

[0133] Example 2: Synthesis of compound ST-04

[0134] Experimental procedure:

[0135] 1) Compound 10 was prepared using the method described in Example 1.

[0136] 2) Preparation of compound 12

[0137]

[0138] Compound 10 (1.0 g, 2.61 mmol) was dissolved in 10 mL of dimethylformamide at 0 °C, and then compound 11 (394 mg, 2.61 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 560 mg of white solid compound 12, in 40.1% yield. 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),9.17(s,1H),8.52(s,1H),8.01(d,J=7.7Hz,1H),7.56(d,J=8.6Hz,2H ),7.36(d,J=8.5Hz,2H),7.11(dd,J=11.3,8.3Hz,1H),6.83–6.78(m,1H),6.76(d,J=7.8Hz,1H),6.67(d,J=7 .6Hz,1H),4.29(s,2H),4.12(t,J=6.4Hz,2H),3.58(s,3H),2.33(t,J=7.4Hz,2H),2.28(s,3H),1.85–1.75( m,2H),1.59(dd,J=15.1,7.5Hz,2H),1.50(dd,J=15.6,7.5Hz,2H),1.41–1.32(m,2H).LC-MS:(ESI)m / z[M+H] + =534.2

[0139] 3) Preparation of compounds ST-04 and ST-04 hydrochloride

[0140]

[0141] 4.2 g of hydroxylamine hydrochloride and 2.4 g of sodium hydroxide were added to 25 mL of methanol and stirred at 0 °C for half an hour. The reaction mixture was filtered to obtain a filtrate. Compound 12 (760 mg, 1.42 mmol) and sodium hydroxide (227 mg, 5.68 mmol) were added to 10 mL of the above filtrate and stirred at room temperature for 2 hours. The pH of the reaction mixture was then adjusted to 7 with 1 mol / L hydrochloric acid. The reaction mixture was filtered to obtain a solid. The solid was washed with methanol and water to give 400 mg of white solid compound ST-04, yield 52.5%. 990 mg of compound ST-04 was then added to water and heated at 80 °C for half an hour. The reaction mixture was cooled to room temperature and filtered to obtain a solid. The solid was added to 30 mL of 2 mol / L hydrochloric acid.

[0142] Stirred at room temperature for 1 hour, then freeze-dried to obtain 760 mg of compound ST-04 hydrochloride (containing one molecule of hydrochloric acid).

[0143] Compound ST-04: 11H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.34 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 6.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 6.83–6.78 (m, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 4.29 (s, 2H), 4.12 (t, J = 6.3 Hz, 2H), 2.28 (s, 3H), 1.97 (t, J = 7.3 Hz, 2H), 1.84–1.73 (m, 2H), 1.59–1.45 (m, 4H), 1.34 (dd, J = 14.6, 7.6 Hz, 2H).

[0144] Compound ST-04 hydrochloride: 1 1H NMR (400 MHz, DMSO-d6) δ 13.26 (br, 1H), 10.42 (br, 1H), 9.79 (s, 1H), 8.78 (s, 1H), 7.98 (dd, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.09 (dd, J = 11.2, 8.3 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.85–6.75 (m, 1H), 4.18 (t, J = 6.2 Hz, 2H), 2.27 (s, 3H), 1.98 (t, J = 7.3 Hz, 2H), 1.86–1.73 (m, 2H), 1.60–1.44 (m, 4H), 1.36–1.29 (m, 2H). 19 19F NMR (400 MHz, DMSO-d6) δ -134.30. 13 13C NMR (101 MHz, DMSO-d6) δ 169.6, 152.8, 152.0, 149.7, 144.1, 139.7, 134.7, 133.9, 133.9, 132.1, 129.7, 127.6, 127.5, 123.2, 122.9, 121.6, 118.6, 115.1, 114.9, 112.7, 108.5, 68.6, 32.7, 28.9, 28.8, 25.6, 25.6, 21.2. LC-MS: (ESI) m / z [M + H] + = 535.2.

[0145] Example 3: Synthesis of compound ST-05

[0146] Experimental procedure:

[0147] 1) Preparation of compound 2

[0148]

[0149] Compound 1 (5 g, 65.71 mmol) was dissolved in 200 mL of anhydrous tetrahydrofuran at 0 °C, and sodium cyanide (2.89 g, 72.28 mmol) was added. After stirring at 0 °C for 30 min, a solution of tert-butyldiphenylchlorosilane (18.1 g, 65.71 mmol) dissolved in 50 mL of tetrahydrofuran was added. The reaction mixture was placed at room temperature and stirred overnight. The reaction mixture was then quenched with an aqueous solution of ammonium chloride at 0 °C and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 10:1) to give 13.6 g of colorless oily compound 2 in 65.8% yield. 1 H NMR (400MHz, DMSO-d6) δ7.63(dd,J=7.4,1.6Hz,4H),7.50–7.38(m,6H),3.74(t,J=6.4Hz,2H),3.53(t,J=6.3Hz,2H),1.70(p,J=6.3Hz,2H),1.00(s,9H).

[0150] 2) Preparation of compound 4

[0151]

[0152] Compound 2 (13.6 g, 43.24 mmol) was dissolved in 170 mL of tert-butanol, and compound 3 (8.31 g, 64.86 mmol) and cesium carbonate (14.09 g, 43.24 mmol) were added. After stirring at room temperature for 6 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 10:1) to give 11.5 g of colorless oily compound 4 in 60% yield. 1 H NMR (400MHz, DMSO-d6) δ7.63–7.60(m,4H),7.49–7.38(m,6H),3.70(t,J=6.3Hz,2H),3.53(t,J=6.2H z,2H),3.48(t,J=6.2Hz,2H),2.38(t,J=6.2Hz,2H),1.74(p,J=6.2Hz,2H),1.36(s,9H),0.99(s,9H).

[0153] 3) Preparation of compound 5

[0154]

[0155] Compound 4 (0.5 g, 1.13 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and tetrabutylammonium fluoride (2.30 mL, 2.26 mmol, 1 mol / L tetrahydrofuran solution) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate, 3:1) to give 180 mg of a pale yellow oil, compound 5, in 78% yield. 1 HNMR (400MHz, DMSO-d6) δ4.34(t,J=5.1Hz,1H),3.53(t,J=6.2Hz,2H),3.41(t,J=6.8Hz,4H),2.39(t,J=6.2Hz,2H),1.68–1.56(m,2H),1.40(s,9H).

[0156] 4) Preparation of compound 7

[0157]

[0158] Compound 6 (1.0 g, 3.80 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran at 0 °C. Compound 5 (853 mg, 4.18 mmol), triphenylphosphine (1.5 g, 5.7 mmol), and diethyl azodicarbonate (1.54 g, 7.6 mmol) were then added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 4:1) to give 1.0 g of a yellow liquid compound 7 in 58.5% yield. 1 H NMR (400MHz, DMSO-d6) δ7.57(dd,J=8.8,1.7Hz,1H),6.96(t,J=8.6Hz,1H),4.13(t,J=6.3Hz,2H),3.67(t,J=6.3Hz, 2H), 3.61 (t, J=5.9Hz, 2H), 2.47 (dd, J=7.5, 5.0Hz, 2H), 2.06 (p, J=6.1Hz, 2H), 1.43 (s, 9H). LC-MS: (ESI) m / z [M+Na] + =472.0

[0159] 5) Preparation of compound 8

[0160]

[0161] Compound 7 (180 mg, 0.4 mmol) and hydrazine hydrate (140 mg, 2.8 mmol) were added to 6 mL of n-butanol, and the suspension was heated to 110 °C and held at that temperature for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 30:1) to give 100 mg of yellow solid compound 8, in 54.1% yield. 1 H NMR (400MHz, CDCl3) δ7.28(d,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),4.18(t,J=6.2Hz,2H),3.69(t,J=6.3Hz, 2H),3.63(t,J=6.0Hz,2H),2.49(t,J=6.3Hz,2H),2.08(p,J=6.1Hz,2H),1.44(s,9H).LC-MS:(ESI)m / z[M+H] + =462.2

[0162] 6) Preparation of compound 10

[0163]

[0164] Compound 8 (1.4 g, 3.03 mmol) was dissolved in a mixture of 12 mL dimethyl ether and 4 mL water. Compound 9 (996 mg, 4.54 mmol), tetrakis(triphenylphosphine)palladium (350 mg, 0.3 mmol), and sodium carbonate (963 mg, 9.09 mmol) were added. The reaction mixture was heated to 80 °C and reacted overnight under nitrogen purging. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 1.2 g of brown solid compound 10, in 92.7% yield. 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),7.07(d,J=8.4Hz,2H),6.69(d,J=7.7Hz,1H),6.65(d,J=8.4Hz,2H),6.57(d,J=7.7Hz,1H),5.19(s,2H),4 .31(s,2H),4.14(t,J=6.2Hz,2H),3.61(dt,J=9.2,6.2Hz,4H),2.43(t,J=6.1Hz,2H),1.99(p,J=6.1Hz,2H),1.37(s,9H).LC-MS: (ESI)m / z[M+H] + =427.2

[0165] 7) Preparation of compound 12

[0166]

[0167] Compound 10 (1.0 g, 2.34 mmol) was dissolved in 10 mL of dimethylformamide at 0 °C, and compound 11 (354 mg, 2.34 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 760 mg of white solid compound 12, in 56.1% yield. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),9.17(s,1H),8.52(d,J=2.5Hz,1H),8.01(dd,J=7.9,1.9Hz,1H),7.56(d,J=8.6Hz,2H),7.36( d,J=8.6Hz,2H),7.11(dd,J=11.4,8.3Hz,1H),6.84–6.78(m,1H),6.75(d,J=7.8Hz,1H),6.67(d,J=7.7Hz,1H),4.30(s,2H),4.17(t ,J=6.2Hz,2H),3.62(dt,J=12.2,6.2Hz,4H),2.44(t,J=6.1Hz,2H),2.28(s,3H),2.01(p,J=6.1Hz,2H),1.37(s,9H).4.31(s,2H),4 .14(t,J=6.2Hz,2H),3.61(dt,J=9.2,6.2Hz,4H),2.43(t,J=6.1Hz,2H),1.99(p,J=6.1Hz,2H),1.37(s,9H).LC-MS:(ESI)m / z[M+H] + =578.4

[0168] 8) Preparation of compound ST-05

[0169]

[0170] 8.4 g of hydroxylamine hydrochloride and 4.8 g of sodium hydroxide were added to 50 mL of methanol, and the suspension was stirred at 0 °C for half an hour. The reaction mixture was filtered to obtain a filtrate. Compound 12 (2.54 g, 4.40 mmol) and sodium hydroxide (704 mg, 17.6 mmol) were added to 30 mL of the above filtrate, and the mixture was stirred at 60 °C for 2 hours. The pH of the reaction mixture was then adjusted to 7 with 1 mol / L hydrochloric acid. The reaction mixture was filtered to obtain a solid. The solid was washed with methanol and water to give 724 mg of a white solid, compound ST-05, in 31% yield. 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),10.43(s,1H),9.20(s,1H),8.79(s,1H),8.54(d,J=2.0Hz, 1H),8.03(d,J=6.4Hz,1H),7.57(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.12(dd,J=11.2,8.4Hz ,1H),6.79(dd,J=16.4,6.4Hz,2H),6.69(d,J=7.6Hz,1H),4.33(s,2H),4.18(t,J=6.0Hz,2H),3. 62(t,J=5.2Hz,4H),2.28(s,3H),2.22(t,J=6.0Hz,2H),2.06–1.96(m,2H).LC-MS:(ESI)m / z[M+H] + =537.2

[0171] Example 4: Synthesis of compound ST-06

[0172] Experimental procedure:

[0173] 1) Preparation of compound 3

[0174]

[0175] Compound 1 (6.0 g, 22.81 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran at 0 °C, followed by the addition of compound 2 (5.6 g, 25.09 mmol), triphenylphosphine (8.97 g, 34.21 mmol), and diethyl azodicarbonate (9.22 g, 45.62 mmol). The reaction mixture was placed at room temperature and stirred for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 4:1) to give 3.5 g of a yellow liquid compound 3 in 36.5% yield. 1 H NMR(400MHz, DMSO-d6)δ7.78(d,J=8.8Hz,1H),7.41(t,J=8.9Hz,1H),4.25(s,2H), 3.54(s,2H),2.84(d,J=9.5Hz,3H),1.34(d,J=25.7Hz,9H).LC-MS:(ESI)m / z[M-55] + =365.0

[0176] 2) Preparation of compound 4

[0177]

[0178] Compound 3 (100 mg, 0.21 mmol) was added to 4 mL of a 4 mol / L solution of dioxane in hydrochloric acid, and the suspension was stirred at room temperature for half an hour. The reaction mixture was then concentrated under vacuum to give 75 mg of crude yellow solid, compound 4, in 98.4% yield. LC-MS: (ESI) m / z [M+H] + =321.0

[0179] 3) Preparation of compound 6

[0180]

[0181] Compound 4 (300 mg, 0.94 mmol) was dissolved in 5 mL of methanol, followed by the addition of compound 5 (149 mg, 0.94 mmol), sodium triacetoxyborohydride (398 mg, 1.88 mmol), and acetic acid (5.83 mg, 0.094 mmol). After stirring at room temperature for half an hour, the reaction mixture was poured into cold water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 340 mg of a yellow liquid compound 6, in 78.5% yield. 1 H NMR (400MHz, DMSO-d6) δ7.77(dd,J=8.8,1.3Hz,1H),7.38(t,J=8.9Hz,1H),4.17(t,J=5.6Hz,2H),2.70(t,J=5.6Hz,2H),2. 36(t,J=7.0Hz,2H),2.21(s,3H),2.17(t,J=7.3Hz,2H),1.59(p,J=7.2Hz,2H),1.37(s,9H).LC-MS: (ESI)m / z[M+H]+=463.2

[0182] 4) Preparation of compound 7

[0183]

[0184] Compound 6 (340 mg, 0.74 mmol) and hydrazine hydrate (556 mg, 11.1 mmol) were added to 8 mL of n-butanol, and the suspension was heated at 110 °C for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 1:1) to give 280 mg of yellow solid compound 7, in 80.3% yield. LC-MS: (ESI) m / z [M+H]+ = 475.1

[0185] 5) Preparation of compound 9

[0186]

[0187] Compound 7 (500 mg, 1.05 mmol) was dissolved in a mixture of 12 mL dimethyl ether and 4 mL water, followed by the addition of compound 8 (276 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium (121 mg, 1.05 mmol), and sodium carbonate (223 mg, 2.1 mmol). The reaction mixture was heated to 80 °C and reacted overnight under nitrogen purging. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 20:1) to give 300 mg of a yellow solid, compound 9, in 64.8% yield. 1 H NMR (400MHz, DMSO-d6) δ11.65(br,1H),7.07(d,J=8.3Hz,2H),6.74(d,J=7.7Hz,1H),6.65(d,J=8.3Hz,2H),6.58(d,J=7.7Hz,1H),5.18(s,2H),4.31 (s,2H),4.19(t,J=5.7Hz,2H),2.80(s,2H),2.43(s,2H),2.28(s,3H),2.2 2(t,J=7.2Hz,2H),1.70–1.60(m,2H),1.38(s,9H).LC-MS:(ESI)m / z[M+Na] + =462.2

[0188] 6) Preparation of Compound 11

[0189]

[0190] Compound 9 (1.8 g, 4.1 mmol) was dissolved in 10 mL of dimethylformamide at 0 °C, followed by the addition of compound 10 (620 mg, 4.1 mmol). The reaction mixture was placed at room temperature and stirred for 2 hours. The reaction mixture was then concentrated under vacuum and purified by silica gel column chromatography (dichloromethane-methanol, 15:1) to give 1.2 g of yellow solid compound 11, in 49.6% yield. LC-MS: (ESI) m / z [M+H] + =591.3

[0191] 7) Preparation of compound ST-06

[0192]

[0193] 4.2 g of hydroxylamine hydrochloride and 2.4 g of sodium hydroxide were added to 25 mL of methanol and stirred at 0 °C for half an hour. The reaction mixture was filtered to obtain a filtrate. Compound 11 (1.2 g, 2.19 mmol) and sodium hydroxide (1.75 g, 4.38 mmol) were added to 10 mL of the above filtrate, and the mixture was heated to 60 °C and stirred at a constant temperature for 2 hours. The pH of the reaction mixture was then adjusted to 7 with 1 mol / L hydrochloric acid. The reaction mixture was filtered to obtain a solid, which was purified by reversed-phase high-performance liquid chromatography (0.1% acetic acid-acetonitrile and water). 590 mg of a white solid, compound ST-06, was given, in 49.1% yield. 1 H NMR(400MHz,DMSO-d6)δ10.48(br,1H),9.34(s,1H),8.63(s,1H),8.24(s,1H),8.00(dd ,J=7.8,1.4Hz,1H),7.58(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.11(dd,J=11.2,8.4H z,1H),6.81(d,J=7.7Hz,2H),6.70(d,J=7.6Hz,1H),4.36–4.24(m,2H),3.03(s,2H),2. 64(t,J=7.0Hz,2H),2.45(s,3H),2.28(s,3H),2.06(t,J=6.9Hz,2H),1.87–1.66(m,2H). 13 C NMR(101MHz,DMSO-d6)δ169.5,164.4,152.7,152.0,149.6,149.0,143.4,139.1,134.2,134.0,133.3,129.8,128.3,1 27.6,127.5,123.2,123.2,121.5,112.0,118.4,115.1,114.9,112.3,106.7,65.6,56.8,55.5,42.1,30.4,22.4,21.2. 19 F NMR(376MHz,DMSO)δ-134.69.LC-MS:(ESI)m / z[M+H] + =550.2

[0194] Example 5: Evaluation of the inhibitory effects of compounds ST-01, ST-04 hydrochloride, ST-05, and ST-06 on the activities of HDAC1, HDAC6, VEGFR2, and PDGFR-β, respectively.

[0195] 5.1 Purpose and Background

[0196] The objective of this experiment is to detect the inhibitory effect of small molecule compounds on kinase activity using a kinase-based drug screening system. The HTRF method works as follows: kinase phosphorylates the substrate; an Eu-labeled antibody binds to the phosphorylated site of the substrate; streptavidin-XL665 binds to the substrate biotin; when Eu and XL665 are close together, Eu, acting as a donor, is excited by a light source (320 nm) and emits light (615 nm), resonantly transferring energy to the nearby receptor XL665, which then emits light (665 nm). A specific signal is proportional to the phosphorylated substrate; when an inhibitor is added, phosphorylation is suppressed, and the 665 nm emission cannot be detected, only the 615 nm emission can be detected. This is used to evaluate the inhibitory level of the compound on kinase activity. The ADP-Glo ​​method works as follows: the kinase undergoes an enzymatic reaction with its substrate, consuming ATP to produce ADP. The amount of product is detected using the ADP-Glo ​​reagent and luminescence method to reflect the kinase activity.

[0197] 5.2 Test Methods

[0198] 5.2.1 Enzyme Reaction Reagent Formulation

[0199] 5.2.1.1 Enzyme Reaction Formulation

[0200] Enzyme reaction formulation

[0201] Name Stock concentration.nM Working concentration.nM HDAC1 2680 5 HDAC6 3040 10 VEGFR2 5900 0.07 PDGFR-beta 2272.72 0.227

[0202] 5.2.1.2 Substrate Formulation

[0203] HDAC substrate formulation

[0204]

[0205] VEGFR2 and PDGFR-β substrate formulations

[0206]

[0207] 5.2.2 Reagents and Consumables

[0208]

[0209]

[0210] 5.2.3 Instruments

[0211] Instrument and equipment Manufacturer Model Multifunctional microplate reader BMG PHERAstar FSX Microplate low speed centrifuge Xiangyi TDZ5-WS ECHO BECKMAN 655 system

[0212] 5.2.4 Test Procedure

[0213] HDAC detection steps:

[0214] 1) Dilute the test compound to 10 concentrations starting from 10 μM with DMSO. Take 6 μL of the compound and add it to 54 μL of DMSO for a 3-fold dilution.

[0215] 2) Transfer 50 nL of the analyte to a 384 reaction plate using an Echo, with two replicates for each compound. Centrifuge at 1000 rpm for 1 minute. The final concentration of DMSO is 1%.

[0216] 3) Add 2.5 μL of HDAC to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0217] 4) Add 2.5 μL of substrate to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 37°C for 30 minutes.

[0218] 5) Add 5 μL of developer mixture to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0219] 6) Read the FI signal (em: 340; ex: 450nm) using an ELISA reader.

[0220] VEGFR2 and PDGFR-β detection steps:

[0221] 1) Dilute the test compound to 10 concentrations starting from 10 μM with DMSO. Take 6 μL of the compound and add it to 54 μL of DMSO for a 3-fold dilution.

[0222] 2) Transfer 25 nL of the analyte to a 384 reaction plate using an Echo, with two replicates for each compound. Centrifuge at 1000 rpm for 1 minute. The final concentration of DMSO is 1%.

[0223] 3) Add 2.5 μL of kinase solution to a 384 reaction plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 10 minutes.

[0224] 4) Add 2.5 μL of ATP & SubMixture to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 50 minutes.

[0225] 5) Add 5 μL Sa-XL 665 / TK-antibody-Cryptate to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 1 hour.

[0226] 6) Read the HTRF signal (Ratio 665 / 620nm) using the BMG high-throughput drug screening multi-functional microplate reader.

[0227] 5.2.3 Data Processing Methods

[0228] Set the reading for the negative control (1% DMSO well) to 0% inhibition rate and the reading for the positive control (positive drug well) to 100% inhibition rate, and calculate the inhibition rate for each test solution.

[0229]

[0230] 10μM Reference

[0231] 1% DMSO

[0232] The IC of the compound is obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0233] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0234] X: Log value of compound concentration

[0235] Y: Compound inhibition rate (% inhibition)

[0236] Equation for calculating Z' factor:

[0237] Z' = 1 - 3(SD) min +SD max ) / (AVE max -AVE min )

[0238] in:

[0239] Min represents the positive control ratio, and Max represents the negative control DMSO ratio. SD represents the standard error, and AVE represents the average ratio.

[0240] 5.2.4 Experimental Results

[0241]

[0242] Positive control: Vorinostat

[0243] Positive control: Sunitinib Example 6: In vitro efficacy assay of compound ST-04 hydrochloride in 20 cell lines

[0244] 1. Research Objectives

[0245] use The in vitro efficacy of one test compound and one positive control drug against 20 cell lines was measured using the (CTG) method.

[0246] 2. Experimental Design

[0247] The IC50 of one test compound and one positive compound was determined in 20 cell lines. 50 The drug treatment time was 3 days, with 9 concentrations and 3 replicates for each concentration.

[0248] 3. Materials

[0249] Cell line:

[0250]

[0251]

[0252] Note: All cells were cultured at 37°C and 5% CO2.

[0253] 4. Reagents and consumables

[0254] 96-well plate (Corning, part number: 3610)

[0255] MEM (Invitrogen, part number: 11095080)

[0256] RPMI 1640 (Invitrogen, part number: C22400500BT)

[0257] FBS (ExCell Bio, Product No.: FND500)

[0258] CellTiter-Glo(CTG)(Promega, Product No.: G7573)

[0259] NEAA (GIBCO, part number: 11140050)

[0260] Penicillin-Streptomycin (Pen-Strep) (Gibco, Product No.: 15070063)

[0261] 5. Test Sample

[0262] Drug to be tested:

[0263] Compound name Weight (mg) Molecular weight Purity Powder storage condition Storage condition after dissolution Solvent Stock solution concentration ST-04 hydrochloride 20 570.22 95.96％ 2-8℃ 2-8℃ DMSO 20 mM

[0264] 6. Instruments

[0265] EnVision 2104 Multilabel Reader: PerkinElmer (Instrument No.: TAREA0011);

[0266] Carbon dioxide incubator: SANYO Electric Co., Ltd. (Instrument No.: 02100400059);

[0267] Biosafety cabinet, Sujing Antai, BFC-1300IIA2 (instrument number: TBBSC0140);

[0268] Inverted microscope: Chongqing Optoelectronics XDS-1B (instrument serial number: TAMIC0200);

[0269] Live cell counter: Vi-Cell XR, Beckman Coulter (instrument serial number: TACEL0030);

[0270] Electronic balance: Mettlertoledo AL104 (instrument serial number: TBBAL0560);

[0271] 7. Methods

[0272] 7.1. 2D inhibitory effect of the test compound on cells

[0273] Cell culture

[0274] 1) Resuscitate cells with culture medium, maintain cell growth to the logarithmic growth phase, digest with trypsin, and centrifuge at 1000 rpm.

[0275] Collect cells after 5 minutes. After centrifugation, discard the supernatant and resuspend the cells in an appropriate amount of culture medium.

[0276] Day 1: Cell Plating

[0277] 2) Count the cells in the above cell suspension using a cell counter;

[0278] 3) Based on the required number of tests, plate the cells, add 90 μL of cell suspension to each well of a 96-well plate, and set up a T0 plate;

[0279] 4) Cell culture was carried out at 37℃, 5% CO2, and 95% humidity;

[0280] Day 2: T0 board reading

[0281] 5) After adding 10 μL of culture medium containing solvent to each well, perform CTG analysis;

[0282] 6) Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes;

[0283] 7) Add 50 μL of CTG solution to each well;

[0284] 8) Vibrate on a fixed-track shaker for 2 minutes to lyse the cells;

[0285] 9) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal;

[0286] 10) Use EnVision to read the cold light value;

[0287] Day 2: Add the drug to be tested

[0288] 11) Dissolve the test compound in solvent to form a stock solution and perform serial dilutions, then dilute it 20 times with culture medium to obtain a 10-fold solution; prepare a 10-fold solution of the positive drug using culture medium;

[0289] 12) Add 10 μL of 10X drug solution to each well (set up three replicates per cell concentration). The highest concentration of the compound to be tested...

[0290] The concentration was 20 μM, with 9 concentrations and a 3-fold dilution.

[0291] 13) Cell culture was carried out at 37°C and 5% CO2.

[0292] Day 5: Plate readings (72 hours after drug treatment)

[0293] 14) Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes;

[0294] 15) Add 100 μL of CTG solution to each well;

[0295] 16) Vibrate the cells on a fixed-track shaker for 2 minutes to induce cell lysis;

[0296] 17) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal;

[0297] 18) Use EnVision to read the cold light value;

[0298] 8. Data Analysis

[0299] Cell viability is expressed by the formula: (V sample -V Medium control ) / (V vehicle control -V Medium control Calculate by multiplying V by 100%. sample For the drug treatment group, V vehicle controlThis represents the average value of the solvent control group. Using GraphPadPrism 9 software, a nonlinear regression model was used to plot an S-shaped dose-survival curve and calculate the IC50. 50 The data also includes the maximum inhibition rate.

[0300] 9. Experimental Results

[0301] 9.1. IC50 of the test compound on cells 50 and maximum inhibition rate inhibition

[0302]

[0303] The above experiments demonstrated the accurate structure of the compound. Compared to the control sample, the compound of this invention exhibits significant inhibitory effects on histone deacetylases 6 (HDAC6), histone deacetylases 1 (HDAC1), two tyrosine kinases (vascular endothelial cell growth factor receptor 2, VEGFR2), and platelet-derived growth factor receptor β (PDGFR-β). This indicates that the compound of this invention targets multiple targets and can serve as a multi-target inhibitor, possessing the pharmacological effects of both sunitinib and vorinostat. Therefore, the compound of this invention can be used to treat diseases mediated by tyrosine kinases and histone deacetylases, such as malignant tumors. Treatable malignant tumors include, but are not limited to, solid tumors such as renal cell carcinoma, liver cancer, colon cancer, gastrointestinal stromal tumors, lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, and prostate cancer, as well as hematologic malignancies such as leukemia and lymphoma.

[0304] These compounds target multiple targets, which can not only fully exert synergistic effects to increase biological activity, but also avoid the problems caused by different properties and metabolisms when multiple drugs are used in combination. They are practical and have good prospects.

[0305] Furthermore, in in vitro efficacy tests of compound ST-04 hydrochloride in 20 cell lines, it showed strong activity against 20 tumor cell lines, with most exceeding the positive control drug and the rest being comparable to the positive control drug. This demonstrates promising potential for its application in the treatment of malignant tumors.

[0306] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0307] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A compound, comprising a pharmaceutically acceptable salt, characterized in that, The compound has the structure shown in general formula (Ⅲ): in: R b Selected from hydrogen, or from unsubstituted or substituted C atoms with 1-3 halogens. 1-6 alkyl; Each R c They may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, or ethoxy; x is 1, 2, 3, or 4; R d R e It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl; R7 is selected from fluorine, chlorine, bromine, iodine, and C. 1-6 Alkyl, halogenated C 1-6 Alkyl group, t is 0, 1, 2, 3, 4 or 5, D and E are both selected from CH; A is O, S, or -N(R6)-, B is CH2, O, S, or -N(R6)-, and R6 is hydrogen or C. 1-6 Alkyl groups, where m and n are independently selected from integers from 0 to 10, and 3 ≤ m + n ≤ 10; When m is 0 or n is 0, B is CH2.

2. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, A is selected from O, S or -NH-, and B is selected from CH2, O, -N(CH3)-, -N(CH2CH3)- or -N(CH2 CH2CH3)-.

3. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, A is O, B is CH2, and m+n is 3, 4, or 5.

4. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, The compound has the structure shown in general formula (Ⅳ): Where: R b R c R d R e , x, A, B, m, n are respectively related to R in general formula (ⅠII) b R c R d R e x, A, B, m, and n are the same; R8 and R9 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, halon-n-butyl, and haloisobutyl.

5. The compound according to any one of claims 1-4, wherein the pharmaceutically acceptable salt is characterized in that, R b R d R e It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

6. The compound according to any one of claims 1-4, wherein the pharmaceutically acceptable salt is characterized in that, R b R c R d R e It is also hydrogen.

7. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, Selected from:

8. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, The compound has the structure shown in general formula (V): Wherein: p is 4, 5, 6, 7, 8, 9 or 10; R8 and R9 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, halon-n-butyl, haloisobutyl.

9. The compound according to claim 1, its pharmaceutically acceptable salt, characterized in that, The structural formula of the compound is shown in any one of formulas (ST-01) to (ST-7), (ST-9), (ST-11), (ST-13)-(ST-16):

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of any one of claims 1-9, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutical composition is a composition for the prevention and / or treatment of malignant tumors, including renal cancer, liver cancer, colon cancer, gastrointestinal stromal tumor, lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, prostate cancer, leukemia, and lymphoma.

12. The use of the compound of any one of claims 1-9, a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 10 in the preparation of a medicament for the prevention and / or treatment of diseases mediated by tyrosine kinases and / or histone deacetylases.

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