Histone deacetylase inhibitors and uses thereof

Abstract

The application discloses a histone deacetylase inhibitor and application thereof. Specifically, the application relates to a compound shown in a general formula (I), a pharmaceutically acceptable salt of the compound, and a preparation method and application of the compound. The compound has a good inhibiting effect on histone deacetylase, and can be used for treating tumors and related diseases.

Description

[0001] This application claims priority to Chinese patent application 2021102612657, filed on March 10, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and more specifically, to a class of histone deacetylase inhibitors, their preparation methods, and the uses of such compounds. Background Technology

[0003] Histones are essential components of eukaryotic chromosomes. The N-terminus of histones can be modified post-translationally, altering chromatin structure and thus affecting gene transcription. One type of modification is the reversible acetylation and deacetylation of lysine residues at the histone tail. Histone acetylation (HAT) acetylates histones, weakening the binding of DNA to histones, promoting the binding of transcription factors to promoters, and upregulating gene expression. Conversely, histone deacetylase (HDAC) binds histones more tightly to DNA, inhibiting gene transcription. Besides acetylation, the N-terminus of histones can also be phosphorylated, methylated, and ADP-ribosylated, further altering chromatin structure and regulating gene expression.

[0004] Excessive / abnormal activation of HDAC leads to structural changes in chromatin, inhibits transcription, and interferes with normal cell differentiation, resulting in tumors and other proliferative diseases. Therefore, inhibiting HDAC activity may be an effective method for treating tumors and other proliferative diseases.

[0005] Organic hydroxamic acids are a crucial class of pan-inhibitors of HDACs. The hydroxamic acid group effectively chelates with zinc ions at the active site of HDACs and forms hydrogen bonds with surrounding residues. However, these inhibitors have significant drawbacks. First, due to their low selectivity, adverse reactions such as bone marrow suppression, diarrhea, and cardiac impairment often occur during clinical application. Second, because hydroxamic acids are rapidly glycosylated or sulfated in vivo, leading to the inactivation of HDAC inhibitors, high doses are required clinically. Therefore, there is a need to develop a class of HDAC inhibitors with higher selectivity and stronger inhibitory activity. Summary of the Invention

[0006] This invention provides a compound of general formula (I) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0007]

[0008] In general formula (I):

[0009] X 1 X 2 and X 3 Independently selected from -C(R) 5 = or -N =;

[0010] A and B are connected by a single bond or a double bond:

[0011] When A and B are connected by a single bond, A is selected from -CH2-, -O-, -S-, -S(O)-, -S(O2)-, or -N(CH3)-, and B is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CH(CN)-, or

[0012] When A and B are connected by a double bond, A is selected from -CH=, -C(CH3)=, -C(CF3)=, -C(CN)=, or -N=, and B is selected from -CH=, -C(CN)=, -C(C 1-3 Alkyl)=、-C(C 1-3 (halogenated alkyl) = or -C(C 3-6 cycloalkyl) =;

[0013] Y is selected from chemical bonds, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -C(C2H5)2-, -CH(CF3)-, -CH(CH2CF3)-, -CH2CH2-, -C(CH3)2CH2- or

[0014] L is selected from aryl or heteroaryl groups, wherein the aryl or heteroaryl group may be substituted by 1 to 3 of the following groups: H, halogen, CN, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Haloalkoxy groups, when substituted by multiple substituents, may be the same or different;

[0015] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-6 (alkylene)-NR 6 R 7 -O-(C 1-6 (alkylene)-NR 6 R 7 -NHCO-(C 1-6(alkylene)-NR 6 R 7 -NHCOR 8 -C(O)NR 6 R 7 -NR 6 R 7 -CONHR 8 , phenyl or 5-7 heteroaryl, wherein the phenyl or 5-7 heteroaryl group can be substituted by 1-3 of the following groups: H, halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, -(C 1-3 (alkylene)-NR 6 R 7 or -NR 6 R 7 When substituted by multiple substituents, the substituents may be the same or different;

[0016] R 2 Selected from H or C 1-3 alkyl;

[0017] R 3 and R 4 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; or R 3 and R 4 It cyclizes with the attached N atom to form a 4-7 membered heterocyclic group;

[0018] R 5 Selected from H, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0019] R 6 and R 7 Independently selected from H and C 1-6 Alkyl, CN-substituted C 1-6 Alkyl, sulfone-substituted C 1-6 Alkyl or C 3-6 cycloalkyl; or R 6 and R 7 Together with the attached N atom, it cyclizes to form a 4-7 membered heterocyclic group, which may be substituted by 1-3 groups selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3Alkoxy groups, when substituted by multiple substituents, may be the same or different;

[0020] R 8 Selected from phenyl, (5-7 quinone) heteroaryl, -(C 1-6 alkylene)-phenyl or -(C 1-6 (alkylene)-(5-7-membered) heteroaryl, wherein the phenyl or (5-7-membered) heteroaryl group may be substituted by 1-3 of the following groups: H, halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, -(C 1-3 (alkylene)-NR 6 R 7 or NR 6 R 7 When substituted by multiple substituents, the substituents may be the same or different.

[0021] In another preferred embodiment, the compound of said general formula (I) has the structure shown in general formula (II):

[0022]

[0023] In general formula (II):

[0024] A 1 Selected from -CH2-, -O-, -S-, -S(O)-, -S(O2)- or -N(CH3)-;

[0025] B 1 Selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CH(CN)- or

[0026] L, R 1 R 3 R 4 and R 5 The definition is as described above.

[0027] In another preferred embodiment, the compound of general formula (I) has the structure shown in general formula (III):

[0028]

[0029] In general formula (Ⅲ):

[0030] A 2 Selected from -CH= or -N=;

[0031] B 2 Selected from -CH=, -C(CN)=, -C(C 1-3 Alkyl)=、-C(C1-3 (halogenated alkyl) = or -C(C 3-6 cycloalkyl) =;

[0032] L, R 1 R 3 R 4 and R 5 As defined above.

[0033] In another preferred embodiment, in the general formula (I), L is selected from...

[0034] The asterisk (*) indicates that it is connected to CO.

[0035] In another preferred embodiment, wherein in the general formula (Ⅰ), R 1 Selected from -OCH3, -OCF3, -OCH2CH3, -OCH2CF3,

[0036] In another preferred embodiment, wherein the general formula (I) is as follows: Selected from

[0037] In another preferred embodiment, in the general formula (Ⅰ), R 5 Selected from H, F, Cl, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, OCF3 or cyclopropyl.

[0038] In some embodiments of the present invention, the compounds of general formula (I) or pharmaceutically acceptable salts thereof are selected from:

[0039]

[0040]

[0041]

[0042]

[0043] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0044] Another object of the present invention is to provide the use of the above-described compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer, or the use of the above-described pharmaceutical compositions in the preparation of medicaments for treating cancer.

[0045] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0046] Compound Synthesis

[0047] The preparation method of the compound of general formula (I) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0048] The compounds of general formula (I) described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered in March, ADVANCED ORGANIC CHEMISTRY 4. th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0049] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compound represented by general formula (I), wherein the compound of general formula (I) can be prepared by the following general reaction procedure 1:

[0050] General reaction process 1

[0051]

[0052] Starting with compound a, intermediate b is obtained through nucleophilic substitution reaction. Intermediate b is then subjected to amine ester exchange to obtain intermediate c. Intermediate c is then subjected to alkylation reaction to obtain compound of general formula (Ⅰ).

[0053] Definitions and Explanations

[0054] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0055] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are defined according to the periodic table of elements, CAS edition, and the Chemical Reagents Handbook, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0056] The term "pharmaceutically acceptable salt" in this invention refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + Salts of (C1-4 alkyl)4. This invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-S sulfonates, and aromatic sulfonates.

[0057] In this invention, "solvate" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0058] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0059] The compounds disclosed in this invention, including their salts, can be prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, the compounds of this invention include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0060] As described in this invention, “pharmaceutically acceptable excipients or carriers” include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature indicate that various carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional carrier media, except for those incompatible with the compounds of this invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0061] Substances that can be used as pharmaceutically acceptable excipients or carriers include, but are not limited to: ion exchangers, aluminum, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as... Sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives, and antioxidants. For convenience, local anesthetics, preservatives, buffers, etc., may be directly dissolved in the carrier.

[0062] As used in this invention, the term "alkyl" refers to a monovalent hydrocarbon group consisting of a saturated straight-chain or branched chain of 1-20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments have an alkyl group containing 1-10 carbon atoms, others have an alkyl group containing 1-8 carbon atoms, still others have an alkyl group containing 1-6 carbon atoms, yet others have an alkyl group containing 1-4 carbon atoms, and still others have an alkyl group containing 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2) CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) ), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH 2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used here, encompassing both straight-chain and branched saturated carbon chains.

[0063] The term "alkoxy" as used in this invention refers to an alkyl group, as defined herein, which is attached to the main carbon chain by an oxygen atom. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. Such embodiments include, but are not limited to, methoxy, ethoxy, propoxy, etc.

[0064] The term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen atoms, without unsaturated bonds, and having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. Alkylene chains can be attached to the remainder of the molecule by any two carbon atoms in the chain.

[0065] The terms "haloalkyl" or "haloalkoxy" indicate that an alkyl or alkoxy group can be substituted by one or more identical or different halogen atoms. The alkyl and alkoxy groups have the meaning as described in this invention, and examples include, but are not limited to, 1,1,1-trifluoro-2-methylpropyl-2-yl (-C(CH3)2CF3), 1,1-difluoro-2-methylpropyl-2-yl (-C(CH3)2CHF2), 1-fluoro-2-methylpropyl-2-yl (-C(CH3)2CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), 2,2,2-trifluoroethoxy (-OCH2CF3), 2,2,3,3-tetrafluoropropoxy (-OCH2CF2CHF2), etc.

[0066] The term "halogen" as used in this invention includes fluorine, chlorine, bromine, and iodine.

[0067] The terms "carbocyclic" or "cyclic aliphatic," "carbocyclic," and "cycloalkyl" refer to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated rings that do not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic or tricyclic rings of 7-12 carbon atoms. A bicyclic ring having 7-12 atoms can be a bicyclic [4,5], [5,5], [5,6], or [6,6] system, while a bicyclic ring having 9 or 10 atoms can be a bicyclic [5,6] or [6,6] system. Depending on the structure, "carbocyclic" or "cyclic aliphatic," "carbocyclic," and "cycloalkyl" can be monovalent or divalent, meaning that in some embodiments of the invention, they can be used instead of or as carbocyclic or cycloalkyl groups. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of cyclic aliphatic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, etc. Furthermore, the terms "carbocyclic" or "cyclic aliphatic," "carbocyclic," and "cycloalkyl" can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C(=O)-NH2, carboxyl, and -S(=O). t OH, -OS (=O) t -H, -S (=O) t NH2, triazolyl, tetrazolyl, -(CR) 3b R 3c ) n -NH2, alkyl, alkyl-S (=O) t - Halogenated alkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, halogenated alkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, sulfhydryl, nitro, aryloxy, hydroxyalkoxy, alkylacyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido or alkoxyalkyl, etc.

[0068] The term "aryl" can be used alone or as a subset of "aralkyl," "ararylalkoxy," or "aryloxyalkyl," and can be a monocyclic, bicyclic, or tricyclic carbocyclic system. In some embodiments of the invention, it can be used instead of arylene. At least one ring system of the aryl group is aromatic, and each ring system contains 3-7 ring atoms. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group can be substituted or unsubstituted, wherein substituents can be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C (=O)-NH2, carboxyl, and -S (=O). t OH, -OS (=O) t -H, -S (=O) t NH2, triazolyl, tetrazolyl, -(CR) 3b R 3c ) n -NH2, alkyl, alkyl-S (=O) t - Halogenated alkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, halogenated alkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, sulfhydryl, nitro, aryloxy, hydroxyalkoxy, alkylacyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamide or alkoxyalkyl, etc.

[0069] The terms "heteroaryl" and "heteroary ring" are used interchangeably herein and may be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy," and in some embodiments of the invention, may be used instead of "heteroarylide." Both refer to monocyclic, bicyclic, tricyclic, or tetracyclic systems, wherein the bicyclic, tricyclic, or tetracyclic heteroaryl systems are fused together. The heteroaryl system is aromatic, and one or more atoms on the ring are independently and optionally replaced by heteroatoms (heteratoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain groups like SO, SO2, PO, PO2). The heteroaryl system can be attached to the host structure at any heteroatom or carbon atom to form a stable compound. The heteroaryl system group can be a monocyclic ring of 3-7 atoms, a bicyclic ring of 7-10 atoms, or a tricyclic ring of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, and tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,6,6], or [6,5,6] systems. Furthermore, the heteroaryl group or heteroaryl ring can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C (=O)-NH2, carboxyl, or -S (=O). tOH, -OS (=O) t -H, -S (=O) t NH2, triazolyl, tetrazolyl, -(CR) 3b R 3c n-NH2, alkyl, alkyl-S (=O) t - Haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, allyl, alkynyl, heterocyclic, thiol, nitro, aryloxy, hydroxyalkoxy, alkylacyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido, or alkoxyalkyl, etc. Depending on the structure, heteroaryl groups can be monovalent or divalent (i.e., heteroaryl derivatives).

[0070] Other embodiments include, but are not limited to, the following examples of heteroaryl systems (containing heteroaryl groups and heteroaryl rings): 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-Thiophene, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2 -yl, 1,3,5-triazinyl, benzo[d]thiazolyl-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8-diazanaphthyl, benzothiopheneyl, benzothiazolyl, purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl) Quinolinyl or 4-isoquinolinyl), benzopyrazolyl, acridineyl, benzoindolyl, benzoisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridyl, benzo[d]imidazo[2,1-b]thiazolyl, benzofuranyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzothiopyranyl, benzooxazinyl, benzooxazolyl, benzothiazolyl β-Carbolinyl, Carbazoleyl, o-diazanaphthyl, Dibenzofuranyl, Imidazolylpyridyl, Imidazolylthiazolyl, Indazoleyl, Indoleazinyl, Indoleyl, Isobenzinyl, Isodihydroindoleyl, Isoquinolinyl, Isothiazolyl, Isothiazolyl, Naphthidyl, Decahydroindoleyl, Decahydroisoindoleyl, Oxazolidinedione, Oxazolyl, Oxazolylpyridyl, Oxazolyl, Ethylene oxide Alkyl, tetroxide-containing phenyl, phenanthridine, phenanthrolinyl, phenanthridine, phenazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, naphthinyl, pyridopyridinyl, quinazolinyl, quinoxolinyl, thiophenyl, triazinyl, 2H-pyrrolo[3,4-c]pyridinyl, pyrazolo[2',1':2,3]oxazolo[4,5-c]pyridinyl, imidazo[3,4-c]pyridinyl [2',1':2,3]thiazo[4,5-c]pyridyl, imidazo[2',1':2,3]thiazo[4,5-b]pyridyl, imidazo[2',1':2,3]thiazo[5,4-b]pyridyl, pyrazol[2',1':2,3]thiazo[4,5-b]pyrazinyl, IH-benzo[4,5]thieno[2,[3-d]imidazolyl, 1-methyl-IH-benzo[4,5]thieno[2,3-d]imidazolyl, imidazo[2',1':2,3]thiazo[4,5-b]pyrazinyl, imidazo[2',1':2,3]thiazo[5,4-b]pyridyl, imidazo[2',1':2,3]thiazo[4,5-c]pyridyl, etc.

[0071] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, tricyclic, or tetracyclic systems in which one or more atoms on the ring are independently and optionally replaced by heteroatoms. The ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatic. Depending on the structure, “heterocyclic group,” “heterocyclic,” and “heterocyclic alicyclic group” may be monovalent or divalent, i.e., in some embodiments of the invention, may be used as or as a subheterocyclic group. Heterocyclic systems can be attached to the host structure at any heteroatom or carbon atom to form stable compounds. One or more hydrogen atoms on the ring are independently and optionally replaced by one or more substituents described in this invention. Some of these embodiments are that the "heterocyclic group," "heterocyclic," "subheterocyclic group," "heterocyclic alicyclic group," or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2; in addition, the carbon atoms can be oxidized to form -C(=O)-; when the ring is a three-membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2).

[0072] In other embodiments, the nitrogen atom in the nitrogen-containing heterocyclic group is replaced by an oxygen atom to form a nitrogen oxide. For example... Formed by oxidation

[0073] "Heterocyclic group" can be carbon-based or heteroatom-based. "Heterocyclic group" also includes groups formed by the fusion of heterocyclic groups with saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, pyridinyl, thiaxyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, homopyridinyl, epioxypropyl, azirroheptanyl, oxacycloheptanyl, thioheptanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazaphenyl, diazaphenyl, thioazaphenyl, pyrrolin-1-yl. 2-Pyrrolinyl, 3-Pyrrolinyl, Dihydroindolyl, 2-Indolinyl, 2H-Pyranyl, 4H-Pyranyl, Dioxacyclohexyl, 1,3-Dioxopentyl, Pyrazolinyl, Dithiaalkyl, Dithiamonyl, Dihydrothiophenyl, Pyrazolinyl, Imidazolinyl, Imidazolinyl, 1,2,3,4-Tetrahydroisoquinolinyl, 1,2,6-Thiadiazine 1,1-Dioxo-2-yl, Hexahydro-2H-[1,4]dioxane[2,3-c]pyrrolyl, Quinazinyl, 1,1-Thiomorpholinyl, 2,3,3a,7a-Tetrahydro-1H-Isoindolyl, Isoindolinyl, 1,2,3,4-Tetrahydroquinolinyl, N -Pyridylurea, dibenzofuranyl, dihydrobenzoisothiazinyl, dihydrobenzoisoxazinyl, dioxopentyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrroleyl, 1,4-dithiaalkyl, furanoneyl, furanyl, imidazoalkyl, imidazolinyl, imidazolyl, imidazopyridyl, imidazothiazolyl, indazoleyl, dihydroindolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiamyl, isobenzothiamyl, isobenzodihydropyranyl, isocoumarinyl, isodihydroindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, isoxazolyl, morpholinyl, decahydroindolyl The following are listed: decahydroisoindolyl, oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridyl, oxazolyl, ethylene oxide, naphthalene-diazine, phenanthinyl, phenanthrinyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, 4-piperidinoneyl, purine, pyrazinyl, pyrazolyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, quinoxolinyl, quininecycloyl, tetrahydroisoquinolinyl, tetrahydrothiazolyl, tetrazolyl, thiadiazopyrimidinyl, thiadiazolyl, thiomorpholinyl, thiazolyl, thiazolyl, thiophenyl, triazolyl, and 1,3,5-trithiazolyl. Furthermore, the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C (=O)-NH2, carboxyl, or -S (=O). tOH, -OS (=O) t -H, -S (=O) t NH2, triazolyl, tetrazolyl, -(CR) 3b R 3c ) n -NH2, alkyl, alkyl-S (=O) t - Halogenated alkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, sulfhydryl, nitro, aryloxy, hydroxyalkoxy, alkylacyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido, or alkoxyalkyl, etc. For example, 1-methylpyridin-2(1H)-one, cyclohexyl-2,4-dienone, 2,6-dimethylmorpholino, etc.

[0074] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0075] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0076] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0077] This invention uses the following abbreviations: room temperature (RT, rt); aqueous solution (aq.); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); 1,2-dichloroethane (DCE); 1,4-dioxane; methanol (MeOH); methyl tert-butyl ether (MTBE); ethanol (EtOH); tetrahydrofuran (THF); dimethylformamide (DMF); acetonitrile (ACN); dimethyl sulfoxide (DMSO); triethylamine (TEA); 4-dimethylaminopyridine (DMAP); iodomethane (CH3I); palladium on carbon (Pd / C); iron powder (Fe); trifluoroacetic acid (TFA); trifluoromethanesulfonic anhydride (Tf2O); acetic acid (AcOH); sodium hydride ( NaH); Sodium borohydride (NaBH4); Sodium triacetoxyborohydride (NaBH(Ac)3); Magnesium sulfate (MgSO4); 2-Dicyclohexylphosphide-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos); Sodium carbonate (Na2CO3); Potassium carbonate (K2CO3); Tripotassium phosphate (K3PO4); Equivalent (eq); g / mg; mol / mmol; L / mL; min(s); h, hr, hrs; Nitrogen (N2); Nuclear magnetic resonance (NMR); Liquid chromatography-mass spectrometry (LC-MS); Thin-layer chromatography (TLC); Preparative liquid chromatography (pre-HPLC).

[0078] Example 1 Synthesis of 4-((7-methoxy-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0079]

[0080] Step 1: Synthesis of 7-methoxy-3,4-dihydroquinoline-2(1H)-one

[0081]

[0082] In a 250 mL single-necked flask, compound A-1 (3 g, 18 mmol, 1 eq), acetonitrile (80 mL), potassium carbonate (7.6 g, 56 mmol, 3 eq), and iodomethane (3.13 g, 36 mmol, 2 eq) were added. The mixture was stirred overnight at 80 °C, filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to obtain compound A-2 (3 g, 92%), LCMS: 178.2 [M+H]. + .

[0083] Step 2: Synthesis of methyl 4-((7-methoxy-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoate

[0084]

[0085] In a 100 mL single-necked flask, A-2 (1 g, 5.64 mmol, 1 eq) and DMF (20 mL) were added. NaH (189 mg, 7.9 mmol, 1.4 eq) was added under ice bath conditions. After allowing the mixture to return to room temperature, the mixture was stirred for 10 min. After cooling to 0 °C, methyl 4-bromomethylbenzoate (1.3 g, 5.64 mmol, 1 eq) was added. After allowing the mixture to return to room temperature, stirring was continued for 10 min. The reaction was monitored by TLC until complete. The system was quenched with water (100 mL) under ice bath conditions. Extraction was performed with EA (100 mL). The organic phase was washed with saturated brine, dried, and concentrated to obtain crude product A-3 (1.5 g). LCMS: 326.2 [M+H] + .

[0086] Step 3: Synthesis of 4-((7-methoxy-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoylhydrazine

[0087]

[0088] In a 50 mL single-necked flask, crude product A-3 (1.5 g) and methanol / hydrazine hydrate (20 mL / 20 mL) were added. The mixture was stirred at 70 °C for 20 min. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was filtered to obtain filter cake A-4 (1.6 g). LCMS: 326.2 [M+H] + .

[0089] Step 4: Synthesis of 4-((7-methoxy-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylene benzoylhydrazine

[0090]

[0091] In a 100 mL single-necked flask, crude product A-4 (1.06 g) and methanol (50 mL) were added, along with anhydrous magnesium sulfate (5.5 g, 45.6 mmol, 7 eq) and n-propionaldehyde (378 mg, 6.51 mmol, 2 eq). The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was concentrated to obtain crude product A-5 (1.1 g). LCMS: 366.2 [M+H] + .

[0092] Step 5: Synthesis of 4-((7-methoxy-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0093]

[0094] In a 50 mL single-necked flask, crude product A-5 (1.1 g) and methanol (20 mL) were added. Sodium borohydride (619 mg, 16.3 mmol, 5 eq) was added under ice bath conditions. The mixture was stirred at room temperature for 0.5 h, and the reaction was monitored by TLC until complete. The mixture was quenched with saturated ammonium chloride, concentrated, and extracted with water (30 mL) and EA (40 mL). The organic phase was washed with saturated brine, dried, and the crude product was separated by column chromatography to obtain compound 32 (800 mg, 72%), LCMS: 368.2 [M+H]. + .

[0095] Example 2 Synthesis of 4-((2-oxo-7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0096]

[0097] Step 1: Synthesis of 7-(2-bromoethoxy)-3,4-dihydroquinoline-2(1H)-one

[0098]

[0099] In a 100 mL flask, B-1 (1 g, 6.13 mmol, 1 eq), 1,2-dibromoethane (4.24 g, 22.7 mmol, 3.7 eq), potassium carbonate (1.69 g, 12.26 mmol, 2 eq), and EtOH (35 mL) were added sequentially. The mixture was stirred at 85 °C for 4 h. The reaction was monitored by TLC until complete. The system was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography (PE / EA 10:1→5:1→3:1→2:1) to obtain compound B-2 (500 mg, 30.2%), LCMS: 270.2 [M+H]. + .

[0100] Step 2: Synthesis of 7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-2(1H)-one

[0101]

[0102] In a 50 mL flask, B-2 (500 mg, 1.85 mmol, 1 eq), hexahydropyridine (236.42 mg, 2.78 mmol, 1.5 eq), potassium carbonate (511.63 mg, 3.7 mmol, 2 eq), and CAN (10 mL) were added sequentially. The mixture was reacted overnight at 85 °C. The reaction was monitored by TLC until complete. The system was filtered, the filtrate was concentrated, and the crude product was subjected to column chromatography to obtain compound B-3 (480 mg, 94%), LCMS: 275.2 [M+H]. + .

[0103] Step 3: Synthesis of methyl 4-((2-oxo-7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoate

[0104]

[0105] In a 25 mL flask, B-3 (480 mg, 1.75 mmol, 1 eq) and DMF (5 mL) were added. After cooling the system to 0 °C, NaH (83.97 mg, 3.5 mmol, 2 eq) was added. After allowing the system to return to room temperature, stirring was continued for 20 min. The reaction system was then cooled to 0 °C again, and methyl 4-bromomethylbenzoate (601.15 mg, 2.62 mmol, 1.5 eq) was added. After allowing the system to return to room temperature, stirring was continued for 30 min. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution in an ice bath. Extraction was performed using EA (30 mL * 3). The organic phases were combined, washed three times with water, dried, and concentrated. The crude product was subjected to column chromatography to obtain compound B-4 (200 mg, 27%), LCMS: 423.2 [M + H]. + .

[0106] Step 4: Synthesis of 4-((2-oxo-7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoylhydrazine

[0107]

[0108] In a 25 mL flask, B-4 (160 mg, 0.38 mmol, 1 eq) and hydrazine hydrate / methanol = 1 / 1 (2 mL / 2 mL) were added. The mixture was refluxed and stirred at 85 °C for 30 min. The reaction was monitored by TLC until complete. The mixture was extracted with EA (30 mL * 3), and the organic phases were combined, washed with saturated brine, dried, and concentrated to obtain crude B-5 (190 mg). LCMS: 423.2 [M + H₂] + .

[0109] Step 5: Synthesis of 4-((2-oxo-7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylene benzoyl hydrazine

[0110]

[0111] In a 25 mL flask, crude B-5 (190 mg), propionaldehyde (0.16 mL, 0.09 mmol, 5 eq), anhydrous magnesium sulfate (54.12 mg, 0.45 mmol, 1 eq), and MeOH (5 mL) were added. The reaction was monitored by TLC until complete. The system was filtered, and the filtrate was concentrated to obtain crude B-6 (205 mg). LCMS: 463.2 [M+H]+ .

[0112] Step 6: Synthesis of 4-((2-oxo-7-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0113]

[0114] In a 25 mL flask, crude B-6 (205 mg) and MeOH (3 mL) were added. NaBH4 (167.65 mg, 4.42 mmol, 10 eq) was added under ice bath conditions. The reaction was carried out for 30 min under ice bath conditions. The reaction was monitored by TLC until complete. The system was directly concentrated, and the crude product was separated by column chromatography to obtain a white solid 38 (110 mg, 52%), LCMS: 465.2 [M+H]. + .

[0115] Example 3 Synthesis of 4-((7-(5-(((2-(methanesulfonyl)ethyl)amino)methyl)furan-2-yl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0116]

[0117] Step 1: Synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-7-yltrifluoromethanesulfonate

[0118]

[0119] C-1 (6 g, 36.80 mmol, 1 eq) was dissolved in DCM (60 mL) in a 100 mL flask, and pyridine (8 g, 101.26 mmol, 2.75 eq) was added. Then, Tf₂O (15.2 g, 53.9 mmol, 1.46 eq) was added dropwise under ice bath conditions. The system was brought to room temperature and stirred at room temperature for 4 h. The reaction was monitored by TLC until complete. The system was washed with saturated sodium bicarbonate solution (50 mL), followed by salt washing (50 mL), dried, concentrated, and the crude product was subjected to column chromatography to give compound C-2 (5.8 g, 53.4%), LCMS: 296.1 [M+H]. + .

[0120] Step 2: Synthesis of methyl 4-((7-((methanesulfonyl)oxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoate

[0121]

[0122] C-2 (2 g, 6.77 mmol, 1 eq) was dissolved in DMF (20 mL) in a 50 mL flask. After cooling the system to 0 °C, NaH (406 mg, 16.93 mmol, 2.5 eq) was added in portions. After allowing the mixture to return to room temperature, stirring was continued for 30 min. The reaction system was then cooled to 0 °C again, and methyl 4-bromomethylbenzoate (2.33 g, 10.16 mmol, 1.5 eq) in DMF (10 mL) was added. After allowing the mixture to return to room temperature, stirring was continued for 30 min. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution in an ice bath, and extracted with EA (30 mL * 3). The organic phases were combined, washed three times with water, dried, and concentrated. The crude product was subjected to column chromatography to obtain C-3 (2.4 g, 80%), LCMS: 444.1 [M + H]. +

[0123] Step 3: Synthesis of methyl 4-((7-(5-formaldehydefuran-2-yl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoate

[0124]

[0125] In a 100 mL flask, C-3 (800 mg, 2.05 mmol, 1 eq), 5-formaldehydefuran-2-boronic acid (430 mg, 3.08 mmol, 1.5 eq), RuPhos-Pd-G3 (171.6 mg, 0.205 mmol, 0.1 eq), RuPhos (191.3 mg, 0.41 mmol, 0.2 eq), potassium phosphate (1.3 g, 6.15 mmol, 3 eq), and DCE / H2O (40 mL / 8 mL) were added sequentially. The mixture was stirred at 90 °C for 4 h under argon protection. The reaction was monitored by TLC until complete. After cooling, EA (100 mL) was added to dilute the mixture. The organic phase was washed with water and saturated brine, dried, and concentrated. The crude product was subjected to column chromatography to obtain compound C-4 (700 mg, 87%), LCMS: 390.1 [M+H]. + .

[0126] Step 4: Synthesis of methyl 4-((7-(5-(((tert-butylcarbonyl)(2-(methanesulfonyl)ethyl)amino)methyl)furan-2-yl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)benzoate

[0127]

[0128] In a 50 mL single-necked flask, 2-(methanesulfonyl)ethylamine hydrochloride (172 mg, 1.08 mmol, 1.2 eq), DCE (25 mL), C-4 (350 mg, 0.9 mmol, 1 eq), and triethylamine (0.15 mL, 1.08 mmol, 1.2 eq) were added sequentially. After stirring at room temperature for 1 h, sodium borohydride acetate (229 mg, 1.08 mmol, 1.2 eq) was added. The system was stirred at room temperature for 12 h, and then Boc₂O (392 mg, 2.16 mmol, 2 eq) was added. The mixture was stirred at room temperature for another 1 h. The reaction was monitored by TLC and found to be complete. The system was diluted with EA (50 mL), the organic phase was washed with water, dried, concentrated, and the crude product was separated by column chromatography to obtain compound C-5 (300 mg, 56%), LCMS: 597.2 [M+H]. + .

[0129] Step 5: Synthesis of tert-butyl ((5-(1-(4-(hydrazine carbonyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)furan-2-yl)methyl)(2-(methanesulfonyl)ethyl)carbamate

[0130]

[0131] In a 50 mL single-necked flask, C-5 (300 mg, 0.5 mmol, 1 eq) and methanol / hydrazine hydrate (10 mL / 10 mL) were added. The mixture was stirred at 70 °C for 20 min, and the reaction was monitored by TLC until complete. After the system was cooled to room temperature, it was filtered, and the filter cake was separated by column chromatography to obtain compound C-6 (200 mg, 67%), LCMS: 597.2 [M+H]. + .

[0132] Step 6: Synthesis of tert-butyl (2-(methanesulfonyl)ethyl)((5-(2-oxo-1-(4-(2-propylhydrazine-1-carbonyl)benzyl)-1,2,3,4-tetrahydroquinoline-7-yl)furan-2-yl)methyl)carbamate

[0133]

[0134] In a 50 mL single-necked flask, C-6 (200 mg, 0.33 mmol, 1 eq), methanol (20 mL), anhydrous magnesium sulfate (800 mg, 6.6 mmol, 20 eq), and n-propanal (38.2 mg, 0.66 mmol, 2 eq) were added sequentially. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The system was filtered, and the filtrate was concentrated to obtain crude C-7 (250 mg). LCMS: 637.2 [M+H] + .

[0135] Step 7: Synthesis of tert-butyl (2-(methanesulfonyl)ethyl)((5-(2-oxo-1-(4-(2-propylhydrazine-1-carbonyl)benzyl)-1,2,3,4-tetrahydroquinoline-7-yl)furan-2-yl)methyl)carbamate

[0136]

[0137] In a 50 mL single-necked flask, C-7 (250 mg) and methanol (10 mL) were added, followed by sodium borohydride (38 mg, 1 mmol) at 0 °C. The mixture was stirred at room temperature for 0.5 h, and the reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution, extracted with EA (20 mL * 2), and the organic phases were combined, washed with saturated brine, dried, and concentrated to obtain crude C-8 (220 mg). LCMS: 639.2 [M + H]. + .

[0138] Step 8: Synthesis of 4-((7-(5-(((2-(methanesulfonyl)ethyl)amino)methyl)furan-2-yl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl)-N'-propylbenzoylhydrazine

[0139]

[0140] In a 50 mL single-necked flask, C-8 (220 mg), DCM (5 mL), and TFA (1.5 mL) were added sequentially. The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by TLC until complete. After concentration, the mixture was diluted with water (10 mL). The aqueous phase was adjusted to neutral pH by adding saturated sodium bicarbonate, and then extracted with EA (20 mL * 2). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to obtain compound 62 (46 mg, 25%), LCMS: 539.2 [M + H]. + .

[0141] Example 4 Synthesis of 4-((3-oxo-6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)-N'-propylbenzoylhydrazine

[0142]

[0143] Step 1: Synthesis of ethyl 2-((4-bromo-2-nitrophenyl)mercapto)ethyl acetate

[0144]

[0145] In a 100 mL flask, 5-bromo-2-chloronitrobenzene (5 g, 21.15 mmol, 1 eq), acetonitrile (40 mL), ethyl mercaptoside (2.78 mL, 25.38 mmol, 1.2 eq), and K₂CO₃ (8.767 g, 63.44 mmol, 3.0 eq) were added. The mixture was refluxed at 85 °C and stirred for 20 min. The reaction was monitored by TLC until complete. The system was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography (PE / EA = 0-10 / 1) to obtain a yellow solid D-2 (6.791 g, 99%), LCMS: 320.1 [M+H₂]. + .

[0146] Step 2: Synthesis of 6-bromo-2H-benzo[b][1,4]thiazine-3(4H)-one

[0147]

[0148] In a 100 mL flask, compound D-2 (3 g, 9.41 mmol) and glacial acetic acid (25 mL) were added, followed by the addition of reduced iron powder (2.11 g, 37.63 mmol, 4.0 eq) in portions. The mixture was purged with nitrogen three times and refluxed overnight at 90 °C. The reaction was monitored by TLC until complete. After dilution with water (200 mL), concentrated hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filter cake was washed with NMP (100 mL). The filtrate was slowly poured into water (600 mL), precipitating a large amount of white solid. This solid was filtered, and the filter cake was dried to obtain white solid D-3 (1.743 g, 76%), LCMS: 244.1 [M+H]. + .

[0149] Step 3: Synthesis of 5-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)furan-2-carboxaldehyde

[0150]

[0151] In a 100 mL flask, compound D-3 (0.8 g, 3.29 mmol, 1 eq), ethylene glycol dimethyl ether / water (40 / 8 mL), 5-formaldehyde furan-2-boronic acid (0.691 g, 4.935 mmol, 1.5 eq), potassium phosphate (2.1 g, 9.87 mmol, 3.0 eq), RuPhos (0.307 g, 0.658 mmol, 0.2 eq), and RuPhos-Pd-G3 (276 mg, 0.329 mmol, 0.1 eq) were added. The system was purged with nitrogen three times and refluxed at 90 °C with stirring for 4 h. The reaction was monitored by LC-MS until complete. The system was filtered, and the filtrate was extracted with DCM (20 mL * 2). The organic phase was dried and concentrated. The crude product was separated by column chromatography (PE / EA = 10 / 1-1 / 1) to obtain a yellow solid D-4 (0.8 g, 94%), LCMS: 260.2 [M + H]. + .

[0152] Step 4: Synthesis of 6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2H-benzo[b][1,4]thiazine-3(4H)-one

[0153]

[0154] In a 50 mL flask, D-4 (300 mg, 1.16 mmol, 1 eq), hexahydropyridine (141.8 mg, 1.74 mmol, 1.5 eq), sodium borohydride acetate (490 mg, 2.3 mmol, 2 eq), and DCE (6 mL) were added. The reaction was carried out overnight at 85 °C. The reaction was monitored by TLC until complete. The system was quenched with saturated ammonium chloride solution, extracted with EA (20 mL * 2), dried over the organic phase, concentrated, and the crude product was subjected to column chromatography to give compound D-5 (289 mg, 76%), LCMS: 329.2 [M + H]. + .

[0155] Step 5: Synthesis of methyl 4-((3-oxo-6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)benzoate

[0156]

[0157] In a 25 mL flask, D-5 (145 mg, 0.44 mmol, 1 eq) and DMF (3 mL) were added. NaH (42 mg, 0.88 mmol, 2 eq) was added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 20 min. Methyl 4-bromomethylbenzoate (180.3 mg, 0.66 mmol, 1.5 eq) was added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 30 min. The reaction was monitored by TLC until complete. The system was quenched by adding saturated ammonium chloride solution under ice bath conditions. Extraction was performed using EA (20 mL * 2). The organic phase was washed with saturated brine, dried, and concentrated to obtain crude D-6 (250 mg). LCMS: 477.2 [M + H]. + .

[0158] Step 6: Synthesis of 4-((3-oxo-6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)benzoylhydrazine

[0159]

[0160] In a 25 mL flask, add crude D-6 (250 mg) and hydrazine hydrate / methanol = 1 / 1 (2 mL / 2 mL), reflux and stir at 85 °C for 30 min, TL C The reaction was monitored until complete. The system was extracted with EA (30 mL * 3), the organic phases were combined, washed with saturated brine, dried, and concentrated to obtain crude D-7 (167 mg). LCMS: 477.2 [M + H]. + .

[0161] Step 7: Synthesis of 4-((3-oxo-6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)-N'-propylene benzoylhydrazine

[0162]

[0163] Crude D-7 (167 mg), propionaldehyde (0.16 mL, 0.75 mmol, 5 eq), anhydrous magnesium sulfate (54 mg, 0.15 mmol, 1 eq), and MeOH (5 mL) were added to a 25 mL flask. The reaction was monitored by TLC until complete. The system was filtered, and the filtrate was concentrated to obtain crude D-8 (190 mg). LCMS: 517.2 [M+H] + .

[0164] Step 8: Synthesis of 4-((3-oxo-6-(5-(piperidin-1-ylmethyl)furan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)-N'-propylbenzoylhydrazine

[0165]

[0166] In a 25 mL flask, crude D-8 (190 mg) and MeOH (3 mL) were added. NaBH4 (145 mg, 3.9 mmol, 10 eq) was added under ice bath conditions. After reacting for 30 min at this temperature, the reaction was monitored by TLC until complete. The system was directly concentrated, and the crude product was separated by column chromatography to obtain a white solid 61 (65 mg, 34%). LCMS: 519.2 [M+H] + .

[0167] Similar to the synthesis of the compounds in Examples 1-4, the compounds listed in Table 1 can be obtained:

[0168] Table 1. List of Compounds 1-89

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] Example 5: Inhibition of enzyme activity by some compounds of the present invention

[0175] HDAC enzyme (recombinant protein HDAC1, 2, or 3), compounds (concentrations of 100, 30, 10, and 3 nM, respectively), trypsin, and Ac-Peptide were mixed and incubated at room temperature for 15 minutes. The substrate was then added to initiate the reaction. The mixture was excited at 335 nm at different time points after the reaction, and the emission light was read at 450 nm to detect the reaction efficiency. The percentage of inhibition was calculated compared to the control group (DMSO).

[0176] Table 2. Percentage of enzyme activity inhibition by some compounds of the present invention

[0177]

[0178] As shown in Table 2, the compounds of this invention have strong HDAC3 inhibitory activity, with most compounds exhibiting an inhibition rate greater than 50% at 30 nM. At the same time, the compounds of this invention have good selectivity for HDAC1 and HDAC2, with most compounds exhibiting an inhibition rate less than 50% at 100 nM.

[0179] Example 6: Anti-cell proliferation experiment of some compounds of the present invention

[0180] 3000 cells (8226 cells per well) were seeded in 384-well plates. A compound diluted serially with DMSO was added, and ATP levels in the cells were measured using the CTG method after 72 hours. The percentage of cell proliferation inhibited by the compound was calculated compared to the DMSO group. The IC50 value of the compound was then calculated to inhibit cell proliferation. 50 .

[0181] Table 3. Antiproliferative activity of the compounds against multiple myeloma RPMI8226 cells

[0182] compound <![CDATA[RPMI8226 IC 50 (μM)]]> 1 0.104 13 0.029 32 0.048 43 0.054 71 0.03

[0183] As shown in Table 3, the compounds of this invention have excellent anti-RPMI8226 cell proliferation activity.

[0184] Example 7: In vivo efficacy test of the compounds of the present invention

[0185] BALB / c nude mice, female, 6-8 weeks old, weighing approximately 18-22 grams. Each mouse was divided into 5*10 groups. 6 One cell per 100 μL per animal was injected subcutaneously into the left axillary region of the forelimb of healthy nude mice. The tumors were allowed to grow to an average size of approximately 130-140 mm. 3 Dosing should begin around 10:00 AM, with a dosing period of 18 days. During the dosing period, tumor volume should be measured every 2 days, calculated in cubic millimeters using the following formula: V = 0.5a × b 2 Where a and b represent the long and short diameters of the tumor, respectively. The tumor-suppressive efficacy of the compound was evaluated using TGI (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is: TGI (%) = [1 - (tumor volume in the treated group at the end of the experiment - tumor volume in the treated group at the beginning of the experiment) / (tumor volume in the control group at the end of the experiment - tumor volume in the control group at the beginning of the experiment)] × 100%.

[0186] Table 4. In vivo efficacy of some compounds of the present invention in a human HepG2 cell subcutaneous xenograft tumor model.

[0187]

[0188] As shown in Table 4, compounds 1 and 32 exhibit excellent in vivo antitumor activity against a human hepatocellular carcinoma HepG2 cell subcutaneous xenograft model. Other compounds of this invention also exhibit strong in vivo antitumor activity.

[0189] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: In general formula (I): X 1 X 2 and X 3 Independently selected from -C(R) 5 = ; A and B are connected by a single bond or a double bond: When A and B are connected by a single bond, A is selected from -CH2-, -O-, -S-, -S(O)-, -S(O2)-, or -N(CH3)-, and B is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CH(CN)-, or When A and B are connected by a double bond, A is selected from -CH=, -C(CH3)=, -C(CF3)=, -C(CN)=, or -N=, and B is selected from -CH=, -C(CN)=, -C(C 1-3 Alkyl)=、-C(C 1-3 (halogenated alkyl) = or -C(C 3-6 cycloalkyl) =; Y is selected from chemical bonds, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -C(C2H5)2-, -CH(CF3)-, -CH(CH2CF3)-, -CH2CH2-, -C(CH3)2CH2- or L represents a phenyl group, which may be substituted by 1-3 of the following groups: H, halogen, CN, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Haloalkoxy groups, when substituted by multiple substituents, may be the same or different; R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-6 (alkylene)-NR 6 R 7 -O-(C 1-6 (alkylene)-NR 6 R 7 -NHCO-(C 1-6 (alkylene)-NR 6 R 7 -NHCOR 8 -C(O)NR 6 R 7 -NR 6 R 7 -CONHR 8 , phenyl or 5-7 heteroaryl, wherein the phenyl or 5-7 heteroaryl group can be substituted by 1-3 of the following groups: H, halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, -(C 1-3 (alkylene)-NR 6 R 7 or -NR 6 R 7 When substituted by multiple substituents, the substituents may be the same or different; R 2 Selected from H; R 3 and R 4 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; R 5 Selected from H, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; R 6 and R 7 Independently selected from H and C 1-6 Alkyl, CN-substituted C 1-6 Alkyl, sulfone-substituted C 1-6 Alkyl or C 3-6 cycloalkyl; or R 6 and R 7 Together with the attached N atom, it cyclizes to form a 4-7 membered heterocyclic group, which may be substituted by 1-3 groups selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy groups, when substituted by multiple substituents, may be the same or different; R 8 Selected from phenyl, (5-7 quinone) heteroaryl, -(C 1-6 alkylene)-phenyl or -(C 1-6 (alkylene)-(5-7-membered) heteroaryl, wherein the phenyl or (5-7-membered) heteroaryl group may be substituted by 1-3 of the following groups: H, halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, -(C 1-3 (alkylene)-NR 6 R 7 or NR 6 R 7 When substituted by multiple substituents, the substituents may be the same or different.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in general formula (II): In general formula (II): A 1 Selected from -CH2-, -O-, -S-, -S(O)-, -S(O2)- or -N(CH3)-; B 1 Selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CH(CN)- or L, R 1 R 3 R 4 and R 5 The definition is as described in claim 1.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in general formula (III): In general formula (Ⅲ): A 2 Selected from -CH= or -N=; B 2 Selected from -CH=, -C(CN)=, -C(C 1-3 Alkyl)=、-C(C 1-3 (halogenated alkyl) = or -C(C 3-6 cycloalkyl) =; L, R 1 R 3 R 4 and R 5 The definition is as described in claim 1.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein L is selected from: The asterisk (*) indicates that it is connected to CO.

5. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OCH3, -OCF3, -OCH2CH3, -OCH2CF3, -OCH2CHF2, 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... Selected from 7. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, R 5 Selected from H, F, Cl, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, OCF3 or cyclopropyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

9. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound or a pharmaceutically acceptable salt thereof as any one of claims 1-8 as an active ingredient.

10. The use of a compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, in the preparation of a medicament for treating cancer.

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