Compounds and methods for treating diseases

Abstract

The present invention provides biometal-modulating heterocyclic compounds of formula (I) and pharmaceutical compositions containing such compounds. The present invention particularly relates to iron-modulating compounds and compounds for the treatment of diseases, particularly neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Alzheimer's dementia, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multiple system atrophy (MSA). (I) [Formula 1] TIFF2023529968000087.tif5260

Description

[Technical Field]

[0001] The present invention provides compounds that regulate biometals and pharmaceutical compositions containing such compounds. The present invention particularly relates to compounds that regulate iron, and compounds for the treatment of diseases, in particular neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Alzheimer's dementia, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multiple system atrophy (MSA). [Background technology]

[0002] Biometals, including iron, are essential for the metabolism of living cells, but they must be maintained under extremely strict control under all physiological conditions. In certain disease states, metal ion management can be disrupted, leading to increased levels of metals accumulating in tissues or organs. For example, excess iron exhibits widespread toxic effects on tissues, depending on the metal's redox activity.

[0003] Oxidative stress is explained as being largely associated with the physical damage observed in many neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). In the presence of molecular oxygen, iron undergoes a redox cycle between its two most stable oxidation states, iron(II) and iron(III), producing hydroxyl radicals. · It can generate oxygen-derived free radicals such as OR. These radicals can interact with multiple biomolecules, leading to tissue damage.

[0004] Cells employ a number of protective strategies to prevent the formation or production of such highly reactive species, but these processes can be overwhelmed depending on the disease state. The brain, like all other tissues, protects itself from the harmful effects of oxygen free radicals by protective enzymes such as glutathione peroxidase (GP), catalase, and superoxide dismutase (SD). Protection is also provided by relatively large amounts of glutathione and ascorbate.

[0005] Parkinson's disease is a progressive neurodegeneration of dopaminergic neurons in the substantia nigra (SN) of the brain. PD patients are identified as having higher levels of iron in the SN of the brain, where the essential neurotransmitter dopamine (DA) has vital physiological functions.

[0006] Postmortem studies of the brains of Parkinson's disease patients suggest the involvement of oxygen free radical-induced oxidative stress, which leads to lipid peroxidation of cell membranes, followed by increased membrane fluidity, and ultimately cell death. Normally, DA is metabolized in a way that results in excess toxic oxygen species such as ·OH, which generate cytotoxic oxygen free radicals, such as peroxides and hydroxyl free radicals (·OR), in the presence of transient metals such as iron.

[0007] In Parkinson's disease (PD), the brain's defense mechanisms against the formation of cytotoxic oxy-free radicals are impaired. In Parkinson's brain SNs, SD and GP activity is reduced, and tissue content of glutathione and ascorbate decreases. Furthermore, iron levels are significantly elevated in Parkinson's disease SNs within dopaminergic neurons. Treatment of mice with the metal modulator cryoquinol has been shown to protect them from the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes Parkinson's syndrome. Further experiments have shown that mice genetically engineered to express ferritin, a native iron-binding protein in mouse SNs, have less available iron in the brain and are also protected from the effects of MPTP. Importantly, the mice tolerated the resulting reduction in available iron in the brain without serious side effects, regardless of how their iron levels decreased.

[0008] While iron itself can induce oxidation processes, evidence suggests that proteins with iron-binding sites can do the same. In AD, plaque-forming Aβ peptides carry out the redox cycle of iron(III), producing hydrogen peroxide (H2O2) through two-electron transfer to O2. H2O2 reacts with reduced metal ions such as iron(II) to form highly reactive hydroxyl radicals via the Fenton reaction. · It is an oxidation-promoting molecule that generates OH. This process then induces many adducts and protein modifications.

[0009] Alzheimer's disease is characterized by widespread alterations to macromolecules of all classes, coupled with apoptotic mechanisms of cell damage / death partially mediated by H2O2. Primarily, the Fenton redox activity of Aβ peptides depends on the iron-metal binding site of the Aβ peptide. The presence of this site suggests that compounds capable of regulating metals, including intracellular metal concentrations, or blocking the metal-binding site, could be direct treatments for AD.

[0010] Subsequently, these conditions lead to the release of cytotoxic free radicals, resulting in neuronal cell death.

[0011] It is highly desirable to find iron-modulating substances that exhibit the remaining properties necessary for treating metal-related disorders. [Overview of the project]

[0012] This invention is at least in part based on the discovery that certain compounds can regulate iron and are therefore suitable candidates for the treatment of Parkinson's disease and other metal-related disorders.

[0013] In the first aspect, the present invention relates to a compound of formula (I), [ka] During the ceremony, Each of X1 to X8 is independently N and CR3, and 0, 1, 2, 3, or 4 of X1 to X8 are N. R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, (C(R7)2) m aryl, C(O)R4, and C(S)R4. R2 is selected from the group consisting of hydrogen, halo, OR5, SR5, C(O)R4, C(S)R4, NO2, CN, N(R6)2, S(O) n N(R6)2, and S(O) n R4. Each R3 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R7)2) m cycloalkyl, (C(R7)2) m cycloalkenyl, (C(R7)2) m aryl, (C(R7)2) m heterocyclyl, (C(R7)2) m heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2, and (C(R7)2) m N(R6)C(S)N(R)2. <了000了840>R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, OR5, SR, and N(R6)2. R5 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, S(O) n R4 and S(O) n Selected from the group consisting of N(R6)2, R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl. Each R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl. m is 0, or an integer from 1 to 6. n is 1 or 2, p is an integer between 1 and 4. Compounds in which each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl are optionally substituted. The present invention provides a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0014] In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0015] In yet another aspect of the present invention, a method is provided for treating or preventing metal ion-related disorders, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0016] In yet another aspect of the present invention, a method is provided for treating or preventing metal ion-related neuropathy, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0017] In further embodiments of the present invention, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are provided for use in the treatment or prevention of metal ion-related disorders. In further embodiments, the disorder is a neurological disorder.

[0018] Further embodiments of the present invention provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for treating or preventing a metal ion-related disorder. In further embodiments, the disorder is a neurological disorder. The present invention includes the following embodiments. [Aspect 1] A compound of formula (I), [ka] During the ceremony, X 1 ~X 8 Each of these independently represents N and CR 3 Selected from the group consisting of X 1 ~X 8 Of these, 0, 1, 2, 3, or 4 are N. R 1 However, hydrogen, alkyl, alkenyl, alkynyl, aryl, (C(R 7 ) 2 ) m Aryl, C(O)R 4 , and C(S)R 4 Selected from the group consisting of, R 2 However, hydrogen, halo, OR 5 , SR 5 , C(O)R 4 , C(S)R 4 NO 2 , CN, N(R 6 ) 2 OS(O) n N(R 6 ) 2 , and OS(O) n R 4 Selected from the group consisting of, Each R 3 However, independently, hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R 7 ) 2 ) m Cycloalkyl, (C(R 7 ) 2 )m Cycloalkenyl, (C(R 7 ) 2 ) m Ariel, (C(R 7 ) 2 ) m Heterocycline, (C(R 7 ) 2 ) m Heteroaryl, (C(R 7 ) 2 ) m Ure 5 , (C(R 7 ) 2 ) m SR 5 , (C(R 7 ) 2 ) m C(O)R 4 , (C(R 7 ) 2 ) m C(S)R 4 , (C(R 7 ) 2 ) m OC(O)R 4 , (C(R 7 ) 2 ) m SC(S)R 4 , (C(R 7 ) 2 ) m OC(S)R 4 , (C(R 7 ) 2 ) m SC(O)R 4 , (C(R 7 ) 2 ) m CN, (C(R 7 ) 2 ) m NO 2 , (C(R 7 ) 2 ) m N(R 6 ) 2 , (C(R 7 ) 2 ) m S(O) nR 4 , (C(R 7 ) 2 ) m N(R 6 )C(O)N(R 6 ) 2 , and (C(R 7 ) 2 ) m N(R 6 )C(S)N(R 6 ) 2 Selected from the group consisting of, R 4 However, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, OR 5 , SR 5 , and N(R 6 ) 2 Selected from the group consisting of, R 5 However, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, S(O) n R 4 , and S(O) n N(R 6 ) 2 Selected from the group consisting of, R 6 However, it is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl. Each R 7 However, independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl, m is 0, or an integer from 1 to 6. n is 1 or 2, p is an integer between 1 and 4. Compounds in which each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl are optionally substituted. or its pharmaceutically acceptable salts, stereoisomers, or solvates. [Aspect 2] X 1 ~X 8 However, CR became independent. 3 A compound according to embodiment 1, selected from . [Aspect 3] X 1 ~X 8 One of them is N, and the rest are CR 3 The compound described in Embodiment 1. [Aspect 4] X 1 ~X 8 Two of them are N, and the rest are CR 3 The compound described in Embodiment 1. [Aspect 5] below, i)X 1 ~X 4 One of them is N, ii)X 5 ~X 8 One of them is N, iii)X 1 The fact that is N, iv)X 5 The fact that is N, v)X 6 The fact that is N, vi)X 7 The fact that is N, or vii)X 8 A compound according to any one of the following descriptions, wherein one of the following conditions is met: the compound is N. [Aspect 6] R 1 However, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C(O)C 1-6 Alkyl, CH 2 Aryl and C(O)OC 1-6 A compound according to any one of embodiments 1 to 5, selected from the group consisting of alkyl groups. [Aspect 7] R 1 However, hydrogen or CH 2 The compound according to embodiment 6, which is phenyl. [Aspect 8] R 2 However, hydrogen, OH, SH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO 2 , CN, NH 2 OS(O) 2 NH 2 OS(O) 2 NH(C 1-6 Alkyl), OS(O) 2 N(C 1-6 Alkyl) 2 , and OS(O) n C 1-6 A compound selected from alkyl groups, according to any one of embodiments 1 to 7. [Aspect 9] R 2 The compound according to embodiment 8, wherein is OH. [Aspect 10] Each R 3 However, independently, hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, (CH 2 ) q Cycloalkyl, (CH 2 ) q Cycloalkenyl, (CH 2 ) q Ariel, (CH 2 ) q Heterocyclyl, (CH 2 ) q Heteroaryl, OH, (CH 2 ) q OH, SH, (CH 2 ) q SH, OC 1-6 Alkyl, SC 1-6 Alkyl, (CH 2 ) q OC 1-6 Alkyl, (CH 2 ) q SC 1-6 Alkyl, OCC(O)C 1-6 Alkyl, (CH 2 ) q OC(O)C 1-6 Alkyl, C(O)C 1-6 Alkyl, (CH 2 ) q C(O)C 1-6 Alkyl, CO 2 H,(CH 2 ) q CO 2 H, C(O)OC 1-6 Alkyl, (CH 2 ) q C(O)OC 1-6 Alkyl, CONH 2 , (CH 2 ) q CONH 2 , CN, (CH 2 ) q CN, NO 2 , (CH 2 ) q NO 2 NH 2 NH(C 1-6 Alkyl), N(C 1-6 Alkyl) 2 , (CH 2 ) q NH 2 , (CH 2 ) q NH(C 1-6 (Alkyl), (CH 2 ) q N(C 1-6 Alkyl) 2 , SO 2 H, (CH 2 ) q SO 2 H, SO 3 H, (CH 2 ) q SO 3 H, S(O) 2 C 1-6 Alkyl, (CH 2 ) q S(O) 2 C 1-6 Alkyl, S(O) 2 OC 1-6 Alkyl, (CH 2 ) q S(O) 2 OC 1-6 Alkyl, S(O) 2 NH 2 , S(O) 2 NH(C 1-6 Alkyl), S(O) 2 N(C 1-6 Alkyl) 2 , (CH 2 ) q S(O) 2 NH 2 , (CH 2 ) q S(O) 2 NH(C 1-6 (Alkyl), (CH 2 ) q S(O) 2 N(C 1-6 Alkyl) 2 , NHC(O)NH 2 , NHC(O)NH(C 1-6 Alkyl), NHC(O)N(C 1-6 Alkyl) 2 , (CH 2 ) q NHC(O)NH 2 , (CH 2 ) q NHC(O)NH(C 1-6 (alkyl), and (CH 2 ) q NHC(O)N(C 1-6 Alkyl) 2 A compound according to any one of embodiments 1 to 9, selected from the group consisting of the above, wherein q is an integer from 1 to 3. [Aspect 11] A compound according to any one of embodiments 1 to 10, wherein p is 1, 2, or 3. [Aspect 12] A compound of formula (II),

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[0019] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention pertains. Any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below:

[0020] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, "an element" means one or more elements.

[0021] As used herein, the term “approximately” means a quantity, level, value, dimension, size, or amount that varies by up to 15% or 10% relative to a reference quantity, level, value, dimension, size, or amount.

[0022] Throughout this specification, unless otherwise specified in the context, the terms “comprise,” “comprises,” and “comprising” imply the inclusion of the step or element, or group of steps or elements, described herein, but not the exclusion of any other step or element, or group of steps or elements.

[0023] 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 include an alkyl group having a specified number of carbon atoms, for example, 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched configuration. 1-6It may have an alkyl group. 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.

[0024] As used herein, the term "haloalkyl" refers to the alkyl groups defined above, including perhalogenated alkyl groups, in which one or more hydrogen atoms are replaced by halogen atoms. Examples of suitable 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, and 3-chloropropyl.

[0025] 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, the C2-C6 in “C2-C6 alkenyl” includes groups having 2, 3, 4, 5, or 6 carbon atoms in a linear or branched configuration. Examples of preferred alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, and decenyl.

[0026] As used herein, the term “alkynyl” refers to a linear or branched hydrocarbon group having one or more triple bonds and containing 2 to 10 carbon atoms. Where appropriate, an alkynyl group may have a specified number of carbon atoms. For example, the C2-C6 in “C2-C6 alkynyl” includes groups having 2, 3, 4, 5, or 6 carbon atoms in a linear or branched configuration. Examples of suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0027] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon. A cycloalkyl ring may contain a specific number of carbon atoms. For example, a 3- to 10-membered cycloalkyl group may contain 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0028] As used herein, the term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbon. A cycloalkenyl ring may contain a specific number of carbon atoms. For example, a 5- to 10-membered cycloalkenyl group contains 5, 6, 7, 8, 9, or 10 carbon atoms. A cycloalkenyl group has one or more double bonds, and if there is more than one double bond, these double bonds may or may not be conjugated, but the cycloalkenyl group is not aromatic. Examples of suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrieyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclononenyl, cyclononadienyl, cyclonononatrienyl, cyclodecenyl, cyclodecadienyl, and cyclodecatrieyl rings.

[0029] 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, where at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, phenantrenyl, biphenyl, and binaphthyl.

[0030] As used herein, the terms "halogen" or "halo" refer to fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iod).

[0031] As used herein, the terms “heterocyclic” or “heterocyclyl” refer to cyclic hydrocarbons such as cycloalkyl or cycloalkenyl, as defined above, in which 1 to 4 carbon atoms are replaced by heteroatoms independently selected from the group consisting of N, N(R), S, S(O), S(O)2, and O. Heterocyclic rings may be saturated or unsaturated, but are not aromatic. Suitable examples of heterocyclyl groups include azetidine, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinil, 2-oxopyrrolidinil, pyrrolinil, pyranil, dioxolanil, piperidinil, 2-oxopiperidinil, pyrazolinil, imidazolinil, thiazolinil, dithiolyl, oxathiolyl, dioxanil, dioxynil, dioxazolyl, oxathiozolyl, oxazolonil, piperazinil, morpholino, thiomorpholinil, 3-oxomorpholinil, dithianil, trithianil, and oxazinil.

[0032] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Heteroaryl groups within this definition include acridinyl, carbazolyl, synnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, Examples include, but are not limited to, pyrazinyl, pyridadinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, 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.

[0033] Each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl may be an individual entity or 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, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6Alkyl)2, -NH(phenyl), -N(phenyl)2, -CN, -NO2, -halogen, -CF3, -OCF3, -SCF3, -CHF2, -OCHF2, -SCHF2, -phenyl, -heterocyclyl, -heteroaryl, -Oheteroaryl, -Oheterocyclyl, -Ophenyl, -C(=O)phenyl, -C(=O)C 1-6 The substituents may be optionally substituted with one or more optional substituents selected from the group consisting of alkyl groups. Examples of preferred substituents include, but are not limited to, 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, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, ethylamino, diethylamino, phenyl, phenoxy, phenylcarbonyl, benzyl, and acetyl.

[0034] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. However, it is 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 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 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, Examples include, but are 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.

[0035] Basic salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, lysine, histidine, meglumine, ammonium, and alkylammonium.

[0036] The basic nitrogen-containing group may be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl sulfate and diethyl sulfate, and others.

[0037] 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 variable stoichiometric complex formed by a solute (compound of formula (I)) and a solvent. Such a solvent must 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.

[0038] The term “prodrug” is used in its broadest sense to encompass 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 formed from amino acids. Conventional procedures for preparing suitable prodrugs are described in textbooks such as “Design of Prodrugs” Ed.H. Bundgaard, Elsevier, 1985.

[0039] Furthermore, it is recognized that the compounds of the present invention may possess a chiral center and therefore may exist in more than one stereoisomer. For this reason, the present invention also relates to compounds in substantially pure isomeric forms with one or more chiral centers, for example, greater than 90% ee, such as greater than 95% or 97% ee or greater than 99% ee, and mixtures comprising racemic mixtures thereof. Such isomers may be prepared, for example, by asymmetric synthesis using a chiral intermediate or by chiral decomposition. 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.

[0040] The compounds of the present invention may also exist in the form of rotational or conformational isomers in which rotation around a single bond is restricted or inhibited.

[0041] Any formula or structure granted 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 metabolic, kinetic, detection, or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or in radiotherapy for patients. An isotope-labeled compound has the structure represented by the formula granted herein, except that one or more atoms are substituted by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 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 C1, and 125 I is an example. Various isotope-labeled compounds of the present disclosure, for example, 3 H, 13 C, and 14 Compounds into which radioactive isotopes such as 13C are incorporated. In addition to their use as pharmaceutical treatments, such isotope-labeled compounds may be useful.

[0042] The compound of the present invention The present invention provides metal ion modulating compounds, particularly iron-selective ion modulating compounds. Such modulating substances may possess one or more desirable properties, such as oral deliverability, low liver extractability, non-toxicity, and the ability to modulate metals, particularly iron, in the central nervous system (CNS). Favorable metal selectivity, affinity, and kinetic stability of the formed complexes are also provided by the preferred compounds.

[0043] For a modifier to exert its pharmacological effect, it needs to reach the target site at a sufficient concentration. Therefore, a desirable key characteristic of orally active iron modifiers is their ability to be efficiently absorbed from the gastrointestinal tract (GI).

[0044] The metabolic properties of regulatory substances play a crucial role in determining both their efficacy and toxicity. Iron-associated toxicity stems from several factors, but decisively, from their ability to inhibit many iron-containing enzymes such as tyrosine hydroxylase (a brain enzyme involved in L-DOPA biosynthesis) and ribonucleotide reductase. Therefore, in a first aspect, the present invention relates to a compound of formula (I), [ka] During the ceremony, Each of X1 to X8 is independently selected from the group consisting of N and CR3, and 0, 1, 2, 3, or 4 of X1 to X8 are N. R1 is hydrogen, alkyl, alkenyl, alkynyl, (C(R7)2) m Selected from the group consisting of aryl, C(O)R4, and C(S)R4, R2 is hydrogen, halo, OR5, SR5, C(O)R4, C(S)R4, NO2, CN, N(R6)2, OS(O) n N(R6)2 and OS(O) n Selected from the group consisting of R4, Each R3 independently comprises hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2)m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m Selected from the group consisting of N(R6)C(S)N(R6)2, R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, OR5, SR5, and N(R6)2. R5 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, S(O) n R4 and S(O) n Selected from the group consisting of N(R6)2, R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl. Each R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl. m is 0, or an integer from 1 to 6. n is 1 or 2, p is an integer between 1 and 4. Compounds in which each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl are optionally substituted. The present invention provides a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0045] In some embodiments, X1 to X8 are each independently CR3. In other embodiments, one of X1 to X8 is N and the rest are CR3. In yet another embodiment, two of X1 to X8 are N and the rest are CR3. In yet another embodiment, three of X1 to X8 are N and the rest are CR3. In yet another embodiment, four of X1 to X8 are N and the rest are CR3. In a particular embodiment, X1 to X8 are each independently CR3, or one of X1 to X8 is N and the rest are CR3.

[0046] In some embodiments, one of X1 to X4 is N. In other embodiments, one of X5 to X8 is N. In a particular embodiment, one of X1, X5, X6, X7, and X8 is N.

[0047] In some embodiments, one of X1 to X4 is N, and two of X5 to X8 are N. In other embodiments, two of X1 to X4 are N, and one of X5 to X8 is N.

[0048] In some embodiments, two of X1 to X4 are N, and two of X5 to X8 are N.

[0049] In other embodiments, one of X1 to X4 and one of X5 to X8 are N. In some embodiments, two of X1, X5, X6, X7, and X8 are N.

[0050] In some embodiments, if two or three of X1 to X8 are N, then two or fewer nitrogen atoms are located adjacent to each other within the ring. For example, if both X5 and X7 are N, then X6 cannot be N.

[0051] In certain embodiments, one or more of the following apply: R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) qAryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, SH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, Each R3 is hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2) q Cycloalkyl, (CH2) q Cycloalkenyl, (CH2) q Ariel, (CH2) q Heterocycline, (CH2) q Heteroaryl, OH, (CH2) q OH, SH, (CH2) q SH, OC 1-6 Alkyl, SC 1-6 Alkyl, (CH2) q OC 1-6Alkyl, (CH2) q SC 1-6 Alkyl, OCC(O)C 1-6 Alkyl, (CH2) q OC(O)C 1-6 Alkyl, C(O)C 1-6 Alkyl, (CH2) q C(O)C 1-6 Alkyl, CO2H, (CH2) q CO2H, C(O)OC 1-6 Alkyl, (CH2) q C(O)OC 1-6 Alkyl, CONH2, (CH2) q CONH2, CN, (CH2) q CN, NO2, (CH2) q NO2, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, (CH2) q NH2, (CH2) q NH(C 1-6 Alkyl), (CH2) q N(C 1-6 Alkyl)2, SO2H, (CH2) q SO2H, SO3H, (CH2) q SO3H, S(O)2C 1-6 Alkyl, (CH2) q S(O)2C 1-6 Alkyl, S(O)2OC 1-6 Alkyl, (CH2) q S(O)2OC 1-6 Alkyl, S(O)2NH2, S(O)2NH(C 1-6 Alkyl), S(O)2N(C 1-6 Alkyl)2, (CH2) q S(O)2NH2, (CH2) q S(O)2NH(C 1-6 Alkyl), (CH2) q S(O)2N(C 1-6 Alkyl)2, NHC(O)NH2, NHC(O)NH(C 1-6 Alkyl), NHC(O)N(C 1-6 Alkyl)2, (CH2) q NHC(O)NH2, (CH2) q NHC(O)NH(C1-6 Alkyl, and (CH2) q NHC(O)N(C 1-6 Alkyl)2 (where q is an integer from 1 to 3), specifically, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, heterocyclyl, heteroaryl, (CH2) q Heterocycline, (CH2) q Heteroaryl, OH, (CH2) q OH, OC 1-6 Alkyl, SC 1-6 Alkyl, (CH2) q OC 1-6 Alkyl, (CH2) q SC 1-6 Alkyl, OCC(O)C 1-6 Alkyl, (CH2) q OC(O)C 1-6 Alkyl, C(O)C 1-6 Alkyl, (CH2) q C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, (CH2) q C(O)OC 1-6 Alkyl, CN, (CH2) q CN, NO2, CH2NO2, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, (CH2) q NH2, (CH2) q NH(C 1-6 Alkyl), (CH2) q N(C 1-6 Alkyl)2, more specifically, hydrogen, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, SC 1-3 Alkyl, CH2OC 1-3 Alkyl, CH2SC 1-3 Alkyl, C(O)C 1-3 Alkyl, CH2C(O)C 1-3 Alkyl, C(O)OC 1-3 Alkyl, CH2C(O)OC 1-3 Alkyl, CN, CH2CN, NO2, CH2NO2, NH2, NH(C1-6 Alkyl), N(C 1-6 Alkyl)2, CH2NH2, CH2NH(C 1-6 Alkyl), CH2N(C 1-6 Alkyl)2, CH2CH2NH2, CH2CH2NH(C 1-6 Alkyl), CH2CH2N(C 1-6 Alkyl)2, CHCH2CH2NH2, CH2CH2CH2NH(C 1-6 Alkyl), CH2CH2CH2N(C 1-6 Selected from the group consisting of alkyl)2, heterocyclyl, CH2 heterocyclyl, CH2CH2 heterocyclyl, and CH2CH2CH2 heterocyclyl, and more specifically, CH3, CH2CH3, chloro, fluoro, trifluoromethyl, CO2CH3, CH2 morpholine, CH2CH2 morpholine, CH2CH2CH2 morpholine, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2-N-pyrrolidine, CH2CH2-N-pyrrolidine, and CH2CH2CH2-N-pyrrolidine, R4 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 alkyl and OC 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl, C 1-3 Haloalkyl, OC 1-3 alkyl and OC 1-3 Haloalkyl groups, more specifically selected from the group consisting of CH3, CF3, OCH3, and OCF3, R5 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, S(O)2OC 1-6 Alkyl, S(O)2NH2, S(O)2NH(C 1-6Alkyl, and S(O)2N(C 1-6 Alkyl)2, specifically, C 1-3 Alkyl, C 1-3 Halowalki and C(O)C 1-3 Selected from alkyl groups, R6 contains hydrogen and C 1-6 Alkyl, specifically hydrogen and C 1-3 Selected from alkyl groups, Each R7 is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl, specifically hydrogen. m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. p is 1, 2, or 3, specifically 1 or 2.

[0052] In some embodiments, the compound of formula (I) is the compound of formula (II), [ka] In the equation, R1, R2, R3, and p are as defined for equation (I), and R 3a ~R 3h However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2)m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0053] In some embodiments, the compound of formula (II) is the compound of formula (IIa), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) nR4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0054] In some embodiments, the compound of formula (II) is the compound of formula (IIb), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) mA compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0055] In some embodiments, the compound of formula (II) is the compound of formula (IIc), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3m However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0056] In a particular embodiment of formula (II), one or more of the following apply: R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) q Aryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, R 3a However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3bHowever, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Alkyl, specifically hydrogen, fluoro, chloro, C 1-3 Alkyl, C 1-3 Haloalkyl and CO2C 1-3 Alkyl, more specifically selected from the group consisting of hydrogen, fluoro, CH3, CF3, and CO2CH3, R 3c However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and (CH2) q Heterocyclines, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl, C 1-3 Haloalkyls and CH2 heterocyclines, more specifically selected from the group consisting of hydrogen, CH3, CF3, fluoro, and CH2 morpholine, R 3d However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, (CH2) q N(C 1-6 Alkyl)2, and (CH2) q Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) q Piperazine, (CH2) q -4-N-methylpiperazine, and (CH2) qPyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R 3e However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3f However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CF3, and CH3, R 3g However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, R 3h However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0057] The specific compounds of formula (II) are compounds 7, 8, 9, 10, 12, 36, 37, and 38 shown in the examples.

[0058] In some embodiments, the compound of formula (I) is the compound of formula (III), [ka] In the formula, R1, R2, and R3, as well as p, are as defined for formula (I), and R 3a ~R 3d and R 3f ~R 3h However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0059] In some embodiments, the compound of formula (III) is the compound of formula (IIIa), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3d and R 3f ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0060] In some embodiments, the compound of formula (III) is the compound of formula (IIIb), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3d and R 3f ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0061] In some embodiments, the compound of formula (III) is the compound of formula (IIIc), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3d and R 3f ~R 3m However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0062] In a particular embodiment of formula (III), one or more of the following apply: R1 is hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) q Aryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, R 3a However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3b However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Alkyl, specifically hydrogen, fluoro, chloro, C 1-3 Alkyl, C 1-3Haloalkyl and CO2C 1-3 Alkyl, more specifically selected from the group consisting of hydrogen, fluoro, CH3, CF3, and CO2CH3, R 3c However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and (CH2) q Heterocyclines (where q is an integer from 1 to 3), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyls and CH2 heterocyclines, more specifically selected from the group consisting of hydrogen, CH3, CF3, fluoro, and CH2 morpholine, R 3d However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, (CH2) q N(C 1-6 Alkyl)2, and (CH2) q Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) q Piperazine, (CH2) q -4-N-methylpiperazine, and (CH2) q Pyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R 3f However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CF3, and CH3, R 3g However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, R 3h However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0063] The specific compounds of formula (III) are compounds 1, 2, 3, 4, 5, 6, 40, 41, 42, 43, 45, 46, 47, 48, 50, 51, 52, 53, 55, 56, 57, 58, and 59 shown in the examples.

[0064] In some embodiments, the compound of formula (I) is the compound of formula (IV), [ka] In the formula, R1, R2, and R3, as well as p, are as defined for formula (I), and R 3a ~R 3e and R 3g ~R 3h However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) mAryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0065] In some embodiments, the compound of formula (IV) is the compound of formula (IVa), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3e and R 3g ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) mHeteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0066] In some embodiments, the compound of formula (IV) is the compound of formula (IVb), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3e and R 3g ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) mSR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2, and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, wherein R4, R5, R6, R7, and m are as defined for formula (I), Or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0067] In some embodiments, the compound of formula (IV) is a compound of formula (IVc),

Chemical formula

[0068] In a particular embodiment of formula (IV), one or more of the following apply: R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) q Aryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6Alkyl, specifically, hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl, and CO2C 1-6 Alkyl, more specifically, hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl, and CO2C 1-6 Alkyl, even more specifically, selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically, OH R 3a is hydrogen, halo, C 1-6 Alkyl, and C 1-6 Haloalkyl, specifically, hydrogen, fluoro, chloro, C 1-3 Alkyl, and C 1-3 Haloalkyl, more specifically, selected from the group consisting of hydrogen and fluoro R 3b is hydrogen, halo, C<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) q Piperazine, (CH2) q -4-N-methylpiperazine, and (CH2) q Pyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R 3e However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3g However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, R 3h However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0069] The specific compounds of formula (IV) are compounds 29 and 30 shown in the examples.

[0070] In some embodiments, the compound of formula (I) is the compound of formula (V), [ka] R1, R2, R3, and p are as defined for equation (I), and R 3a ~R 3f , and R 3h However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0071] In some embodiments, the compound of formula (V) is the compound of formula (Va), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3f and R 3h ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0072] In some embodiments, the compound of formula (V) is the compound of formula (Vb), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3f and R 3h ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0073] In some embodiments, the compound of formula (V) is the compound of formula (Vc), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3f and R 3h ~R 3m However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0074] In a particular embodiment of formula (V), one or more of the following apply: R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) qAryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, R 3a However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3b However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Alkyl, specifically hydrogen, fluoro, chloro, C 1-3 Alkyl, C 1-3 Haloalkyl and CO2C 1-3Alkyl, more specifically selected from the group consisting of hydrogen, fluoro, CH3, CF3, and CO2CH3, R 3c However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and (CH2) q Heterocyclines (where q is an integer from 1 to 3), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl and (CH2) q Heterocyclines, more specifically selected from the group consisting of hydrogen, CH3, CF3, fluoro, and CH2 morpholine, R 3d However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, (CH2) q N(C 1-6 Alkyl)2, and (CH2) q Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) q Piperazine, (CH2) q -4-N-methylpiperazine, and (CH2) q Pyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R3e However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3f However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CF3, and CH3, R 3h However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0075] The specific compounds of formula (V) are compounds 21, 22, 23, 24, 25, 26, 27, and 28 shown in the examples.

[0076] In some embodiments, the compound of formula (I) is the compound of formula (VI), [ka] In the equation, R1, R2, R3, and p are as defined for equation (I), and R 3a ~R 3g However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) mC(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0077] In some embodiments, the compound of formula (VI) is the compound of formula (VIa), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3g and R 3i ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) mOC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0078] In some embodiments, the compound of formula (VI) is the compound of formula (VIb), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3g and R 3i ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) mOC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0079] In some embodiments, the compound of formula (VI) is the compound of formula (VIc), [ka] In the formula, R1 and R2 are as defined for formula (I), and R 3a ~R 3g and R 3i ~R 3m However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) mCN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0080] In certain embodiments of formula (VI), one or more of the following apply: R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) q Aryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, R 3a However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3b However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Alkyl, specifically hydrogen, fluoro, chloro, C 1-3 Alkyl, C 1-3 Haloalkyl and CO2C 1-3 Alkyl, more specifically selected from the group consisting of hydrogen, fluoro, CH3, CF3, and CO2CH3, R 3c However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and (CH2) q Heterocyclines (where q is an integer from 1 to 3), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyls and CH2 heterocyclines, more specifically selected from the group consisting of hydrogen, CH3, CF3, fluoro, and CH2 morpholine, R 3d However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, (CH2) q N(C 1-6 Alkyl)2, and (CH2) q Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) qPiperazine, (CH2) q -4-N-methylpiperazine, and (CH2) q Pyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R 3e However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3f However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CF3, and CH3, R 3g However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0081] The specific compounds of formula (VI) are compounds 13, 14, 15, 16, 17, 18, 19, 20, and 39 shown in the examples.

[0082] In some embodiments, the compound of formula (I) is the compound of formula (VII), [ka] In the formula, R1, R2, R3, and p are as defined for formula (I), and X5 is N or CR. 3e And X6 is N or CR 3f And X7 is N or CR 3g And X8 is N or CR 3h And R 3b ~R 3h However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, where R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0083] In some embodiments, the compound of formula (VII) is the compound of formula (VIIa), [ka] In the formula, R1 and R2 are as defined for formula (I), and X5 is N or CR. 3e And X6 is N or CR 3f And X7 is N or R 3g And X8 is N or CR 3h And R 3b ~R 3k However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, wherein R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0084] In some embodiments, the compound of formula (VII) is the compound of formula (VIIb), [ka] In the formula, R1 and R2 are as defined for formula (I), and X5 is N or CR. 3e And X6 is N or CR 3f And X7 is N or R 3g And X8 is N or CR 3h And R 3b ~R 3l However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) m N(R6)C(O)N(R6)2 and (C(R7)2) mA compound selected from the group consisting of N(R6)C(S)N(R6)2, wherein R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0085] In some embodiments, the compound of formula (VII) is the compound of formula (VIIc), [ka] In the formula, R1 and R2 are as defined for formula (I), and X5 is N or CR. 3e And X6 is N or CR 3f And X7 is N or R 3g And X8 is N or CR 3h And R 3b ~R 3m However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, and (C(R7)2). m Cycloalkyl, (C(R7)2) m Cycloalkenyl, (C(R7)2) m Aryl, (C(R7)2) m Heterocycline, (C(R7)2) m Heteroaryl, (C(R7)2) m OR5, (C(R7)2) m SR5, (C(R7)2) m C(O)R4, (C(R7)2) m C(S)R4, (C(R7)2) m OC(O)R4, (C(R7)2) m SC(S)R4, (C(R7)2) m OC(S)R4, (C(R7)2) m SC(O)R4, (C(R7)2) m CN, (C(R7)2) m NO2, (C(R7)2) m N(R6)2, (C(R7)2) m S(O) n R4, (C(R7)2) mN(R6)C(O)N(R6)2 and (C(R7)2) m A compound selected from the group consisting of N(R6)C(S)N(R6)2, wherein R4, R5, R6, R7, and m are as defined for formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0086] In a particular embodiment of formula (VII), one or more of the following apply: X5 is CR 3e Plays, X6 is CR 3f And X7 is CR 3g And X8 is CR 3g And, One of X5, X6, X7, and X8 is N. R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, aryl, (CH2) q Aryl, C(O)C 1-6 Alkyl and C(O)OC 1-6 Alkyl (where q is an integer from 1 to 3), specifically hydrogen, C 1-6 Alkyl, CH2 aryl, and C(O)C 1-6 Alkyl, more specifically, hydrogen, C 1-3 Alkyl and CH2-phenyl, most specifically selected from the group consisting of hydrogen, CH3, and CH2-phenyl, R2 is hydrogen, OH, fluoro, chloro, bromo, OC 1-6 Alkyl, SC 1-6 Alkyl, C(O)OC 1-6 Alkyl, NO2, CN, NH2, OS(O)2NH2, OS(O)2NH(C 1-6 Alkyl), OS(O)2N(C 1-6 Alkyl)2, and OS(O) n C 1-6 Alkyl, specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C 1-6 Alkyl, more specifically hydrogen, OH, halo, CN, NO2, OC 1-6 Alkyl and CO2C1-6 Alkyl, more specifically selected from the group consisting of hydrogen, OH, halo, CN, NO2, OCH3, and CO2CH3, most specifically OH, R 3b However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Alkyl, specifically hydrogen, fluoro, chloro, C 1-3 Alkyl, C 1-3 Haloalkyl and CO2C 1-3 Alkyl, more specifically selected from the group consisting of hydrogen, fluoro, CH3, CF3, and CO2CH3, R 3c However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl and (CH2) q Heterocyclines (where q is an integer from 1 to 3), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyls and CH2 heterocyclines, more specifically selected from the group consisting of hydrogen, CH3, CF3, fluoro, and CH2 morpholine, R 3d However, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, (CH2) q N(C 1-6 Alkyl)2, and (CH2) q Heterocyclines (where q is 1-3 in the formula), specifically hydrogen, fluoro, chloro, and C. 1-3 Alkyl, C 1-3 Haloalkyl, (CH2) q N(C 1-3 Alkyl)2, (CH2) q Morpholine, (CH2) q Piperazine, (CH2) q -4-N-methylpiperazine, and (CH2) qPyrrolidine (wherein q is 1 to 3), more specifically selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH2CH3)2, CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2, CH2morpholine, CH2CH2morpholine, CH2CH2CH2morpholine, CH2piperazine, CH2CH2piperazine, CH2CH2CH2piperazine, CH2-4-N-methylpiperazine, CH2CH2-4-N-methylpiperazine, CH2CH2CH2-4-N-methylpiperazine, CH2pyrrolidine, CH2CH2pyrrolidine, and CH2CH2CH2pyrrolidine. R 3e However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyl, more specifically selected from the group consisting of hydrogen and fluoro, R 3f However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CF3, and CH3, R 3g However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, R 3h However, hydrogen, halo, C 1-6 Alkyl and C 1-6 Haloalkyls, specifically hydrogen, fluoro, chloro, and C 1-3 Alkyl and C 1-3Haloalkyls, more specifically selected from the group consisting of hydrogen, fluoro, CH3, and CF3, Each R 3i However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3j However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3k However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3l However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, Each R 3m However, independently, hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl groups, specifically hydrogen and C 1-3 Alkyl and C 1-3 Haloalkyls, more specifically selected from the group consisting of hydrogen, CH3, and CF3, m is an integer between 0 and 3, specifically, here m is 0, 1, or 2. Compounds in which p is 1, 2, or 3, or its pharmaceutically acceptable salts, stereoisomers, or solvates.

[0087] The specific compounds of formula (VII) are compounds 11, 44, 49, and 54 shown in the examples.

[0088] The compound of formula (I) may be prepared by methods known in the art. For example, Scheme 1 shows the preparation of major intermediates I-II. A representative methodology for Method A is described in Tao X. et al. J. Org. Chem. 2012, 77, pp612-616, Method B is described in Azzouz, R. et al. Synlett, 2006, 12, pp1908-1912, and Method C is described in Deane K J et al., ACS Med. Chem. Lett., 2014, 5, pp576-581 and Shi J. et al, ACS Omega, 2017, 2, 3406-3416. The general conversions of methods D, E, and G shown in Schemes 1-3 are well known and generally described in references such as Protective Groups in Organic Synthesis, Green TWand Wuts PGM, John Wiley & Sons, New York, 1999, and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, RC, John Wiley & Sons, New York, 2018. Scheme 2 outlines the conversion of major intermediates I / II to compounds of formula (I), and Scheme 3 outlines the preparation of intermediates III-IV and their subsequent conversion to compounds of formula (I). Additional representative methodologies are also described in the literature, in which Method F is extensively described and exemplified by the study in Wu, J. et al. Chem. Commun., 2010, 46, pp3687-3689, and Method H uses the method generally described by Beak P. et al. J. Org. Chem. 1993, 58, pp1109-1117 or Barker G. et al. Org. Lett. 2010, 12, pp4176-4179. [ka] [ka] [ka]

[0089] Method of the present invention For the treatment of metal-related neurological disorders such as Parkinson's disease, it is highly desirable to find iron-modulating substances. According to the present invention, it has been found that certain iron-modulating substances are capable of removing iron from cells and are therefore suitable candidates for the treatment of Parkinson's disease and other metal-related neurological disorders.

[0090] One aspect of the present invention provides a method for treating or preventing a metal ion-related disorder, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In a particular embodiment, the disorder is a neurological disorder.

[0091] In further aspects of the present invention, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are provided for use in the treatment or prevention of metal ion-associated neuropathy. In particular embodiments, the disorder is a neuropathy.

[0092] Further embodiments of the present invention provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for treating or preventing a metal ion-related disorder. In certain embodiments, the disorder is a neurological disorder.

[0093] Excess iron in vital organs increases the risk of many diseases, including liver disease (cancer, cirrhosis), heart attack or heart failure, cardiotoxicity, diabetes, osteoarthritis, osteoporosis, metabolic syndromes, hypothyroidism, and hypogonadism, and is associated with the onset or acceleration of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and multiple sclerosis.

[0094] In certain embodiments, metal-associated neurological disorders include Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple system atrophy (MSA), tardive dyskinesia (TD), Harrellforden-Spats syndrome, Friedreich's ataxia, epilepsy, and multiple sclerosis.

[0095] The subjects, individuals, or patients treated are mammals, including but not limited to humans, primates, domestic animals such as sheep, cattle, pigs, horses, donkeys, and goats, laboratory animals such as mice, rats, rabbits, and guinea pigs, companion animals such as cats and dogs, or captured wild animals such as those kept in zoos. In certain embodiments, the subject is a human.

[0096] "Effective dose" means the amount at least partially required to achieve the desired response, to delay the onset or inhibit its progression, or to completely halt the onset or progression of the particular condition being treated. This amount varies depending on the health and physical condition of the individual being treated, the taxonomic group of the individual being treated, the desired degree of protection, the formulation of the composition, the assessment of the medical situation, and other relevant factors. This amount is expected to be within a relatively wide range, which can be determined through routine trials. For human patients, the effective dose may be, for example, in the range of approximately 0.1 ng to 1 g per kg of body weight per dose. The dose is preferably in the range of 1 μg to 1 g per kg of body weight per dose, for example, in the range of 1 mg to 1 g per kg of body weight per dose. In one embodiment, the dose is in the range of 1 mg to 500 mg per kg of body weight per dose. In another embodiment, the dose is in the range of 1 mg to 250 mg per kg of body weight per dose. In another embodiment, the dose ranges from 1 mg to 100 mg per kg of body weight per dose, for example, up to 50 mg per kg of body weight per dose. In yet another embodiment, the dose ranges from 1 μg to 1 mg per kg of body weight per dose. The dosing regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily, weekly, monthly, or at other preferred time intervals, or the dose may be relatively reduced as indicated by the urgency of the situation.

[0097] References to “treatment” and “prevention” in this specification should be considered in their broadest context. The term “treatment” does not necessarily imply that the subject will be treated until full recovery. “Treatment” may also mean reducing the severity of an existing condition. The term “prevention” does not necessarily mean that the subject will never develop a disease state. The term “prevention” may be considered to include delaying the onset of a particular condition. Thus, treatment and prevention include improving or alleviating the symptoms of a particular condition, or preventing or otherwise reducing the risk of developing a particular condition.

[0098] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in conjunction with another therapy. Administration may be carried out in a single composition or in separate compositions, simultaneously or sequentially, so that both the compound or therapy are simultaneously active in the body. Other therapies may include MAO-B inhibitors such as selegiline, rasagiline, lasabemide, and caloxazone; dopamine agonists such as bromocriptine, cabergoline, rislid, and pergolide; levodopa; carbidopa; inirole; apomorphine, smanilol; rotigotine; talipexole; dihydroergocriptine; or catechol-O-methyltransferase inhibitors such as tolcapone or entacapone. Further therapies may include those administered for ALS, such as riluzole or edaravone.

[0099] Composition of the present invention While the compounds of the present invention can be administered as pure chemical substances for therapeutic use, it is preferable to present the active ingredients as a pharmaceutical composition.

[0100] Therefore, in a further aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0101] Carriers and / or excipients must be "acceptable" in the sense that they are compatible with the other components of the composition and must not be harmful to the recipient.

[0102] Examples of pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including oral and sublingual), or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or those suitable for inhalation or inhalation administration. For this reason, the compounds of the present invention may be in the form of pharmaceutical compositions and their unit dosage forms together with conventional adjuvants, carriers, excipients, or diluents, in which case they may be used as solids such as tablets or filled capsules, or as liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled therein (all for oral use), as suppositories for rectal administration, or as sterile injection solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their unit dosage forms may contain conventional components in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended daily dose range. Preparations containing 10 milligrams, or more broadly 0.1 to 1000 milligrams, of the active ingredient per tablet are reasonably suitable representative unit dosage forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, either the compounds of the present invention or pharmaceutically acceptable salts or derivatives of the compounds of the present invention.

[0103] To prepare a pharmaceutical composition from the compounds of the present invention, the pharmaceutically acceptable carrier may be either solid or liquid. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0104] In powder formulations, the carrier is a finely divided solid, which is present in a mixture with the finely divided active ingredient.

[0105] In tablets, the active ingredient is mixed in a suitable ratio with a carrier having the necessary binding ability and compressed into the desired shape and size.

[0106] Powders and tablets preferably contain 5 or 10 to about 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, and cocoa butter. The term “composition” is intended to include formulations of the active compound having an encapsulating material as a carrier, which provides a capsule in which the active ingredient is surrounded by a carrier and thus associated therewith, with or without the carrier. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0107] To prepare the suppositories, a low-melting-point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active ingredient is uniformly dispersed within it by stirring. Next, the molten, homogeneous mixture is poured into a mold of a convenient size and allowed to solidify by cooling.

[0108] Liquid preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions. For example, a liquid preparation for parenteral injection can be formulated as a solution in an aqueous polyethylene glycol solution.

[0109] Therefore, the compounds according to the present invention may be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume injectors, or multi-dose containers with preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain compounding agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form obtained by sterile isolation of a sterile solid or by lyophilization from a solution for reconstitution using a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0110] An aqueous solution suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners as needed.

[0111] Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water with a viscous material such as natural or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0112] The preparations also include solid forms intended to be converted into liquid preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0113] The solution or suspension is applied directly to the nasal cavity by conventional means, such as a dropper, pipette, or spray. The formulation may be provided in single-dose or multi-dose forms. In the latter case of a dropper or pipette, this can be achieved by administering an appropriate predetermined volume of the solution or suspension to the patient. In the case of a spray, this can be achieved, for example, by a metered spray pump. To improve nasal delivery and retention, the compounds according to the present invention may be encapsulated with cyclodextrin or formulated with a drug expected to enhance delivery and retention in the nasal mucosa.

[0114] Administration to the airways can also be achieved by an aerosol formulation in which the active ingredient is supplied in a pressurized pack with a suitable propellant such as a hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The drug dose may be controlled by providing a metering valve.

[0115] Alternatively, the active ingredient may be provided in the form of a dry powder, for example, a powder mixture of compounds in a suitable powder base such as lactose, starch, starch derivatives, for example, hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP).

[0116] In a simpler form, the powder carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example, in a gelatin capsule or cartridge, or in a blister pack that allows the powder to be administered by an inhaler.

[0117] In formulations intended for administration into the airways, including intranasal formulations, the compounds generally have small particle sizes, for example, 1 to 50 microns or less. Such particle sizes can be obtained by means known in the art, such as micronization.

[0118] If desired, formulations adapted to impart sustained release of the active ingredient may be used.

[0119] The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged composition, and the package may contain distinct amounts of the composition, such as tablets, capsules, and powders, packaged in vials or ampoules. Alternatively, the unit dosage form may be the capsule, tablet, cachet, or lozenge itself, or an appropriate number of any of these in packaged form.

[0120] The present invention will now be described with reference to the following examples illustrating some preferred embodiments of the invention. However, it should be understood that the specifics of the following description of the present invention are not in lieu of the generalities of the preceding description of the present invention. [Examples]

[0121] [Table 1]

[0122] HPLC HPLC was performed using the following columns: Alltech Hypersil BDS C18 5μm and 4.6mm × 150mm, both using a water / ACN eluent containing 0.1% TFA. Two gradient methods, designated as HPLC1 or HPLC2, were used, as detailed in the following protocols. [Table 2]

[0123] The compounds of intermediates I-VII and the compound of formula I, as mentioned in schemes 1, 2, and 3, were prepared using the following generalized method.

[0124] Method A i) Grignard: Magnesium (1.1 eq) was placed in RBF and covered with THF, then iodine crystals were added, followed by a small amount of pure bromoanisole. Alternatively, the mixture was sonicated and heated until Grignard formation began. Once started, the remaining bromoanisole in THF was added, and the resulting mixture was heated under reflux for 0.5 hours. The Grignard solution was cooled to 0°C, and then a suitable nitrile, ester, or amide (0.9 eq) in THF was added dropwise, followed by quenching after 1-2 hours or overnight at 4°C. The reaction was then saturated with NH4Cl. (水溶液)Quenched and extracted with DCM. The combined organic extracts were dried and concentrated under reduced pressure to obtain crude ketones. When nitrile was used, the isolated imine intermediate was suspended / dissolved in ether and concentrated HCl (3:1). This mixture was stirred for 0.5 hours and then in 2M NaOH (水溶液) After neutralization using [method], the mixture was extracted with ELISA. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to obtain crude ketones. The crude ketones were used directly or purified by crystallization or flash chromatography.

[0125] ii) Organolithium: After cooling aryl iodide (1-2 eq) in Et2O or THF to approximately -70°C, n-BuLi in hexane was slowly added to the mixture while maintaining the temperature below -65°C. The resulting solution was stirred for 15 minutes, after which nitrile, ester, or amide (1-2 eq) in Et2O or THF was added. The reactants were left to cool, or, in the case of nitriles, warmed to -10°C over 2 hours, followed by saturated NH4Cl (水溶液) The mixture was quenched and extracted with DCM. The combined extracts were dried, and the solvent was evaporated to obtain crude ketone. When nitrile was used, the imine was treated as described in i) to obtain crude ketone. The crude ketone was used as is, or purified by crystallization or flash chromatography.

[0126] Method B 3-(ethoxymethoxy)pyridine (1 eq) was dissolved in THF and cooled to -78°C. While maintaining the temperature below -78°C, n-BuLi (1 eq) in hexane was added. The reaction mixture was stirred for 0.5 hours, after which an ester or amide (1 eq) dissolved in THF was added while maintaining the temperature below -70°C. While maintaining cooling, the reaction mixture was stirred for 1.5 hours, after which i-PrOH and then saturated NH4Cl were added. (水溶液) The mixture was quenched. After warming the reaction to room temperature, it was extracted with ELISA (three times), dried, and the solvent was evaporated to obtain the crude ketone. The crude ketone was used as is, or purified by crystallization or flash chromatography.

[0127] Method C These methods are based on the methods described in the literature by Deane K. et al., ACS Med. Chem. Lett., 2014, 5, pp. 576-581 and Shi J. et al., ACS Omega, 2017, 2, pp. 3406-3416.

[0128] i) n-BuLi (1.17 eq) in hexane was added to a solution of 2-bromopyridine (1.0 eq) in THF and ether (1:1) at -110°C. The reaction mixture was warmed to -10°C over 0.5 hours. The flask was cooled again to -110°C, and a suspension of ester (1.0 eq) in toluene (1.3 mL / mmol) was added. The reaction mixture was stirred at room temperature for 17 hours, and then saturated with NH4Cl. (水溶液) The mixture was then quenched with water. The mixture was extracted with ELISA (three times), and the combined layers were washed with water and brine, then dried (Na2SO4). After concentration under reduced pressure, the crude product was adsorbed onto SiO2 and purified by flash chromatography.

[0129] ii) 2-bromopyridine (1.0 eq) in THF (5.5 mL / mmol) was added dropwise to a solution of n-BuLi (1.0 eq) in hexane over 1 hour at -78°C. The reaction mixture was stirred at -78°C for another 1 hour, then a concentrated THF solution of ester (1.0 eq) was added, and the reaction mixture was slowly warmed to -20°C and maintained at this temperature for 2 hours, or until the departure of the starting materials was indicated by MS. Once complete, the reaction was drained in 10% HCl. (水溶液) Quench with 2M HCl (水溶液) The pH was adjusted to pH 6 using [a specific method]. The mixture was extracted by DCM (three times), dried, and concentrated under reduced pressure to obtain crude ketone. The crude ketone was used directly or purified by crystallization or flash chromatography.

[0130] Method D Intermediates I, III, IV, VI, or formula IA were deprotected using the standard techniques described in Protective Groups in Organic Synthesis, Green, TW, and Wuts PGM, John Wiley & Sons, New York, 1999. Generally, HBr or BBr3, or hydrogenation where applicable, was used to remove methyl and benzyl ethers. Acetal or Boc groups were removed using HCl, TFA, or TMSOTf.

[0131] i) Ether in 48% HBr (水溶液) The mixture was suspended and heated at 60-130°C for 0.5-5 days. After cooling the reaction mixture, it was concentrated under reduced pressure to obtain a solid. The solid was then converted to saturated NaHCO₃⁻. 3(水溶液) The mixture was treated with HCl and extracted with HCl (three times). The combined organic extracts were washed with brine, dried, and concentrated under reduced pressure to obtain the crude product. Alternatively, the reaction mixture was diluted with water and concentrated with NH4. 3(水溶液) After neutralization (and rebuffering with AcOH if necessary), the sample can be extracted with ethyl acetate. If necessary, the sample was further purified by flash chromatography or crystallization.

[0132] ii) The ether was dissolved in DCM and cooled to 0°C. Boron tribromide (6-12 eq) was added dropwise, and the reaction mixture was warmed to room temperature. The mixture was stirred for 17-48 hours, then MeOH was added and the solvent was evaporated. MeOH was added again and the solvent was evaporated (twice), the residue was dissolved in ethyl acetate, and washed with water (once). The organic extract was dried and concentrated under reduced pressure to obtain the crude product. Further purification may be achieved by polishing, crystallization, or chromatography.

[0133] Method E Using the standard techniques described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, RC. John Wiley & Sons, New York, 2018, intermediate III was converted to IV, or intermediate VI to intermediate VII. Generally, mild oxidizing agents such as SeO2, pyridine, SO3, or des-martin periodinane were used.

[0134] Method F This general methodology is extensively described in the literature and is exemplified by the methodology described by Wu, J. et al. Chem. Commun., 2010, 46, pp3687-3689.

[0135] Intermediate I, II, V, or VII (1.0 eq), aldehyde (1.5–3 eq, excluding intermediate VII), and NH4OAc (5–10 eq) were suspended in AcOH in a sealed vial. The contents were heated at 40–110°C for 16–72 hours, and then cooled. The reaction mixture was poured into ice water, and the product was isolated by filtration or extraction. If necessary, the crude product was further purified by polishing, crystallization, or flash chromatography.

[0136] Method G Hydrogenation was performed by supplying H through a balloon using 10% Pd / C (0.1-1 w / w equivalent). 2(g) The reaction was carried out at room temperature under a specific atmosphere. The starting materials were dissolved or suspended in low MW alcohol, THF, siRNA, or a combination of these solvents. The reaction time ranged from 1 to 48 hours and was usually determined by MS. Upon completion, the reaction catalyst was filtered, the solvent was evaporated to obtain the crude product, which was purified using conventional techniques as needed.

[0137] Method H Boc-cyclic amines were metallized with sec-BuLi using a suitable electrophile under conditions described by either Beak P. et al. J. Org. Chem. 1993, 58, pp1109-1117 or Barker G. et al. Org. Lett. 2010, 12, pp4176-4179.

[0138] Method I CDI (1.1 eq) was added to carboxylic acid (1.5 eq) in THF, and the solution was heated to 50°C. After stirring for 30 minutes, the reaction mixture was cooled to room temperature and then added to a solution / suspension of amine or ammonium salt. The resulting mixture was stirred for 15–72 hours, after which the reaction mixture was diluted with water and extracted with HCl (three times). Subsequently, HCl was added to 10% HCl. (水溶液) Extraction was performed (twice), and the resulting aqueous extract was saturated with NaHCO3 3(水溶液) After neutralization, the solution was extracted again with pharmaceutically acceptable solvent (three times). The combined extract was dried, the solvent evaporated, and the crude product was obtained, which was used directly or purified using standard techniques.

[0139] Method J Two equivalents of CDI were added to two equal parts of salicylic acid in one mL of 1,4-dioxane, and the mixture was heated to 50°C. After stirring for 30 minutes, the reaction was cooled to obtain the acylated solution.

[0140] Simultaneously, Boc-amine (1 eq) in 1,4-dioxane was treated with HCl in 1,4-dioxane, and the solution was stirred at room temperature. After about 30 minutes, Et2O, hexane, or a mixture was added to aid in the precipitation of the HCl salt. The solvent was decanted, and the hygroscopic solid was washed with Et2O or filtered and washed with Et2O (3 times), then briefly dried under vacuum and resuspended in 1,4-dioxane. In the case of the pyrrolidine salt, this suspension was added to the cooled acylation solution, while the acylation solution was added to the cooled azepane salt solution. The reaction mixture was stirred overnight, after which the sample was diluted with water and extracted with ethyl acetate (3 times). The combined extract was passed through an SiO2 plug for elution with ethyl acetate, and the solution was evaporated to obtain the crude acylated amine. After confirming the target by MS, the material was used without further processing. The crude product was mostly a mixture of targets, each containing a diacylated target, presumably with acylation occurring at the phenol. This acyl group was removed under the conditions used in the next step.

[0141] Synthesis of selected starting materials and condensation precursors Synthesis of substituted benzaldehydes 2-Hydroxy-3-(morpholinomethyl)benzaldehyde [ka] Morpholine (10.7 g, 12.2 mmol) was added to a solution of salicylaldehyde (10.0 g, 0.08 mol) and paraformaldehyde (3.7 g, 12.2 mmol) in EtOH (80 mL), and the mixture was heated under reflux for 17 hours. The reaction mixture was cooled and concentrated under reduced pressure, after which the residue was redissolved in DCM and dried (Na2SO4). Upon further concentration, an orange oily substance was obtained, which was packed into silica (5 g). This product (two batches) was purified by column chromatography (silica, 40 g) using hexane (3 CV) followed by elution with 0 to 40% siRNA in hexane to obtain 2-hydroxy-3-(morpholinomethyl)benzaldehyde (total yield 1.00 g, 6%). MS: m / z (MH) + )222.11. 1H NMR(CDCl3,600MHz)δ 10.22(1H,s),7.60(1H,dd,J 1.8,7.8Hz),7.37(1H,d,J 7.2Hz),6.91(1H,t,7.2Hz),3.75(4H,t,J 4.8Hz),3.68(2H,s),2.57(4H,s).

[0142] Synthesis of 2-hydroxy-3-(2-morpholinoethyl)benzaldehyde [ka] 2-(2-methoxyphenyl)-1-morpholinoethanone 2-(2-methoxyphenyl)acetic acid (10.0 g, 0.06 mol) was dissolved in DCM (78 mL), and thionyl chloride (10.7 g, 0.09 mol) and DMF (0.04 g, 0.6 mol) were added. The reaction mixture was stirred under argon at room temperature for 17 hours, and then concentrated under reduced pressure to obtain yellow, oily 2-(2-methoxyphenyl)acetyl chloride. Acid chloride (2.0 g, 11.0 mmol) was diluted in DCM (44 mL) and cooled to 0°C. Morpholine (2.8 g, 0.03 mol) was diluted in DCM (27 mL), added dropwise to the cooled solution, and left at 0°C for 15 minutes. The reaction mixture was then stirred at room temperature for 5.5 hours, or until one spot was shown by TLC. A 10% aqueous solution of HCl (20 mL) was added to the reaction mixture, and the DCM layer was removed. The aqueous solution was extracted again with DCM (20 mL x 2), and the combined organic layer was washed with brine (20 mL) and dried (Na2SO4). Upon concentration, a yellow, oily 2-(2-methoxyphenyl)-1-morpholinoethanone was obtained (2.58 g, 100%). 1 H NMR(CDCl3,600MHz)δ 7-24-7.21(2H,m),6.90(1H,td,0.6,7.2Hz),6.85(1H,d,J 8.4Hz),3.81(3H,s),3.68(2H,s),3.63(4H,bs),3.51(2H,bs),3.45(2H,bs).

[0143] 4-(2-methoxyphenethyl)morpholine 2.87 g, 12.0 mmol of 2-(2-methoxyphenyl)-1-morpholinoethanone in 24 mL of THF was added dropwise to a suspension of LiAlH4 (0.65 g, 17.0 mmol) in 18 mL of THF at room temperature. The reaction was stirred for 2 hours and then cooled to approximately 0°C. The reaction was quenched by carefully adding a 2 M aqueous solution of NaOH. The reaction was filtered through Celite, washed with ether (4 times), and the filtrate was dried (Na2SO4). Concentration under reduced pressure yielded a yellow, oily 4-(2-methoxyphenethyl)morpholine (2.15 g, 81%). 1 H NMR(CDCl3,600MHz)δ 7.16(1H,td,J 1.8,7.8Hz),7.13(1H,d,1.0,7.8Hz),6.89(1H,t,J 7.8Hz),6.83(1H,d,J 7.8Hz),3.80(3H,s),3.75(2H,s),3.74(2H,s),2.81(2H,m),2.56-2.54(6H,m).

[0144] 2-(2-morpholinoethyl)phenol 4-(2-methoxyphenethyl)morpholine (2.15 g, 9.70 mmol) was heated in 1 mL of 48% HBr aqueous solution at 120°C for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made basic by adding an aqueous solution of NaHCO3. The aqueous mixture was extracted with DCM (50 mL x 3). The extracts were combined, washed with brine (5 mL), dried, and concentrated to obtain red solid / oily 2-(2-morpholinoethyl)phenol (1.90 g, 95%). 1 H NMR(CDCl3,600MHz)δ 7.12(1H,td,J 1.8,8.4Hz),6.98(1H,dd,1.2,7.2Hz),6.87(1H,dd,J 1.2,8.4Hz),6.74(1H,td,J 1.2,7.2Hz),3.82(4H,t,J 4.2Hz),2.84(2H,t,J 4.8Hz),2.73(6H,m).

[0145] 2-Hydroxy-3-(2-morpholinoethyl)benzaldehyde 2-(2-morpholinoethyl)phenol (1.90 g, 9.20 mmol) was dissolved in MeCN (6 mL), and triethylamine (4.8 mL, 0.25 mol) was added. Paraformaldehyde (1.86 g, 0.06 mol) and magnesium chloride (1.77 g, 18.0 mmol) were added, and the reaction mixture was heated under argon for 17 hours under reflux. After cooling the reaction mixture, it was diluted with 0.1 M sodium / potassium tartrate aqueous solution (100 mL). The mixture was extracted with DCM (20 mL x 3), washed with brine (20 mL), dried, and concentrated to obtain brown oily 2-hydroxy-3-(2-morpholinoethyl)benzaldehyde, which was used in the next step without further purification (1.01 g, 47%). 1 H NMR(CDCl3,600MHz)δ 11.95(1H,bs),10.05(1H,s),7.48(1H,d,J 7.8Hz),7.36(1H,d,6.6Hz),6.90(1H,t,J 7.2Hz),3.79(4H,bs),2.91(2H,s),2.45(6H,m).MS:m / z(MH + )236.13.

[0146] Synthesis of 3-(2-(diethylamino)ethyl)-2-hydroxybenzaldehyde The procedure for the synthesis of 2-hydroxy-3-(2-morpholinoethyl)benzaldehyde was used with diethylamine to obtain 3-(2-(diethylamino)ethyl)-2-hydroxybenzaldehyde as a yellow solid (2.92 g, 26%). 1 H NMR(CDCl3,600MHz)δ 10.31(1H,bs),7.55(1H,dd,J 1.8,7.8Hz),7.26(1H,d,6.6Hz),6.79(1H,t,J 7.2Hz),2.89(2H,bs),2.81-2.77(6H,m),1.16(6H,t,J 6.6Hz).MS:m / z(MH + )222.15.

[0147] Synthesis of 2-hydroxy-3-(2-(4-methylpiperazine-1-yl)ethyl)benzaldehyde The procedure for the synthesis of 2-hydroxy-3-(2-morpholinoethyl)benzaldehyde was used together with 1-methylpiperazine to obtain 2-hydroxy-3-(2-(4-methylpiperazine-1-yl)ethyl)benzaldehyde as a brown, rubbery solid (0.22 g, 14%). 1 H NMR(CDCl3,600MHz)δ 10.20(1H,s),7.51(1H,dd,J 1.2,7.2Hz),7.30(1H,dd,J 1.2,7.8Hz),6.84(1H,t,7.8Hz),2.86(2H,t,6.6Hz),2.69-2.40(10H,m),2.32(3H,s).MS:m / z(MH + )249.16.

[0148] Synthesis of 2-hydroxy-3-(2-(pyrrolidine-1-yl)ethyl)benzaldehyde The procedure for the synthesis of 2-hydroxy-3-(2-morpholinoethyl)benzaldehyde was used together with pyrrolidine to obtain 2-hydroxy-3-(2-(pyrrolidine-1-yl)ethyl)benzaldehyde (0.22 g, 7%). 1 H NMR(CDCl3,600MHz)δ 11.50(1H,bs),10.30(1H,s),7.55(1H,d,J 7.8Hz),7.24(1H,d,J 7.2Hz),6.77(1H,t,7.2Hz),2.87(2H,d,5.4Hz),2.82(2H,d,5.4Hz),2.77(4H,bs),1.89(4H,bs).MS:m / z(MH + )220.13.

[0149] Synthesis of 2-hydroxy-3-(3-morpholinopropyl)benzaldehyde Based on the methodology of Fumitaka, I, Hiroki K, and Asata M, WO03064425(A1), 2003. [ka]

[0150] (E)-3-(2-methoxyphenyl)acrylic acid A well-stirred solution of 2-methoxybenzaldehyde (10.9 g, 0.08 mol), malonic acid (19.7 g, 0.16 mol), piperidine (3.1 g, 0.04 mol), and pyridine (100 ml) was heated at 80-90°C for 2.5 hours, and then stirred overnight at room temperature. The reaction mixture was poured into a 3 M aqueous solution of HCl in ice water (700 mL) and stirred. After filtering off the precipitate, it was resuspended in cold water (500 mL) and stirred for 10 minutes. After filtration, the solid was washed with water, hexane, and ether to obtain a white solid, which was dried under reduced pressure (11.6 g, 81%). 1 H NMR(d6-acetone,600MHz)δ 7.98(1H,d,J 16.2Hz),7.65(1H,dd,1.8,7.8Hz),7.39(1H,td,J 1.8,7.8Hz),7.07(1H,d,J 8.4Hz),6.98(1H,t,J 7.8Hz),6.53(1H,d,J 16.2Hz),3.92(3H,s).

[0151] 3-(2-methoxyphenyl)propanoic acid (E)-3-(2-methoxyphenyl)acrylic acid (11.6 g, 0.07 mol) was reduced in EtOH (500 mL) using 10% Pd-C (1.5 g) according to general method G. A yellowish-white solid was isolated, which did not require further purification (11.4 g, quantitative yield). 1 H NMR(CDCl3,600MHz)δ 7.19(1H,td,J 1.2,7.8Hz),7.15(1H,dd,1.2,7.2Hz),6.87(1H,dd,1.2,7.8Hz),6.84(1H,d,8.4Hz),3.01(3H,s),2.94(2H,t,7.8Hz),2.65(2H,t,7.8Hz).

[0152] 3-(2-methoxyphenyl)propan-1-ol 3-(2-methoxyphenyl)propanoic acid (11.4 g, 0.0 mol) dissolved in ether (126 mL) was slowly added at room temperature to a suspension of LiAlH4 (6.0 g, 0.16 mol) in ether (190 mL). The reaction mixture was heated under reflux overnight, then cooled to room temperature, and subsequently quenched with water (100 mL). The reaction mixture was filtered through a Celite pad while washing with water (20 mL) and HCl (200 mL). The HCl layer was removed, and the aqueous layer was extracted with additional HCl (100 mL x 2). The HCl layer was washed with brine (100 mL) and dried (Na2SO4). Upon concentration, a yellow / brown oily substance was obtained (5.1 g). The Celite pad was washed again with water (100 mL) and DCM (200 mL), and the aqueous layer was extracted with additional DCM (20 mL x 3) to obtain an additional product (1.61 g). Total yield (6.71g, 67%). 1 H NMR(CDCl3,600MHz)δ 7.18(1H,t,J 7.8Hz),7.14(1H,d,J 6.6Hz),6.89(1H,t,J 7.2Hz),6.85(1H,d,J 7.8Hz),3.82(3H,s),3.60(2H,t,J 6.0Hz),2.71(2H,t,J 7.2Hz),1.90(1H,bs),1.84(2H,t,J 6.6Hz).

[0153] 1-(3-bromopropyl)-2-methoxybenzene 3-(2-methoxyphenyl)propan-1-ol (1.6 g, 9.7 mmol) was dissolved in DCM (43 mL), and triphenylphosphine (2.7 g, 0.01 mol) was added. The solution was cooled in an ice bath, and bromine (1.6 g, 0.01 mol) was added dropwise over 4 hours, during which time the reaction mixture was maintained at 0-5°C. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (15 mL), the DCM layer was removed, and the aqueous layer was extracted with additional DCM (50 mL x 3). The combined organic layers were dried (Na2SO4) and concentrated to obtain a yellow solid. The solid was packed into silica (1 g) and purified by chromatography (silica, 24 g) using elution with hexane (3 CV), hexane (40 CV) at 0-100% HCl, and HCl(CV). A clear oily substance was obtained (1.81 g, 81%).1 H NMR(CDCl3,600MHz)δ 7.19(1H,td,J 1.8,7.8Hz),7.14(1H,dd,J 1.2,7.2Hz),6.87(1H,td,J 0.6,7.2Hz),6.84(1H,d,J 8.4Hz),8.31(3H,s),3.39(2H,t,J 6.6Hz),2.75(2H,t,J 7.2Hz),2.13(2H,t,J 7.2Hz).

[0154] 4-(3-(2-methoxyphenyl)propyl)morpholine 1-(3-bromopropyl)-2-methoxybenzene (1.8 g, 7.9 mmol), potassium carbonate (2.17 g, 16.0 mmol), and morpholine (1.1 g, 0.01 mol) were heated under reflux in ACN (4 mL) for 17 hours. After concentrating the reaction mixture, it was resuspended in SiO2 (50 mL) and washed with a 10% aqueous solution of HCl (50 mL). The aqueous layer was made basic with a 2 M aqueous solution of NaOH and extracted with DCM (20 mL x 3). The combined organic layers were dried (Na2SO4), concentrated to obtain an oily substance, which was packed into silica (2 g). Purification by chromatography (silica, 12 g) using elution with 0 to 100% SiO2 in hexane (30 CV) yielded a colorless oily substance (0.88 g, 48%). 1 H NMR(CDCl3,500MHz)δ7.18(1H,td,J 1.5,7.5Hz),7.13(1H,d,J 7.5Hz),6,88(1H,td,J 0.5,7.0Hz),6.84(1H,d,J 8.5Hz),3.82(3H,s),3.72(4H,m),2.64(2H,t,J 8.0Hz),2.45(4H,bs),2.38(2H,m),1.78(2H,m).

[0155] 2-(3-morpholinopropyl)phenol 4-(3-(2-methoxyphenyl)propyl)morpholine (0.88 g, 3.73 mmol) was diluted with a 48% aqueous solution of HBr (7 mL) and heated at 120°C for 17 hours. After concentrating the reaction product, a saturated aqueous solution of NaHCO3 was added to the residue (pH 10-12). The solution was extracted with SiO4 (50 mL), the pH of the aqueous solution was adjusted to pH 9, and the solution was extracted again with SiO4 (2 mL x 2). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and concentrated to obtain a reddish oily substance (0.73 g, 93%). 1 H NMR(CDCl3,500MHz)δ 7.12(1H,td,J 2.0,7.0Hz),7.07(1H,dd,J 1.5,7.5Hz),6.88(1H,d,J 7.5Hz),6.84(1H,td,J 1.5Hz,7.5Hz),3.84(4H,bs),2.69(2H,t,J 6.0Hz),2.53(4H,bs),2.31(2H,t,4.5Hz),1.89(2H,t,6.0Hz).

[0156] 2-Hydroxy-3-(3-morpholinopropyl)benzaldehyde 2-(3-morpholinopropyl)phenol (0.73 g, 3.3 mmol) was diluted in ACN (33 mL), and triethylamine (1.0 g, 9.9 mmol), magnesium chloride (0.63 g, 6.6 mmol), and finally paraformaldehyde (0.50 g, 16.0 mmol) were added. The reaction mixture was heated under reflux for 17 hours, cooled, and then concentrated under reduced pressure. 10% aqueous solutions of HCl (50 mL) and DCM (50 mL) were added, and the DCM layer was removed. The aqueous layer was thoroughly extracted with DCM (30 mL x 3) and siRNA (30 mL x 3). The combined organic layers were washed with saturated aqueous solution of NaHCO3 (20 mL), dried, and concentrated to obtain a yellow, rubbery substance (0.68 g, 83%). 1H NMR(CDCl3,500MHz)δ 9.98(1H,s),7.45(1H,dd,J 1.5,8.0Hz),7.39(1H,dd,1.0,7.0Hz),6.95(1H,t,J 8.0Hz),3.78-3.77(4H,m),2.73-2.68(2H,m),2.52(4H,bs),2.46-2.38(2H,m),1.91-1.85(2H,m).MS:m / z(MH + )250.14.

[0157] Synthesis of 3-(3-(diethylamino)propyl)-2-hydroxybenzaldehyde The procedure for the synthesis of 2-hydroxy-3-(3-morpholinopropyl)benzaldehyde was used with diethylamine to obtain 3-(3-(diethylamino)propyl)-2-hydroxybenzaldehyde (1.17 g, 78%) as a rubbery solid. MS: m / z (MH) + )236.16.

[0158] Synthesis of 2-hydroxy-4-(morpholinomethyl)benzaldehyde 3-(morpholinomethyl)phenol (1.60 g, 8.3 mmol) was diluted in ACN (42 mL), and triethylamine (4.2 g, 0.04 mol), magnesium chloride (1.6 g, 16.5 mmol), and finally paraformaldehyde (2.5 g, 0.08 mmol) were added. The reaction was carried out according to the method for 2-hydroxy-3-(3-morpholinopropyl)benzaldehyde, except that the pH of the aqueous solution was adjusted to pH 7 using a 2 M aqueous solution of NaOH for the initial extraction. A yellow oily substance was obtained (1.32 g, 72%). 1 H NMR(CDCl3,500MHz)δ 11.04(1H,s),9.87(1H,s),7.51(1H,d,J 8.0Hz),7.02(2H,m),3.73(4H,m),3.51(2H,s),2.45(4H,t,J 4.5Hz).

[0159] Synthesis of ketone precursors (2-methoxypyridine-3-yl)(pyridine-2-yl)methanone [ka] Ketones were formed using 2-bromopyridine (1.86 g, 11.7 mmol) in THF (50 mL) and 2.37 M n-BuLi in hexane (5.0 mL, 11.7 mmol), followed by methyl 2-methoxynicotinate (1.8 g, 11.7 mmol) in THF (3 mL), according to general method C(ii). The green solid was used without any further purification (1.86 g, 74%). 1 H NMR(CDCl3,600MHz)δ 8.62(1H,dq,J 1.2,5.4Hz),8.31(1H,dd,J 1.8,4.8Hz),8.01(1H,dd,J 1.2,7.8Hz),7.86(2H,dd,J 1.8,7.2Hz),7.44(1H,dddd,J 1.2,4.2,7.2,12.0Hz),6.99(1H,dd,J 5.4,7.2Hz),3.81(3H,s).MS:m / z(MH + )215.08.

[0160] (3-hydroxypyridine-4-yl)(pyridine-2-yl)methanone [ka] (3-methoxypyridine-4-yl)(pyridine-2-yl)methanone Ketones were formed according to general method C(i) using 2-bromopyridine (0.56 g, 3.5 mmol) in THF (4 mL) and ether (4 mL), followed by a 2.28 M n-BuLi solution in hexane (1.8 mL, 4.1 mmol), and then methyl 3-methoxyisonicotinate (0.59 g, 3.5 mmol). The brown, rubbery substance was dry-packed into silica and purified by chromatography (silica, 12 g) eluting with 0 to 100% siRNA in hexane over 50 CV. The desired product was finally eluted from the column to obtain a pale yellow solid (0.30 g, 42%). 1H NMR(CDCl3,600MHz)δ 8.63(1H,dd,J 0.6,4.8Hz),8.43(1H,s),8.39(1H,d,J 4.8Hz),8.09(1H,d,J 7.8Hz),7.89(1H,td,J 1.2,7.8Hz),7.47(1H,dd,J 4.8,7.8Hz),7.31(1H,d,J 4.8Hz),3.79(3H,s).

[0161] (3-hydroxypyridine-4-yl)(pyridine-2-yl)methanone (3-methoxypyridine-4-yl)(pyridine-2-yl)methanone (0.30 g, 1.4 mmol) was reacted with a concentrated aqueous solution of HBr (4 mL) according to general method D(i) and heated for 48 hours. A yellow solid was obtained (0.24 g, 86%). 1 H NMR(d6-DMSO,600MHz)δ 13.7(1H,bs),8.72(1H,ddd,J 1.2,1.8,5.4Hz),8.57(1H,d,J 1.8Hz),8.23(1H,dt,J 0.6,7.8Hz),8.21(1H,dd,J1.8,5.4Hz),8.06(1H,td,J 1.8,7.8Hz),7.96(1H,dd,J 1.2,5.4Hz),7.67(1H,td,J 4.8,7.2Hz).

[0162] (4-methoxypyridine-3-yl)(pyridine-2-yl)methanone [ka] 2-bromopyridine (0.87 g, 5.5 mmol), methyl 4-methoxynicotinate (0.92 g, 5.5 mmol) diluted in THF (2 mL), and a 2.37 M solution of n-butyllithium in hexane (2.3 mL, 5.5 mmol) were reacted in THF (25 mL) according to general method C(ii). A light brown, rubbery solid was obtained (0.78 g, 67%), which was used in the next step without further purification. 1H NMR(CDCl3,600MHz)δ8.62(1H,dq,J 0.6,4.8Hz),8.61(1H,s),8.60(1H,d,J 6.0Hz),8.05(1H,td,J 1.2,7.8Hz),7.87(1H,td,J 1.2,7.8Hz),7.45(1H,dddd,J 1.2,4.8,7.8,12.0Hz),6.90(1H,d,J 5.4Hz),3.75(3H,s).MS:m / z(MH + )215.08.

[0163] (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone [ka] The compound was prepared using general method A ii) with 3-(benzyloxy)-2-iodo-6-methylpyridine (130 mg), picolinonitrile containing THF as a solvent (390 mg), and 2.27 M n-BuLi in hexane (1.94 mL). The crude product was purified with 12 g of SiO2 using an siRNA / hexane gradient of 0 to 0% 3 CV and 0 to 100% 30 CV. The product fractions were combined and evaporated to obtain an oily title compound, which was slowly solidified (456 mg) and used without further processing. 1 H NMR(CDCl3,600MHz)δ 8.63(1H,d,J 4.2Hz),8.12(1H,d,J 7.8Hz),7.84(1H,t,J 7.8Hz),7.42(1H,dd,J 4.7,7.4Hz),7.27-7.18(5H,m),7.07-7.03(2H,m),4.99(2H,s),2.55(3H,s).

[0164] (2-Hydroxyphenyl)(pyridine-2-yl)methanone [ka] (2-Methoxyphenyl)(pyridine-2-yl)methanone This compound was prepared according to general method A(i) from 2-bromoanisole (6.0 g, 32 mmol), 2-pyridylcarbonite (3.0 g, 29 mmol), and magnesium (0.86 g, 35 mmol). The title compound was isolated as a pale yellow crystalline substance (1.76 g, 26%). 1 H NMR(d6-DMSO,600MHz)δ 8.63(1H,d,J 3.6Hz),7.97(1H,d,J 7.8Hz),7.84(1H,t,J 7.8Hz),7.52(1H,d,J 7.2Hz),7.47(1H,d,J 7.8Hz),7.41(1H,t,J 4.8Hz),7.04(1H,t,J 7.2Hz),7.96(1H,d,J 8.4Hz),3.64(3H,s).

[0165] (2-Hydroxyphenyl)(pyridine-2-yl)methanone (2-methoxyphenyl)(pyridine-2-yl)methanone (0.15 g, 0.7 mmol) was prepared according to general method D(i) and HBr (水溶液) The mixture was reacted with (12 mL) and stirred for 17 hours. The title compound was isolated as a brown oily substance (0.11 g, 78%). 1 H NMR(d6-DMSO,600MHz)δ 10.90(1H,bs),8.65(1H,d,J 4.8Hz),8.02(1H,t,J 7.8Hz),7.90(1H,d,J 7.8Hz),7.61(2H,d,J 7.8Hz),7.44(1H,t,J 7.2Hz),6.88-6.93(2H,m).

[0166] 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate tert-butyl and 2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-carboxylate tert-butyl [ka] 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate tert-butyl 4 g of pyrrolidine-1-carboxylate tert-butyl was dissolved in 35 mL of Et2O, cooled to -78°C, and treated with 3.3 mL of distilled TMEDA. 17.2 mL of 1.28 M s-BuLi was added, while maintaining the temperature below -78°C. Once complete, the reaction mixture was stirred at this temperature for 30 minutes, and then 4.0 g of 2-carboxy-3-benzyloxy-6-methylpyridine in 100 mL of Et2O was added while maintaining the temperature below -78°C again. The reaction was continued for a further 1.5 hours while warming the reaction mixture to approximately -60°C. The reaction mixture was then saturated with NH4Cl. (水溶液) The sample was quenched, warmed to room temperature, and then extracted with Et2O (3 times). The combined extract was dried, and the solvent was evaporated to obtain the crude product (8.66 g). After adsorbing the sample onto SiO2, it was purified with 40 g of SiO2 (254 / 280 nm) using an siRNA / hexane gradient of 0 to 0% 3 CV, 0 to 25% 20 CV, and 25 to 50% 10 CV to obtain the title compound as a mixture of diastereomers and rotational isomers (3.41 g, m / z (MH)). + 399.23) This was used without any further processing.

[0167] 2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-carboxylate tert-butyl 1.04 g of 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate tert-butyl was dissolved in 15 mL of DCM, and 2.44 g of Des-Martin periodinane was slowly added. The reaction mixture was stirred at room temperature for 22 hours, then diluted with water (approximately 10 mL) and stirred for 10 minutes. The resulting precipitate was filtered, and the DCM layer was separated. The DCM extract was treated with 2 M NaOH (水溶液) (Twice), then saturated NaHCO₃ 3(水溶液)The mixture was further washed. The combined extracts were dried, and the solvent was evaporated to obtain the crude product. The crude product was adsorbed onto SiO2 and purified using a 12 g SiO2 column (254 / 280 nm) with an siRNA / hexane gradient of 0 to 0% 3 CV and 0 to 50% 30 CV. The fractions containing the product were combined and evaporated to obtain the oily title compound, which was allowed to stand for a long time to solidify and obtain a waxy solid (805 mg). NMR showed that the product was a mixture of rotational isomers in a 3:2 ratio. Unless otherwise specified, the peaks point to both rotational isomers. 1 ¹H NMR (CDCl3, 500MHz) δ 7.49-7.44 (2H,m), 7.44-7.26 (3H,m), 7.23-7.14 (2H,m), 5.63 (1H minor rotational isomer,dd,J 8.9, 3.1Hz), 5.41 (1H major,dd,J 8.9, 4.5Hz), 5.17 (1H minor,d not decomposed), 5.16 (2H major,s), 5.14 (1H minor,d,J 12.6Hz), 3.67-3.59 (2H,m), 3.55-3.50 (2H,m), 2.50 (3H major,s), 2.48 (3H minor,s), 2.33-2.23 (2H major,m), 2.05-1.80 (2H major, 4H minor,m), 1.45 (9H minor,s), 1.27 (9H major,s); m / z (MH) + )397.21.

[0168] 2-(2-methoxynicotinoyl)pyrrolidine-1-carboxylate tert-butyl [ka] Pyrrolidine-1-carboxylate tert-butyl (1.5 mmol, 0.26 g) was diluted with THF (10 mL) and cooled to -40°C. sec-BuLi was added dropwise to this solution, and the reaction was maintained at -40°C for 5 minutes. Then, methyl 2-methoxynicotinate (3.0 mmol, 0.50 g) in THF (2 mL) was added. The reaction was stirred at -40°C for 10 minutes, and then warmed to room temperature over 15 minutes. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with DCM (15 mL x 3). The combined organic extracts were dried (Na2SO4) and then concentrated under reduced pressure to obtain a clear oily substance. The oily substance was packed into silica and purified by chromatography (silica, 12 g) using hexane (3 CV), followed by elution with 0 to 50% siRNA in hexane (40 CV), and then 50 to 80% siRNA in hexane (15 CV). The product was the last to exit the column and was isolated as a clear, rubbery substance (0.20 g, 43%). The title compound appeared as a 1.1 (major):1 (minor) mixture of rotational isomers. Unless otherwise specified, peaks refer to both rotational isomers. 1 ¹H NMR (CDCl3, 500MHz) δ 8.29 (1H major, dd, J 1.5, 5.9Hz), 8.28 (1H minor, dd, J 2.0, 4.5Hz), 8.19 (1H minor, dd J 2.0, 4.5Hz), 8.11 (1H major, dd J 2.0, 7.5Hz), 7.01-6.95 (1H major, 1H minor, m), 5.29 (1H minor, dd, J 3.0, 9.0Hz), 5.21 (1H major, dd, J 3.5, 9.0Hz), 4.04 (3H major, s), 4.02 (3H minor, s), 3.66-3.56 (2H minor, m), 3.48-3.41 (2H major, m), 2.30-2.24 (2H minor, m), 1.95-1.92 (2H major, m), 1.91-1.86 (2H, m), 1.45 (9H major, s), 1.26 (9H minor, s). MS: m / z (MH) + )307.16.

[0169] 2-(3-(benzyloxy)-6-methylpicolinoyl)azepan-1-carboxylate tert-butyl [ka] 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)azepan-1-carboxylate tert-butyl The general method H was used according to Beak, P. et al., in which 2.6 g of tert-butyl azepane-1-carboxylate was dissolved in 20 mL of Et2O, cooled to -78°C, treated with 1.9 mL of distilled TMEDA, and then 10.2 mL of 1.28 M sec-BuLi was added, while maintaining the temperature below -78°C. After completion, the reaction mixture was stirred and warmed to -40°C for about 1.5 hours. The reaction mixture was cooled, and 2.3 g of 2-carboxy-3-benzyloxy-6-methylpyridine in 50 mL of Et2O (dissolved in a dropping funnel by gently heating) was prepared and added to the reaction mixture while maintaining the temperature below -78°C. The reaction was continued for another hour, and the temperature was raised to about -60°C. The reaction mixture was then saturated with NH4Cl. (水溶液) The sample was quenched, warmed to room temperature, and then extracted with Et2O (3 times). The combined extract was dried, and the solvent was evaporated to obtain crude alcohol. After adsorbing the sample onto SiO2, it was purified with 40 g of SiO2 (254 / 280 nm) using an siRNA / hexane gradient of 0 to 0% 2 CV and 0 to 25% 30 CV. The fraction containing the target clump was identified by MS, and together the diastereomer and rotational isomer mixture was obtained to obtain the title compound (898 mg, m / z (MH)). + (427.26) This was used without any further processing.

[0170] 2-(3-(benzyloxy)-6-methylpicolinoyl)azepan-1-carboxylate tert-butyl 1.04 g of 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)azepan-1-carboxylate tert-butyl was dissolved in 15 mL of DCM, and 2.44 g of DMP was slowly added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with water (approximately 10 mL) and stirred for 10 minutes. The resulting precipitate was filtered to separate the DCM. The DCM extract was then mixed with 2 M NaOH (水溶液) Then saturated NaHCO₃ 3(水溶液)The mixture was washed. The combined extracts were dried, and the solvent was evaporated to obtain the crude ketone. The crude product was adsorbed onto SiO2 and purified using a 12 g SiO2 column (254 / 280 nm) with an siRNA / hexane gradient of 0 to 0% 3 CV and 0 to 50% 30 CV. The fractions containing the product were combined and evaporated to obtain the oily title compound, which was allowed to stand for a long time to solidify, yielding a waxy solid as a 1.4:1 mixture of rotational isomers (676 mg). Unless otherwise specified, the peaks refer to both rotational isomers. 1 ¹H NMR (CDCl3, 500MHz) δ 7.45-7.41 (2H,m), 7.40-7.26 (3H,m), 7.22 (1H major,d,J 8.5Hz), 7.18 (1H minor,d,J 8.5Hz), 7.15 (1H major,d,J 8.6Hz), 7.12 (1H minor,d,J 8.5Hz), 5.78 (1H minor,dd,J 6.4,12.1Hz), 5.39 (1H major,dd,J 5.1,11.8Hz), 5.17 (1H minor,d,J 12.7Hz), 5.15 (1H minor,d unresolved), 5.15 (1H major,d unresolved), 5.13 (1H major,d,J 13.0Hz), 3.94-3.85 (1H minor, m), 3.22 (1H major, dd, J 10.4, 14.0Hz), 3.07 (1H minor, ddd, J 1.6, 11.6, 14.8Hz), 2.49 (3H major, s), 2.48 (3H minor, s), 2.44 (1H minor, m), 2.23-2.16 (1H major, m), 1.86-1.67 (4H, m), 1.59-1.42 (3H, m), 1.43 (9H minor, s), 1.27 (9H major, s).

[0171] Synthesis of the compound of formula I 2-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(1) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)phenol The title compound was prepared using general method F with 2-hydroxybenazaldehyde (39 μL), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) suspended in AcOH (0.5 mL), while heating the reaction mixture at 40°C for 40 hours. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 75% 30 CV IgG / hexane gradient of 0. The desired fractions were combined and evaporated to obtain the title compound (50 mg). 1 H NMR(CDCl3,600MHz)δ 12.5(1H,bs),8.56(1H,d,J 7.2Hz),8.43(1H,d,J 9.2Hz),7.80(1H,dd,J 1.0,7.7Hz),7.44(2H,bd,J 7.3Hz),7.33-7.28(3H,m),7.28-7.23(1H,m),7.20(1H,d,J 8.4Hz),7.16(1H,d,J 8.1Hz),7.00(1H,t,J 7.5Hz),6.95(1H,d,J 8.4Hz),6.91(1H,dd,J 6.6,8.9Hz),6.74(1H,t,J 6.9Hz), 5.27(2H,s), 2.56(3H,s).

[0172] 2-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(1) The title compound was prepared using general method G, with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)phenol (48 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a yellowish-brown solid (26 mg). R 4.64 minutes (HPLC1); 1H NMR(d6-acetone,600MHz)δ 7.44(1H,dd,J 1.5,7.4Hz),7.39-7.31(1H,m),7.10-7.04(1H,bs),7.05(1H,d,8.2Hz),6.99(1H,t,7.4Hz),6.89(1H,d,8 m / z(MH + )322.16,(MH2 2+ )161.58.

[0173] 2-(3-(3-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(2) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-6-fluorophenol The title compound was prepared using the general method F, with 3-fluoro-2-hydroxybenzaldehyde (68 mg), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) suspended in AcOH (0.5 mL), while heating the reaction mixture at 40°C for 40 hours. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 75% 30 CV IgG / hexane gradient of 0. The desired fractions were combined and evaporated to obtain the title compound (40 mg). 1 H NMR(CDCl3,600MHz)δ 13.0(1H,vbs),8.57(1H,d,J 7.2Hz),8.50(1H,d,J 9.2Hz),7.60(1H,d,J 7.9Hz),7.43(2H,d,J 7.3Hz),7.34-7.29(2H,m),7.28-7.24(1H,m),7.21(1H,d,J 8.4Hz),7.13(1H,t,9.4Hz),6.99-6.89(3H,m),6.80(1H,t,J 6.7Hz),5.30(2H,s),2.57(3H,s).

[0174] 2-(3-(3-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(2) The title compound was prepared using general method F with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-6-fluorophenol (41 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a beige solid (24 mg). R 4.74 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 7.29-7.25(2H,m),7.05(1H,d,8.2Hz),6.98(1H,dt m / z(MH) + )340.15,(MH2 2+ )170.58.

[0175] 2-(3-(5-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(3) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-4-fluorophenol The title compound was prepared using a general method H with 5-fluoro-2-hydroxybenzaldehyde (54 mg), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) suspended in AcOH (0.5 mL), while heating the reaction mixture at 40°C for 40 hours. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 75% 30 CV HCl gradient. The desired fractions were combined and evaporated to obtain the title compound (48 mg). 1H NMR(CDCl3,600MHz)δ 12.4(1H,vbs),8.53(1H,d,J 7.2Hz),8.46(1H,d,J 9.2Hz),7.50(1H,dd,J 2.9,9.5Hz),7.43(2H,d,J 7.3Hz),7.33-7.28(2H,m),7.28-7.24(1H,m),7.22(1H,d,J 8.4Hz),7.08(1H,dd,J 5.0,8.9Hz),7.01(1H,dt,J 3.0,9.0Hz),6.99-6.40(2H,m),6.82(1H,dt,1.2,6.7Hz),5.27(2H,s),2.57(3H,s).

[0176] 2-(3-(5-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(3) The title compound was prepared using general method G, with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-4-fluorophenol (50 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a light brown solid (32 mg). R 4.84 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 7.21(1H,dd,J 2.9,9.0Hz),7.16-7.10(1H,m),7.08-7.02(1H,bm),7.05(1H,d,J 8.2Hz),6.89(1H,d,J 8.2Hz),4.09(2H,bt,J 5.6Hz),3.35(2H,t,J 6.6Hz),2.42(3H,s),2.01-1.95(2H,m),1.95-1.89(2H,m);m / z(MH + )340.15,(MH2 2+ )170.58.

[0177] 2-(3-(2-fluoro-6-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(4) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-3-fluorophenol The title compound was prepared using general method F, by suspending 2-fluoro-6-hydroxybenzaldehyde (68 mg), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) in AcOH (0.5 mL). The reaction mixture was heated at 40°C for 20 hours, followed by a further 20 hours at 60°C. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 0 HCl / hexane gradient and 75% 30 CV. The desired fractions were combined and evaporated to obtain the title compound (43 mg). 1 H NMR(CDCl3,600MHz)δ 11.4(1H,vbs),8.38(1H,d,J 9.1Hz),8.00(1H,dd,J 4.9,6.0Hz),7.44(2H,d,J 7.1Hz),7.33-7.25(4H,m),7.23(1H,d,J 8.3Hz),7.00-6.95(2H,m),6.93(1H,d,J 8.1Hz),6.80-6.75(2H,m),5.26(2H,s),2.58(3H,s).

[0178] 2-(3-(2-fluoro-6-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(4) The title compound was prepared using general method G with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-3-fluorophenol (45 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a beige solid (28 mg). R 4.87 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 7.38(1H,m),7.04(1H,d,J 8.2Hz),6.92-6.87(1H,bm),6.88(1H,d,J 8.2Hz),6.76(1H,t,J 8.8Hz),3.92(2H,t,J 5.9Hz),3.35(2H,t,J 6.5Hz),2.42(3H,s),2.00-1.95(2H,m),1.94-1.89(2H,m);m / z(MH + )340.15,(MH22+ )170.58.

[0179] 2-(3-(2-hydroxy-5-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(5) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol The title compound was prepared using general method F with 2-hydroxy-5-methylbenzaldehyde (54 mg), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) suspended in AcOH (0.5 mL), while heating the reaction mixture at 40°C for 40 hours. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 0 HCl / hexane gradient and 75% 30 CV. The desired fractions were combined and evaporated to obtain the title compound (46 mg). 1 H NMR(CDCl3,600MHz)δ 12.2(1H,vbs),8.59(1H,d,J 7.3Hz),8.42(1H,d,J 9.2Hz),7.60(1H,bs),7.43(2H,d,J 7.3Hz),7.33-7.28(2H,m),7.28-7.23(1H,m),7.20(1H,d,J 8.4Hz),7.12(1H,d,J 8.4Hz),7.06(1H,d,J 8.3Hz),6.95(1H,d,J 8.4Hz),6.92(1H,dd,J 6.4,9.2Hz),6.77(1H,t,J 6.8Hz),5.27(2H,s),2.57(3H,s),2.40(3H,s).

[0180] 2-(3-(2-hydroxy-5-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(5) The title compound was prepared using general method G with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol (46 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a dark mustard-colored solid (25 mg). R4.94 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 7.25-7.23(1H,m),7.17-7.14(1H,m),7.04(1H,d,J 8.2Hz),6.98-6.92(1H,bm),6.88(1H,d,J m / z(MH + )336.17,(MH2 2+ )168.59.

[0181] 2-(3-(2-hydroxy-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(6) [ka] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-6-methylphenol The title compound was prepared using general method F, by reacting 2-hydroxy-3-methylbenzaldehyde (60 μL), (3-(benzyloxy)-6-methylpyridine-2-yl)(pyridine-2-yl)methanone (50 mg), and NH4OAc (126 mg) suspended in AcOH (0.5 mL). The reaction mixture was heated at 40°C for 40 hours, followed by a further 28 hours at 60°C. The extracted crude product was adsorbed onto SiO2 and purified by flash chromatography using a 75% 30 CV HCl gradient. The desired fractions were combined and evaporated to obtain the title compound (47 mg). 1 H NMR(CDCl3,600MHz)δ 12.4(1H,bs),8.57(1H,d,J 7.2Hz),8.43(1H,d,J 9.1Hz),7.64(1H,d,J 7.5Hz),7.47(2H,d,J 7.1Hz),7.35-7.29(2H,m),7.29-7.22(2H,m),7.17(1H,d,J 7.0Hz),6.98(1H,d,J 8.4Hz),7.93-6.88(2H,m),6.73(1H,t,J 6.7Hz),5.27(2H,s),2.58(3H,s),2.38(3H,s).

[0182] 2-(3-(2-hydroxy-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)-6-methylpyridine-3-ol(6) The title compound was prepared using general method G with 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)imidazo[1,5-a]pyridine-3-yl)-6-methylphenol (48 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered, and the solvent was evaporated to obtain the title compound as a yellowish-brown solid (28 mg). R 4.91 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 7.33(1H,dd,J 1.5,7.6Hz),7.24(1H,dd,J 1.2,7.4Hz),7.08(1H,d,J 8.2Hz),6.92(1H,d,J 8.2Hz),6.91(1H,t,J m / z(MH + )336.17,(MH2 2+ )168.59.

[0183] 2,2'-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3-diyl)diphenol(7) [ka] The title compound was prepared using general method G, with 2,2'-(imidazo[1,5-a]pyridine-1,3-diyl)diphenol (50 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of siRNA:EtOH (4 mL). The reaction mixture was stirred at room temperature for 16 hours, filtered, and the solvent was evaporated to obtain the title compound as a pale gray solid (44 mg). R 5.22 minutes (HPLC1); 1H NMR(d6-acetone,600MHz)δ 11(1H,vbs),7.49(1H,dd,J 1.6,7.7Hz),7.48(1H,dd,J 1.6,7.7Hz),7.34(1H,t,J 7.6Hz),7.10(1H,dt,J 1.6,8.9Hz),7.04(1H,bd,J 8.1Hz),6.98(1H,t,J 7.5Hz),6.88-6.83(2H,m),4.17(2H,t,J 6.0Hz),3.09(2H,t,J 6.2Hz),2.02-1.93(4H,m);m / z(MH + )307.14.

[0184] 2-(1-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)-4-methylphenol(8) [ka] The title compound was prepared using general method G, with 2-(1-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol (20 mg) and 10% Pd / C (25 mg) in a 1:1 mixture of SiO:EtOH (1 mL). The reaction mixture was stirred at room temperature for 6 hours, filtered, and the solvent was evaporated to obtain the title compound as a lyophilized white solid (17 mg). R 5.42 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 11.8(1H,vbs),9.6(1H,vbs),7.48(1H,d,J 7.8Hz),7.29(1H,bs),7.15(1H,bd,J 6.9Hz),7.09(1H,ddd,J 1.5,7.1,8.2Hz),6.93(1H,bd,J 7.9Hz),6.87-6.83(2H,m),4.11(2H,bt,J 5.5Hz),3.09(2H,bt,J 6.1Hz),2.30(3H,s),2.02-1.93(4H,m);m / z(MH + )321.16.

[0185] 3-Fluoro-2-(1-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)phenol(9) [ka] The title compound was prepared using general method G, with 3-fluoro-2-(1-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-3-yl)phenol (15 mg) and 10% Pd / C (10 mg) in a 1:1 mixture of HCl:EtOH (1 mL). The reaction mixture was stirred at room temperature for 5 hours, filtered, and the solvent was evaporated to obtain the title compound as a lyophilized white solid (14 mg). R 5.29 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 12.4(1H,vbs),9.3(1H,vbs),7.50(1H,d,J 7.7Hz),7.39(1H,q,J 7.6Hz),7.08(1H,t,J 7.8Hz),6.91(1H,bd,J 8.1Hz),6.86-6.77(3H,m),3.96-3.93(2H,m),3.14-3.10(2H,m),2.03-1.96(4H,m);m / z(MH + )325.13.

[0186] 4-Hydroxy-3-(1-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)methyl benzoate (10) [ka] The title compound was prepared using general method G, with methyl 4-hydroxy-3-(1-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-3-yl)benzoate (20 mg) and 10% Pd / C (10 mg) in a 1:1 mixture of SiO:EtOH (1 mL). The reaction mixture was stirred at room temperature for 5 hours, filtered, and the solvent was evaporated to obtain the title compound as a lyophilized white solid (18 mg). R 5.33 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 11.1(1H,vbs),8.16(1H,d,J 2.0Hz),7.96(1H,d,J 7.0Hz),7.47(1H,d,J m / z(MH) + )365.15.

[0187] 2-(3-(pyridine-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)phenol(11) [ka] The title compound was prepared using general method G with 10% Pd / C (5 mg) in a 1:1 mixture (1 mL) of 2-(3-(pyridine-2-yl)imidazo[1,5-a]pyridine-1-yl)phenol and butyl:EtOH. The reaction mixture was stirred at room temperature for 5 hours, filtered, and the solvent was evaporated to obtain the title compound as a lyophilized white solid (5 mg);t R 5.21 minutes (HPLC1); 1 H NMR(d6-acetone,600MHz)δ 12.6(1H,bs),8.65(1H.bd,J 4.8Hz),8.09(1H,d,J 8.0Hz),7.93(1H,dt,J 1.4,7.6Hz),7.52(1H,dd,J 1.3,7.8Hz),7.36(1H,dd,J 6.0,7.5Hz),7.11(1H,dt,J 1.3,8.3Hz),6.89(1H,d,J 8.2Hz),6.85(1H,t,J 7.5Hz),4.68(2H,t,J 6.0Hz),3.15(2H,t,J 6.4Hz),2.08-2.04(2H,m),2.00-1.96(2H,m);m / z(MH + )292.14.

[0188] Synthesis of 2-(1-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)-6-(morpholinomethyl)phenol(12) [ka] 2-(1-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-3-yl)-5-(morpholinomethyl)phenol 2-Hydroxy-4-(morpholinomethyl)benzaldehyde (0.26 g, 1.2 mmol), (2-hydroxyphenyl)(pyridine-2-yl)methanone (1.2 g, 6.0 mmol), and NH4OAc (2.3 g, 30.0 mmol) were suspended in AcOH (3 mL) and reacted according to general method F. The crude product was isolated by extraction with butyl (3 times). The resulting brown, rubbery substance was adsorbed onto silica (0.5 g) and purified by silica chromatography (12 g) by elution with 0 to 100% butyl in hexane over 25 CV, followed by butyl (20 CV). A solid was obtained, which was sonicated in butyl, filtered, washed with ether, and air-dried. A pale yellow solid was obtained (120 mg, 50%). HPLC (230 nm; HPLC2) t R 8.68(99%) minutes. 1 H NMR(d6-DMSO,600MHz)δ 12.01(1H,s),10.38(1H,s),8.08(1H,d,J 9.6Hz),7.85(2H,m),7.45(1H,d,7.8Hz),7.12(1H,td,J 1.8,9.0Hz),7.05(1H,s),7.00(1H,dd,J 5.4,9.0Hz),6.94-6.90(3H,m),6.82(1H,t,J 7.2Hz),3.58(4H,s),3.47(2H,s),2.47(4H,s).MS:m / z(MH + )402.18.

[0189] 2-(1-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)-6-(morpholinomethyl)phenol(12) 2-(1-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-3-yl)-5-(morpholinomethyl)phenol (47.0 mg, 0.12 mmol) was suspended in MeOH (7 mL) and THF (7 mL), and palladium carbon (10 wt%) (10 mg) was added. The mixture was reacted for 17 hours according to general method G. A cream-colored solid was obtained, which was sonicated in SiO2, filtered, washed with SiO2, and air-dried to obtain the title compound (21.0 mg, 45%) as a white solid. HPLC (230 nm; HPLC2) t R 11.13(99%) minutes. 1H NMR(d6-DMSO,600MHz)δ 7.41(1H,dd,J 1.2,7.8Hz),7.18(1H,d,7.8Hz),7.04(1H,td,J MS:m / z(MH) + )406.21.

[0190] Synthesis of 3-(3-(2-hydroxy-5-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (13), 3-(3-(3-chloro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (14), and 3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (15) [ka] 3-(3-(2-hydroxy-5-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol(13) 2-(1-(2-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol (2-methoxypyridine-3-yl)(pyridine-2-yl)methanone (0.15 g, 0.70 mmol), 5-methylsalicyaldehyde (0.29 g, 2.1 mmol), and NH4OAc (0.2 g, 3.5 mmol) were suspended in AcOH (4.0 mL) and reacted according to general method F. The product was isolated by extraction with ELISA (3 times). The resulting yellow solid was purified with silica (12 g) eluted with 0 to 30% ELISA in hexane (30 CV) to obtain a pale yellow solid (0.14 g, 59%). HPLC (280 nm; HPLC2) t R 8.60(99%) minutes. 1 H NMR(CDCl3,600MHz)δ 8.45(1H,bd,J 4.2Hz),8.20(1H,dd,1.8,4.8Hz),8.05(1H,d,J 6.6Hz),7.70(1H,td,J MS:m / z(MH) + )332.14.

[0191] 3-(3-(2-hydroxy-5-methylphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-2-ol 2-(1-(2-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol (0.13 g, 0.40 mmol) was dissolved in 48% HBr according to general method D(i). (水溶液) The solution was heated at 120°C for 17 hours in a 0.5 mL solution. The resulting solid was treated with a saturated aqueous solution of NaHCO3 (10 mL), sonicated to obtain a homogeneous suspension, filtered, and the residue was washed with water (twice), hexane (once), and ether (once), and then air-dried. A yellow solid was obtained (108 mg, 85%). HPLC (280 nm; HPLC2) t R 7.66(98%) minutes. 1 H NMR(CDCl3,600MHz)δ 12.21(1H,s),10.59(1H,s),8.06(1H,d,J 9.6Hz),7.99(1H,d,6.6Hz),7.95(1H,d,J 7.2Hz),7.54(1H,d,J 6.0Hz),7.40(1H,s),7.32(1H,d,J 7.8Hz),7.16(1H,t,J 7.2Hz),7.01-7.05(2H,m),6.43(1H,t,J 6.6Hz),2.29(3H,s).MS:m / z(MH + )318.12.

[0192] 3-(3-(2-hydroxy-5-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol(13) 3-(3-(2-hydroxy-5-methylphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (0.02 g, 0.06 mmol) was dissolved in MeOH (2 mL) and siRNA (2 mL), and palladium carbon (10 wt%) (2 mg) was added. The reaction was carried out according to general method G, and the mixture was stirred at room temperature for 1.5 hours. A gray solid was obtained (17.1 mg, 84%). HPLC (280 nm; HPLC2) t R 7.55(94%) minutes. 1H NMR(CDCl3,600MHz)δ 7.83(1H,d,J 6.6Hz),7.48(1H,d,6.0Hz),7.28(1H,s),7.22(1H,d,J 8.4Hz),6.88(1H,d,J 8.4Hz),6.51(1H,t,J 6.0Hz),4.09(2H,t,J 6.0Hz),2.95(2H,t,J 6.6Hz),2.30(3H,s),2.00(2H,m),1.92(2H,m).MS:m / z(MH + )322.16.

[0193] 3-(3-(3-chloro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (14) and 3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (15) 2-Chloro-6-(1-(2-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)phenol (2-methoxypyridine-3-yl)(pyridine-2-yl)methanone (0.15 g, 0.70 mmol), 3-chloro-2-hydroxybenzaldehyde (0.33 g, 2.1 mmol), and NH4OAc (0.26 g, 3.5 mmol) were suspended in AcOH (4.0 mL) and reacted according to general method F. The product was isolated by extraction with siRNA (3 times). The resulting yellow solid was purified with silica (12 g) eluted with 0 to 30% siRNA in hexane (30 CV) to obtain a pale yellow solid (0.17 g, 70%). HPLC (280 nm; HPLC2) t R 8.77(92%) minutes. 1 H NMR(CDCl3,600MHz)δ 8.48(1H,d,J 7.2Hz),8.21(1H,dd,1.8,5.4Hz),8.04(1H,dd,J 1.8,7.2Hz),7.75(1H,dt,J 1.2,9.0Hz),7.71(1H,dd,J 1.2,7.8Hz),7.41(1H,dd,J 1.2,7.8Hz),7.04(1H,dd,J 4.8,7.2Hz),6.97(1H,t,J 7.8Hz),6.91(1H,ddd,J 0.6,6.6,9.0Hz),6.78(1H,td,J 1.2,7.8Hz),4.06(3H,s).MS:m / z(MH + )352.08.

[0194] 3-(3-(3-chloro-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-2-ol 2-Chloro-6-(1-(2-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)phenol (0.16 g, 0.46 mmol) was dissolved in 48% HBr according to general method D(i). (水溶液) The solution was heated at 120°C for 17 hours in a 0.5 mL solution. The resulting solid was treated with a saturated aqueous solution of NaHCO3 (10 mL), sonicated to obtain a homogeneous suspension, filtered, and the residue was washed with water (twice), hexane (twice), and ether (twice), and then air-dried. A yellow solid was obtained (15 mg, 100%). HPLC (280 nm; HPLC2) t R 7.45(100%) minutes. 1 H NMR(d6-DMSO,600MHz)δ 11.67(1H,s),8.11(1H,d,J 9.6Hz),7.97(1H,dd,1.8,6.6Hz),7.83(1H,bs),7.30(1H,bs),7.20(1H,bs),1.65(1H,bs),6.72(1H,t,J 7.2Hz),6.54(1H,bs),6.32(1H,bs),6.18(1H,bs).MS:m / z(MH + )338.07.

[0195] 3-(3-(3-chloro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (14) and 3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (15) 3-(3-(3-chloro-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (46 mg, 0.14 mmol) was suspended in MeOH (10 mL) and  (10 mL), and palladium carbon (10 wt%) (2 mg) was added. The mixture was reacted for 48 hours according to general method G. The gray solid was packed into silica (0.5 g) and purified by column chromatography (silica, 4 g) using elution with 0 to 10% MeOH in DCM (100 CV). 3-(3-(3-chloro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol (6.5 mg, 16%) was obtained as a yellow solid. HPLC (280 nm; HPLC2) t R 9.10(84%) minutes. 1H NMR(CDCl3,600MHz)δ 7.81(1H,dd,J 1.8,7.2Hz),7.49(1H,d,7.8Hz),7.37(1H,dd,J 1.8,6.6Hz),7.32(1H,d,J 8.4Hz),6.81(1H,t,J 7.8Hz),7.37(1H,t,J 6.6Hz),4.28(2H,m),3.05(2H,m),2.05(2H,m),1.9(2H,m).MS:m / z(MH + 342.10.3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-2-ol was also obtained as a white solid (4.8 mg, 10%). HPLC (280 nm; HPLC2) R 8.66(99%) minutes. 1 H NMR(CDCl3,600MHz)δ 7.81(1H,d,J 6.0Hz),7.55(1H,d,7.8Hz),7.37(1H,d,J 6.0Hz),7.22(1H,m),7.08(1H,d,J 7.8Hz),6.87(1H,t,J 7.2Hz),6.38(1H,t,J 6.6Hz),4.29(2H,t,J 6.0Hz),3.05(2H,t,J 6.6Hz),2.03-2.00(2H,m),1.92-1.89(2H,m).MS:m / z(MH + )308.14.

[0196] The following compounds were prepared in a similar manner. [ka] [Table 3]

[0197] Synthesis of 4-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (21) and 4-(3-(3-(2-(diethylamino)ethyl)-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (22) [ka] 4-(3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (3-hydroxypyridine-4-yl)(pyridine-2-yl)methanone (0.05 g, 0.24 mmol), salicylaldehyde (0.09 g, 0.72 mmol), and NH4OAc (0.09 g, 1.2 mmol) were suspended in AcOH (2.5 mL) and reacted according to general method F. The crude product was isolated by extraction with ELISA (3 times). The resulting solid was sonicated in hexane / ether, and a yellow solid was obtained upon filtration and drying (48 mg, 66%). HPLC (280 nm; HPLC2) t R 7.95(95%) minutes. 1 H NMR(d6-DMSO,500MHz)δ 12.16(1H,bs),10.37(1H,bs),8.25-8.24(2H,m),8.11(1H,d,J 5.0Hz),7.93(1H,d,J 7.0Hz),7.86(1H,d,J 5.5Hz),7.53(1H,d,J 6.5Hz),7.44(1H,t,J 8.0Hz),7.17(1H,dd,J 6.5,9.0Hz),7.09(1H,d,J 8.0Hz),7.05(1H,t,J 7.5Hz),6.92(1H,t,J 5.5Hz).MS:m / z(MH + )304.11.

[0198] 4-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-3-ol(21) 4-(3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (0.2 g, 0.73 mmol) was suspended in MeOH (10 mL) and HCl (10 mL), and 10% palladium carbon (20 mg) was added. The mixture was reacted for 48 hours according to Method G. A brown solid was obtained, which was sonicated in HCl to obtain a yellow solid 4-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (84.0 mg, 37%). HPLC (254 nm; HPLC2) t R 7.94(94%) minutes. 1H NMR(d6-DMSO,500MHz)δ 8.13(1H,s),8.00(1H,d,5.4Hz),7.37(1H,d,J 4.8Hz),7.33-7.30(2H,m),6.99(1H,d,J 7.8Hz),6.90(1H,t,J 7.2Hz),3.89(2H,s),3.09(2H,bs),1.89(4H,bs),1.9(2H,m).MS:m / z(MH + )308.14.

[0199] 4-(3-(3-(2-(diethylamino)ethyl)-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-3-ol(22) (3-hydroxypyridine-4-yl)(pyridine-2-yl)methanone (0.05 g, 0.26 mmol), 3-(2-diethylamino)ethyl-2-hydroxybenzaldehyde (0.12 g, 0.52 mmol), and NH4OAc (0.10 g, 1.3 mmol) were resuspended in AcOH (3.0 mL) and reacted according to Method F. The crude product was isolated by extraction with butyl (3 times). A yellow oily / rubbery substance was obtained by chromatography on silica (4 g) eluted with hexane (2 CV), hexane (20 CV) with 0 to 100% butyl, and finally with butyl (50 CV). A yellow solid was obtained and, after sonication in ethyl acetate, was identified as 4-(3-(3-(2-(diethylamino)ethyl)-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (34 mg, 34%). HPLC (230 nm; HPLC2) R 9.05(99%) minutes. 1H NMR(d6-DMSO,600MHz)δ 12.30(1H,bs),8.22(1H,d,J 9.6Hz),8.21(1H,s),8.08(1H,d,J 4.8Hz),7.86(1H,d,J 7.2Hz),7.84(1H,d,J 4.8Hz),7.31(1H,d,J 7.8Hz),7.23(1H,d,J 7.8Hz),7.14(1H,dd,J 6.6,7.2Hz),6.87(1H,t,J 7.2Hz),6.79(1H,t,J 7.8Hz),2.88(2H,t,J 3.6Hz),2.79(2H,t,J 5.4Hz),2.68(4H,q,J 7.2Hz),0.95(6H,t,J 7.2Hz) MS:m / z(MH + )403.22.

[0200] 4-(3-(3-(2-(diethylamino)ethyl)-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-3-ol(22) 4-(3-(3-(2-(diethylamino)ethyl)-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-3-ol (0.02 g, 0.06 mmol) was suspended in MeOH (10 mL) and THF (10 mL), and palladium carbon (10 wt%) (2 mg) was added. The mixture was reacted for 17 hours according to general method G. A gray solid was obtained, which was sonicated in ether to obtain the title compound as a white solid (8.0 mg, 37%). HPLC (230 nm; HPLC2) t R 7.89(93%) minutes. 1 H NMR(d6-DMSO,500MHz)δ 8.11(1H,s),8.00(1H,d,4.8Hz),7.37(1H,d,J 4.8Hz),7.16(1H,dd,J 0.6,7.2Hz),7.11(1H,d,J 7.2Hz),6.19(1H,t,J 7.2Hz),3.87(2H,s),3.09(2H,m),2.81(2H,m),2.71(2H,m),2.62(4H,q,J 6.6Hz),1.85(4H,m),0.96(6H,t,J 7.2Hz).MS:m / z(MH + )407.24.

[0201] Additional compounds were prepared using the same methodology. [ka] [Table 4]

[0202] Synthesis of 3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-4-ol (29) and 3-(3-(3-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-4-ol (30) [ka] 2-(1-(4-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)phenol (4-methoxypyridine-3-yl)(pyridine-2-yl)methanone (0.24 g, 1.1 mmol), salicylaldehyde (0.41 g, 3.4 mmol), and NH4OAc (0.26 g, 3.5 mmol) were suspended in AcOH (10.0 mL) and reacted according to general method F. The crude product was isolated by extraction with HCl (3 times). The resulting brown rubbery substance was purified with silica (12 g) eluted with 0 to 100% HCl in hexane (15 CV), followed by elution with 100% HCl (15 CV), to obtain a yellow solid (166 mg, 36%). 1 H NMR(CDCl3,500MHz)δ 8.81(1H,s),8.57(1H,d,6.0Hz),8.53(1H,d,J 6.0Hz),7.81(1H,dd,J 2.0,8.0Hz),7.62(1H,d,J 9.5Hz),7.33(1H,dt,J 2.0,8.5Hz),7.19(1H,dd,J 1.0,8.0Hz),7.03(1H,dt,J 1.5,9.0Hz),6.97(1H,d,6.0Hz),6.88(1H,dd,J 6.5,10.0Hz),6.75(1H,dt,1.5,7.5Hz),3.98(3H,s).MS:m / z(MH + )318.12.

[0203] 3-(3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-4-ol 2-(1-(4-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)-phenol (0.17 g, 0.52 mmol) was heated in a 48% aqueous solution of HBr (0.5 mL) and reacted at 125°C for 24 hours according to general method D(i). The solid precipitate was isolated at workup and no solvent extraction was performed. After adjusting the pH to pH 6, the mixture was filtered. A yellow solid was obtained (80 mg, 60%). 1 H NMR(d6-DMSO,600MHz)δ 10.4(1H,bs),8.39(1H,s),8.06(1H,d,9.6Hz),7.84(1H,bd,J 6.6Hz),7.81(1H,d,J 7.2Hz),7.51(1H,d,J 6.6Hz),7.36(1H,t,J 7.2Hz),7.04(1H,d,J 7.8Hz),6.98(1H,t,J 6.6Hz),6.81(1H,t,J 7.2Hz),6.72(1H,t,J 6.6Hz),6.53(1H,bd,J 5.4Hz).

[0204] 3-(3-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-4-ol(29) 3-(3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-4-ol (0.08 g, 0.2 mmol) was suspended in MeOH (15 mL) and siRNA (15 mL), and palladium carbon (10 wt%) (8 mg) was added. The mixture was reacted for 72 hours according to general method G. A gray solid was obtained, which was packed into silica and purified by column chromatography (silica, 4 g) using elution with 0 to 15% MeOH in DCM (70 CV). A clear rubbery substance / solid was obtained and sonicated in ether / siRNA to obtain the title compound (10.0 mg, 12%) as a white solid. HPLC (254 nm; HPLC2) t R 7.14(93%) minutes. 1H NMR(CD3OD,600MHz)δ 8.09(1H,s),7.82(1H,d,7.2Hz),7.48(1H,d,J 6.6Hz),7.42(1H,t,J 7.8Hz),7.02-7.00(2H,m),6.57(1H,d,J 7.2Hz),4.09(2H,t,5.4Hz),2.92(2H,t,6.6Hz),2.01(2H,m),1.93(2H,m).MS:m / z(MH + )308.14.

[0205] 3-(3-(3-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-4-ol(30) 2-Fluoro-6-(1-(4-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)phenol (4-methoxypyridine-3-yl)(pyridine-2-yl)methanone (0.24 g, 1.1 mmol), 3-fluoro-2-hydroxybenzaldehyde (0.47 g, 3.4 mmol), and NH4OAc (0.43 g, 5.6 mmol) were resuspended in AcOH (10.0 mL) and reacted according to general method F. The crude product was isolated by extraction with HCl (3 times). The resulting brown rubbery substance was purified with silica (12 g) eluted with 0 to 100% HCl in hexane (15 CV), followed by elution with 100% HCl (15 CV), to obtain a yellow solid (164 mg, 44%). 1 H NMR(CDCl3,500MHz)δ 8.79(1H,s),8.56-8.54(2H,m),7.66(1H,d,J 9.5Hz),7.60(1H,d,J 8.5Hz),7.16(1H,t,J 9.0Hz),7.00-6.69(2H,m),6.92(1H,t,J 7.0Hz),6.80(1H,t,6.0Hz),3.98(3H,s).MS:m / z(MH + )336.11.

[0206] 3-(3-(3-fluoro-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-4-ol 2-Fluoro-6-(1-(4-methoxypyridine-3-yl)imidazo[1,5-a]pyridine-3-yl)phenol (0.16 g, 0.49 mmol) was heated in a 48% aqueous solution of HBr (0.5 mL) and reacted at 125°C for 24 hours according to general method D(i). The precipitate was isolated at workup and no solvent extraction was performed. After adjusting the pH to pH 6, the mixture was filtered. A yellow solid was obtained (91 mg, 58%). 1 H NMR(d6-DMSO,600MHz)δ 8.19(1H,bs),8.05(1H,d,J 9.0Hz),7.86(1H,d,7.2Hz),7.66(1H,bs),7.21(1H,bs),7.10(1H,bs),6.75(1H,bs),6.63(1H,bs),6.55(1H,bs),6.32(1H,bs).

[0207] 3-(3-(3-fluoro-2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-yl)pyridine-4-ol(30) 3-(3-(3-fluoro-2-hydroxyphenyl)imidazo[1,5-a]pyridine-1-yl)pyridine-4-ol (0.09 g, 0.28 mmol) was suspended in MeOH (15 mL) and HCl (15 mL), and palladium carbon (10 wt%) (8 mg) was added. The mixture was reacted for 17 hours according to general method G. A brown, rubbery substance was obtained, which was sonicated in HCl / MeOH to obtain a solid. This was further sonicated in THF to obtain the title compound (10.0 mg, 12%) as a gray solid. HPLC (254 nm; HPLC2) t R 7.85(90%) minutes. 1 H NMR(CD3OD,600MHz)δ 8.09(1H,s),7.82(1H,d,J 6.6Hz),7.32(1H,d,9.6Hz),7.30(1H,d,J 7.8Hz),6.98-7.01(1H,m),6.58(1H,d,J 7.2Hz),4.11-4.06(2H,m),2.93(2H,t,J,6.6Hz),2.02-2.04(2H,m),1.95-1.93(2H,m).MS:m / z(MH + )326.13.

[0208] Synthesis of 2,2'-(6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3-diyl)diphenol (36) [ka] 2,2'-(6-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3-diyl)diphenol(36) 2,2'-(6-(trifluoromethyl)imidazo[1,5-a]pyridine-1,3-diyl)diphenol (15 mg, 0.044 mmol) was dissolved in MeOH (7 mL) and 10% Pd / C (8 mg) was added. The reaction was carried out as outlined in General Method G to obtain the title compound as a light brown powder (4.0 mg, 24%). 1 H NMR(CDCl3,600MHz)δ 7.41(1H,dd,J 1.2,8.4Hz),7.37-7.33(2H,m),7.22-7.19(1H,m),7.10(1H,dd,J 1.2,8.4Hz),7.01(2H,m),6.91(1H,dt,J 1.2,7.2Hz),4.46(1H,dq,J 5.4,13.2Hz),4.17(1H,t,J 11.4Hz),3.5-3.32(1H,m),3.15-3.09(1H,m),2.78-2.68(1H,m),2.45-2.40(1H,m),1.92(1H,ddd,J 13.2, 5.4 Hz). MS: m / z (MH) + )375.13.

[0209] 2-(1-(2-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)-4-methylphenol(37) 2-(1-(2-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridine-3-yl)-4-methylphenol (12 mg, 0.03 mmol) was dissolved in MeOH (7 mL) and 10% Pd / C (9 mg) was added. The reaction was carried out as outlined in General Method G to obtain the title compound as a pale gray powder (1.5 mg, 12%). 1H NMR(CDCl3,600MHz)δ 10.01(1H,bs),9.90(1H,s),7.58-7.52(1H,m),7.37(1H,d,J 7.8Hz),7.24(1H,m),7.18(1H,t,J 7.2Hz),7.11(1H,d,J 7.8Hz),7.04-6.98(1H,m),6.92(1H,t,J 7.2Hz),4.32-4.28(1H,m),4.21-4.15(1H,m),3.23-3.18(1H,m),2.67-2.62(1H,m),2.34(3H,s),2.10(1H,d,J 13.0Hz),2.08-2.01(1H,m),1.67-1.62(1H,m),1.24(3H,d,J 6.0Hz).MS:m / z(MH + )335.17.

[0210] 2-(1-(2-hydroxyphenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-yl)-4-methylphenol(38) To a solution of 2-(1-(2-hydroxyphenyl)-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-yl)-4-methylphenol (21 mg, 0.054 mmol) in MeOH (8 mL), 10% Pd / C (11 mg) was added. The reaction was carried out as outlined in General Method G, yielding the title compound as a pink solid (10 mg, 20%). 1 H NMR(CDCl3,600MHz)δ 9.77(2H,bs),7.34(1H,d,J 7.2Hz),7.21(1H,t,J 7.2Hz),7.19-7.14(2H,m),7.01(2H,t,J 9.0Hz),6.92(1H,t,J 7.2Hz),4.43(1H,dd,J 4.2,12.0Hz),4.16(1H,t,J 12.0Hz),3.36-3.32(1H,m),3.15-3.10(1H,m),3.12-3.08(1H,m),2.77-2.73(1H,m),2.37(3H,s),1.96-1.92(1H,m).MS:m / z(MH + )389.14.

[0211] Synthesis of 2-(1-(2-methoxypyridine-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)phenol (39) [ka] (2-methoxypyridine-3-yl)(pyrrolidine-2-yl)methanone 2-(2-methoxynicotinoyl)pyrrolidine-1-carboxylate tert-butyl (0.20 g, 0.66 mmol) was diluted with 1,4-dioxane (5 mL) containing 4 M aqueous solution of HCl (0.66 mL). This solution was stirred at room temperature for 2.5 hours. The reaction mixture was made basic with 2 M aqueous solution of NaOH, extracted with DCM (15 mL x 3), dried to (Na2SO4), and then concentrated under reduced pressure to obtain a brown, rubbery substance (0.10 g), which was used directly in the next step. MS: m / z (MH) + )207.11.

[0212] 2-(1-(2-methoxypyridine-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)phenol(39) (2-methoxypyridine-3-yl)(pyrrolidin-2-yl)methanone (0.10 g, 0.48 mmol), salicylaldehyde (0.18 g, 1.5 mmol), and NH4OAc (0.19 g, 2.4 mmol) were heated in AcOH (4.5 mL) and reacted according to general method F. The crude product was isolated by extraction with ELISA (15 mL × 3). The brown rubbery substance was packed into silica and purified by chromatography (silica, 12 g) by eluting with hexane (3 CV), hexane (30 CV) with 0 to 60% ELISA, and then with 60 to 100% (20 CV). 2-(1-(2-methoxypyridine-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)phenol was isolated as a yellowish-brown solid (6.2 mg, 4%). 1 H NMR(CDCl3,500MHz)δ 8.14(1H,dd,J 1.5,7.5Hz),8.09(1H,dd,J 1.5,4.5Hz),7.57(1H,J 1.0,7.5Hz),7.24(1H,dd,J 1.0,8.0Hz),7.08(1H,dd,J 1.0,8.5Hz),6.99(1H,dd,J 5.0,7.5Hz),6.89(1H,td,J 1.0,8.0Hz),4.38(2H,t,J 7.0Hz),4.04(3H,s),3.16(2H,t,J 7.5Hz),2.73(2H,m).MS:m / z(MH + )308.14.

[0213] Synthesis of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole and 6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine [ka] (2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-yl)(2-hydroxyphenyl)methanone(A) [ka] The general method J was used for the acylation solution, with CDI (106 mg) and salicylic acid (91 mg) in 1,4-dioxane (1 mL). Separately, 2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-carboxylate tert-butyl (130 mg) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (1 mL) at room temperature. The solid was isolated by rubbing with an Et2O / hexane mixture. After removing the residual solvent under vacuum, the solid was resuspended in 1,4-dioxane and used with the acylation solution as described in the general method. Upon completion by MS, the reaction products were treated as outlined, and the crude product was isolated (42 mg, m / z (MH)). + )417.18). The crude product was a mixture of both the target and the diacylated target (m / z(MH). + 537.20). The sample was used without any further processing.

[0214] The following examples were also prepared using the same methodology. [ka] [Table 5]

[0215] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)phenol(40) [ka] The general method F is used with (2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-yl)(2-hydroxyphenyl)methanone A (42 mg) and NH4OAc (10 equivalents) in AcOH (1 mL), the mixture is heated at 50°C for 40 hours, and then the reaction product is dissolved in a sufficiently saturated NaCl (水溶液) The organic layer was separated into water and ethyl acetate using a solvent. After separating the ethyl acetate layer, the aqueous layer was further extracted with ethyl acetate (three times). The combined extract was dried, and the solvent was evaporated to obtain the crude product. The sample was adsorbed onto SiO2 and purified over 4 g of SiO2 (254 / 280 nm) using an ethyl acetate / hexane gradient of 0 to 0% 3 CV and 0 to 100% 30 CV. The target was identified by MS. The desired fractions were combined, and the solvent was evaporated to obtain the title compound (26 mg) as a white solid. 1 H NMR(CDCl3,500MHz)δ 9.1(1H,vbs),7.51(1H,d,J 8.3Hz),7.41(2H,d,J 7.5Hz),7.34(2H,t,J 7.3Hz),7.31-7.26(1H,m),7.21(1H,t,J 7.6Hz),7.11(1H,d,J 8.5Hz),7.07(1H,d,J 8.1Hz),6.90(1H,d,J 8.4Hz),6.84(1H,t,J 7.4Hz),5.18(2H,s),4.29(2H,t,J 7.5Hz),3.01(2H,t,J 7.5Hz),2.63(2H,p,J 7.5Hz), 2.50(3H,s).

[0216] The following examples were also prepared using the same methodology. [ka] [Table 6-1] [Table 6-2]

[0217] 2-(3-(2-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1-yl)-6-methylpyridine-3-ol(50) [ka] Using the general method G, 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)phenol (40) (26 mg) was dissolved / suspended in siRNA / EtOH (approximately 1:2, 6 mL). 10% Pd / C (approximately 20 mg) was added, and the system was heated to H 2(g) After being placed in the atmosphere for 30 minutes, the completion of the reaction was indicated by MS. The catalyst was filtered off, and the solvent was evaporated to obtain the crude product. The sample was adsorbed onto SiO2 and purified using a MeOH / DCM gradient of 0 to 0% 5CV and 0 to 5% 20CV. The target fractions were combined to obtain the title compound as a pale yellow amorphous solid (6.5 mg). HPLC 1 t R 5.74 minutes. 1 H NMR(d6-acetone,500MHz)δ 10.5-10(1H,bs),7.65(1H,dd,J 1.2,7.8Hz),7.31(1H,t,7.5Hz),7.11(1H,d,J 8.3Hz),7.03(1H,d,J 8.2Hz),6.99(1H,t,J m / z(MH + )308.14,(M2H 2+ )154.57.

[0218] The following examples were also prepared using the same methodology. [ka] [Table 7-1] [Table 7-2]

[0219] 2-(3-(3-fluoro-2-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1-yl)-6-methylpyridine-3-ol(59) [ka] (3-(benzyloxy)-6-methylpyridine-2-yl)(pyrrolidine-2-yl)methanol 2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate tert-butyl (245 mg) was dissolved in DCM (10 mL), cooled to 0°C, and then treated with TMSOTf (222 μL). The reaction mixture was stirred for 1 hour, and then the reaction mixture was saturated with NaHCO3. 3(水溶液) The extract was diluted and the DCM layer was separated. The aqueous layer was further extracted with DCM (twice), and the combined extract was dried and the solvent evaporated to obtain the crude product (163 mg, m / z 299.175 (MH)). + A mixture of diastereomers was obtained and used without further processing.

[0220] (2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-yl)(3-fluoro-2-hydroxyphenyl)methanone General method I was used with CDI (90 mg) and 3-fluoro-2-hydroxybenzoic acid (117 mg). After preparation, the acylating agent was added to (3-(benzyloxy)-6-methylpyridine-2-yl)(pyrrolidine-2-yl)methanol (150 mg). The resulting solution was stirred for a total of 72 hours, after which the title compound was the main product with a small amount of diacylated material. The reaction product was treated as described in the general method to obtain the crude title product (184 mg, m / z 437.187 (MH)). + We obtained this and used it here without any further operations.

[0221] (2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-yl)(3-fluoro-2-hydroxyphenyl)methanone (2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-yl)(2-hydroxyphenyl)methanone (93 mg) was dissolved in DMSO (1 mL) and treated with triethylamine (310 μL). Pyridine sulfur trioxide complex (354 mg) was dissolved in DMSO (1 mL), allowed to stand for 5 minutes, and then added to a cooled (approximately 10°C) solution of alcohol. The reaction mixture was warmed to room temperature and stirred for 1 hour, after which the reaction mixture was diluted with CHCl3 and ice-cold water. The organic layer was separated, the aqueous layer was extracted with CHCl3 (twice), and the combined aqueous layer was mixed with water and saturated NaHCO3 3(水溶液) The sample was washed, dried, and the solvent evaporated to obtain the crude product (256 mg). The sample was adsorbed onto SiO2 and purified on 5 g (254 / 280 nm) using an HCl / hexane gradient of 0 to 0% 3V and 0 to 75% 30CV. The fraction containing the title compound (m / z 435.172 (MH)) was obtained. + )) combined, but this was not decomposed from the thiomethyl ether byproducts of both the target and SM (m / z 497.191 (MH) + The sample was used without any further processing.

[0222] 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)-6-fluorophenol(58) A mixture of (2-(3-(benzyloxy)-6-methylpicolinoyl)pyrrolidine-1-yl)(3-fluoro-2-hydroxyphenyl)methanone and (2-((3-(benzyloxy)-6-methylpyridine-2-yl)(hydroxy)methyl)pyrrolidine-1-yl)(3-fluoro-2-hydroxy-4-(methylthiomethyl)phenyl)methanone (approximately 96 mg) and NH4OAc (256 mg) was dissolved in AcOH (2 mL), and the mixture was heated at 80°C for 23 hours. After diluting the sample with water, it was extracted with ethyl acetate (3 times), and the combined extract was mixed with water and saturated NaCl. (水溶液)The sample was washed, dried, and the solvent evaporated to obtain the crude product (82 mg). The sample was adsorbed onto SiO2 and purified over 4 g of SiO2 (254 / 280 nm) using MeOH / DCM gradients of 0 to 0% 3 CV, 0 to 10% 30 CV, and 10 to 20% 20 CV. The fractions containing the desired compound were combined to obtain the title compound (28 mg). 1 H NMR(CDCl3,600MHz)δ 7.41-7.39(2H,m),7.35-7.32(2H,m),7.30-7.26(2H,m),7.11(1H,d,J 8.5Hz),7.02(1H,ddd,J 1.4,8.1,8.4Hz),6.90(1H,d,J 8.4Hz),6.73(1H,dt,J 4.8,8.0Hz),5.20(2H,s),4.28(2H,t,J 7.2Hz),3.04(2H,t,J 7.3Hz),2.64(2H,p,J 7.3Hz),2.49(3H,s).m / z 416.172(MH + ).

[0223] 2-(3-(3-fluoro-2-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1-yl)-6-methylpyridine-3-ol(59) 2-(1-(3-(benzyloxy)-6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)-6-fluorophenol (58) (28 mg) was dissolved in EtOH (approx. 4 mL), then treated with 10% Pd / C (approx. 15 mg), and the mixture was heated to H 2(g) The mixture was placed under a specific atmosphere. The reactants were stirred for 23 hours, then filtered, and the solvent was evaporated to obtain the crude product. The sample was adsorbed onto SiO2 and purified over 4 g of SiO2 (254 / 280 nm) using a MeOH / DCM gradient of 0 to 0% 3CV and 0 to 10% 30CV. The desired fractions were combined, and the solvent was evaporated to obtain the title compound (7.2 mg) as a pale yellow solid. HPLC (HPLC1) t R 5.84 minutes, 1H NMR(d6-DMSO,600MHz)δ 12.0(1H,vbs),11.2(1H,bs),7.39(1H,d,J 7.8Hz),7.26(1H,dd,J 8.3,11.1Hz),7.12(1H,d,J 8.3Hz),6.94(1H,d,J m / z(MH) + )326.13.

[0224] Biological examples Measurement of Fe efflux from cells The compounds of the present invention were evaluated for their ability to excrete iron (Fe) from cells using the following protocol.

[0225] Human neuroblastoma cell cultures of the BE(2)-M17 (M17) strain were obtained from Sigma Aldrich (catalog number: 95011816). M17 cells were maintained in Opti-MEM reduced serum medium supplemented with 10% fetal bovine serum (Bovogen, SFBSF) and subcultured twice weekly. Cells were cultured at 37°C in the presence of 5% CO2. Unless otherwise specified, culture supplies were obtained from Thermo Fisher.

[0226] 57 A solution of iron isotope, 57 The master solution was prepared by dissolving Fe metal (over 95% enriched, Trace Sciences International) in concentrated HCl to obtain a final concentration of 573 mM. From this master solution, a 10 mM working solution was prepared in sterile water. The working solution was used within two months of preparation.

[0227] First, 0.15 × 10 per well in 0.5 mL of culture medium. 6 M17 cells were loaded with iron by seeding them in a 48-well plate at a cell density. After 48 hours, the old medium was discarded. 10 mM 57 Add fresh culture medium replenished from the Fe working solution, and 20 μM 57A culture medium containing Fe isotopes was obtained. 57 0.2 mL of Fe-enriched medium was added, and the cells were returned to the incubator for 20 hours.

[0228] The ability of the experimental compound to excrete iron was determined by dissolving the compound in DMSO and diluting it in Hanks equilibrium salt solution (HBSS) for treatment of M17 cells. 57 After incubation in fluorine (F), cells were rinsed twice with HBSS and treated with 0.15 ml of the test compound for 2 hours. The experimental substances were periodically screened at a concentration of 20 μM, with occasional dilutions in the range of 1–40 μM to further characterize the major compounds. All assays included the relevant vehicle (0.4%–0.8% DMSO) and a positive control. After the treatment period, 0.1 mL of culture medium was collected from the cells, and extracellular samples were taken. 57 The Fe content was analyzed via inductively coupled mass spectrometry (ICP-MS, Agilent 7700x series instrument).

[0229] The ability of the compound of the present invention to excrete Fe from cells was determined using the protocol described above. Subsequently, cells pretreated with Fe in culture medium for 24 hours were washed and treated with fresh Fe-free medium, with 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 compared to the cell medium in the absence of the compound.

number

[0230] Representative data is provided in Table 1, where the Fe emission percentages of the specific compounds of the present invention are within the following ranges: A < 30%, B 30-100%, C 100-150%, D > 150%. [Table 8]

Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony, X １ ~X ８ Each of them independently, N and CR ３ Selected from the group consisting of X １ ~X ８ Of these, 0, 1, 2, 3, or 4 are N. R １ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, (C(R ７ )) ２ aryl, C(O)R ｍ ), and C(S)R ４ ; and ４ is selected from the group consisting of R ２ However, OR ５ , SR ５ , and N(R ６ ) ２ Selected from the group consisting of, Each R ３ However, independently, hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ )) ２ )) ｍ S(O) ｎ R ４ , (C(R ７ )) ２ )) ｍ N(R ６ )(C(O)N(R ６ )) ２ , and (C(R ７ )) ２ )) ｍ N(R ６ )(C(S)N(R ６ )) ２ selected from the group consisting of, R ４ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, OR ５ , SR ５ , and N(R ６ ), ２ and is selected from the group consisting of: R ５ However, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, and S(O) ｎ N(R) ６ ) ２ Selected from the group consisting of, R ６ However, it is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl. Each R ７ However, independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl, m is 0 or an integer from 1 to 6. n is 1 or 2, p is an integer between 1 and 4, Each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted. A compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

2. X １ ~X ８ However, CR became independent. ３ A compound according to claim 1, selected from the following.

3. X １ ~X ８ One of them is N, and the rest are CR ３ The compound according to claim 1.

4. X １ ~X ８ Two of them are N, and the rest are CR ３ The compound according to claim 1.

5. below, i) X １ ~X ４ One of them is N, ii) X ５ ~X ８ One of them is N, iii) X １ The fact that is N, iv) X ５ The fact that is N, v) X ６ The fact that is N, vi)X ７ The fact that is N, or vii)X ８ The compound according to any one of claims 1 and 3, wherein one of the following conditions is met: the compound is N.

6. R １ However, hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C(O)C １－６ Alkyl, CH ２ Aaryl, and C(O)OC １－６ A compound according to any one of claims 1 to 5, selected from the group consisting of alkyl groups.

7. R １ However, hydrogen or CH ２ The compound according to claim 6, wherein it is phenyl.

8. R ２ However, OH, SH, OC １－６ Alkyl, SC １－６ alkyl and NH ２ A compound selected from any one of claims 1 to 7.

9. R ２ The compound according to claim 8, wherein is an OH group.

10. Each R ３ However, independently, hydrogen, halo, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, (CH ２ ) ｑ Cycloalkyl, (CH ２ ) ｑ Cycloalkenyl, (CH ２ ) ｑ Ayl, (CH ２ ) ｑ Heterocyclyl, (CH ２ ) ｑ Heteroaryl, OH, (CH ２ ) ｑ OH, SH, (CH ２ ) ｑ SH, OC １－６ Alkyl, SC １－６ Alkyl, (CH ２ ) ｑ OC １－６ Alkyl, (CH ２ ) ｑ SC １－６ Alkyl, OC(O)C １－６ Alkyl, (CH ２ ) ｑ OC(O)C １－６ Alkyl, C(O)C １－６ Alkyl, (CH ２ ) ｑ C(O)C １－６ Alkyl, CO ２ H, (CH ２ ) ｑ CO ２ H, C(O)OC １－６ Alkyl, (CH ２ ) ｑ C(O)OC １－６ Alkyl, CONH ２ , (CH ２ ) ｑ CONH ２ , CN, (CH ２ ) ｑ CN, NO ２ , (CH ２ ) ｑ NO ２ NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ , (CH ２ ) ｑ NH ２ , (CH ２ ) ｑ NH(C) １－６ (alkyl), (CH ２ ) ｑ N(C) １－６ Alkyl) ２ SO ２ H, (CH ２ ) ｑ SO ２ H, SO ３ H, (CH ２ ) ｑ SO ３ H, S(O) ２ C １－６ Alkyl, (CH ２ ) ｑ S(O) ２ C １－６ Alkyl, S(O) ２ OC １－６ Alkyl, (CH ２ ) ｑ S(O) ２ OC １－６ Alkyl, S(O) ２ NH ２ , S(O) ２ NH(C) １－６ Alkyl), S(O) ２ N(C) １－６ Alkyl) ２ , (CH ２ ) ｑ S(O) ２ NH ２ , (CH ２ ) ｑ S(O) ２ NH(C) １－６ (alkyl), (CH ２ ) ｑ S(O) ２ N(C) １－６ Alkyl) ２ NHC(O)NH ２ ,NHC(O)NH(C １－６ Alkyl), NHC(O)N(C １－６ Alkyl) ２ , (CH ２ ) ｑ NHC(O)NH ２ , (CH ２ ) ｑ NHC(O)NH(C １－６ (alkyl), and (CH ２ ) ｑ NHC(O)N(C) １－６ Alkyl) ２ A compound according to any one of claims 1 to 9, selected from the group consisting of the above, wherein q is an integer from 1 to 3.

11. The compound according to any one of claims 1 to 10, wherein p is 1, 2, or 3.

12. A compound of formula (II), 【Chemistry 2】 In the formula, R １ , R ２ , R ３ , and p are as defined for equation (I), and R ３ａ ~R ３ｈ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

13. A compound of formula (III), 【Transformation 3】 In the formula, R １ , R ２ , and R ３ , and p are as defined for equation (I), R ３ａ ~R ３ｄ and R ３ｆ ~R ３ｈ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

14. A compound of formula (IV), 【Chemistry 4】 In the formula, R １ , R ２ , and R ３ , and p are as defined for equation (I), R ３ａ ~R ３ｅ and R ３ｇ ~R ３ｈ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R) ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

15. A compound of formula (V), 【Transformation 5】 R １ , R ２ , R ３ , and p are as defined for equation (I), and R ３ａ ~R ３ｆ , and R ３ｈ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

16. A compound of formula (VI), 【Transformation 6】 In the formula, R １ , R ２ , R ３ , and p are as defined for equation (I), and R ３ａ ~R ３ｇ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

17. A compound of formula (VII), 【Transformation 7】 In the formula, R １ , R ２ , R ３ , and p are as defined for equation (I), and X ５ However, N or CR ３ｅ X ６ However, N or CR ３ｆ X ７ However, N or CR ３ｇ X ８ However, N or CR ３ｈ And R ３ｂ ~R ３ｈ However, each is independent of hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, (C(R) ７ ) ２ ) ｍ Cycloalkyl, (C(R ７ ) ２ ) ｍ Cycloalkenyl, (C(R) ７ ) ２ ) ｍ Ariel, (C(R ７ ) ２ ) ｍ Heterocycline, (C(R ７ ) ２ ) ｍ Heteroaryl, (C(R ７ ) ２ ) ｍ OR ５ , (C(R ７ ) ２ ) ｍ SR ５ , (C(R ７ ) ２ ) ｍ C(O)R ４ , (C(R ７ ) ２ ) ｍ C(S)R ４ , (C(R ７ ) ２ ) ｍ OC(O)R ４ , (C(R ７ ) ２ ) ｍ SC(S)R ４ , (C(R ７ ) ２ ) ｍ OC(S)R ４ , (C(R ７ ) ２ ) ｍ SC(O)R ４ , (C(R ７ ) ２ ) ｍ CN, (C(R ７ ) ２ ) ｍ NO ２ , (C(R ７ ) ２ ) ｍ N(R) ６ ) ２ , (C(R ７ ) ２ ) ｍ S(O) ｎ R ４ , (C(R ７ ) ２ ) ｍ N(R) ６ ) C(O)N(R ６ ) ２ , and (C(R ７ ) ２ ) ｍ N(R) ６ ) C(S)N(R ６ ) ２ Selected from the group consisting of R ４ , R ５ , R ６ , R ７ , and m are as defined for equation (I), The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier and / or excipient.

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of metal ion-related disorders.

20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of metal ion-associated neurological disorders.

21. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for treating or preventing metal ion-related disorders.

22. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for treating or preventing metal ion-associated neurological disorders.

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