Compounds for treating diseases and methods for treating diseases

Abstract

The present invention relates to compounds having zinc and / or iron ionophore activity and their use in the treatment of diseases modulated by reducing zinc and / or iron. In certain embodiments, the compound is a compound of formula (I): [Formula 1] JPEG2023539859000152.jpg4138

Description

[Technical Field]

[0001] The present invention relates to compounds having zinc and / or iron ionophore activity and their use in the treatment of diseases regulated by reducing zinc and / or iron. [Background technology]

[0002] Zinc and iron are micronutrients involved in several biological processes, including immune responses, metabolism, nucleic acid synthesis and repair, apoptosis, and redox homeostasis, and may be important in host-pathogen interactions.

[0003] Zinc has been linked to processes involved in diseases such as cancer and neurological disorders, and has been shown to possess antiviral, antibiotic, and antiinfective activities.

[0004] Iron is linked to processes involved in neurodegenerative disorders and disorders associated with iron overload.

[0005] The ability to chelate zinc and / or iron, and to transport them, for example, from the extracellular environment to the intracellular environment, is useful in various disease processes. Further zinc and iron ionophores are needed that may be useful in the treatment or management of disease processes. [Overview of the Initiative]

[0006] Formula (I):

[0007] [ka] (In the formula, X is either O or S, R1 is

[0008] [ka] Selected from, Y1 is CR8 or N, Y2 is CR8 or N, provided that both Y1 and Y2 are not N, Y3 is C(R8)2, NR9 or S, Y4 is CR8 or N, provided that when Y4 is CR8, Y3 is not C(R8)2, R6 and R7 are independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxy, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halo, CN, CO2R9 and N(R9)2, or R6 and R7 together with the atom to which they are attached form an optionally substituted 6-membered aryl or heteroaryl ring, each R8 is independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxy, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halo, (C(R 10 )2) m CO2R9 and (C(R 10 )2) m N(R9)2, each R9 is independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and C 1~6 haloalkyl, R2 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 3~8 cycloalkyl and

[0009]

Chemical formula

[0010] [ka] (In the formula, R 14 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m It forms a heteroaryl (wherein the formula, aryl and heteroaryl are optionally substituted), or R 4a There is no such group, and R4 and R5 together form an optionally substituted aryl or optionally substituted heteroaryl group. Each R 10 is hydrogen, C 1~6 Alkyl, C 2~6Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Selected independently from haloalkoxy, CN, halo, and N(R9)2, m is an integer from 0 to 6. It is a compound of or a pharmaceutically acceptable salt thereof.

[0011] Also described herein is formula (Ia):

[0012] [ka] (In the formula, X is either O or S, R1 is

[0013] [ka] Selected from, Y1 is CR8, Y2 is either CR8 or N. Y3 is C(R8)2, NR9, or S. Y4 is CR8 or N, However, if Y4 is not CR8, then Y3 is C(R8)2. R6 and R7 are hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Independently selected from haloalkoxy, halo, CN, CO2R9 and N(R9)2, or R6 and R7, together with the atom to which they are bonded, form an unsubstituted six-membered aryl or heteroaryl ring. Each R8 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C1~6 Haloalkyl, C 1~6 Haloalkoxy, halo, (CH2) m CO2R9 and (CH2) m independently selected from N(R9)2, each R9 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and C 1~6 independently selected from haloalkyl, R2 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 3~8 cycloalkyl and

[0014]

Chemical formula

[0015] [Chemistry] (wherein, R 14 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m heteroaryl (wherein, aryl and heteroaryl are optionally substituted), or R 4a [[ID=2,1]]does not exist, and R4 and R5 together form an optionally substituted aryl or an optionally substituted heteroaryl group, each R 10 is independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxy, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, CN, halo and N(R9)2, [[ID=3,8]]m is an integer of 0 or 1 to 6) is a compound of or a pharmaceutically acceptable salt thereof.

[0016] Also described herein is a compound of formula (Ib):

[0017] [Chemistry] (wherein, X is O, R1 is

[0018] [Chemistry] selected from R6 and R7 are hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxy, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 ​Independently selected from haloalkoxy, halo, CN, CO2R9 and N(R9)2, or R6 and R7, together with the atom to which they are bonded, form an optionally substituted 6-membered aryl or heteroaryl ring. Each R8 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, (C(R 10 )2) m CO2R9 and (C(R 10 )2) m Selected independently from N(R9)2, Each R9 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Selected independently from haloalkyl groups, R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl and

[0019] [ka] Select from, or R1 and R2 together,

[0020] [ka] (In the formula, V is CH, O or S, and R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo, C 1~6 Haloalkyl, (CH2) m C 3~8Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 A cycloalkyl, heterocycloalkyl, or heteroaryl ring of a bicyclic structure formed from R1 and R2 (selected independently from alkynyl and N(R9)2) may be optionally substituted, or Both R1 and R2

[0021] [ka] And, R3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and (C(R 10 )2) m Selected from CO2R9, R4 and R 4a is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Each is independently selected from haloalkyls, and R5 is hydrogen, (C(R 10 )2) m Ariel, (C(R 10 )2) m Heteroaryl, O(C(R 10 )2) m Aryl or O(C(R 10 )2) m It is a heteroaryl (where aryl and heteroaryl are optionally substituted), or R 4a is CN, and R4 and R5 are either hydrogen or together,

[0022] [ka] (In the formula, R 14 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m It forms a heteroaryl (wherein the formula, aryl and heteroaryl are optionally substituted), or R 4a There is no such group, and R4 and R5 together form an optionally substituted aryl or optionally substituted heteroaryl group. Each R 10 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Selected independently from haloalkoxy, CN, halo, and N(R9)2, m is an integer from 0 to 6. It is a compound of or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials are described. In the present invention, the following terms are defined below.

[0024] The articles "a" and "an" are used herein to refer to one or more grammatical objects (i.e., at least one) of which the article is present. For example, "an element" means one or more elements.

[0025] As used herein, the term “about” means a quantity, level, value, dimension, size, or amount that differs by 15% or 10% from a given quantity, level, value, dimension, size, or amount.

[0026] Throughout this specification, unless otherwise specifically required by the context, the terms “comprise,” “comprises,” and “comprising” are understood to mean including the steps or elements or groups of steps or elements described, but not to mean excluding any other steps or elements or groups of steps or elements.

[0027] As used herein, the term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Where appropriate, an alkyl group may have a specified number of carbon atoms (for example, an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement). 1~6 Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl, and decyl.

[0028] As used herein, the term “haloalkyl” refers to the alkyl group defined above in which one or more hydrogen atoms are replaced by halogen atoms, and includes perhalogenated alkyl groups. Suitable examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, difluorochloromethyl, dichlorofluoromethyl, bromomethyl, iodomethyl, 1-fluoroethyl, 2-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-bromoethyl, 1-iodoethyl, 2-iodoethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, and the like.

[0029] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 10 carbon atoms. Where appropriate, an alkenyl group may have a specified number of carbon atoms. For example, “C 2-6 C in "Alkenil" 2-6 This includes groups having 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, and decenyl.

[0030] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group having one or more triple bonds and 2 to 10 carbon atoms. Where appropriate, the alkynyl group may have a specified number of carbon atoms. For example, "C 2-6 C in "Alkinil" 2-6 This includes groups having two, three, four, five, or six carbon atoms in a linear or branched arrangement. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0031] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon. A cycloalkyl ring may contain a specified number of carbon atoms. For example, a 3- to 10-membered cycloalkyl group contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0032] As used herein, the term “aryl” is intended to mean any stable monocyclic, bicyclic, or tricyclic carbocyclic system having up to seven atoms in each ring, with at least one ring being aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, phenantrenyl, biphenyl, and binaphthyl.

[0033] As used herein, the terms "halogen" or "halo" refer to fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iod).

[0034] As used herein, the terms “alkoxy” and “haloalkyloxy” refer to the alkyl and haloalkyl groups defined above, respectively, when bonded to oxygen. Suitable examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, 2-methylbutoxy, 3-methylbutoxy, 4-methylbutoxy, n-hexoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 5-methylpentoxy, 2-ethylbutoxy, 3-ethylbutoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloro This includes methoxy, chlorofluoromethoxy, difluorochloromethoxy, dichlorofluoromethoxy, bromomethoxy, iodomethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1-chloroethoxy, 2-chloroethoxy, 1-bromoethoxy, 2-bromoethoxy, 1-iodoethoxy, 2-iodoethoxy, 1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, 1-chloropropoxy, 2-chloropropoxy, and 3-chloropropyl.

[0035] As used herein, the terms “heterocyclic” or “heterocyclyl” refer to cyclic hydrocarbons such as the cycloalkyl groups defined above, in which one to four carbon atoms are replaced by heteroatoms independently selected from the group consisting of N, N(R), S, S(O), S(O)2, and O. The heterocyclic ring may be saturated or unsaturated, but it is not aromatic. Suitable examples of heterocyclyl groups include azetidine, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinil, pyranil, dioxolanil, piperidinyl, 2-oxopiperidinyl, pyrazolinil, imidazolinil, thiazolinil, dithiolyl, oxathiolyl, dioxanil, dioxynyl, dioxazolyl, oxathiozolyl, oxazolonyl, piperazinyl, morpholino, thiomorpholinil, 3-oxomorpholinil, dithianil, trithianil, and oxazinil.

[0036] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic ring with at least one aromatic ring and at least one ring containing 1 to 4 heteroatoms selected from the group consisting of O, N, and S, with each ring containing up to 7 atoms. Heteroaryl groups within this definition include acridinyl, carbazolyl, synnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, 4H-thieno[3,2-c]chromene, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazoli This includes, but is not limited to, tetrahydroquinolinyl, imidazolyl, pyrazinyl, pyridadinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetradinyl, and tetrazolyl.

[0037] Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may exist as an individual entity or as part of a larger entity, C 1~6 Alkyl, C 2~6 Alkenil, C 3~6 Cycloalkyl, oxo (=O), -OH, -SH, C 1~6 Alkyl O-, C 2~6 Alkenyl O-, C 3~6 Cycloalkyl O-, C 1~6 Alkyl S-, C 2~6 Alkenil S-, C 3~6 Cycloalkyl S-, -CO2H, -CO2C 1~6 Alkyl, -OC(=O)C 1~6 Alkyl, -NH2, -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH(phenyl),-N(phenyl)2,-C 1~6Alkyl NH2, -C 1~6 Alkyl NH(C 1~6 Alkyl), -C 1~6 Alkyl N(C) 1~6 Alkyl)2,-C 1~6 Alkyl NH(phenyl), -C 1~6 Alkyl N(phenyl)2, -OC 1~6 Alkyl NH2, -OC 1~6 Alkyl NH(C 1~6 Alkyl), -OC 1~6 Alkyl N(C) 1~6 Alkyl)2,-OC 1~6 Alkyl NH(phenyl), -OC 1~6 Alkyl N(phenyl)2, -CN, -NO2, -halogen, -CF3, -OCF3, -SCF3, -CHF2, -OCHF2, -SCHF2, -phenyl, -heterocyclyl, -heteroaryl, -Oheteroaryl, -Oheterocyclyl, -Ophenyl, -OC 1~6 Alkyl heteroaryl, -OC 1~6 Alkyl heterocyclyl, -OC 1~6 Alkylphenyl, -C(=O)phenyl, -C(=O)C 1~6 The molecule may be optionally substituted with one or more optional substituents selected from the group consisting of alkyl groups. Examples of suitable substituents include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, oxo, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro, chloro, bromo, iodine, cyano, nitro, -CO2H, -CO2CH3, -OC(=O)CH3, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, ethylamino, diethylamino, aminoC 1~6 Alkyl, methylamino C 1~6 Alkyl, dimethylamino C 1~6 Alkyl, ethylamino C 1~6Alkyl, diethylamino C 1~6 Alkyl, amino C 1~6 Alkoxy, Methylamino C 1~6 Alkoxy, Dimethylamino C 1~6 Alkoxy, ethylamino C 1~6 Alkoxy, Diethylamino C 1~6 This includes, but is not limited to, alkoxy, phenyl, phenoxy, phenylcarbonyl, benzyl, phenylethoxy, phenylmethoxy, phenylpropoxy, pyrrolidinyl methoxy, pyrrolidinyl ethoxy, pyrrolidinyl propoxy, pyridinyl methoxy, pyridinyl ethoxy, pyridinyl propoxy, and acetyl.

[0038] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. However, it should be understood that pharmaceutically acceptable salts are also within the scope of the present invention, as they may be useful as intermediates in the preparation of pharmaceutically acceptable salts, or useful during storage or transport. Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid, or formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucinic acid, malonic acid, malic acid (L), lactic acid (DL), mandelic acid (DL), gluconic acid, carbonic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, This includes, but is not limited to, salts of pharmaceutically acceptable organic acids such as ethanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, salicylic acid, cinnamic acid, cyclamic acid, sulfanilic acid, aspartic acid, glutamic acid, glutaric acid, galactaric acid, gentisic acid, hippuric acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0039] Basic salts include, but are not limited to, those produced by pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, lysine, histidine, meglumine, ammonium, and alkylammonium.

[0040] The basic nitrogen-containing group may be quaternized with agents such as chloride, bromide, and lower alkyl halides such as methyl, ethyl, propyl, and butyl iodides; dialkyl sulfates such as dimethyl sulfate and diethyl sulfate; and other agents.

[0041] The compounds of the present invention may also be in the form of solvates containing hydrates. The term "solvate" is used herein to refer to a complex of variable stoichiometry formed by a solute (compound of formula (I)) and a solvent. Such a solvent should not interfere with the biological activity of the solute. Solvents that may be included in the solvate include, but are not limited to, water, ethanol, propanol, and acetic acid. Methods of solvation are generally known in the art.

[0042] The term "prodrug," used in its broadest sense, encompasses derivatives that are converted in vivo to the compound of formula (I). Such derivatives are readily conceivable to those skilled in the art and include, for example, compounds in which a free hydroxyl group is converted to an ester derivative, or a cyclic nitrogen is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters, and those derived from amino acids. Conventional procedures for the preparation of suitable prodrugs are described in textbooks such as "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.

[0043] It will also be recognized that the compounds of the present invention may possess a chiral center and therefore may exist in more than one stereoisomer. Accordingly, the present invention also relates to compounds in substantially pure isomeric forms, such as those with approximately 90% ee or 99% ee, for example, about 95% or 97% ee, and mixtures thereof, including racemic mixtures. Such isomers may be prepared, for example, by asymmetric synthesis using a chiral intermediate or by chiral resolution. The compounds of the present invention may exist as geometric isomers. The present invention also relates to compounds that are substantially pure cis(Z) or trans(E) or mixtures thereof.

[0044] The compounds of the present invention may exist in the form of rotational isomers or conformational isomers, where restricting or bound rotations exist around a single bond.

[0045] Any formula or structure described herein, including the compound of formula (I), is also intended to represent both an unlabeled and isotope-labeled form of the compound for use as a pharmaceutical or research tool. This may include detection or imaging techniques such as drug or substrate tissue distribution assays, metabolic studies, reaction kinetic studies, positron emission tomography (PET), or single-photon emission computed tomography (SPECT), including in radiotherapy for patients. An isotope-labeled compound has the structure shown by the formula described herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include, but are not limited to, 2 H (deuterium, D), 3 H (tritium), 10 B, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125This includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotope-labeled compounds of this disclosure, for example, 3 H, 13 C and 14 These are compounds that incorporate radioactive isotopes such as 13C. In addition to their use in medical treatment, such isotope-labeled compounds may be useful.

[0046] The compound of the present invention The present invention provides metal ion modulating compounds, particularly zinc and iron selective ionophores. Such ionophores may have one or more of the following desirable properties: orally deliverable; low liver extractability; non-toxicity; and the ability to modulate metals, particularly zinc and iron, within biological systems. Favorable metal selectivity, affinity, and kinetic stability of the formed complex can also be achieved by certain compounds.

[0047] Formula (I):

[0048] [ka] (In the formula, X is either O or S, R1 is

[0049] [ka] Selected from, Y1 is either CR8 or N. Y2 is either CR8 or N. However, if both Y1 and Y2 are not N, Y3 is C(R8)2, NR9, or S. Y4 is CR8 or N, However, if Y4 is CR8, then Y3 is not C(R8)2, R6 and R7 are hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C1~6 Haloalkyl, C 1~6 Independently selected from haloalkoxy, halo, CN, CO2R9 and N(R9)2, or R6 and R7, together with the atom to which they are bonded, form an optionally substituted 6-membered aryl or heteroaryl ring. Each R8 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, (C(R 10 )2) m CO2R9 and (C(R 10 )2) m Selected independently from N(R9)2, Each R9 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Selected independently from haloalkyl groups, R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl and

[0050] [ka] Select from, or R1 and R2 together form a 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring condensed with a 6-membered nitrogen-containing heteroaryl ring, and the cycloalkyl, heterocycloalkyl, or heteroaryl ring may be optionally substituted. R3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and (C(R 10 )2) m Selected from CO2R9, R4 and R 4a is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Each is independently selected from haloalkyls, and R5 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m It is a heteroaryl (where aryl and heteroaryl are optionally substituted), or R 4a is CN, and R4 and R5 together are,

[0051] [ka] (In the formula, R 14 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m It forms a heteroaryl (wherein the formula, aryl and heteroaryl are optionally substituted), or R 4a There is no such group, and R4 and R5 together form an optionally substituted aryl or optionally substituted heteroaryl group. Each R 10 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Selected independently from haloalkoxy, CN, halo, and N(R9)2, m is an integer from 0 to 6. It is a compound of or a pharmaceutically acceptable salt thereof.

[0052] In a particular embodiment, formula (Ib):

[0053] [ka] (In the formula, X is O, R1 is

[0054] [ka] Selected from, R6 and R7 are hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Independently selected from haloalkoxy, halo, CN, CO2R9 and N(R9)2, or R6 and R7, together with the atom to which they are bonded, form an optionally substituted 6-membered aryl or heteroaryl ring. Each R8 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, (C(R 10 )2) m CO2R9 and (C(R 10 )2) m Selected independently from N(R9)2, Each R9 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Selected independently from haloalkyl groups, R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl and

[0055] [ka] Select from, or R1 and R2 together,

[0056] [ka] (In the formula, V is CH, O or S, and R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo, C 1~6 Haloalkyl, (CH2) m C 3~8 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 A cycloalkyl, heterocycloalkyl, or heteroaryl ring of a bicyclic structure formed from R1 and R2 (selected independently from alkynyl and N(R9)2) may be optionally substituted, or Both R1 and R2

[0057] [ka] And, R3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and (C(R 10 )2) m Selected from CO2R9, R4 and R 4a is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Each is independently selected from haloalkyls, and R5 is hydrogen, (C(R10 )2) m Ariel, (C(R 10 )2) m Heteroaryl, O(C(R 10 )2) m Aryl or O(C(R 10 )2) m It is a heteroaryl (where aryl and heteroaryl are optionally substituted), or R 4a is CN, and R4 and R5 are both hydrogen, or together they are

[0058] [ka] (In the formula, R 14 is hydrogen, (C(R 10 )2) m aryl or (C(R 10 )2) m It forms a heteroaryl (wherein the formula, aryl and heteroaryl are optionally substituted), or R 4a There is no such group, and R4 and R5 together form an optionally substituted aryl or optionally substituted heteroaryl group. Each R 10 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Selected independently from haloalkoxy, CN, halo, and N(R9)2, m is an integer from 0 to 6. Compounds or pharmaceutically acceptable salts thereof are provided.

[0059] In certain embodiments of the compound of formula (I), one or more of the following apply: X is O; R1 is

[0060] [ka] especially

[0061] [ka] More especially

[0062] [ka] Selected from; R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl and

[0063] [ka] especially C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 Cycloalkyl and

[0064] [ka] More especially C 1~4 Alkyl, C 3~6 Cycloalkyl and

[0065] [ka] Selected from, R1

[0066] [ka] If so, R2 is

[0067] [ka] And in particular, both R1 and R2

[0068] [ka] And, R1

[0069] [ka] In that case, R2 can be hydrogen. or R1 and R2 together form a 5 or 6-membered cycloalkyl or heterocycloalkyl ring condensed with a 6-membered nitrogen-containing heteroaryl ring, and the cycloalkyl and heteroaryl rings may be optionally substituted, in particular when R1 and R2 together

[0070] [ka] (wherein V is CH, O or S, in particular CH or O), in particular

[0071] [ka] Selected from, R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo, C 1~6 Haloalkyl, (CH2) m C 3~8 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6(Selected from alkynyl and N(R9)2), especially hydrogen, C 1~6 Alkyl and COR 13 (In the formula, R 13 , OC 1~6 (Selected from alkyl and N(R9)2), more particularly hydrogen, C 1~3 Alkyl and COOC 1~3 Each alkyl group is independently selected; R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Ariel, (CH2) m The heteroaryl or Oaryl rings are selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl, and pyridizinyl, particularly phenyl, indolyl, and pyridizinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they may form a 5- or 6-membered heterocyclic ring), and may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl, or R 4a CN is CN, and R4 and R5 are either hydrogen or together,

[0072] [ka] (In the formula, R 14 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), in particular (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is either unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 (However, together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocyclic ring), which may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl) or R 4a In the absence of R4 and R5, R4 and R5 combine to form an optionally substituted aryl or optionally substituted heteroaryl group, in particular R4 and R5 together to form a phenyl ring, 2-pyridinyl ring, 3-pyridinyl ring, 4-pyridinyl ring, 3-pyridazinyl ring, 4-pyridazinyl ring, 2-furanyl, 3-furanyl, 2-thiophenyl ring, 3-thiophenyl ring, 2-thiazolyl ring, 3-thiazolyl ring, 4-thiazolyl ring, 3-isoxazolyl ring, 4-isoxazolyl ring, 5-isoxazolyl ring, 4-(1,2,3-thiadiazolyl) ring, 5-(1,2,3-thiadiazolyl) ring, 4-thiadia The rings form a zolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-benzothiophenyl ring, a -3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, particularly a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 2-furanyl ring, a 2-thiophenyl ring, a 3-thiazolyl ring, a 3-isoxazolyl ring, a 5-(1,2,3-thiadiazolyl) ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, and each aryl or heteroaryl ring is unsubstituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 They may be substituted with one or more substituents selected from, more particularly, methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl; R6 and R7 are hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6Haloalkyl, C 1~6 Haloalkoxy, Halo, CN, CO2H, CO2C 1~3 Alkyl and N(R9)2, especially hydrogen, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, Halo, CN, CO2H, CO2CH3 and N(C) 1~3 Alkyl)2, more particularly hydrogen, methyl, ethyl, or CF3, most particularly hydrogen or methyl, independently selected, or R6 and R7, together with the atoms to which they are bonded, optionally form a substituted phenyl, more particularly an unsubstituted phenyl ring; Each R8 contains hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, (CH2) 1~3 CO2H and (CH2) 1~3 N(R9)2, especially hydrogen, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, Halo, CH2CO2H, CH2CH2CO2H and N(C) 1~3 Alkyl)2, more particularly hydrogen, methyl, ethyl, or CF3, most particularly hydrogen or methyl, independently selected; Each R9 is hydrogen, C 1~6 Alkyl and C 1~6 Haloalkyls, especially hydrogen, C 1~6 Alkyl, especially hydrogen, C 1~3 Alkyl, most particularly selected independently from hydrogen and methyl; Each R 10 However, hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxys, CN, halo and N(R9)2, in particular hydrogen, C 1~3 Alkyl, hydroxy, C 1~3Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, CN, Halo and N(C) 1~3 Alkyl)2, more particularly independently selected from hydrogen, methyl, ethyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethyloxy, fluoro and chloro; m is 0 or an integer from 1 to 3, and in particular, m is 0 or an integer of 1 or 2.

[0073] In some embodiments, the compound of formula (I) is of formula (II):

[0074] [ka] (In the formula, X, R3, R4, R 4a And R5 is as defined for equation (I), and R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo, C 1~6 Haloalkyl, (CH2) m C 3~6 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 A compound of alkynyl (selected independently from N(R9)2) (where r is 1, 2, or 3), or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound of formula (II) is formula (IIa):

[0076] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (II)) or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound of formula (II) is formula (IIb):

[0078] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (II)) or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of formula (II) is formula (IIc):

[0080] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (II)) or a pharmaceutically acceptable salt thereof.

[0081] In certain embodiments of the compound of formula (II), one or more of the following apply: X is O; R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Aryl, O(CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl and pyridinyl, in particular phenyl, indolyl and pyridinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they may form a 5- or 6-membered heterocyclic ring), and may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl, or R 4a CN is CN, and R4 and R5 are either hydrogen or together,

[0082] [ka] (In the formula, R 14 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), in particular (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is either unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 (However, together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocyclic ring), which may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl) or R 4aIn the absence of R4 and R5, R4 and R5 combine to form an optionally substituted aryl or optionally substituted heteroaryl group, in particular R4 and R5 together to form a phenyl ring, 2-pyridinyl ring, 3-pyridinyl ring, 4-pyridinyl ring, 3-pyridazinyl ring, 4-pyridazinyl ring, 2-furanyl, 3-furanyl, 2-thiophenyl ring, 3-thiophenyl ring, 2-thiazolyl ring, 3-thiazolyl ring, 4-thiazolyl ring, 3-isoxazolyl ring, 4-isoxazolyl ring, 5-isoxazolyl ring, 4-(1,2,3-thiadiazolyl) ring, 5-(1,2,3-thiadiazolyl) ring, 4-thiadia The rings form a zolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-benzothiophenyl ring, a -3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, particularly a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 2-furanyl ring, a 2-thiophenyl ring, a 3-thiazolyl ring, a 3-isoxazolyl ring, a 5-(1,2,3-thiadiazolyl) ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, and each aryl or heteroaryl ring is unsubstituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 They may be substituted with one or more substituents selected from, more particularly, methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl; R 11 and R 12 However, hydrogen, C 1~6 alkyl, halo, C 1~6 Haloalkyl, (CH2) m C 3~8 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl and N(R9)2 are independently selected from each, and in particular R 11 and R 12 However, hydrogen, C 1~6 Alkyl, C1~6 Haloalkyl, C 3~8 Cycloalkyl, CH2phenyl, CH2pyridyl, and CO2C 1~6 Selected independently of alkyl, and more particularly R 11 and R 12 However, hydrogen, C 1~3 Alkyl, C 1~3 Haloalkyl, fluoro, C 3~6 Cycloalkyl, CH2phenyl, CH2pyridyl and COC 1~3 Selected independently of alkyl, most particularly R 11 and R 12 All are hydrogen, all are methyl, all are ethyl, or R 11 and R 12 One of the atoms is hydrogen, and the other is methyl, ethyl, fluoro, CH2phenyl, CH2pyridyl, CO2methyl, or CO2ethyl.

[0083] The specific compounds of formula II include compounds 1-42, 156-159, and compounds 145, 170, 179, and 180, as listed in Tables 1-3.

[0084] In some embodiments, the compound of formula (I) is formula (III):

[0085] [ka] (In the formula, X, Y1, Y2, R2, R3, R4, R 4a R5, R6, and R7 are compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0086] In some embodiments, the compound of formula (III) is formula (IIIa):

[0087] [ka] (In the formula, R2, R3, R4, R 4aR5, R6, R7, and R8 are compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0088] In some embodiments, the compound of formula (III) is formula (IIIb):

[0089] [ka] (In the formula, R2, R3, R4, R 4a R5, R6, R7, and R8 are compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0090] In some embodiments, the compound of formula (III) is formula (IIIc):

[0091] [ka] (In the formula, R2, R3, R4, R 4a R5, R6, R7 and each R8 are compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0092] In some embodiments, the compound of formula (III) is formula (IIId):

[0093] [ka] (In the formula, R3, R4, R 4a And R5 is a compound of (as defined for formula (III)) or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments of the compound of formula (III), one or more of the following apply: X is O; R1 is

[0095] [ka] especially

[0096] [ka] More especially

[0097] [ka] Selected from; R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl and

[0098] [ka] especially C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 Cycloalkyl and

[0099] [ka] More especially C 1~4 Alkyl, C 3~6 Cycloalkyl and

[0100] [ka] Selected from, R1

[0101] [ka] If so, R2 is

[0102] [ka] And in particular, both R1 and R2

[0103] [ka] is; R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Aryl, O(CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl and pyridinyl, in particular phenyl, indolyl and pyridinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they may form a 5- or 6-membered heterocyclic ring), and may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl, or R 4a CN is CN, and R4 and R5 are either hydrogen or together,

[0104] [ka] (In the formula, R 14 is hydrogen, (CH2)m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), in particular (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is either unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups15 (However, together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocyclic ring), which may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl) or R 4a In the absence of R4 and R5, R4 and R5 combine to form an optionally substituted aryl or optionally substituted heteroaryl group, in particular R4 and R5 together to form a phenyl ring, 2-pyridinyl ring, 3-pyridinyl ring, 4-pyridinyl ring, 3-pyridazinyl ring, 4-pyridazinyl ring, 2-furanyl, 3-furanyl, 2-thiophenyl ring, 3-thiophenyl ring, 2-thiazolyl ring, 3-thiazolyl ring, 4-thiazolyl ring, 3-isoxazolyl ring, 4-isoxazolyl ring, 5-isoxazolyl ring, 4-(1,2,3-thiadiazolyl) ring, 5-(1,2,3-thiadiazolyl) ring, 4-thiadia The rings form a zolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-benzothiophenyl ring, a -3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, particularly a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 2-furanyl ring, a 2-thiophenyl ring, a 3-thiazolyl ring, a 3-isoxazolyl ring, a 5-(1,2,3-thiadiazolyl) ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, and each aryl or heteroaryl ring is unsubstituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 They may be substituted with one or more substituents selected from, more particularly, methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl; R6 and R7 are hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, CN, CO2H, CO2C 1~3Alkyl and N(R9)2, especially hydrogen, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, halo, CN, CO2H, CO2CH3 and N(C 1~3 Alkyl)2, more especially hydrogen, methyl, ethyl, or CF3, most especially hydrogen or methyl, independently selected, or R6 and R7, together with the atom to which they are attached, form an optionally substituted phenyl, especially an unsubstituted or substituted phenyl ring, more especially an unsubstituted benzene ring; Each R8 is hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, halo, (CH2) 1~3 CO2H and (CH2) 1~3 N(R9)2, especially hydrogen, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, halo, CH2CO2H, CH2CH2CO2H and N(C 1~3 Alkyl)2, more especially hydrogen, methyl, ethyl, or CF3, most especially hydrogen or methyl, independently selected; Each R9 is hydrogen, C 1~6 Alkyl and C 1~6 Haloalkyl, especially hydrogen, C 1~6 Alkyl, more especially hydrogen, C 1~3 Alkyl, most especially hydrogen and methyl, independently selected.

[0105] Specific compounds of Formula III include compounds 44-92 and 160-169 as listed in Tables 5 and 6, compounds 122-137, 140-144, 154, 155 and 181-191 as listed in Table 8, compounds 192-196 from Table 9, and compounds 146-153 as listed in Example 10 and Tables 10 and 11, in particular compounds 44-54, 56-62, 76-92, 122-137, 140-144, 154, 155, 160-169, 181-183 and 192-194.

[0106] In some embodiments, the compound of formula (I) is of formula (IV):

[0107] [ka] (In the formula, X, Y3, Y4, R2, R3, R4, R 4a R5, R6, and R7 are compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0108] In some embodiments, the compound of formula (IV) is formula (IVa):

[0109] [ka] (In the formula, R2, R3, R4, R 4a R5, R6, R7, and R8 are as defined for formula (IV), and Y3 is a compound of (S or NR9), or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound of formula (IV) is formula (IVb):

[0111] [ka] (In the formula, R2, R3, R4, R 4aR5, R6, and R7 are compounds of formula (IV) or pharmaceutically acceptable salts thereof.

[0112] In some embodiments, the compound of formula (IV) is formula (IVc):

[0113] [ka] (In the formula, R2, R3, R4, R 4a R5, R6, R7, and R8 are compounds of formula (IV) or pharmaceutically acceptable salts thereof.

[0114] In certain embodiments of the compound of formula (IV), one or more of the following apply: X is O; R1 is

[0115] [ka] especially

[0116] [ka] More especially

[0117] [ka] etc.

[0118] [ka] Selected from, R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 3~8 Cycloalkyls, especially hydrogen, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 3~6Cycloalkyl, especially hydrogen, C 1~4 Alkyl and C 3~6 Selected from cycloalkyl groups, R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl, O(CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl and pyridinyl, in particular phenyl, indolyl and pyridinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and C 1~6 selected independently from haloalkyl, or two Rs 15 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring), particularly C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, C 1~3 haloalkyl, halo, hydroxy, -OC 1~3 alkyl, -OC 2~3 alkenyl, -OC 2~3 alkynyl, -OC 1~3 haloalkyl, N(C 1~3 alkyl)2 and O(CH2) q N(R 15 )2 (where q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl and C 1~3 haloalkyl, selected independently, or two Rs 15 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring), more particularly methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2 piperidinyl, OCH2CH2 pyrrolyl and -OCH2CH2CH2 piperidinyl, may be substituted with one or more substituents selected from, or R 4a is CN, R4 and R5 are each hydrogen, or together

[0119]

Chemical formula

[0120] The specific compounds of formula (IV) include compounds 93-119 and 163-169, as listed in Table 6, and especially compounds 110-113, 116, 117 and 163-169.

[0121] In some embodiments, the compound of formula (I) is of formula (V):

[0122] [ka] (In the formula, R2, R3, R4, R 4a And R5 is a compound of formula (I) as defined.

[0123] In certain embodiments of the compound of formula (V), one or more of the following apply: R2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 3~8 Cycloalkyls, especially hydrogen, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 3~6 Cycloalkyl, especially hydrogen, C 1~4 Alkyl and C 3~6 Selected from cycloalkyl groups, R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl, O(CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Aryl or (CH2) mIt is a heteroaryl, and each aryl or heteroaryl ring is selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl and pyridazinyl, in particular from phenyl, indolyl and pyridinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15However, together with the nitrogen atom to which they are bonded, they may form a 5- or 6-membered heterocyclic ring), and may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl, or R 4a CN is CN, and R4 and R5 are either hydrogen or together,

[0124] [ka] (In the formula, R 14 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), in particular (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is either unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 (However, together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocyclic ring), which may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl) or R 4aIn the absence of R4 and R5, R4 and R5 combine to form an optionally substituted aryl or optionally substituted heteroaryl group, in particular R4 and R5 together to form a phenyl ring, 2-pyridinyl ring, 3-pyridinyl ring, 4-pyridinyl ring, 3-pyridazinyl ring, 4-pyridazinyl ring, 2-furanyl, 3-furanyl, 2-thiophenyl ring, 3-thiophenyl ring, 2-thiazolyl ring, 3-thiazolyl ring, 4-thiazolyl ring, 3-isoxazolyl ring, 4-isoxazolyl ring, 5-isoxazolyl ring, 4-(1,2,3-thiadiazolyl) ring, 5-(1,2,3-thiadiazolyl) ring, 4-thiadia The rings form a zolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-benzothiophenyl ring, a -3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, particularly a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 2-furanyl ring, a 2-thiophenyl ring, a 3-thiazolyl ring, a 3-isoxazolyl ring, a 5-(1,2,3-thiadiazolyl) ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, and each aryl or heteroaryl ring is unsubstituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 They may be substituted with one or more substituents selected from, more particularly, methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl; Each R8 contains hydrogen, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Halo, (CH2) 1~3 CO2H and (CH2) 1~3 N(R9)2, especially hydrogen, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, Halo, CH2CO2H, CH2CH2CO2H and N(C) 1~3 Alkyl)2, more particularly hydrogen, methyl, ethyl, or CF3, most particularly hydrogen or methyl, independently selected; Each R9 is hydrogen, C 1~6 Alkyl and C 1~6 Haloalkyls, especially hydrogen, C 1~6 Alkyl, especially hydrogen, C 1~3 Alkyl, most particularly hydrogen and methyl, are selected independently.

[0125] Specific compounds of formula V include compounds 120, 121, 138, and 139, as listed in Table 7.

[0126] In some embodiments, the compound of formula (I) is of formula (VI):

[0127] [ka] (In the formula, X, V, R3, R4, R 4a And R5 is as defined for equation (I), and R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo, C 1~6 Haloalkyl, (CH2) m C 3~6 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 A compound of alkynyl (selected independently from N(R9)2) (where s is 0, 1, or 2), or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula (VI) is formula (VIa):

[0129] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (VI)) or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the compound of formula (VI) is formula (VIb):

[0131] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (VI)) or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the compound of formula (VI) is formula (VIc):

[0133] [ka] (In the formula, R3, R4, R 4a , R5, R 11 and R 12 is a compound of (as defined for formula (VI)) or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments of the compound of formula (VI), one or more of the following apply: X is O; V is O; R3 is hydrogen, C 1~6 Alkyl, (CH2) m CO2H and (CH2) m CO2C 1~3 Alkyl, especially hydrogen, C 1~3 Selected from alkyl, CH2CO2H, and CH2CO2CH3, more particularly from hydrogen; R4 and R 4a However, hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C2~3 Alkinyl and C 1~3 Each is independently selected from haloalkyl groups, and R5 is hydrogen, (CH2) m Aryl, O(CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), particularly R4 and R 4a However, each is hydrogen independently, and R5 is (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is selected from phenyl, pyridinyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, benzothiophenyl and pyridinyl, in particular phenyl, indolyl and pyridinyl, and each aryl or heteroaryl ring is unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they may form a 5- or 6-membered heterocyclic ring), and may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl, or R 4a CN is CN, and R4 and R5 are either hydrogen or together,

[0135] [ka] (In the formula, R 14 is hydrogen, (CH2) m Aryl or (CH2) m Heteroaryls (where aryls and heteroaryls are optionally substituted), in particular (CH2) m Aryl or (CH2) m It is a heteroaryl, and each aryl or heteroaryl ring is either unsubstituted or C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15 However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 (However, together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocyclic ring), which may be substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl) or R 4aIn the absence of R4 and R5, R4 and R5 combine to form an optionally substituted aryl or optionally substituted heteroaryl group, in particular R4 and R5 together to form a phenyl ring, 2-pyridinyl ring, 3-pyridinyl ring, 4-pyridinyl ring, 3-pyridazinyl ring, 4-pyridazinyl ring, 2-furanyl, 3-furanyl, 2-thiophenyl ring, 3-thiophenyl ring, 2-thiazolyl ring, 3-thiazolyl ring, 4-thiazolyl ring, 3-isoxazolyl ring, 4-isoxazolyl ring, 5-isoxazolyl ring, 4-(1,2,3-thiadiazolyl) ring, 5-(1,2,3-thiadiazolyl) ring, 4-thiadia The rings form a zolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-benzothiophenyl ring, a -3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, particularly a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 2-furanyl ring, a 2-thiophenyl ring, a 3-thiazolyl ring, a 3-isoxazolyl ring, a 5-(1,2,3-thiadiazolyl) ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring, and each aryl or heteroaryl ring is unsubstituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, halo, hydroxy, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, -OC 1~6 Haloalkyl, N(R9)2, (CH2) q N(R 15 )2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 6, and each R 15 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Independently selected from haloalkyl groups, or two R groups 15However, together with the nitrogen atom to which they are bonded, they form a 5- or 6-membered heterocyclic ring), especially C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Haloalkyl, halo, hydroxy, -OC 1~3 Alkyl, -OC 2~3 Alkenyl, -OC 2~3 Alkinyl, -OC 1~3 Haloalkyl, N(C) 1~3 Alkyl)2 and O(CH2) q N(R 15 )2(In the formula, q is an integer from 1 to 3, and each R 15 is hydrogen, C 1~3 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl and C 1~3 Independently selected from haloalkyl groups, or two R groups 15 They may be substituted with one or more substituents selected from, more particularly, methyl, ethyl, propyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, -OCH2CH2N(CH3)2, -OCH2CH2piperidinyl, OCH2CH2pyrrolyl and -OCH2CH2CH2piperidinyl; R 11 and R 12 However, hydrogen, C 1~6 alkyl, halo, C 1~6 Haloalkyl, (CH2) m C 3~8 Cycloalkyl, (CH2) m Ariel, (CH2) m Heterocycline, (CH2) m Heteroaryl and COR 13 (In the formula, R 13 OH, OC 1~6 Alkyl and N(R9)2 are independently selected from each, and in particular R 11 and R 12 However, hydrogen, C 1~6 Alkyl, C1~6 Haloalkyl, C 3~8 Cycloalkyl, CH2phenyl, CH2pyridyl, and CO2C 1~6 Selected independently of alkyl, and more particularly R 11 and R 12 However, hydrogen, C 1~3 Alkyl, C 1~3 Haloalkyl, fluoro, C 3~6 Cycloalkyl, CH2phenyl, CH2pyridyl and COC 1~3 Selected independently of alkyl, most particularly R 11 and R 12 All are hydrogen, all are methyl, all are ethyl, or R 11 and R 12 One of the atoms is hydrogen, and the other is methyl, ethyl, fluoro, CH2phenyl, CH2pyridyl, CO2methyl, or CO2ethyl.

[0136] The specific compounds of formula VI include compounds 171-178 in Table 12.

[0137] The compounds of the present invention may be synthesized from commercially available starting materials using known methods. For example, hydrazides may be prepared by reacting a suitable ketone with a hydrazine carboxylic acid in the presence of a catalytic amount of acid.

[0138] [ka]

[0139] Suitable catalytic acids include concentrated hydrochloric acid or toluenesulfonic acid.

[0140] The resulting hydrazide may be further derivatized, for example, by alkylation of the hydroxyl group or formation of a double bond from a ketone and aldehyde. Suitable reactions are described in the following examples. [Examples]

[0141] Abbreviation

[0142] [Table 1]

[0143] Various acylhydrazones can be prepared by the synthetic routes shown in Scheme 1. An equimolar mixture of dihydroquinolone ketone derivative A and a substituted acylhydrazide in ethanol or another suitable solvent was heated with a catalytic amount of acid to obtain the target acylhydrazone product B. Ketone starting materials were available from commercial suppliers or from methods in known literature. For example, 5,6-dihydro-7,7-dimethylquinoline-8-one could be prepared as described by Chuang Bing et al, New Journal of Chemistry 2016, 40, 9329-9346. Ethyl 8-oxo-5,6,7,8-tetrahydroquinoline-7-carboxylate starting material is known from the literature (Takashi et al, Synthesis 2005, 10, 1593-1600). The compound could be synthesized by heating 6,7-dihydroquinoline-8(5H)-one, sodium hydride, and diethyl carbonate at 130°C.

[0144] [ka]

[0145] [Example 1] (Table 1) (E)-N'-(6,7-dihydroquinoline-8(5H)-yridene)nicotinohydrazide(1). Nicotinic acid hydrazide (575 mg, 4.22 mmol) was added to a solution of 6,7-dihydroquinoline 8(5H)-one (622 mg, 4.22 mmol) in EtOH, followed by the addition of the catalyst p-toluenesulfonic acid (7 mg). The reaction mixture was heated to 45°C for 1 hour and then allowed to cool overnight. The cream-colored solid was collected by filtration and suspended in MeOH. The filtrate was cooled to 4°C overnight. The off-white needle-shaped substance was collected by filtration to obtain the target compound (E)-N'-(6,7-dihydroquinoline-8(5H)-ylidene)nicotinohydrazide 1 (112 mg). 1 H NMR (600MHz, d6-DMSO) δ 1.96 (t, J=6.0Hz, 2H), 2.99 (t, J=6.0Hz, 4H), 7.64 (dd, J=7.8, 4.8Hz, 1H), 7.85 (br s, 1H), 8.38 (d, J=6.6Hz, MS m / z 267.12 [M+H] +.

[0146] [Table 2-1]

[0147] [Table 2-2]

[0148] [Table 2-3]

[0149] [Table 2-4]

[0150] [Table 2-5]

[0151] [Table 2-6]

[0152] [Table 2-7]

[0153] [Table 2-8]

[0154] [Table 2-9]

[0155] Similarly, the condensed cyclopentane derivative D could be synthesized according to Scheme 2.

[0156] [ka]

[0157] [Example 2] (Table 2) (E)-N'-(5H-cyclopenta[b]pyridine-7(6H)-ylidene)-3,4-dimethoxybenzohydrazide(38) To a solution of 5H-cyclopenta[b]pyridine-7(6H)-one (40 mg, 0.30 mmol) in MeOH (8 mL), 3,4-dimethoxybenzhydrazide (59 mg, 1 mol equivalent) was added, followed by one drop of concentrated hydrochloric acid. The reaction was stirred overnight. The off-white solid was collected by filtration to obtain the desired (E)-N'-(5H-cyclopenta[b]pyridine-7(6H)-ylidene)-3,4-dimethoxybenzohydrazide 38 (30 mg). 1H NMR (600MHz, d6-DMSO) δ 2.95(t, J=6.0Hz, 2H), 3.11-3.16 (m , 2H), 3.84 (s, 3H), 3.87 (s, 3H), 7.14 (d, J=8.4Hz, 1H), 7.46 (s, 1H), 7.52 (dd, J=7.8, 4.8Hz, 2H), 8.02 (d, J=7.2Hz, 1H), 8.68 (d, J=4.8Hz, 1H). MS m / z 312.13[M+H] + .

[0158] [Table 3]

[0159] The following 2-O-phenol-substituted benzohydrazide derivatives were synthesized according to Scheme 3. The phenol intermediate E synthesized using the procedure outlined in Scheme 1 was reacted with an alkyl halide in the presence of potassium carbonate to obtain the required alkylamino-substituted ether F.

[0160] [ka]

[0161] [Example 3] (E)-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-2-(2-(pyrrolidine-1-yl)ethoxy)benzohydrazide hydrochloride (41). A suspension of (E)-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-2-hydroxybenzohydrazide 12 (149 mg, 0.530 mmol) in dry DMF (10 mL) was mixed with K2CO3 (246 mg, 1.78 mmol) and chloroethylpyrrolidine hydrochloride (95 mg, 0.55 mmol). The reaction mixture was heated to 45°C for 2 days and then cooled to room temperature. The reaction mixture was extracted with ELISA (×3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to obtain a rubbery brown solid. The residue was placed in MeOH (7 mL) and treated with concentrated hydrochloric acid (0.3 mL). The solvent was removed under vacuum, the flask was cooled to room temperature, and then ACN (5 mL) was slowly added. The flask was polished and sonicated to obtain (E)-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-2-(2-(pyrrolidine-1-yl)ethoxy)benzohydrazide hydrochloride 41 as a pale yellowish-brown solid, which was collected by filtration and dried with a pump. Yield: 114 mg. 1 H NMR (500MHz, d6-DMSO) δ 1.85-1.92 (m, 2H), 1.94-1.99 (m, 4H), 2.95 (t, J=6.0Hz, 2H), 2.99-3.07 (m, 4H), 3.54-3.62 (m, 4H), 4.22-4.26 (m, 2H), 7.16 (t, J=7.8Hz, 1H), 7.24 (d, J=7.8Hz, 1H), 7.58 (t, J=7.2Hz, 1H), 7.83 (s, 1H), 7.89 (s, 1H), 8.41 (br s, 1H), 8.67 (br s, 1H), 11.37 (s, 1H), 11.45 (br s, 1H). MS m / z 379.21[M+H] + .

[0162] [Table 4]

[0163] Various acylhydrazones can be prepared by the synthetic route shown in Scheme 4. Target acylhydrazone compounds H (see Table 4) were obtained by heating an equimolar mixture of a six-membered heterocyclic ketone G and an acylhydrazide in ethanol or another suitable solvent in the presence of a catalytic amount of acid. Ketone starting materials were available from commercial suppliers or from methods in known literature.

[0164] [ka]

[0165] [Example 4] (E)-4-methyl-N'-(1-(pyrimidine-2-yl)propyridene)-1,2,3-thiadiazole-5-carbohydrazide(43). (Pyrimidine-2-yl)propan-1-one (114 mg) was heated in EtOH (10 mL) in the presence of concentrated hydrochloric acid (1 drop) with 4-methyl-1,2,3-thiadiazole-5-carbohydrazide (132 mg) to 60°C for 30 minutes. The reaction mixture was cooled to room temperature, and the off-white solid was collected by filtration. The crude product was further washed with ACN (×2) to produce (E)-4-methyl-N'-(1-(pyrimidine-2-yl)propyridene)-1,2,3-thiadiazole-5-carbohydrazide 43 (60 mg) as a white powder. 1 H NMR (600MHz, d6-DMSO) δ 1.07 (t, J=7.2Hz, 3H), 2.97 (s, 3H), 3.06 (q, J=7.2Hz, 2H), 7.57 (t, J=6.6Hz, 1H), 9.01 (d, J=6.6Hz, 2H), 11.96 (s, 1H). MS m / z 277.0865 [M+H] + .

[0166] [Table 5-1]

[0167] [Table 5-2]

[0168] [Table 5-3]

[0169] [Table 5-4]

[0170] [Table 5-5]

[0171] [Table 5-6]

[0172] Various substituted quinoline acylhydrazones can be prepared by the synthetic route shown in Scheme 5. Target compound J was obtained by heating an equimolar mixture of acetylquinoline I and a substituted acylhydrazide in ethanol or another suitable solvent with a catalytic amount of acid.

[0173] [ka]

[0174] [Example 5] (E)-N'-(1-(quinoline-2-yl)ethylidene)picolinohydrazide(80). 2-acetylquinoline (162 mg) and pyridine-2-carboxylic acid hydrazide (113 mg) were heated together in 7 mL of EtOH at 60°C. One drop of concentrated hydrochloric acid was added, and the reaction mixture was stirred for 15 minutes, during which time a precipitate was formed. The reaction mixture was cooled, and the precipitate was collected by filtration to obtain (E)-N'-(1-(quinoline-2-yl)ethylidene)picolinohydrazide 80 as an off-white powder (50 mg). 1H NMR (600MHz, d6-DMSO) δ 2.64 (s, 3H), 7.62-7.65 (m, 1H), 7.74-7.77 (m, 1H), 7.80 (t, J=8.4Hz, 1H), 8.02 (d, J=7.2Hz, 1H), 8.07-8.11 (m, 2H), 8.19 (d, J=7.2Hz, 1H), 8.33 (d, J=9.Hz, 1H), 8.43 (d, J=9.0Hz, 1H), 8.76 (d, J=3.6 Hz, 1H), 11.26 (s, 1H). MS m / z 291.1321 [M+H]+.

[0175] [Table 6-1]

[0176] [Table 6-2]

[0177] [Table 6-3]

[0178] [Table 6-4]

[0179] [Table 6-5]

[0180] Various condensed heterocyclic and heterocyclic substituted acylhydrazones were synthesized as outlined in Scheme 6. The starting ketone / aldehyde K is defined below in Scheme 6. The heterocyclic or condensed heterocyclic ketone / aldehyde K was heated with a suitable ketohydrazide in the presence of a catalytic acid and a suitable solvent to obtain the target compound L.

[0181] [ka]

[0182] [Example 6] (E)-4-methyl-N'-(1-(4-methylthiazole-2-yl)ethylidene)-1,2,3-thiadiazole-5-carbohydrazide(100). 4-methyl-2-acetylthiazole (76 mg) was heated with 4-methyl-1,2,3-thiadiazole-5-carbohydrazide (81 mg) in 7 mL of EtOH at 65°C. Concentrated hydrochloric acid (2 drops) was added, and the reaction was heated for 1.5 hours. After cooling to room temperature, a pale yellow solid precipitated from the solution, which was collected by filtration to obtain 100 (124 mg) of the precipitate. 1 H NMR (600MHz, d6-DMSO) δ 2.42 (s, 3H), 2.50 (s, 3H), 2.97 (s, 3H), 7.48 (s, 1H), 11.85 (s, 1H). MS m / z 282.0477[M+H] + .

[0183] [Table 7-1]

[0184] [Table 7-2]

[0185] [Table 7-3]

[0186] [Table 7-4]

[0187] [Table 7-5]

[0188] [Table 7-6]

[0189] Similarly, imidazopyridine derivatives were synthesized according to Scheme 7.

[0190] [ka]

[0191] [Example 7] (Z)-N'-(imidazo[1,2-a]pyridine-2-ylmethylene)-3-methoxybenzohydrazide (120) Imidazon[1,2-a]pyridine-2-carboxaldehyde (101 mg) and 3-methoxybenzohydrazide (114 mg) were heated under reflux in EtOH (7 mL) for 2 hours in the presence of concentrated hydrochloric acid. The reaction mixture was slowly cooled, and the resulting white precipitate was collected by filtration to obtain (Z)-N'-(imidazo[1,2-a]pyridine-2-ylmethylene)-3-methoxybenzohydrazide 120 (61 mg) as an off-white solid. 1 H NMR (600MHz, d6-DMSO) δ 3.85 (s, 3H), 7.19 (dd, J=8.4, 2.4 Hz, 1H), 7.44-7.48 (m, 2H), 7.56-7.60 (m, 2H), 7.85 (d, J=3.0Hz, 1H), 7.93 (t, J=7.8Hz, 1H), 8.73 (s, 1H), 8.89 (d, J=6.0Hz, 1H), 8.91 (s, 1H), 12.62 (s, 1H). MS m / z 295.1191[M+H] + .

[0192] [Table 8]

[0193] Various dipyridylacylhydrazones were synthesized according to Scheme 8. Dimethyldipyridyl ketone O was heated with a substituted arylbenzhydrazide to obtain the target acylhydrazone P.

[0194] [ka]

[0195] [Example 8] N'-(bis(6-methylpyridine-2-yl)methylene)-4-hydroxy-3-methoxybenzohydrazide(130). Bis(6-methylpyridine-2-yl)methanone (227 mg) and vanillic acid hydrazide (195 mg) in EtOH (10 mL) were treated with two drops of concentrated hydrochloric acid, and the reaction mixture was heated to 60°C for 1 hour. The reaction mixture was slowly cooled, and the yellow solid was collected by filtration to obtain N'-(bis(6-methylpyridine-2-yl)methylene)-4-hydroxy-3-methoxybenzohydrazide 130 (248 mg) as a beige solid. 1 H NMR (600MHz, d6-DMSO) δ 2.61 (s, 3H), 2.70 (s, 3H), 3.84 (s, 3H), 6.98 (d, J=8.4Hz, 1H), 7.31(d, J=8.4Hz, 1H), 7.41-7.45 (m, 2H), 7.55 (d, J=7.8Hz, 1H), 7.64 (s, 1H), 7.83 (d, J=7.8Hz, 1H), 7.97 (d, J=7.8Hz, 1H), 8.16 (s, 1H), 10.02 (br s, 1H), 15.25 (br s, 1H). MS m / z 377.1611[M+H] + .

[0196] In further examples, the phenolic hydrazone derivative 184 was converted to dimethylaminomethyl compound 185 in refluxed toluene via the action of tetramethylenediamine (see Example 8a below).

[0197] [Example 8a] 5-Chloro-N'-(di(pyridine-2-yl)methylene)-3-((dimethylamino)methyl)-2-hydroxybenzohydrazide(185) 5-Chloro-N'-(di(pyridine-2-yl)methylene)-2-hydroxybenzohydrazide 184 (801 mg, 2.27 mmol) was suspended in toluene (95 mL) and treated with N,N,N,N,-tetramethylenediamine (4 mL). The reaction mixture was heated under reflux for 4 hours and then slowly cooled to room temperature overnight. Volatile substances were removed under vacuum, and the resulting residue was placed in acetonitrile (4 mL), to which ether (20 mL) was slowly added. The resulting precipitate was collected by filtration to obtain 5-Chloro-N'-(di(pyridine-2-yl)methylene)-3-((dimethylamino)methyl)-2-hydroxybenzohydrazide (747 mg) as a yellow solid. 1 H NMR (600MHz, d6-DMSO) δ 2.60 (s, 6H), 3.98 (s, 2H), 7.12 (s, 1H), 7.37-7.43 (m, 2H), 7.51 (d, J=6.0Hz, 1H), 7.69 (s, 1H), 7.90-7.94 (m, 2H), 8.14 (d, J=9.6Hz, 1H), 8.46 (s, 1H), 8.76-8.78 (m, 1H), 8.60 (br s, 1H), 8.76 (14.48 (s, 1H). 410.2014[M+H] + .

[0198] [Table 9-1]

[0199] [Table 9-2]

[0200] [Table 9-3]

[0201] [Table 9-4]

[0202] [Table 9-5]

[0203] [Table 9-6]

[0204] Acrylonitrile derivatives could be synthesized as outlined in Scheme 9 below.

[0205] The quinolone ketone was converted to acetocyanohydrazide Q by reacting it with 2-cyanoacethydrazide under standard conditions. Then, the intermediate Q was reacted with an aldehyde in the presence of the catalyst piperidine to obtain the required acrylonitrile derivative R.

[0206] [ka]

[0207] Synthesis of (E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene)acetohydrazide A mixture of 6,7-dihydroquinoline-8-one (906 mg) Q (R1, R2 = condensed quinoline) and acetocyanohydrazide (712 mg) in EtOH (40 mL) was mixed with concentrated hydrochloric acid (3 drops), and the reaction was heated to 50°C for 1 hour. After cooling to room temperature, (E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene)acetohydrazide R (R1, R2 = condensed quinoline) precipitated from the solution as a yellowish-brown solid. The solid was collected by filtration and dried with a pump to obtain 1.2 g of material. MS m / z 229.1081 [M+H] + .

[0208] [Example 9] (2E,N'E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-3-(2-hydroxyphenyl)acrylohydrazide 145 Salicylaldehyde (110 μL) was added to a mixture of (E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene) acetohydrazide (70 mg) R (179) in EtOH (8 mL). Subsequently, a 0.1 M solution of piperidine in EtOH (0.2 mL) was added while vigorously stirring at room temperature, and the mixture was gently heated until all of it was in solution. After 30 minutes, the pale yellow solid was collected by filtration and washed with EtOH (×3). After drying, 17 mg of (2E,N'E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-3-(2-hydroxyphenyl)acrylohydrazide S (145) was obtained. 1 H NMR (600MHz, d6-DMSO) δ 1.89 (t, J=6.0Hz, 2H), 2.70 (t, J=6.0Hz, 2H), 2.80 (t, J=6.0Hz, 2H), 7.24-7.31 (m, 3H), 7.58 (dt, J=8.4, 1.2Hz, MS m / z 333.1347 [M+H] + .

[0209] [Table 10-1]

[0210] [Table 10-2]

[0211] In further examples, substitution of the hydrazide group was achieved by reacting the acylhydrazone compound with a substituted alkyl halide in the presence of potassium carbonate to produce compound U, as described in Scheme 10 below. Acylhydrazone T was obtained by heating 2-acetylpyridine together with the substituted hydrazide. T was alkylated by the action of methylbromoacetate in DMF and potassium carbonate to produce ester U. In addition, compound U could be readily hydrolyzed to carboxylic acid derivative V by reaction with lithium hydroxide in a mixture of THF and water.

[0212] [ka]

[0213] [Example 10] (E)-N'-(1-(pyridine-2-yl)ethylidene)benzo[b]thiophene-2-carbohydrazide (146) Three drops of concentrated HCl were added to a mixture of 2-acetylpyridine (326 mg) and benzothiophene-2-carboxylic acid hydrazide (518 mg) in 60°C EtOH (15 mL). After heating for 30 minutes, the reaction mixture was cooled overnight, and a white solid precipitated from the solution, yielding (E)-N'-(1-(pyridine-2-yl)ethylidene)benzo[b]thiophene-2-carbohedrazide (650 mg). MS m / z 296.0460[M+H] + .

[0214] [Table 11]

[0215] (E)-Methyl 2-(1-(benzo[b]thiophene-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetate (147) To a solution of (E)-N'-(1-(pyridine-2-yl)ethylidene)benzo[b]thiophene-2-carbozide (190 mg) in DMF (8 mL), methyl bromoacetate (200 μL) and K2CO3 (210 mg) were added. The reaction mixture was heated to 50 °C for 1.5 hours, during which time a white precipitate formed. The reaction mixture was cooled, and H2O (8 mL) was slowly added. After standing for 30 minutes, (E)-methyl 2-(1-(benzo[b]thiophene-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetate precipitated from the solution as a yellow solid (90 mg) 147. 1 H NMR (d6-DMSO) δ 2.44 (s, 3H), 3.73 (s, 3H), 5.06 (s, 2H), 7.44-7.49 (m, 2H), 7.53 (d, J=7.2Hz, 1H), 8.00-8.06 (m, 3H), 8.21 (s, 1H), 8.41 (d, J=7.8Hz, 1H), 8.69 (d, J=3.6Hz, 1H). MS m / z 368.1061 [M+H] + .

[0216] (E)-2-(1-(benzo[b]thiophen-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetic acid (148). A solution of (E)-methyl 2-(1-(benzo[b]thiophene-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl) acetate (64 mg) in THF (7 mL) was mixed with LiOH (65 mg) and H2O (3 mL). The reaction mixture was heated to 50 °C for 2 hours and then cooled to room temperature. The THF was removed under vacuum, and a yellow precipitate was formed. The product was collected by filtration to obtain (E)-2-(1-(benzo[b]thiophene-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetic acid as a yellow powder. MS m / z 354.09 [M+H] + .

[0217] [Table 12]

[0218] In further examples, several condensed pyridopyranoacylhydrazones were synthesized according to Scheme 11. Ketone V was heated with a substituted arylbenzhydrazide in the presence of a catalytic acid to obtain the target acylhydrazone W.

[0219] [ka]

[0220] [Example 11] (E)-N'-(2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-ylidene)nicotinohydrazide (171) To a mixture of 2H-pyran[3,2-b]pyridine-4(3H)-one V (49 mg, 0.33 mmol) in EtOH (6 mL), nicotinic acid hydrazide (44 mg, 0.32 mmol) was added, followed by one drop of concentrated HCl. The reaction mixture was heated to 55°C for 30 minutes and then cooled to room temperature to obtain (E)-N'-(2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-ylidene)nicotinohydrazide 171 as an off-white solid (34 mg). 1 H NMR (500MHz, d6-DMSO) δ 2.96 (t, J=6.0Hz, 2H), 4.47 (t, J=6.0Hz, 2H), 7.56-7.64 (m, 2H), 7.77 (t, J=5.0Hz, 1H), 8.41 (d, J=7.5Hz, 1H), 8.50 (d, J=5Hz, 1H), 8.88 (d, J=5.0Hz, 1H), 9.13 (s, 1H), 15.63 (s, 1H). MS: m / z 269.1033 [M+H]+.

[0221] [Table 13]

[0222] Biological examples GSK-3β assay The phosphorylation of GSK-3β is enhanced when Zn is taken up into cells by a Zn ionophore. This property was measured for the compounds of the present invention using the following protocol, and data are presented for the known Zn ionophore PBT2.

[0223] Human neuroblastoma SH-SY5Y cells were obtained from Cell Bank Australia (catalog number: 94030304). SH-SY5Y cell cultures were maintained in DMEM / F12 + 15% FBS in an incubator at 37°C in the presence of 5% CO2. Cells were subcultured once a week, and the culture medium was changed once a week. Cells for the assay were seeded at a density of 60,000 cells / well.

[0224] A stock solution of the sample was prepared as a 5 mM stock in DMSO, and a stock solution of 1 mM ZnCl2 / 3 mM glutamic acid was prepared in water. Immediately before use, the compound was diluted 1:10 with water and then added to Locke buffer in a treatment tube. The sample was further treated with either distilled water or the ZnCl2 / glutamic acid solution to obtain a treatment solution with a final concentration of 2 μM test compound + / - 5 μM ZnCl2.

[0225] The culture medium was aspirated from the wells and replaced with the treatment solution prepared above. In addition to the relative standard (PBT2+ / -ZnCl2), control wells consisting of + / - 5 μM ZnCl2, in which all treatments were performed in triplicate, were also included. The plates were incubated with the treatment solution at 37°C for 2 hours. After this time, the wells were aspirated and washed with sterile PBS.

[0226] Cells were processed according to the manufacturer's instructions using an initial incubation of 2 hours at 24°C and a final incubation of 16 hours at 24°C, and the changes in phospho-GSK-3β were measured using the AlphaScreen® SureFire® Phospho-GSK 3β (Ser9) Kit.

[0227] Fluorescence was measured using an Enspire plate reader. In the absence of metal, the compounds did not affect the signal, whereas in the presence of metal, the positive compounds showed an increase in signal, presented as a percentage relative to the positive standard PBT2+ZnCl2, which was set to 100%. Representative data are presented in Table 12 using the following ranges: A < 50%, B 50 to less than 100%, C 100 to less than 150%, D > 150%.

[0228] [Table 14] Method I: Measurement of Fe efflux from cells The compounds of the present invention were evaluated for their ability to extract iron (Fe) from cells using the following protocol.

[0229] Human neuroblastoma cell line BE(2)-M17 (M17) cell culture medium was obtained from Sigma Aldrich (catalog number: 95011816). M17 cells were maintained in Opti-MEM serum-reduced medium supplemented with 10% fetal bovine serum (Bovogen, SFBSF) and passaged twice weekly. Cells were cultured at 37°C in the presence of 5% CO2. Culture supplies were obtained from Thermo Fisher unless otherwise specified.

[0230] 57 By dissolving Fe metal (enrichment >95%, Trace Sciences International) in concentrated HCl... 57 A solution of non-radioactive Fe isotopes was prepared to obtain a final concentration of 573 mM. From this stock solution, a 10 mM working solution was prepared in sterile water. The working solution was used within two months of preparation.

[0231] First, 0.15 × 10 in 0.5 mL of culture medium 6 M17 cells were iron-loaded by seeding them in a 48-well plate at a cell / well density. After 48 hours, the old medium was discarded. Fresh medium was added at 10 mM. 57 20 μM Fe solution 57 The cells were supplemented with Fe isotopes. 57The cells were treated with Fe-enhanced medium and returned to an incubator for 20 hours. The ability of the experimental compound to leach iron was determined by dissolving the compound in DMSO and then diluting it in Hanks equilibrium salt solution (HBSS) for treatment of M17 cells. 57 After Fe incubation, cells were rinsed twice with HBSS and treated with 0.15 mL of the test compound at a concentration of 20 μM for 2 hours. All assays included the relevant vehicle (0.4%–0.8% DMSO) and a positive control (20 μM). After the treatment period, 0.1 mL of culture medium was taken from the cells and analyzed extracellularly by inductively coupled mass spectrometry (ICP-MS, Agilent 7700x series instrument). 57 The iron content was analyzed.

[0232] To implement this protocol, the following supplies were purchased from Sigma Aldrich: anhydrous dimethyl sulfoxide (DMSO, catalog number: 276855), Hanks equilibrium salt solution (HBSS, pH: 7.4, catalog number: H1387) supplemented with 20 mM HEPES and 4.2 mM sodium bicarbonate.

[0233] Using the protocol described above, the ability of the compound of the present invention to leach Fe from cells was determined. Therefore, cells pretreated with Fe in medium for 24 hours were subsequently washed and treated with fresh Fe-free medium containing or without the compound (20 μM). After 2 hours, the Fe level in the medium was measured, and the increase was determined as the percentage increase relative to the cell medium in the absence of the compound.

[0234]

number

[0235] Representative data is shown in Table 13, where the %Fe leaching amounts of the specific compounds of the present invention are within the following ranges: A < 30%, B 30-100%, C 100-150%, D > 150%.

[0236] [Table 15] The present invention includes the following embodiments. <1> Formula (Ib):

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Claims

1. Formula (Ib): 【Chemistry 1】 (In the formula, X is O, R １ teeth, 【Chemistry 2-2】 Selected from, R ６ and R ７ are each independently selected from hydrogen, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, hydroxy, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halo, CN, CO ２ R ９ and N(R ９ ) ２ or are independently selected from, or R ６ and R ７ These, together with the atoms to which they are bonded, form an unsubstituted six-membered aryl or heteroaryl ring. Each R ８ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, hydroxy, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, Halo, (CH ２ ) ｍ CO ２ R ９ and (CH ２ ) ｍ N(R) ９ ) ２ Selected independently from, Each R ９ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected independently from haloalkyl groups, R ２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, and 【Transformation 3】 Select from, or R １ and R ２ They came together, 【Chemistry 4】 (In the formula, V is CH ２ , O or S, R １１ and R １２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinil, Halo, C １～６ Haloalkyl, (CH ２ ) ｍ C ３～８ Cycloalkyl, (CH ２ ) ｍ Ayl, (CH ２ ) ｍ Heterocyclyl, (CH ２ ) ｍ Heteroaryl and COR １３ (In the formula, R １３ OH, OC １～６ Alkyl, OC ２～６ Alkenil, OC ２～６ Alkynyl and N(R) ９ ) ２ (selected from) and (each independently selected from) form R １ and R ２ The bicyclic cycloalkyl, heterocycloalkyl, or heteroaryl ring formed by the above may be optionally substituted, or R １ and R ２ All 【Transformation 5】 And, R ３ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and (C(R) １０ ) ２ ) ｍ CO ２ R ９ Selected from, R ４ and R ４ａ are each independently selected from hydrogen, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl and C １～６ haloalkyl, and R ５ is hydrogen, (C(R １０ )) ２ )) ｍ aryl, (C(R １０ )) ２ )) ｍ heteroaryl, or O(C(R １０ )) ２ )) ｍ heteroaryl, wherein said aryl and heteroaryl are optionally substituted), or R ４ａ is CN, and R ４ and R ５ are both hydrogen or together form 【Transformation 6】 (In the formula, R １４ is hydrogen, (C(R １０ ) ２ ) ｍ Aryl or (C(R) １０ ) ２ ) ｍ It forms a heteroaryl (wherein the formula, the aryl and heteroaryl are optionally substituted), or R ４ａ It does not exist, R ４ and R ５ They combine to form an optionally substituted aryl or optionally substituted monocyclic or bicyclic heteroaryl group. Each R １０ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, hydroxy, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, CN, Halo and N(R) ９ ) ２ Selected independently from, m is an integer from 0 to 6. Compounds of or pharmaceutically acceptable salts thereof.

2. R １ but, 【Chemistry 7-2】 A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

3. R ２ However, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C ３～８ A compound according to claim 1 or 2, selected from cycloalkyl groups.

4. R １ and R ２ However, all of them 【Transformation 8】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ and R ２ Together, 【Chemistry 9】 (In the formula, V is CH ２ or O, R １１ and R １２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, halo, (CH ２ ) ｍ C ３～８ Cycloalkyl, (CH ２ ) ｍ Ayl, (CH ２ ) ｍ Heterocyclyl, (CH ２ ) ｍ Heteroaryl and COR １３ (In the formula, R １３ OH, OC １～６ Alkyl, OC ２～６ Alkenil, OC ２～６ Alkynyl and N(R) ９ ) ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from (each independently selected from) (selected from)

6. R ３ However, hydrogen, C １～６ Alkyl, and CH ２ CO ２ CH ３ A compound according to any one of claims 1 to 5, selected from the above, or a pharmaceutically acceptable salt thereof.

7. R ４ and R ４ａ However, hydrogen, C １～３ Alkyl, C ２～３ Alkenil, C ２～３ Alkinyl and C １～３ Each is independently selected from haloalkyl groups, R ５ However, hydrogen, (CH ２ ) ｍ Aryl or (CH ２ ) ｍ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a heteroaryl (wherein the formula, the aryl and heteroaryl are optionally substituted).

8. R ４ａ It does not exist, R ４ and R ５ A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein these groups combine to form an optionally substituted aryl or optionally substituted heteroaryl group.

9. R ４ and R ５ The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the rings together form a phenyl ring, a 2-pyridinyl ring, a 3-pyridinyl ring, a 4-pyridinyl ring, a 3-pyridazinyl ring, a 4-pyridazinyl ring, a 2-furanyl, a 3-furanyl, a 2-thiophenyl ring, a 3-thiophenyl ring, a 2-thiazolyl ring, a 3-thiazolyl ring, a 4-thiazolyl ring, a 3-isoxazolyl ring, a 4-isoxazolyl ring, a 5-isoxazolyl ring, a 4-(1,2,3-thiadiazolyl) ring, a 5-(1,2,3-thiadiazolyl) ring, a 4-thiadiazolyl ring, a 5-thiadiazolyl ring, a 2-benzo[b]thiophenyl, a 3-benzothiophenyl ring, a 3-(1H)-indolyl ring, or a 4H-thieno[3,2-c]chromene ring.

10. i) R ４ａ CN is R ４ and R ５ They came together, 【Chemistry 10】 (In the formula, R １４ is hydrogen, (C(R １０ ) ２ ) ｍ Aryl or (C(R) １０ ) ２ ) ｍ It forms a heteroaryl (wherein the formula, aryl and heteroaryl are optionally substituted); or, ii) R ４ａ CN is R ４ and R ５ Both are hydrogen. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

11. Formula (II): 【Chemistry 11】 (In the formula, X, R ３ , R ４ , R ４ａ and R ５ This is as defined in claim 1, and R １１ and R １２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, halo, (CH ２ ) ｍ C ３～８ Cycloalkyl, (CH ２ ) ｍ Ayl, (CH ２ ) ｍ Heterocyclyl, (CH ２ ) ｍ Heteroaryl and COR １３ (In the formula, R １３ OH, OC １～６ Alkyl, OC ２～６ Alkenil, OC ２～６ Alkynyl and N(R) ９ ) ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is independently selected from (where r is 1, 2, or 3), each of which is a compound of (where r is 1, 2, or 3).

12. Formula (IIa): 【Chemistry 12】 (In the formula, R ３ , R ４ , R ４ａ , R ５ , R １１ and R １２ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II) as defined above.

13. Equation (IIb): 【Chemistry 13】 (In the formula, R ３ , R ４ , R ４ａ , R ５ , R １１ and R １２ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II) as defined above.

14. Formula (IIc): 【Chemistry 14】 (In the formula, R ３ , R ４ , R ４ａ , R ５ , R １１ and R １２ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein is a compound of formula (II) as defined for formula (II).

15. Formula (IIIa): 【Chemistry 15】 (In the formula, R ２ , R ３ , R ４ , R ４ａ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in claim 1.

16. Equation (IIId): 【Chemistry 17】 (In the formula, R ３ , R ４ , R ４ａ and R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in claim 1.

17. Formula (V): 【Chemistry 19】 (In the formula, X, R ２ , R ３ , R ４ , R ４ａ and R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in claim 1.

18. Equation (VI): 【Chemistry 20】 (In the formula, X, V, R ３ , R ４ , R ４ａ and R ５ This is as defined for equation (Ib), and R １１ and R １２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinil, Halo, C １～６ Haloalkyl, (CH ２ ) ｍ C ３～６ Cycloalkyl, (CH ２ ) ｍ Ayl, (CH ２ ) ｍ Heterocyclyl, (CH ２ ) ｍ Heteroaryl and COR １３ (In the formula, R １３ OH, OC １～６ Alkyl, OC ２～６ Alkenil, OC ２～６ Alkynyl and N(R) ９ ) ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is independently selected from (where s is 0, 1, or 2).

19. Formula (VIb): 【Chemistry 21】 (In the formula, R ３ , R ４ , R ４ａ , R ５ , R １１ and R １２ The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein is a compound of formula (VI) as defined for formula (VI).

20. The following compounds 1-117, 119-151, or 153-197: (E)-N'-(6,7-dihydroquinoline-8(5H)-yridene)nicotinohydrazide (1); (E)-N'-(5H-cyclopenta[b]pyridine-7(6H)-ylidene)-3,4-dimethoxybenzohydrazide (38); (E)-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-2-(2-(pyrrolidine-1-yl)ethoxy)benzohydrazide hydrochloride (41); (E)-4-methyl-N'-(1-(pyrimidine-2-yl)propyridene)-1,2,3-thiadiazole-5-carbohydrazide (43); (E)-N'-(1-(quinoline-2-yl)ethylidene)picolinohydrazide (80); (E)-4-methyl-N'-(1-(4-methylthiazole-2-yl)ethylidene)-1,2,3-thiadiazole-5-carbohydrazide (100); (Z)-N'-(imidazo[1,2-a]pyridine-2-ylmethylene)-3-methoxybenzohydrazide (120); N'-(bis(6-methylpyridine-2-yl)methylene)-4-hydroxy-3-methoxybenzohydrazide (130); (2E,N'E)-2-cyano-N'-(6,7-dihydroquinoline-8(5H)-ylidene)-3-(2-hydroxyphenyl)acrylohydrazide (145); (E)-N'-(1-(pyridine-2-yl)ethylidene)benzo[b]thiophene-2-carbozide(146); (E)-Methyl 2-(1-(benzo[b]thiophen-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetate (147); (E)-2-(1-(benzo[b]thiophen-2-carbonyl)-2-(1-(pyridine-2-yl)ethylidene)hydrazinyl)acetic acid (148); (E)-N'-(2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-ylidene)nicotinohydrazide (171); 5-Chloro-N'-(di(pyridine-2-yl)methylene)-3-((dimethylamino)methyl)-2-hydroxybenzohydrazide (185); Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 A compound that is one of these, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 21 for the treatment of a disease regulated by reducing zinc and / or iron.

23. Use of the pharmaceutical composition according to claim 21 in the manufacture of a pharmaceutical for the treatment of a disease regulated by reducing zinc and / or iron.

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