Novel dihydroacridine derivative and pharmaceutical composition comprising same

Abstract

The present invention relates to: a compound of chemical formula 1; a pharmaceutical composition comprising same as an active ingredient; and a use thereof. The compound of chemical formula 1 according to the present invention may exhibit inhibitory activity against cell necrosis and ferroptosis in various cells such as heart cells, kidney cells, nerve cells, retina cells, liver cells, or lung cells, and thus can be effectively used for preventing or treating cell diseases related to cell necrosis or ferroptosis.

Description

Novel dihydroacridine derivatives and pharmaceutical compositions comprising the same

[0001] The present invention relates to a novel dihydroacridine derivative, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and a use thereof.

[0002] Apoptosis contributes to the maintenance and transformation of cellular functions necessary for the survival of living organisms, and maintains cell population by balancing cell proliferation and proliferation for processes such as embryonic development. Furthermore, it serves as a method for the immune system to effectively and quickly notify various external danger signals, such as viral or bacterial invasion or localized injury.

[0003] However, cell death caused by external threats or localized injury can lead to local or systemic inflammation due to excessive activation of the immune system, potentially posing a threat to the organism. This type of cell death is primarily observed in the form of necrotic cell death (or necrosis), and researchers have conducted extensive research to treat and improve disease by inhibiting necrosis.

[0004] Cell necrosis is known as cell death characterized by oxygen depletion, energy depletion, and cell membrane collapse due to sudden physical or chemical shock to the cell. Cell necrosis is characterized by loss of ATP (Adenosine triphosphate), Ca 2+Damage-associated molecular patterns (DAMPs), such as calcium ions, reactive oxygen species (ROS), and high mobility group box 1 (HMGB1), are released outside the cell, and these are known to stimulate or damage surrounding cells, inducing a chain reaction of inflammation and cell death. Therefore, research into suppressing cell necrosis for disease prevention and treatment has been conducted for a long time.

[0005] As various characteristics of necrosis have been discovered, the Nomenclature Committee on Cell Death (NCCD) has refined the classification of necrosis. Necrotic cell death, initially known as necrosis, occurs due to sudden causes such as physical or chemical damage (accidental cell death), and is non-regulated cell death (NRCD) that cannot control biological processes. In contrast, regulated necrotic cell death (RNCD) has been recently recognized as occurring through various mechanisms due to physiological causes. Cell death classified as regulated necrosis includes necroptosis through the RIPK1, RIPK3, and MLKL mechanisms, pyroptosis through the inflammasome, and ferroptosis caused by lipid peroxide and iron accumulation. Among them, ferroptosis has been reported to be observed in various physiological or pathological situations.

[0006] Ferroptosis is caused by excessive lipid ROS and iron ions (Fe 2+; It is a cell death characterized by the accumulation of ferrous ions. Cells are generally treated with system Xc - (System Xc - ) maintains the concentration of glutathione by supplying cystine, and operates an antioxidant system that removes intracellular lipid peroxidation substances by activating glutathione peroxidase 4 (GPX4). However, if the glutathione concentration is low or GPX4 does not function, excessive accumulation of lipid peroxides induces damage to lipids, proteins, nucleic acids, and cell membrane collapse, resulting in cell death. Another factor in excessive accumulation of lipid peroxides is known to involve ROS generated when iron ions combine with intracellular hydrogen peroxide through the Fenton reaction. Cell death due to lipid peroxides also has a similar pattern to cell necrosis, in which a large amount of DAMPs leak out of the cell, causing inflammation and death of surrounding cells.

[0007] Cell necrosis, which is unregulated cell death, and ferroptosis, which is regulated cell death, are involved in ischemic diseases (e.g., myocardial infarction, stroke, neuropathy), neurodegenerative diseases, inflammatory diseases, aging, macular degeneration, pulmonary diseases, and neuropathic pain (see Neuropathic pain: Inhibition of ferroptosis-like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats. Eur J Pain. 2021 Jan; 25:1227-1240;. Ferroptosis is involved in the development of neuropathic pain and allodynia. Mol Cell Biochem. 2021 Aug; 476(8):3149-3161; Iron Metabolism and Ferroptosis in Peripheral Nerve Injury. Oxid Med Cell Longev. 2022 Dec; 5918218.). A correlation has been reported in numerous diseases. Accordingly, the discovery and development of substances that inhibit apoptosis and ferroptosis are actively underway for disease research and treatment.

[0008] Recently, numerous inhibitors of apoptosis and ferroptosis have been developed and released. A representative apoptosis inhibitor is IM-54, and ferroptosis inhibitors, such as radical-trapping antioxidants (RTAs), include ferrostatin-1 (Fer-1), UAMC-3203, liproxstatin-1 (Liprox-1), 2-(1-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine, and 3-CF3-8-tBu-phenoxazine (see Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors. Trends in Pharmacological Sciences. Sep. 26, 2023). However, these inhibitors have faced challenges in developing therapeutics.

[0009] Therefore, there is an urgent need to develop new cell necrosis and ferroptosis inhibitors for disease prevention and treatment.

[0010] The present inventors conducted research on whether the compound of chemical formula 1 of the present invention exhibits pharmaceutically significant efficacy against necrosis, which is an unregulated cell death, and ferroptosis, which is a regulated cell death, as a novel structure distinct from phenothiazine and phenoxazine, which are in the form of a 6-membered tricycle, and confirmed its efficacy. Accordingly, the present inventors continuously conducted research on various compounds that exhibit preventive or therapeutic and ameliorating effects on diseases related to necrosis and ferroptosis, and thereby synthesized novel compounds and confirmed their effects, thereby completing the present invention.

[0011] An object of the present invention is to provide a novel compound of chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0012] In addition, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating a disease related to cell necrosis or ferroptosis, which comprises a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0013] Hereinafter, the present invention will be described in detail by way of an example.

[0014] In the definition of a substituent according to the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. The alkyl may be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety.

[0015] “Alkenyl” refers to a group containing at least one carbon-carbon double bond, and “alkynyl” refers to a group containing at least one carbon-carbon triple bond. Alkenyl and alkynyl can refer to straight-chain or branched-chain acyclic hydrocarbons.

[0016] An alkyl group may have from 1 to 20 carbon atoms unless otherwise defined. An alkyl group may be a medium-sized alkyl having from 1 to 10 carbon atoms. An alkyl group may be a lower alkyl having from 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. For example, C 1-4 Alkyl has 1 to 4 carbon atoms in the alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.

[0017] The term 'alkylene' refers to a divalent hydrocarbon group in which a radical is further formed from the above alkyl, examples of which include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene.

[0018] The term 'alkoxy', unless otherwise defined, means alkyloxy, examples of which include, but are not limited to, methoxy, ethoxy, and propoxy.

[0019] The term 'haloalkyl' can mean -RX (wherein X is one or more halogens (F, Cl, Br, or I, etc.)), i.e., "haloalkyl" can be an alkyl form substituted with one or more halogens. For example, " 1-8 “Haloalkyl” may include, but is not limited to, trifluoromethyl, difluoromethyl, etc.

[0020] The term "cycloalkyl" refers to a saturated or unsaturated aliphatic ring, unless otherwise defined. Furthermore, the ring may contain from 3 to 12 atoms. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] The term 'heterocycloalkyl' means a cycloalkyl as defined above containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, unless otherwise defined. A heterocycloalkyl may be monocyclic or polycyclic, such as a spiro ring, a bridged ring or a fused ring. Examples of heterocycloalkyl include, but are not limited to, pyrrolidine, piperidine, tetrahydropyran, oxetane, thiopyran and similar groups.

[0022] The term 'aryl' includes at least one ring having a shared pi electron system, for example a monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group. That is, as used herein, unless otherwise defined, aryl means a 4- to 10-membered, preferably 6- to 10-membered aromatic monocyclic or multicyclic ring, including phenyl, naphthyl, etc.

[0023] The term 'heteroaryl', unless otherwise defined, contains one to three heteroatoms selected from the group consisting of N, O and S, and is selected from the group consisting of benzo or C 3-8 It refers to an aromatic 3-10 membered ring, preferably a 4-8 membered ring, and more preferably a 5-6 membered ring, which can be fused with a cycloalkyl. Examples of monocyclic heteroaryl include, but are not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and similar groups. Examples of bicyclic heteroaryl include, but are not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine and similar groups.

[0024] The term 'non-hydrogen substituent' refers to a substituent other than hydrogen among the substituents defined in the present invention.

[0025] Terms and abbreviations used in this specification may be interpreted as having the meaning commonly understood by those skilled in the art to which the present invention pertains, unless otherwise defined.

[0026] As used herein, “hydrate” may refer to a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound represented by the above chemical formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent, preferably, 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by the above chemical formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

[0027] As used herein, the term "solvate" may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0028] As used herein, “stereoisomer” may mean a compound of the present invention that has the same chemical formula or molecular formula but is sterically different. In the present invention, stereoisomers include “enantiomers” and “diastereomers,” and diastereomers also include conformational isomers such as rotamers and cis / trans isomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention.

[0029] The present invention provides a compound of the following chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[0030] [Chemical Formula 1]

[0031]

[0032] In the above chemical formula 1,

[0033] R 1 are each independently hydrogen, halogen, -OC 1-4 Haloalkyl, -NH-C 3-6 Cycloalkyl, or -O-5 to 10-membered aryl,

[0034] R 2 is hydrogen, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Alkylene-OH, -C 1-8 Alkoxy, -C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, - C 1-8 alkylene-C 1-8 Alkoxy, or -L 1 -W 1 And,

[0035] L 1 is a direct bond, or -O-, -O-(CH2) m -, or -(CH2) m - and m is an integer from 1 to 4,

[0036] W 1 Silver -NR 8 R 9 , -C 3-8 Cycloalkyl, heterocycloalkyl of -5 to 11 atoms or aryl of -5 to 10 atoms, wherein aryl of 5 to 10 atoms is halogen, -C 1-4 Alkoxy and -OC 1-4 It may be substituted with one or more selected from the group consisting of haloalkyl,

[0037] R 8 and R 9 are each independently hydrogen or -C1-6 It is alkyl,

[0038] R 3 is hydrogen, halogen, -C 1-8 Alkylene-OH, or -L 2 -X 1 and,

[0039] L 2 -C(=O)-, -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH2) n - and n is an integer from 1 to 4,

[0040] X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl,

[0041] X 1 Heterocycloalkyl of -5 to 11 atoms is -C 1-4 Alkyl, -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NH-C 1-4 alkyl, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 10-membered heterocycloalkyl, -C(=O)-5 to 10-membered aryl, -C(=O)-5 to 10-membered heteroaryl, and -(CH2) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the aryl having 5 to 10 atoms or the heteroaryl having 5 to 10 atoms may be substituted with halogen, and o is an integer from 1 to 4,

[0042] R 4 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-4 Haloalkyl, -C1-3 alkylene-C 1-4 Alkoxy, -C 2-6 Alkenyl, -C 1-4 Alkoxy, -C 1-4 Alkylene-OH, -C 3-8 Cycloalkyl, aryl of -5 to 10 atoms, or aryl of -O-5 to 10 atoms, wherein aryl is -CN, -C(=O)NR 8 R 9 , -NHS(=O)2R 9 or -S(=O)2R 9 is unsubstituted or substituted with one or more substituents selected from the group consisting of

[0043] R 5 is hydrogen, halogen, -CN, -C 1-8 Alkyl, -(OC 1-4 alkylene) p -Alkoxy, -(C 1-4 alkylene-O) p -R 9 , -C 1-4 Alkylene-OC 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -C 1-4 Alkoxy, or -L 3 -Z 1 , p is an integer from 1 to 4, and R 5 can be substituted with -OH,

[0044] L 3 is a direct bond, or -NH-, -C 1-4 Alkylene-, -O-(C 1-4 alkylene)-, or -(C 1-4 alkylene)-O-,

[0045] Z 1 is -C 3-8 Cycloalkyl, heterocycloalkyl having 5 to 11 atoms, aryl having 5 to 10 atoms or heteroaryl having 5 to 10 atoms, Z 1 Silver -C(=O)NR 8 R 9 , -C 1-4 alkylene-C 1-4 Alkoxy, -C 1-4which may be substituted with one or more substituents selected from the group consisting of alkoxy, and -CN,

[0046] R 6 and R 7 are each independently -C 1-6 Alkyl or R 6 and R 7 are connected to each other -C 3-6 Forms cycloalkyl,

[0047] R 1 Inland R 3 At least one of them is not hydrogen, and R 4 and R 5 At least one of them is not hydrogen.

[0048] According to a specific example of the present invention,

[0049] R 1 and R 4 is hydrogen,

[0050] R 2 is hydrogen, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, - C 1-8 alkylene-C 1-8 Alkoxy, or -L 1 -W 1 And,

[0051] L 1 is a direct bond, or -O-, -O-(CH2) m -, or -(CH2) m - and m is an integer from 1 to 4,

[0052] W 1 Silver -NR 8 R 9 , -C 3-8 Cycloalkyl, heterocycloalkyl of -5 to 11 atoms or aryl of -5 to 10 atoms, wherein aryl of 5 to 10 atoms is halogen, -C 1-4 Alkoxy and -OC 1-4It may be substituted with one or more selected from the group consisting of haloalkyl,

[0053] R 3 is hydrogen, halogen, -C 1-8 Alkylene-OH, or -L 2 -X 1 and,

[0054] L 2 is -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH2) n - and n is an integer from 1 to 4,

[0055] X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl,

[0056] X 1 Heterocycloalkyl of -5 to 11 atoms is -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 11-membered heterocycloalkyl, and -(CH2) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the heteroaryl having 5 to 10 atoms is unsubstituted, and o can be an integer from 1 to 4.

[0057] According to one specific example of the present invention,

[0058] R 1 , R 2 and R 4 is hydrogen,

[0059] R 3 is hydrogen, halogen, -C 1-8Alkylene-OH, or -L 2 -X 1 and,

[0060] L 2 is -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH2) n - and n is an integer from 1 to 4,

[0061] X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl,

[0062] X 1 Heterocycloalkyl of -5 to 11 atoms is -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 11-membered heterocycloalkyl, and -(CH2) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the heteroaryl having 5 to 10 atoms is unsubstituted, and o can be an integer from 1 to 4.

[0063] According to one specific example of the present invention,

[0064] R 1 , R 2 , and R 4 is hydrogen,

[0065] R 3 is -L 2 -X 1 and,

[0066] L 2 is -C(=O)NH-C 1-4 Alkylene- or -(CH2) n- and n is an integer from 1 to 4,

[0067] X 1 is morpholinyl, piperidinyl or piperazinyl,

[0068] X 1 Silver -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, and -OC 1-4 Alkylene-NH-C 1-4 is unsubstituted or substituted with one or more substituents selected from the group consisting of alkylene-OH, and o is an integer from 1 to 4,

[0069] R 5 is -(OC 1-4 alkylene) p -Alkoxy, -(C 1-4 alkylene-O) p -R 9 , -C 1-4 Alkylene-OC 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -C 1-4 Alkoxy, or -L 3 -Z 1 , p is an integer from 1 to 4, and R 5 can be substituted with -OH,

[0070] L 3 is a direct bond, or -C 1-4 Alkylene-, -O-(C 1-4 alkylene)-, or -(C 1-4 alkylene)-O-,

[0071] Z 1 is -C 3-8 It may be cycloalkyl, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, piperidine, piperazine, oxazepaine, pyrazole, imidazole or pyridine.

[0072] According to one specific example of the present invention,

[0073] R 1 , R 2 and R 5 is hydrogen,

[0074] R 4 is -C 1-6 Alkyl, -OC 1-4 Haloalkyl, -C 1-3 alkylene-C 1-4 Alkoxy, -C 2-6 Alkenyl, -C 1-4 Alkoxy, -C 1-4 It may be alkylene-OH.

[0075] According to one specific example of the present invention,

[0076] R 3 If R is not hydrogen, 1 and R 2 is hydrogen, or

[0077] R 6 and R 7 These ethyl groups or are linked to each other -C 3-6 When forming a cycloalkyl, R 4 and R 5 can all be hydrogen.

[0078] According to one specific example of the present invention, R 6 and R 7 can each independently be -CH3 or -CH2CH3.

[0079] According to a specific example of the present invention, R 1 are each independently hydrogen, halogen, -OC 1-4 Haloalkyl, -NH-C 3-6 Cycloalkyl, or -O-5 to 6-membered aryl.

[0080] According to a specific example of the present invention, R 2 is hydrogen, hydroxy, halogen, -C 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, - C 1-4alkylene-C 1-4 Alkoxy, or -L 1 -W 1 And,

[0081] L 1 is a direct bond, or -O-, -O-(CH2) m -, or -(CH2) m - and m is an integer from 1 to 2,

[0082] W 1 Silver -NR 8 R 9 , -C 3-6 Cycloalkyl, -5 to 7-membered heterocycloalkyl or -5 to 6-membered aryl, wherein the 5 to 6-membered aryl is halogen, -C 1-4 Alkoxy and -OC 1-4 It may be substituted with one or more selected from the group consisting of haloalkyl,

[0083] R 8 and R 9 are each independently hydrogen or -C 1-4 It could be an alkyl.

[0084] According to a specific example of the present invention, R 3 is hydrogen, halogen, -C 1-4 Alkylene-OH, or -L 2 -X 1 and,

[0085] L 2 -C(=O)-, -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH2) n - and n is an integer from 1 to 2,

[0086] X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl,

[0087] X 1 Heterocycloalkyl of -5 to 11 atoms is -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -C 1-4Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NH-C 1-4 alkyl, -NR 9 -C 1-4 Alkylene-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 7-membered heterocycloalkyl, -C(=O)-5 to 6-membered aryl, -C(=O)-5 to 7-membered heteroaryl, and -(CH2) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 7 atoms, wherein the aryl having 5 to 6 atoms or the heteroaryl having 5 to 7 atoms may be substituted with halogen, and o may be an integer of 1 to 2.

[0088] X 1 -NR of 8 R 9 is -N(C 1-4 alkyl)(C 1-4 alkyl), or -NHC 1-4 It could be an alkyl.

[0089] X 1 The 5 to 11-membered heterocycloalkyl may be a 5 to 11-membered heterocycloalkyl containing at least one N, and more specifically may be piperazine, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, diazaspiro[5.5]undecane, diazaspiro[3.5]nonane, diazaspiro[3.3]heptane, diazabicyclo[3.2.1]octane, morpholine, piperidine, thiomorpholine, thiomorpholine 1,1-dioxide, or pyrrolidine.

[0090] -L 2 -X 1 Is

[0091]

[0092]

[0093] According to a specific example of the present invention, R 4 is hydrogen, halogen, -C 1-4 Alkyl, -OC 1-4 Haloalkyl, -C 1-3 alkylene-C 1-4 Alkoxy, -C 2-6 Alkenyl, -C 1-4 Alkoxy, -C 1-4 Alkylene-OH, -C 3-6 Cycloalkyl, aryl of -5 to 6 atoms, or aryl of -O-5 to 6 atoms, wherein aryl is -CN, -C(=O)NR 8 R 9 , -NHS(=O)2R 9 or -S(=O)2R 9 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of .

[0094] According to a specific example of the present invention, R 5 is hydrogen, halogen, -CN, -C 1-4 Alkyl, -(OC 1-4 alkylene) p -Alkoxy, -(C 1-4 alkylene-O) p -R 9 , -C 1-4 Alkylene-OC 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -C 1-4 Alkoxy, or -L 3 -Z 1 , p is an integer from 1 to 2, and R 5 can be substituted with -OH,

[0095] L 3 is a direct bond, or -NH-, -C 1-4 Alkylene-, -O-(C 1-4 alkylene)-, or -(C 1-4 alkylene)-O-,

[0096] Z 1 is -C 3-6Cycloalkyl, heterocycloalkyl having 5 to 11 atoms, aryl having 5 to 6 atoms or heteroaryl having 5 to 7 atoms, Z 1 Silver -C(=O)NR 8 R 9 , -C 1-4 alkylene-C 1-4 Alkoxy, -C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkoxy, -OH, and -CN.

[0097] The above R 5 of -(OC 1-4 alkylene) p and -(C 1-4 alkylene-O) p is -OC 1-4 Alkylene- or -C 1-4 Alkylene-O- means a divalent group in which p is repeated, and the number of carbon atoms in the alkylene groups in the p repetitions can be different or the same. Specifically, -(OC 1-4 alkylene) p -Alkoxy is -OC 1-4 Alkylene-alkoxy, or -OC 1-4 Alkylene-OC 1-4 It can be alkylene-alkoxy, -(C 1-4 alkylene-O) p -R 9 is -C 1-4 alkylene-OR 9 , or -C 1-4 Alkylene-OC 1-4 alkylene-OR 9 It could be.

[0098] The above Z 1 It can be phenyl, cyclohexyl, cyclopropyl, cyclobutyl, tetrahydro-2H-pyran, oxetane, morpholine, thiomorpholine, thiomorpholine-S,S-oxide, azetedine, piperidine, piperazine, oxazepaine, pyrazole, imidazole, or pyridine.

[0099] According to one specific example of the present invention, R 3 If R is a non-hydrogen substituent, 2can be hydrogen, R 1 and R 2 If is hydrogen, R 3 It may be a non-hydrogen substituent.

[0100] According to one specific example of the present invention, R 5 is hydrogen, and R 6 and R 7 If this is a methyl group, R 4 may be a non-hydrogen substituent.

[0101] According to one specific example of the present invention, R 6 and R 7 If these are not methyl groups, specifically, they are all ethyl or linked together to form -C 3-6 When forming a cycloalkyl, R 1 Inland R 3 Two of them are hydrogen and one is a non-hydrogen substituent, or R 4 and R 5 Either one of them can be hydrogen and either one can be a non-hydrogen substituent.

[0102] According to one embodiment of the compound of chemical formula 1 of the present invention, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof,

[0103] The compound of the above chemical formula 1 may be characterized by being any one selected from the following group of compounds:

[0104] <1> 2-Bromo-7,9,9-trimethyl-9,10-dihydroacridine; <2> 6-methoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <3> 6-methoxy-9,9-dimethyl-2-((4-(oxetan-3-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <4> 2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethan-1-ol; <5> 2-((2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethyl)amino)ethan-1-ol; <6> 2-Isopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <7> 2-Cyclopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <8> 2-(tert-butyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <9> 1-(6-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <10> 3-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <11> 8-Bromo-9,9-dimethyl-9,10-dihydroacridin-3-ol; <12> 1-Bromo-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <13> 6-(Difluoromethoxy)-2-isopropyl-9,9-dimethyl-9,10-dihydroacridine; <14> 2-Isopropyl-9,9-dimethyl-6-(2,2,2-trifluoroethoxy)-9,10-dihydroacridine; <15> 1-Chloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine; <16> (9,9-dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone; <17> 2-Bromo-10H-spiro[acridine-9,1'-cyclopentane]; <18> 3-Ethoxy-10H-spiro[acridine-9,1'-cyclopentane]; <19> N,N-Dimethyl-1-(10H-spiro[acridin-9,1'-cyclopentan]-2-yl)methanamine;<20> Cyclopropyl(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone; <21> 6-(tert-butyl)-9,9-dimethyl-2-(trifluoromethyl)-9,10-dihydroacridine; <22> 9,9-diethyl-3-methoxy-9,10-dihydroacridine; <23> 3-chloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <24> 1-chloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <25> 3-chloro-6,9,9-trimethyl-9,10-dihydroacridine; <26> 2-chloro-6,9,9-trimethyl-9,10-dihydroacridine; <27> 1-chloro-6,9,9-trimethyl-9,10-dihydroacridine; <28> 7-Bromo-1-chloro-9,9-dimethyl-9,10-dihydroacridine; <29> 5-chloro-3-methoxy-9,9-dimethyl-9,10-dihydroacridine; <30> 2-Bromo-6-chloro-9,9-dimethyl-9,10-dihydroacridine; <31> 2-Bromo-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <32> 2-Bromo-6-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridine; <33> 2-(tert-butyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <34> 3-(tert-butyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <35> 2-Bromo-7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridine; <36> 3-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <37> 1-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <38> 2-Bromo-9,9-diethyl-9,10-dihydroacridine; <39> 6-(tert-butyl)-2-fluoro-9,9-dimethyl-9,10-dihydroacridine; <40> 6-(tert-butyl)-2-chloro-9,9-dimethyl-9,10-dihydroacridine; <41> 2-(tert-butyl)-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <42> 2-Bromo-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine;<43> 2-Bromo-6-fluoro-9,9-dimethyl-9,10-dihydroacridine; <44> 2-Bromo-6,9,9-trimethyl-9,10-dihydroacridine; <45> 7-Bromo-1-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <46> 2-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <47> 2-Isopropyl-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <48> 7-Bromo-3-chloro-1,9,9-trimethyl-9,10-dihydroacridine; <49> 7-Bromo-1-chloro-3,9,9-trimethyl-9,10-dihydroacridine; <50> 1-chloro-6-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <51> 3-chloro-6-methoxy-1,9,9-trimethyl-9,10-dihydroacridine; <52> 1,3-Dichloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <53> 1-chloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <54> 3-chloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <55> 1,3-Dichloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <56> 1,3-Dichloro-9,9-dimethyl-8-(trifluoromethoxy)-9,10-dihydroacridine; <57> 2-Bromo-6-chloro-9,9-diethyl-9,10-dihydroacridine; <58> 2,9,9-trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <59> 1,9,9-trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <60> 3,9,9-trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <61> 6-(tert-butyl)-1-chloro-9,9-dimethyl-9,10-dihydroacridine; <62> 1-Chloro-6-isopropyl-9,9-dimethyl-9,10-dihydroacridine; <63> 2-(8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)propan-2-ol; <64> 1-Chloro-6-cyclopropyl-9,9-dimethyl-9,10-dihydroacridine;<65> 1-Chloro-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <66> 1-Chloro-9,9-dimethyl-8-phenoxy-9,10-dihydroacridine; <67> 2-methoxy-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <68> 1-(7-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <69> 6-(tert-butyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <70> 1-(8-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <71> 2-(tert-butyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <72> 1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N-methylmethanamine; <73> 9,9-Diethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <74> 2-(piperazin-1-ylmethyl)-10H-spiro[acridine-9,1'-cyclopentane]; <75> 2-((2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <76> 2-((2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <77> 2-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <78> 2-((3,5-dimethylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <79> 2-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <80> 2-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <81> 2-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine;<82> 2-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <83> 2,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <84> 2-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <85> 2-((3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <86> 6-Fluoro-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <87> 6,9,9-Trimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <88> 6-methoxy-9,9-dimethyl-2-((4-phenylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <89> 2-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <90> 2-((4-(4-chlorobenzyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <91> 6-methoxy-9,9-dimethyl-2-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <92> (4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)(phenyl)methanone; <93> (4-chlorophenyl)(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone; <94> 6-methoxy-9,9-dimethyl-2-((4-phenethylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <95> 6-methoxy-9,9-dimethyl-2-((4-propylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <96> 2-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <97> 6-methoxy-9,9-dimethyl-2-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine;<98> 2-((4-cyclopropylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <99> 6-methoxy-9,9-dimethyl-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <100> 7-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-1-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <101> 4-((7,9,9-trimethyl-9,10-dihydroacridin-3-yl)methyl)morpholine; <102> 2,9,9-trimethyl-6-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <103> 4-((7,9,9-trimethyl-9,10-dihydroacridin-3-yl)methyl)thiomorpholine 1,1-dioxide; <104> 6-(Ethoxymethyl)-9,9-dimethyl-2-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <105> 4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)thiomorpholine; <106> 4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)thiomorpholine 1,1-dioxide; <107> 6-(Ethoxymethyl)-9,9-dimethyl-2-(pyrrolidin-1-ylmethyl)-9,10-dihydroacridine; <108> 2-((4-benzylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <109> 6-Methoxy-9,9-dimethyl-2-((4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <110> 6-methoxy-9,9-dimethyl-2-((4-oxetan-3-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <111> 2-((4-cyclopentylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <112> 2-((4-(cyclopentylmethyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <113> 6-methoxy-9,9-dimethyl-2-((4-(tetrahydrofuran-3-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine;<114> 2-((4-cyclohexylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <115> 6-methoxy-9,9-dimethyl-2-((4-(oxepan-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <116> 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethan-1-ol; <117> 2-(2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethoxy)ethan-1-ol; <118> 2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol; <119> 3-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)propan-1-ol; <120> 4-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)-2-methylbutan-2-ol; <121> 5-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)pentan-1-ol; <122> 2-(2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethoxy)ethan-1-ol; <123> N-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)propan-1-amine; <124> 2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)(methyl)amino)ethan-1-ol; <125> 1-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)-2-methylpropan-2-ol; <126> 2-((2-(4-((9,9-dimethyl-6-morpholino-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol;<127> 2-(2-(4-((6-ethoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethan-1-ol; <128> 2-((2-(4-((6-ethoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol; <129> 2-Cyclopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <130> 2-Isopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <131> 2,9,9-trimethyl-6-phenoxy-9,10-dihydroacridine; <132> 9,9-Dimethyl-6-phenoxy-2-(prop-1-en-2-yl)-9,10-dihydroacridine; <133> 1-chloro-9,9-dimethyl-6-phenyl-9,10-dihydroacridine; <134> 1-Chloro-6-ethyl-9,9-dimethyl-9,10-dihydroacridine; <135> 1-Chloro-9,9-dimethyl-6-propyl-9,10-dihydroacridine; <136> 3,9,9-trimethyl-6-(2,2,2-trifluoroethyl)-9,10-dihydroacridine; <137> 1-Chloro-9,9-dimethyl-6-(2,2,2-trifluoroethyl)-9,10-dihydroacridine; <138> 1,3-Dichloro-9,9-dimethyl-6-phenyl-9,10-dihydroacridine; <139> 1,3-Dichloro-6-(4-chlorophenyl)-9,9-dimethyl-9,10-dihydroacridine; <140> 1,3-Dichloro-6-(4-methoxyphenyl)-9,9-dimethyl-9,10-dihydroacridine; <141> 1,3-Dichloro-9,9-dimethyl-6-(4-(trifluoromethoxy)phenyl)-9,10-dihydroacridine; <142> 6-(2-ethoxyethyl)-2,9,9-trimethyl-9,10-dihydroacridine; <143> 2-Isopropyl-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <144> 4-(7-isopropyl-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <145> 2-Isopropyl-9,9-dimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <146> 2,9,9-trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine;<147> 4-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <148> 2,9,9-trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <149> 1,9,9-trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <150> 3,9,9-trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <151> 4-(8,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <152> 4-(6,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <153> 1,9,9-trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <154> 3,9,9-trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <155> 4-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)thiomorpholine 1,1-dioxide; <156> 1,3-Dichloro-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <157> 4-(6,8-dichloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <158> 4-(2-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)ethyl)morpholine; <159> 2,9,9-Trimethyl-6-(2-(piperidin-1-yl)ethyl)-9,10-dihydroacridine; <160> 2,9,9-Trimethyl-6-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine; <161> 4-(2-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)ethyl)thiomorpholine 1,1-dioxide; <162> 4-(7-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <163> 2-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <164> 4-(2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)ethyl)morpholine; <165> 1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <166> 6-chloro-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine;<167> 3-methoxy-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <168> 9,9-Dimethyl-6-phenoxy-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <169> 1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <170> 1-methoxy-3,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <171> (9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methanol; <172> (9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)methanol; <173> 1-Chloro-3,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <174> 3-chloro-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <175> 1-Chloro-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <176> 1-Chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <177> 2-chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <178> 3-chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <179> 6-(ethoxymethyl)-1,9,9-trimethyl-9,10-dihydroacridine; <180> 1-Chloro-6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridine; <181> 1,3-Dichloro-6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridine; <182> 1-Chloro-6-(ethoxymethyl)-3,9,9-trimethyl-9,10-dihydroacridine; <183> 3-chloro-6-(ethoxymethyl)-1,9,9-trimethyl-9,10-dihydroacridine; <184> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-((trifluoromethoxy)methyl)-9,10-dihydroacridine; <185> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(trifluoromethoxy)-9,10-dihydroacridine;<186> 9,9-Dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine-3-carbonitrile; <187> 6-((2-methoxyethoxy)methyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <188> 6-(Ethoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <189> 2-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <190> 1-Chloro-3-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <191> 3-chloro-1-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <192> 9,9-Dimethyl-6-(phenoxymethyl)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <193> 2-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <194> 6-(Ethoxymethyl)-9,9-diethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <195> 3-chloro-1-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <196> 6-(Butoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <197> 3-(Ethoxymethyl)-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <198> 1-Chloro-3-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <199> 6-(Ethoxymethyl)-2-(piperazin-1-ylmethyl)-10H-spiro[acridine-9,1'-cyclopentane]; <200> 9,9-Dimethyl-6-phenyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <201> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-N,N-dimethylbenzamide; <202> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-N-methylbenzamide;<203> 9,9-Dimethyl-2-phenyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <204> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N,N-dimethylbenzamide; <205> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <206> 1-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <207> 1-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <208> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)propan-2-ol; <209> 6-(methoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <210> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(1H-pyrazol-5-yl)-9,10-dihydroacridine; <211> 6-(1H-imidazol-1-yl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <212> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(pyridin-2-yl)-9,10-dihydroacridine; <213> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <214> 4-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methyl)morpholine; <215> 6-(1H-imidazol-2-yl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <216> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-1-yl)-9,10-dihydroacridine; <217> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)morpholine; <218> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)thiomorpholine; <219> 2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methoxy)ethan-1-ol;<220> 3-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <221> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <222> N-(4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)phenyl)methanesulfonamide; <223> 2-(2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methoxy)ethoxy)ethan-1-ol; <224> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)thiomorpholine 1,1-dioxide; <225> 9,9-Dimethyl-6-(piperazin-1-yl)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <226> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-1,4-oxazepaine; <227> 9,9-Dimethyl-N-phenyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <228> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)benzonitrile; <229> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)benzonitrile; <230> 9,9-Dimethyl-2-(4-(methylsulfonyl)phenyl)-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <231> 9,9-Dimethyl-2-(2-(methylsulfonyl)phenyl)-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <232> N-(2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)phenyl)methanesulfonamide; <233> 4-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide; <234> 3-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide; <235> 2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide;<236> N-(4-(ethoxymethyl)phenyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <237> N-(2-(ethoxymethyl)phenyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <238> 7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol; <239> 6-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol; <240> 9,9-Diethyl-9,10-dihydroacridin-3-ol; <241> 6,8-Dichloro-9,9-dimethyl-9,10-dihydroacridin-3-ol; <242> 8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-ol; <243> 3-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <244> 2-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <245> 3-Ethoxy-9,9-diethyl-9,10-dihydroacridine; <246> 1-Chloro-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <247> 3-chloro-6-ethoxy-1,9,9-trimethyl-9,10-dihydroacridine; <248> 1-Chloro-6-ethoxy-3,9,9-trimethyl-9,10-dihydroacridine; <249> 1-Chloro-6-(difluoromethoxy)-9,9-dimethyl-9,10-dihydroacridine; <250> 1,3-Dichloro-6-(difluoromethoxy)-9,9-dimethyl-9,10-dihydroacridine; <251> 1,3-Dichloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine; <252> 1,3-Dichloro-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <253> 6-(difluoromethoxy)-2,9,9-trimethyl-9,10-dihydroacridine; <254> 6-Ethoxy-1,9,9-trimethyl-9,10-dihydroacridine; <255> 1-Chloro-9,9-dimethyl-6-(2-(piperidin-1-yl)ethoxy)-9,10-dihydroacridine; <256> 4-(2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine;<257> 1-Chloro-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <258> 4-(2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)thiomorpholine 1,1-dioxide; <259> 2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-N-methylethan-1-amine; <260> 2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-N,N-dimethylethan-1-amine; <261> 6-Ethoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <262> 6-(cyclohexylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <263> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-9,10-dihydroacridine; <264> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-4-ylmethoxy)-9,10-dihydroacridine; <265> 6-(Cyclopropylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <266> 4-(2-((6,8-dichloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine; <267> 1,3-Dichloro-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <268> 4-(2-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine; <269> 6-Isopropoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <270> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-propoxy-9,10-dihydroacridine; <271> 9,9-dimethyl-6-(neopentyloxy)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <272> 6-(Cyclobutylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <273> 6-(2-methoxyethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine;<274> 3-(Ethoxymethyl)-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <275> 9,9-Dimethyl-6-(oxetan-3-ylmethoxy)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <276> 1-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)oxy)-2-methylpropan-2-ol; <277> 6-(azetidin-3-ylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <278> 6-(2-methoxy-2-methylpropoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <279> 1-(((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)oxy)methyl)cyclopropan-1-ol; <280> 6-((1-methoxycyclopropyl)methoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <281> 9,9-Dimethyl-N-(2-(methylamino)ethyl)-9,10-dihydroacridine-2-carboxamide; <282> 9,9-Dimethyl-N-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine-2-carboxamide; <283> (4-(cyclopentylamino)-9,9-dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone; <284> 4-(cyclopentylamino)-9,9-dimethyl-N-(2-(methylamino)ethyl)-9,10-dihydroacridine-2-carboxamide and <285> 4-(Cyclopentylamino)-9,9-dimethyl-N-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine-2-carboxamide.;

[0105] The present invention also provides a pharmaceutical composition comprising a compound of the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0106] Specifically, the present invention provides a pharmaceutical composition for preventing or treating a disease related to cell necrosis or ferroptosis, comprising a compound of the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0107] Another aspect of the present invention provides a method for preventing or treating a disease related to cell necrosis or ferroptosis, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of the above chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0108] The above-mentioned cell necrosis or ferroptosis-related diseases include acute or chronic liver diseases including hepatitis, liver fibrosis or cirrhosis; neurodegenerative diseases including dementia including Alzheimer's disease and vascular dementia, Parkinson's disease, epilepsy, dementia with Lewy bodies or Huntington's disease; ischemic diseases including ischemic heart disease, reperfusion injury, ischemic stroke or ischemic injury; pancreatitis, bacterial or viral sepsis, diabetes or diabetic complications, diabetic vascular disease; Necrotizing proctitis, cystic fibrosis, rheumatoid arthritis, osteoarthritis, nephrotic syndrome, bacterial infections, viral infections including SARS-CoV or HIV, multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, asphyxia, tuberculosis, endometriosis, vascular insufficiency, psoriasis, frostbite, course / complication of steroid injections, vibrio sepsis, tenderness, hemoglobinuria, burns, hyperpyrexia, Crohn's disease, celiac disease, compartment syndrome, spinal cord injury, glomerulonephritis, renal failure, muscular dystrophy, metabolic inherited disorders, mycoplasma infection, anthrax, Anderson's disease, Fabry disease, congenital mitochondrial diseases, phenylketonuria, placental infarction, syphilis, and aseptic necrosis; It may be at least one selected from the group consisting of necrosis associated with exposure to or administration or self-administration of antibiotics, anticancer agents, drugs including doxorubicin, puromycin, bleomycin, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclosporine; chemical toxins including carbon tetrachloride, cyanide, methanol, or ethylene glycol; toxic gases, pesticides, heavy metals including lead, mercury, or cadmium; damage caused by exposure to radiation or ultraviolet rays and cell necrosis associated therewith;

[0109] In addition, the compound of the above chemical formula 1 is expected to exhibit preventive or therapeutic and improvement effects in acute or chronic kidney disease, traumatic brain injury, necrotizing enterocolitis, viral infections including SARS-CoV, skin diseases including psoriasis and allergic dermatitis, organ preservation or organ transplantation (see Korean Patent Nos. 10-1098583 and 10-1941004).

[0110] In addition, the compound of formula 1 can inhibit cell death through ferroptosis caused by the Fenton reaction by ferroptosis-inducing substances such as RSL3, erastin or glutamate and lipid peroxide accumulation resulting from GPX4 pathway interference.

[0111] Therefore, a pharmaceutical composition comprising the compound of chemical formula 1 may exhibit preventive, therapeutic, and ameliorating effects on cell necrosis or ferroptosis diseases. Related diseases include the following.

[0112] Chronic inflammatory pulmonary disease including acute respiratory distress syndrome or acute lung disease, pneumonia, tuberculosis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (see Mitochondrial dysfunction in fibrotic diseases. Cell Death Discov. 2020 Sep 5; 6:80., Mitochondrial dysfunction in lung aging and diseases. Eur Respir Rev. 2020 Oct 15; 29(157): 200165., and Korean registered patent 10-1636563);

[0113] Demyelination and demyelinating diseases including amyotrophic lateral sclerosis (ALS), hypertension including pulmonary hypertension, stroke, prion disease, epilepsy, ataxia, migraine, memory and cognitive decline, seizures, tremors, or psychiatric disorders including depression (see Neuronal and glial calcium signaling in Alzheimer's disease. Cell Calcium. Oct-Nov 2003;34(4-5):385-97., Mitochondrial disorders: challenges in diagnosis & treatment. Indian J Med Res. 2015 Jan;141(1):13-26.);

[0114] Spinocerebellar degeneration including Friedreich's ataxia (see Ferroptosis in Friedreich's Ataxia: A Metal-Induced Neurodegenerative Disease. Biomolecules. 2020 Nov 13; 10(11): 1551., The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 2023 Jan; 20(1): 7-23.);

[0115] Insulin resistance, dyslipidemia including hyperlipidemia, atherosclerosis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis;

[0116] Various cancers and cancer metastasis (see Reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 2014 Jul 20; 21(3): 396-413.);

[0117] Diseases associated with visual impairment including macular degeneration, retinitis pigmentosa, cataracts, and glaucoma, anemia, cholestasis, hypoparathyroidism, pancytopenia, pancreatic disorders, lactic acidosis, lactic acidemia, hearing loss, short stature, intestinal obstruction, cardiac conduction defects including arrhythmia, cardiomyopathy, myocardial infarction, ischemia-reperfusion heart injury, heart failure, endometriosis, infertility, and premature menopause (Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol. 2018 Feb; 19(2): 77-92., Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. N Engl J Med. 1995 Sep 7;333(10):638-44.,Mitochondrial injury and dysfunction in hypertension-induced cardiac damage.Eur Heart J.2014 Dec 7; 35(46): 3258-3266. reference);

[0118] Muscular dystrophy diseases, including limb-girdle muscular dystrophy (LGMD), Becker muscular dystrophy (BMD), and Duchenne muscular dystrophy (DMD) (Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition. Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165674.);

[0119] Aging and Age-Related Diseases (Interrelation between ROS and Ca 2+ in aging and age-related diseases.Redox Biology.2020;6:101678. reference);

[0120] Neuropathic pain (Inhibition of ferroptosis-like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats. Eur J Pain. 2021 Jan; 25:1227-1240., Ferroptosis is involved in the development of neuropathic pain and allodynia.Mol Cell Biochem.2021 Aug; 476(8):3149-3161., Iron Metabolism and Ferroptosis in Peripheral Nerve Injury.Oxid Med Cell Longev.2022 Dec 2;2022:5918218.see);

[0121] Mucositis, including oral mucositis and gastrointestinal mucositis (see Emerging role of mitochondrial DAMPs, aberrant mitochondrial dynamics and anomalous mitophagy in gut mucosal pathogenesis.Life Sci.2022 Sep 15;305:120753., The Impacts of Iron Overload and Ferroptosis on Intestinal Mucosal Homeostasis and Inflammation,Int J Mol Sci.2022 Nov 17;23(22):14195.).

[0122] In the present invention, the disease related to cell necrosis or ferroptosis may specifically be a degenerative neurological disease, liver disease, kidney disease, stroke, myocardial infarction, ocular disease, or lung disease.

[0123] The above-mentioned neurodegenerative disease may be at least one selected from Alzheimer's Disease, Parkinson's Disease, Epilepsy, Huntington's Disease, Amyotrophic lateral sclerosis, Friedreich's ataxia, multiple sclerosis, Charcot-Marie-Tooth (CMT) disease, Dementia with Lewy Bodies, and Traumatic Brain Injury.

[0124] In this specification, “treatment” means stopping or delaying the progression of a disease, or reversing or alleviating its symptoms, when used on a subject exhibiting symptoms of the disease, and “prevention” means stopping or delaying the signs of the disease, when used on a subject not exhibiting symptoms of the disease but at high risk of such symptoms.

[0125] In the present invention, “administration” means providing a predetermined compound of the present invention to a subject by any appropriate method.

[0126] In the present invention, the “pharmaceutical composition” may include a pharmaceutically acceptable carrier as needed together with the compound of the present invention.

[0127] The compound of chemical formula 1 according to the present invention can be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, it is manufactured using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0128] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc., and these solid preparations are manufactured by mixing one or more compounds of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included.

[0129] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, glycerol, and gelatin.

[0130] In addition, the effective dosage for the human body of the compound of chemical formula 1 of the present invention may vary depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity, and is generally about 0.001-100 mg / kg / day, and preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, the dosage is generally 0.07-7000 mg / day, and preferably 0.7-2500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

[0131] A pharmaceutical composition containing the compound of the above chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or may be used in combination with other therapeutic agents currently in use.

[0132] Another aspect of the present invention is a method for treating a disease, comprising administering to a patient a compound of formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof,

[0133] A method for preventing or treating a disease related to cell necrosis or ferroptosis is provided, comprising administering to a subject a pharmaceutically effective amount.

[0134] In the present invention, the disease related to cell necrosis or ferroptosis may be accompanied by lipid peroxidation.

[0135] In the present invention, “lipid peroxidation” means oxidative decomposition of fats, oils, waxes, sterols, triglycerides, etc., and lipid peroxidation is considered to be one of the main causes of the development of various degenerative diseases.

[0136] Another aspect of the present invention provides a method for inhibiting ferroptosis, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0137] Another aspect of the present invention provides a method for inhibiting reactive oxygen species (ROS) in a cell, comprising the step of contacting the cell with a compound of formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0138] In the present invention, “reactive oxygen species (ROS)” refers to chemically active molecules containing oxygen, such as free radicals. Examples of reactive oxygen species include oxygen ions and peroxides. Ferroptosis is characterized by the rapid accumulation of reactive oxygen species in an iron-dependent manner, and the compound of Chemical Formula 1 can inhibit ferroptosis by suppressing reactive oxygen species.

[0139] In the present invention, the "subject" requiring administration may include both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, non-human primates such as chimpanzees or monkeys, and livestock animals such as cows, horses, and sheep.

[0140] The present invention provides a use of a compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the prevention or treatment of diseases related to cell necrosis or ferroptosis.

[0141] The use and preventive or therapeutic method of the present invention can be applied in accordance with the contents of the pharmaceutical composition above.

[0142] The compound of chemical formula 1 according to the present invention can exhibit apoptosis inhibition effect in various cells such as heart, kidney, nerve, retinal, liver, or lung cells, and in particular can efficiently inhibit ferroptosis.

[0143] Accordingly, the compound of chemical formula 1 according to the present invention can be usefully used for the prevention or treatment of diseases related to cell necrosis or ferroptosis of various cells.

[0144] Figure 1 is a graph showing the intracellular lipid reactive oxygen species regulating effects of compounds 15, 77, 96, 188, and 246 of the examples through RSL3 treatment of lung epithelial cells according to Experimental Example 4-1.

[0145] Figure 2 is a graph showing the intracellular lipid reactive oxygen species regulating effects of compounds 15, 77, 96, 188, and 246 of the examples through RSL3 treatment of retinal epithelial cells according to Experimental Example 4-2.

[0146] Figure 3 is a graph showing the intracellular lipid reactive oxygen species regulating effects of compounds 15, 73, 74, 77, 188, and 246 of the examples through RSL3 treatment in hippocampal neurons according to Experimental Example 4-3.

[0147] Figure 4 is a graph showing the intracellular iron ion regulation effect of Example compounds 15, 77, 96, 188, and 246 through RSL3 treatment on retinal epithelial cells according to Experimental Example 5-1.

[0148] Figure 5 is a graph showing the intracellular iron ion regulation effect of compounds 15, 77, 96, 188, and 246 of the examples through RSL3 treatment on lung epithelial cells according to Experimental Example 5-2.

[0149] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms. These embodiments are provided solely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the invention. The present invention is defined solely by the scope of the claims.

[0150] [Example]

[0151] The following manufacturing examples more specifically illustrate the preparation of intermediates necessary for the synthesis of the exemplary compounds according to the present invention. The abbreviations used in the manufacturing examples and examples below are as follows.

[0152]

[0153] AcOH: Acetic acid

[0154] ACN: Acetonitrile

[0155] BBr3: Boron tribromide

[0156] BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0157] Boc: t-Butoxycarbonyl

[0158] Boc2O: di-tert-butyl dicarbonate

[0159] n-BuLi: n-Butyl Lithium

[0160] t-BuONa: Sodium tert-butoxide

[0161] Cs2CO3: Cesium carbonate

[0162] Cu(OAc)2: Copper(II) acetate

[0163] DCE: 1,2-Dichloroethane

[0164] DCM: Dichloromethane

[0165] DIEA: N,N-Diisopropylethylamine {N,N-Diisopropylethylamine}

[0166] DIAD: Diisopropyl azodicarboxylate

[0167] DMAP: 4-Dimethylaminopyridine

[0168] DMF: N,N-dimethylformamide {N,N-dimethylformamide}

[0169] DMSO: Dimethylsulfoxide

[0170] EA: Ethyl acetate

[0171] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0172] EtOH: Ethyl alcohol {Ethanol}

[0173] EtI: 2-Iodoethyl {2-Iodoethyl}

[0174] HOBt: 1-Hydroxybenzotriazole

[0175] H3PO4: Phosphoric acid

[0176] Prep-HPLC: preparative-High Performance Liquid Chromatography

[0177] KHMDS: Potassium bis(trimethylsilyl)amide

[0178] KHF2: Potassium hydrogenfluoride

[0179] KI: Potassium iodide

[0180] K3PO4: Tripotassium phosphate

[0181] KOH: Potassium hydroxide

[0182] LAH: Lithium aluminum hydride

[0183] LCMS: Liquid chromatography mass spectrometry

[0184] MeOH: Methanol

[0185] MS: Molecular sieve

[0186] NaBH(OAc)3: Sodium triacetoxyborohydride

[0187] NaBH3CN: Sodium cyanoborohydride

[0188] Na2CO3: Sodium carbonate

[0189] NaHCO3: Sodium Bicarbonate

[0190] NaOH: Sodium hydroxide

[0191] NBS: N-Bromosuccinimide

[0192] Pd2(dba)3: Tris(dibenzyldenacetone)dipalladium

[0193] {Tris(dibenzylideneacetone)dipalladium}

[0194] Pd / C: Palladium on carbon

[0195] Pd(dppf)Cl2: [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride

[0196] Pd(OAc)2: Tris(dibenzyldenacetone)dipalladium

[0197] {Tris(dibenzylideneacetone)dipalladium}

[0198] PPh3: Triphenylphosphine

[0199] TEA: Triethylamine

[0200] TfOH: Triflic acid

[0201] THF: Tetrahydrofuran

[0202] TLC: Thin layer chromatography

[0203] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0204]

[0205] Synthetic Route I

[0206] Manufacturing Example M1: Methyl 5-bromo-2-(p-tolylamino)benzoate {methyl 5-bromo-2-(p-tolylamino)benzoate}

[0207]

[0208] p-Tolylboronic acid (2.36 g, 2 eq.) was added to DCM (40 mL), followed by methyl 2-amino-5-bromobenzoate (2 g, 1 eq.), Cu(OAc)2 (2.37 g, 1.5 eq.), TEA (3.63 mL, 3 eq.), and 4A MS (1 g), and stirred at 30°C for 12 h. The reaction was confirmed by LCMS, and the filtrate was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound as a yellow solid (2.3 g, 82%).

[0209] 1 H NMR (400 MHz, DMSO-d6) δ9.21 (br s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 9.2, 2.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 2.30 (s, 3H);

[0210] Manufacturing Example M2: 2-(5-bromo-2-(p-tolylamino)phenyl)propan-2-ol {2-(5-bromo-2-(p-tolylamino)phenyl)propan-2-ol}

[0211]

[0212] Manufacturing Example M1 Compound (2.3 g, 1 eq.) was added to THF (30 mL), and methylmagnesium bromide (3 M, 23.94 mL, 10 eq.) was added at 0°C, and the mixture was stirred at 50°C for 2 hours under nitrogen conditions. After confirming the reaction by LCMS, the mixture was extracted with saturated ammonium chloride aqueous solution (sat. NH4Cl, 80 mL) and EA (3 * 100 mL), and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (2.3 g, 99%).

[0213] 1 H NMR (400 MHz, DMSO-d6) δ8.37 (br s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 - 7.10 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 5.88 (br s, 1H), 2.37 (s, 3H), 1.52 (s, 6H);

[0214] Manufacturing Example M3-1 (Example 1): 2-bromo-7,9,9-trimethyl-9,10-dihydroacridine {2-bromo-7,9,9-trimethyl-9,10-dihydroacridine}

[0215]

[0216] Manufacturing Example M2 Compound (1 g, 1 eq.) was added to DCM (20 mL), and TfOH (2.76 mL, 10 eq.) was added at 0°C, followed by stirring for 1 h under nitrogen conditions at 0°C. After confirming the reaction by LCMS, saturated Na2SO4 aqueous solution was added to adjust the pH to 8-9, and extracted with DCM (3 * 50 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the title compound as a yellow oil (870 mg, 91%).

[0217] 1 H NMR (400 MHz, DMSO-d6) δ8.88 (br s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.13 - 7.23 (m, 2H), 6.84 - 6.92 (m, 1H), 6.64 - 6.76 (m, 2H), 2.23 (s, 3H), 1.47 (s, 6H);

[0218] Intermediate compounds in Table 1 below were prepared using the manufacturing methods of M1, M2, and M3-1 above. The chemical structures, compound names, and NMR analysis results of each intermediate compound are shown in Table 1.

[0219]

[0220]

[0221]

[0222]

[0223] Synthetic Route II

[0224] Manufacturing Example M4: tert-butyl 2-bromo-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-bromo-7,9,9-trimethylacridine-10(9H)-carboxylate}

[0225]

[0226] Example 46 (1.4 g, 1 eq.) was added to THF (20 mL), and DMAP (591.24 mg, 1.1 eq.) and Boc2O (1.15 g, 1.2 eq.) were added at 10°C, followed by stirring at 10°C for 12 hours. After confirming the reaction by TLC, water was added to stop the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the title compound as a colorless oil (2.1 g, crude).

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 7.2, 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.8 Hz, 1H), 3.75 (s, 3H), 1.46 (s, 9H), 1.45 (s, 6H);

[0228] Synthetic route II-a-1

[0229] Manufacturing Example M5: tert-butyl 2-formyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-formyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate}

[0230]

[0231] Manufacturing Example M4 Compound (500 mg, 1 eq.) was added to THF, n-BuLi (2.5 M, 717.15 μL, 1.5 eq.) was added at -60°C, and stirred for 30 minutes. DMF (551 μL, 6 eq.) was added at -60°C, and stirred for 12 minutes. After confirming the reaction by LCMS, saturated ammonium chloride aqueous solution was added, EA was added, and extraction was performed. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (93 mg, 21%).

[0232] 1 H NMR (400 MHz, CDCl3) δ9.99 (br s, 1H), 7.98 (s, 1H), 7.76 - 7.82 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.83 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H), 1.51 (s, 6H), 1.48 (s, 9H);

[0233] Manufacturing Example M5-1: tert-butyl 6-(ethoxymethyl)-2-formyl-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 6-(ethoxymethyl)-2-formyl-9,9-dimethylacridine-10(9H)-carboxylate}

[0234]

[0235] Manufacturing Example M3-8 was treated in the same manner as Manufacturing Examples M4, M13-3 and M5 to obtain the title compound as a yellow oil.

[0236]

[0237] Manufacturing Example M6: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate}

[0238]

[0239] Manufacturing Example M5 Compound (93 mg, 1 eq.) and tert-butyl piperazine-1-carboxylate (94.2 mg, 2 eq.) were added to DCE (2 mL), AcOH (1.45 μL, 0.1 eq.), followed by NaBH(OAc)3 (107.2 mg, 2 eq.) and stirred at 30°C for 3 h. After confirming the reaction by LCMS, saturated Na2CO3 aqueous solution was added, adjusted to pH 7-8, EA was added, extracted, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (154 mg, crude).

[0240] Manufacturing Example M7 (Example 2): 6-methoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine {6-methoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine}

[0241]

[0242] Manufacturing Example M6 Compound (154 mg, 1 eq.) was dissolved in DCM (2 mL), and 2,6-lutidine (122.7 mg, 4 eq.) and TMSOTf (509.2 mg, 8 eq.) were added at 0°C, followed by stirring for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, and DCM was added to extract. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC to obtain the title compound as a green solid (22.1 mg, 22.8%).

[0243] 1 H NMR (400 MHz, DMSO-d6) δ11.58 (br s, 1H), 9.50 (br s, 2H), 9.09 (br s, 1H), 7.63 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.28 - 6.47 (m, 2H), 4.27 (br s, 2H), 3.70 (s, 3H), 3.38 - 3.59 (br s, 7H), 3.16 (br s, 2H), 1.47 (s, 6H); MS (ESI): m / z 337.8 [M+H]+

[0244] Synthetic route II-a-2

[0245] Manufacturing Example M8-1 (Example 3): 6-methoxy-9,9-dimethyl-2-((4-(oxetan-3-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine {6-methoxy-9,9-dimethyl-2-((4-(oxetan-3-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine}

[0246]

[0247] Example 2 (50 mg, 1 eq.) and oxetane-3-carbaldehyde (19.1 mg, 1.5 eq.) were added to DCM (1 mL), AcOH (889.7 μg, 0.1 eq.) was added, and the mixture was stirred at 15°C for 30 min. NaBH(OAc)3 (62.8 mg, 2 eq.) was added to the reaction mixture and stirred for 1.5 h. After confirming the reaction by LCMS, saturated NaHCO3 aqueous solution was poured, pH = 8 was adjusted, water and EA were added, and extraction was performed. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC to obtain the title compound as a white solid (25.5 mg, 42.2%).

[0248] 1 H NMR (400 MHz, DMSO-d6) δ8.76 (br s, 1H), 7.14 - 7.26 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.27 - 6.42 (m, 2H), 4.60 (t, J = 6.0 Hz, 2H), 4.21 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H), 3.36 (s, 2H), 3.05 - 3.21 (m, 1H), 2.52 - 5.62 (m, 2H), 2.30 (br s, 8H), 1.43 (s, 6H); MS (ESI): m / z 402.3 [M+H]+

[0249] Manufacturing Example M8-2 (Example 4): 2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethan-1-ol {2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethan-1-ol}

[0250]

[0251] Example 188 (100 mg, 1 eq.) and 2-bromoethanol (137 mg, 4 eq.) were added to ACN (4 mL), K2CO3 (189 mg, 5 eq.) was added, and the mixture was stirred at 25°C for 12 hours. After confirming the reaction by LCMS, saturated aqueous NaHCO3 solution was poured to adjust the pH to 8, water and EA were added, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC to obtain the title compound as a white solid.

[0252] 1 H NMR (400 MHz, DMSO-d6) δ8.80 (s, 1 H) 7.32 (d, J=8.0 Hz, 1 H) 7.17 - 7.22 (m, 1 H) 6.90 - 6.98 (m, 1 H) 6.68 - 6.76 (m, 3 H) 4.35 (s, 2 H) 3.40 - 3.51 (m, 6 H) 2.19 - 2.46 (m, 10 H) 1.46 (m, 6 H) 1.14 (t, J=6.8 Hz, 3 H); MS (ESI): m / z 410.2 [M+H]+

[0253] Manufacturing Example M8-3-a: Methyl 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)acetate {methyl 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)acetate}

[0254]

[0255] Example 188 (200 mg, 1 eq.) and methyl 2-(2-chloroethoxy)acetate (45.4 mg, 0.5 eq.) were treated in the same manner as in Preparation Example M8-2 to obtain the title compound as a white solid (170 mg, 64%).

[0256] Manufacturing Example M8-3-b: 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)acetic acid {2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)acetic acid}

[0257]

[0258] Manufacturing Example M8-3-a was treated in the same manner as Manufacturing Example M19 to obtain the title compound as a white solid, which was used in the next reaction without purification.

[0259] Manufacturing Example M8-3-c: 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)-N-(2-hydroxyethyl)acetamide {2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)-N-(2-hydroxyethyl)acetamide}

[0260]

[0261] Manufacturing Example M8-3-b and 2-aminoethanol were treated in the same manner as in Manufacturing Example M20 to obtain the title compound as a white solid.

[0262] Manufacturing Example M8-3-d (Example 5): 2-((2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethyl)amino)ethan-1-ol {2-((2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethyl)amino)ethan-1-ol}

[0263]

[0264] Manufacturing Example M8-3-c Compound (14 mg, 1 eq.) was added to THF (1 mL), LAH (2.5 M, 43.8 uL, 4 eq.) was added, and the mixture was reacted in a microwave for 30 minutes at 0°C. After confirming the reaction by LCMS, water was added to terminate the reaction, and the residue was concentrated under reduced pressure and purified by prep-HPLC to obtain the title compound as a yellow oil (6.7 mg, 49%).

[0265] 1H NMR (400 MHz, CDCl3) δ8.59 (br s, 1H), 7.34 (br d, J = 8.0 Hz, 1H), 7.04 (br d, J = 8.0 Hz, 1H), 6.87 (br d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.66 (br d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 4.46 (s, 2H), 3.87 (br s, 2H), 3.71-3.79 (m, 2H), 3.61-3.68 (m, 2H), 3.49-3.61 (m, 4H), 3.00-3.14 (m, 4H), 2.55-2.89 (m, 10H), 1.57 (s, 6H), 1.27 (t, J = 6.8 Hz, 3H); MS (ESI): m / z 497.3 [M+H]+

[0266]

[0267] Synthetic route II-b

[0268] Manufacturing Example M9-1-a: tert-butyl 6-methoxy-9,9-dimethyl-2-(prop-1-en-2-yl)acridine-10(9H)-carboxylate {tert-butyl 6-methoxy-9,9-dimethyl-2-(prop-1-en-2-yl)acridine-10(9H)-carboxylate}

[0269]

[0270] Manufacturing Example M4 Compound (170 mg, 1 eq.) was added to 1,4-dioxane (4 mL) and water (0.8 mL), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (102.43 mg, 1.5 eq.), Pd(dppf)Cl2 (29.74 mg, 0.1 eq.), and Na2CO3 (86.14 mg, 2 eq.), and stirred under nitrogen at 100°C for 12 hours. After confirming the reaction by LCMS, celite filtration was performed, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound as a yellow oil (119 mg, 77.1%).

[0271] Manufacturing Example M9-1-b: tert-butyl 2-isopropyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-isopropyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate}

[0272]

[0273] Manufacturing Example M9-1-a Compound (119 mg, 1 eq.) was dissolved in THF (5 mL), Pd / C (100 mg, 10% purity, 0.3 eq.) was added, and the mixture was stirred at 15°C for 2 hours under hydrogen balloon conditions. After confirming the reaction by LCMS, the residue was filtered through celite and concentrated under reduced pressure to obtain the title compound (124 mg, crude) as a yellow oil.

[0274] Manufacturing Example M9-1-c (Example 6): 2-isopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine {2-isopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine}

[0275]

[0276] Manufacturing Example M9-1-b Compound was reacted and treated in the same manner as Manufacturing Example M7 to obtain the title compound as a white solid.

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (br s, 1H), 7.12 - 7.25 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.32 - 6.38 (m, 1H), 6.27 - 6.32 (m, 1H), 3.69 (s, 3H), 2.73 - 2.86 (m, 1H), 1.44 (s, 6H), 1.16 (d, J = 6.8 Hz, 6H); MS (ESI): m / z 282.2 [M+H]+

[0278] Manufacturing Example M9-2: tert-butyl 2-cyclopropyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-cyclopropyl-6-methoxy-9,9-dimethylacridine-10(9H)-carboxylate}

[0279]

[0280] Manufacturing Example M4 Compound (200 mg, 1 eq.) was added to water (0.8 mL) and toluene (4 mL), and cyclopropylboronic acid (53.39 mg, 1.3 eq.), tricyclohexyl phosphane (13.41 mg, 0.1 eq.), K3PO4 (355.20 mg, 3.5 eq.), and Pd(OAc)2 (10.73 mg, 47.81 μmol, 0.1 eq.) were added. The mixture was stirred at 100°C under nitrogen for 12 hours. After confirming the reaction by LCMS, celite filtration was performed, concentration under reduced pressure, and purification by silica gel column chromatography was performed to obtain the title compound as a yellow oil (131 mg, 72.2%).

[0281] 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.10 - 7.13 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 1.90 - 1.95 (m, 1H), 1.46 (s, 9H), 1.44 (s, 6H), 0.90 - 0.94 (m, 2H), 0.64 - 0.67 (m, 2H);

[0282] Manufacturing Example M10 (Example 7): 2-cyclopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine {2-cyclopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine}

[0283]

[0284] Manufacturing Example M9-2 Compound was reacted and treated in the same manner as Manufacturing Example M7 to obtain the title compound as a white solid.

[0285] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (br s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.66 - 6.76 (m, 1H), 6.60 - 6.65 (m, 1H), 6.31 - 6.42 (m, 1H), 6.25 - 6.31 (m, 1H), 3.68 (s, 3H), 1.72 - 1.95 (m, 1H), 1.44 (s, 6H), 0.76 - 0.95 (m, 2H), 0.49 - 0.65 (m, 2H); MS (ESI): m / z 280.0 [M+H]+

[0286] Synthetic route II-c

[0287] Manufacturing Example M11-1: tert-butyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(tert-butyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(tert-butyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0288]

[0289] Manufacturing Example M3-21 (100 mg, 1 eq.) obtained through Manufacturing Example M4 was added to toluene (4 mL) and tert-butyl piperazine-1-carboxylate; hydrochloride (60.14 mg, 1.2 eq.), BINAP (14.01 mg, 0.1 eq.), Pd2(dba)3 (20.61 mg, 0.1 eq.), and t-BuONa (54.06 mg, 2.5 eq.) were added. The mixture was stirred at 100°C for 3 hours under nitrogen conditions. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (60 mg, 48.5%).

[0290] 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.24 - 7.28 (m, 4H), 3.57 - 3.62 (m, 4H), 3.12 - 3.16 (m, 4H), 1.56 (s, 9H), 1.55 (s, 6H), 1.50 (s, 9H), 1.33 (s, 9H)

[0291] Manufacturing Example M11-2-a: tert-butyl 6-(2-hydroxyethyl)-2,9,9-trimethylacridine-10(9H)-carboxylate {tert-butyl 6-(2-hydroxyethyl)-2,9,9-trimethylacridine-10(9H)-carboxylate}

[0292]

[0293] Manufacturing example M3-4 (200 mg, 1 eq.) that went through the M4 step was added to THF (5 mL) and -78 o Add n-BuLi to C and stir for 30 minutes, then 0 o Add oxirane (21.9 mg, 1 eq.) to C and 0 o C, stirred under nitrogen conditions for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (50 mg, 27.3%).

[0294] Manufacturing Example M11-2-b: tert-butyl 2,9,9-trimethyl-6-(2-((methylsulfonyl)oxy)ethyl)acridine-10(9H)-carboxylate {tert-butyl 2,9,9-trimethyl-6-(2-((methylsulfonyl)oxy)ethyl)acridine-10(9H)-carboxylate}

[0295]

[0296] Manufacturing Example M11-2-a (50 mg, 1 eq.) was added to DCM (5 mL) and 0 o Add DIEA (52.7 mg, 3 eq.) and methylsulfonyl methanesulfonate (35.5 mg, 1.5 eq.) to C and 15 oThe mixture was stirred at C for 1 hour. After confirming the reaction by LCMS, water was added to terminate the reaction, and DCM was added to extract the organic layer. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow oil (50 mg, crude).

[0297] Manufacturing Example M11-2-c: tert-butyl 2,9,9-trimethyl-6-(2-morpholinoethyl)acridine-10(9H)-carboxylate {tert-butyl 2,9,9-trimethyl-6-(2-morpholinoethyl)acridine-10(9H)-carboxylate}

[0298]

[0299] Manufacturing Example M11-2-b (50 mg, 1 eq.) and morpholine (19.5 mg, 2 eq.) were added to ACN (3 mL) and TEA (34 mg, 3 eq.) was added under nitrogen conditions and 0 o 55 after inserting from C o The mixture was stirred for 12 hours at C. After confirming the reaction by LCMS, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain the title compound as a yellow oil (45 mg, 91%).

[0300] Manufacturing Example M11-3: tert-butyl 2-(ethoxymethyl)-9,9-dimethyl-6-morpholinoacridine-10(9H)-carboxylate {tert-butyl 2-(ethoxymethyl)-9,9-dimethyl-6-morpholinoacridine-10(9H)-carboxylate}

[0301]

[0302] The starting material obtained in the same manner as in Preparation Example M11-1 was treated in the same manner as in Preparation Example M13-3 to obtain the title compound as a yellow oil.

[0303] Manufacturing Example M11-4: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(2-morpholinoethyl)acridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(2-morpholinoethyl)acridine-10(9H)-carboxylate}

[0304]

[0305] The starting material obtained in the same manner as in Manufacturing Example M11-2-c was treated in the same manner as in Manufacturing Example M13-2 to obtain the title compound as a yellow oil.

[0306]

[0307] Manufacturing Example M12 (Example 8): 2-(tert-butyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine {2-(tert-butyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine}

[0308]

[0309] Manufacturing Example M11-1 Compound was reacted and treated in the same manner as Manufacturing Example M7 to obtain the title compound as a gray solid.

[0310] 1 H NMR (400 MHz, DMSO-d6) δ8.56 (br s, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.02 - 7.08 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.39 - 6.45 (m, 1H), 6.28 (d, J = 2.4 Hz, 1H), 3.08 - 3.15 (m, 4H), 2.99 - 3.07 (m, 4H), 1.46 (s, 6H), 1.26 (s, 9H)

[0311] Synthetic route II-d

[0312] Manufacturing Example M13-1: tert-butyl 6-chloro-2-((dimethylamino)methyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 6-chloro-2-((dimethylamino)methyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0313]

[0314] Example 30 (100 mg, 1 eq.) that went through the manufacturing example M4 step was added to THF (4 mL) and water (0.4 mL), potassium; (dimethylamino)methyl-trifluoro-boranuide (M13-R1, 46.8 mg, 1.2 eq.), Xphos-Pd-G2 (3.72 mg, 0.02 eq.), and Cs2CO3 (231.22 mg, 3 eq.) were added, and the mixture was stirred at 70°C for 12 hours under nitrogen. After confirming the reaction by LCMS, water was poured to stop the reaction, and EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow oil (110 mg, crude); MS (ESI): m / z 256.0 [M+H]+

[0315] Manufacturing Example M13-2: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-chloro-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-chloro-9,9-dimethylacridine-10(9H)-carboxylate}

[0316]

[0317] Example 30 (200 mg, 1 eq.) and M13-R2 (144.8 mg, 1 eq.) that had undergone Manufacturing Example M4 step were added to 1,4-dioxane (2 mL) and water (0.4 mL), and Cs2CO3 (462.44 mg, 3 eq.), Xphos (22.55 mg, 0.1 eq.), and Pd(Oac)2 (5.31 mg, 0.05 eq.) were added, followed by stirring at 70°C for 3 hours. After confirming the reaction by LCMS, water was poured to terminate the reaction, EA was added, and extraction was performed. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by prep-TLC to obtain the title compound as a yellow oil (159 mg, 62%).

[0318] Manufacturing Example M13-3: tert-butyl 1-chloro-6-(ethoxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 1-chloro-6-(ethoxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0319]

[0320] Compound M3-5-1 (240 mg, 1 eq.) obtained through Manufacturing Example M4 and potassium ethoxymethyl (trifluoro) boranuide (M13-R3, 122.5 mg, 1.3 eq.) were added to 1,4-dioxane (12 mL) and water (2.5 mL), and Pd (dppf) Cl 2 (41.54 mg, 0.1 eq.) and Na 2 CO 3 (120.34 mg, 2 eq.) were added, followed by stirring at 100°C for 3 hours under nitrogen conditions. After confirming the reaction by LCMS, water was added to terminate the reaction, and EA was added for extraction. The organic layer was washed with water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (130 mg, 56.9%).

[0321] 1H NMR (400 MHz, CDCl3) δ7.58 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.13 - 7.17 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.51 - 3.54 (m, 2H), 1.79 (s, 6H), 1.50 (s, 9H), 1.23 (t, J = 6.8 Hz, 3H)

[0322] Manufacturing Example M13-4: tert-butyl 2-bromo-7-(hydroxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-bromo-7-(hydroxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0323]

[0324] Commercially available 2,7-dibromo-9,9-dimethyl-9,10-dihydroacridine (600 mg, 1 eq.) which had gone through the M4 step was added to 1,4-dioxane (10 mL). Xphos-Pd-G2 (101.05 mg, 0.1 eq.) and tributylstannylmethanol (M13-R4, 618.54 mg, 1.5 eq.) were added, and the mixture was stirred at 90°C for 4 hours under nitrogen. After confirming the reaction by LCMS, water was added to stop the reaction, and EA was added for extraction. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to give the title compound as a yellow oil (100 mg, 18.6%).

[0325] Synthetic route II-d-1

[0326] Manufacturing Example M14 (Example 9): 1-(6-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine {1-(6-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine}

[0327]

[0328] Manufacturing Example M13-1 Compound was reacted and treated in the same manner as Manufacturing Example M7 to obtain the title compound as a gray solid.

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 6.95 - 7.01 (m, 1H), 6.77 - 6.81 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 3.29 (s, 2H), 2.11 (s, 6H), 1.47 (s, 6H);

[0330] Synthetic route II-d-2

[0331] Manufacturing Example M15-1: tert-butyl 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(ethoxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(ethoxymethyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0332]

[0333] Manufacturing Example M3-11 Compound was obtained from the above starting materials through Manufacturing Examples M4 and M13-2, and then reacted and treated in the same manner as Manufacturing Example M13-3 to obtain the title compound as a yellow oil.

[0334] Manufacturing Example M15-2: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-phenylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-phenylacridine-10(9H)-carboxylate}

[0335]

[0336] The starting material of Manufacturing Example M15-1 was reacted and treated in the same manner as Manufacturing Example M9-1 to obtain the title compound as a yellow oil.

[0337] Manufacturing Example M15-3-a: tert-butyl 6-acetyl-2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 6-acetyl-2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0338]

[0339] The starting material (320 mg, 1 eq.) obtained through Manufacturing Example M3-14 and Manufacturing Examples M4, M13-2 and M15-1 was added to toluene (6 mL), and Pd2(dba)3 (50 mg, 0.1 eq.), BINAP (33.9 mg, 0.1 eq.) and tributyl(1-ethoxyvinyl)stannane (M15-R1, 394 mg, 2 eq.) were added, and then the mixture was stirred at 110 o C was stirred for 12 hours. After confirming the reaction by LCMS, 2N HCl was added, and EA was added at pH 3 to 4 to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (180 mg, 60%).

[0340] Manufacturing Example M15-3-b: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(2-hydroxypropan-2-yl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(2-hydroxypropan-2-yl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0341]

[0342] Manufacturing Example M15-3-a was reacted and treated in the same manner as Manufacturing Example M2 to obtain the title compound as a yellow oil.

[0343] Manufacturing Example M15-4: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(1H-imidazol-1-yl)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-(1H-imidazol-1-yl)-9,9-dimethylacridine-10(9H)-carboxylate}

[0344]

[0345] Manufacturing Example The starting material of M15-3-a (100 mg, 1 eq.) and imidazole (17.4 mg, 1.5 eq.) were added to DMSO (2 mL), and CuI (3.24 mg, 0.1 eq.), (2S)-pyrrolidine-2-carboxylic acid (1.96 mg, 0.1 eq.) and K3PO4 (72.3 mg, 2 eq.) were added, and then the mixture was stirred at 130 °C under nitrogen conditions. oThe mixture was stirred for 1 hour in C. After confirming the reaction by LCMS, 2N HCl was added, and EA was added at pH 3 to 4 to extract the mixture. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (50 mg, 51%).

[0346] Manufacturing Example M15-5: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(piperidin-1-yl)acridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(piperidin-1-yl)acridine-10(9H)-carboxylate}

[0347]

[0348] The starting material of Manufacturing Example M15-3-a was reacted and treated in the same manner as Manufacturing Example M11-1 to obtain the title compound as a yellow oil.

[0349] Manufacturing Example M15-6: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(phenylamino)acridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-9,9-dimethyl-6-(phenylamino)acridine-10(9H)-carboxylate}

[0350]

[0351] Manufacturing Example The starting material of M15-3-a (150 mg, 1 eq.) and aniline (35.7 mg, 1.5 eq.) were added to toluene (3 mL), and Pd2(dba)3 (23.4 mg, 0.1 eq.), BINAP (15.9 mg, 0.1 eq.) and t-BuONa (36.8 mg, 1.5 eq.) were added, and then the mixture was stirred at 100 °C under nitrogen conditions. o The mixture was stirred for 4 hours in C. After confirming the reaction by LCMS, water and EA were added for extraction, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow solid (80 mg, 52%).

[0352]

[0353] Manufacturing Example M15-R2: Potassium;butoxymethyl-trifluoro-boranuide

[0354]

[0355] Butan-1-ol (704.64 mg, 3 eq.) was dissolved in THF (15 mL), and KHMDS (1 M, 9.82 mL, 3.1 eq.) was added at 0°C, followed by stirring at 25°C for 10 min. 2-(Bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (700 mg, 1 eq.) and KI (52.60 mg, 0.1 eq.) were added to the reaction mixture, and the mixture was stirred at 60°C for 4 h. After cooling the reaction mixture to 0°C, KHF2 (1.48 g, 6 eq.) was added, and then water (15 mL) was slowly added dropwise. The reaction was confirmed by TLC, and the reaction mixture was filtered and concentrated under reduced pressure. Acetone (70 mL) was added to the concentrated residue, filtered, and the filtrate was concentrated under reduced pressure, washed with EA, and filtered to obtain the title compound as a yellow solid (1 g, crude).

[0356] 1H NMR (400 MHz, CDCl3) δ 3.42 (t, J = 7.2 Hz, 2H), 3.33 (s, 2H), 1.57 - 1.62 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H);

[0357] Manufacturing Example M15-R3: Potassium; trifluoro((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)methyl)borate {potassium; trifluoro((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)methyl)borate}

[0358]

[0359] The starting material (3.4 g, 3 eq.) was placed in THF (60 mL), and NaH (60%, 428 mg, 1.8 eq.) was added at 0°C, and stirred at 15°C for 1 h. Potassium bromomethyl(trifluoro)branide (1.2 g, 1 eq.) was added and stirred at 40 o After stirring at C for 4 hours, potassium fluoride hydrofluoride (930 mg, 2 eq.) was added and stirred at 25°C for 30 minutes. After cooling the reaction mixture to 0°C, water was added dropwise and the mixture was concentrated under reduced pressure. Acetone (100 mL) was added to the concentrated residue and heated under reflux for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil (3 g, crude).

[0360] Manufacturing Example M15-R4: Sodium; trifluoro((2-hydroxyethoxy)methyl)borate {Sodium; trifluoro((2-hydroxyethoxy)methyl)borate}

[0361]

[0362] The starting material (1.4 g, 1 eq.) was added to MeOH (30 mL), and KHF2 (1.09 g, 2 eq.) was added at 0°C, followed by water (20 mL), and the mixture was stirred at 15°C for 1 hour and 30 minutes. After confirming the reaction by TLC, the mixture was concentrated under reduced pressure, and acetone (100 mL) and MeOH (1 mL) were added to the concentrated residue, and the mixture was heated under reflux at 40°C, filtered, and washed with PE (10 mL) to obtain the title compound as a white solid (120 mg, 12%).

[0363]

[0364] Manufacturing Example M16 (Example 10): 3-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine {3-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine}

[0365]

[0366] Manufacturing Example M15-1 Compound was reacted and treated in the same manner as Manufacturing Example M7 to obtain the title compound as a white solid.

[0367] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 7.39 - 7.42 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.73 - 6.88 (m, 4H), 4.36 (s, 2H), 3.40 - 3.50 (m, 4H), 3.22 - 3.38 (m, 8H), 1.48 (s, 6H), 1.15 (t, J = 6.8 Hz, 3H); MS (ESI): m / z 366.2 [M+H]+

[0368]

[0369] Synthetic Route III

[0370] Manufacturing Example M17-1 (Example 11): 8-bromo-9,9-dimethyl-9,10-dihydroacridin-3-ol {8-bromo-9,9-dimethyl-9,10-dihydroacridin-3-ol}

[0371]

[0372] Example 37 (370 mg, 1 eq.) was added to DCM (10 mL) at -60°C, BBr3 (2.62 g, 1.01 mL, 9 eq.) was added, and the mixture was stirred at 20°C for 12 hours under nitrogen conditions. After confirming the reaction by LCMS, saturated NaHCO3 aqueous solution was added to adjust the pH to 8-9, and water and DCM were added to extract. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (44 mg, 12.4%).

[0373] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (br s, 1H), 8.83 (br s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.94 - 6.99 (m, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.68 - 6.73 (m, 1H), 6.18 - 6.24 (m, 1H), 6.07 (d, J = 2.4 Hz, 1H), 1.78 (s, 6H); MS (ESI): m / z 303.9 [M+H]+

[0374] Manufacturing Example M17-2: 7-isopropyl-9,9-dimethyl-9,10-dihydroacridin-3-ol {7-isopropyl-9,9-dimethyl-9,10-dihydroacridin-3-ol}

[0375]

[0376] Example 6 was reacted and treated in the same manner as Manufacturing Example M17-1 to obtain the title compound as a green solid.

[0377] 1H NMR (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 8.54 (br s, 1H), 7.15 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.17 - 6.22 (m, 2H), 2.76 - 2.82 (m, 1H), 1.43 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H);

[0378] Manufacturing Example M18-1 (Example 12): 1-Bromo-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine {1-bromo-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine}

[0379]

[0380] Example 11 (35 mg, 1 eq.) was dissolved in DMF (2 mL), followed by NaOH (9.20 mg, 2 eq.), and stirred at 15°C for 2 hours. EtI (89.7 mg, 46.01 μL, 5 eq.) was added to the reaction mixture, and stirred at 60°C for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, and EA was added to extract the organic layer. Washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure, the concentrated residue was purified by silica gel column chromatography to obtain the title compound as a brown solid (20.6 mg, 53.7%).

[0381] 1H NMR (400 MHz, DMSO-d6) δ8.93 (br s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.96 - 7.01 (m, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.68 - 6.73 (m, 1H), 6.31 - 6.38 (m, 1H), 6.16 (d, J = 2.8 Hz, 1H), 3.89 - 4.01 (m, 2H), 1.80 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m / z 332.0 [M+H]+

[0382] Manufacturing Example M18-2 (Example 13): 6-(difluoromethoxy)-2-isopropyl-9,9-dimethyl-9,10-dihydroacridine {6-(difluoromethoxy)-2-isopropyl-9,9-dimethyl-9,10-dihydroacridine}

[0383]

[0384] KOH (209.85 mg, 20 eq.) was added to ACN (1 mL) and water (1 mL), and the compound of Preparation Example M17-2 (50 mg, 1 eq.) was added. 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (M18-R1, 99.87 mg, 2 eq.) was added at -78°C and stirred at 25°C for 30 minutes. After confirming the reaction by LCMS, water was added to stop the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (27.9 mg, 46.1%).

[0385] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (br s, 1H), 7.38 - 7.33 (m, 1H), 7.20 (s, 1H), 6.93 - 6.98 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.66 - 6.72 (m, 1H), 6.50 - 6.58 (m, 2H), 2.75 - 2.87 (m, 1H), 1.48 (s, 6H), 1.18 (d, J = 6.8 Hz, 6H); MS (ESI): m / z 318.0 [M+H]+

[0386] Manufacturing Example M18-3 (Example 14): 2-isopropyl-9,9-dimethyl-6-(2,2,2-trifluoroethoxy)-9,10-dihydroacridine {2-isopropyl-9,9-dimethyl-6-(2,2,2-trifluoroethoxy)-9,10-dihydroacridine}

[0387]

[0388] Manufacturing Example M17-2 Compound (100 mg, 1 eq.) was dissolved in DMF (3 mL), Cs2CO3 (243.73 mg, 2 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (M18-R2, 95.49 mg, 1.1 eq.) were added, and the mixture was stirred at 25°C for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, and EA was added to extract. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow solid (53.9 mg, 41.1%).

[0389] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (br s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.15 - 7.20 (m, 1H), 6.90 - 6.95 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.44 - 6.50 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.60 - 4.72 (m, 2H), 2.75 - 2.86 (m, 1H), 1.46 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H); MS (ESI): m / z 350.1 [M+H]+

[0390] Manufacturing Example M18-4 (Example 15): 1-chloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine {1-chloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine}

[0391]

[0392] Example 242 (60 mg, 1 eq.), cyclopropylmethanol (M18-R3, 33.31 mg, 36.53 μL, 2 eq.) and PPh3 (121.1 mg, 2 eq.) were added to THF (2 mL) under nitrogen conditions at 0°C, DIAD (93.42 mg, 89.57 μL, 2 eq.) was added, and the mixture was stirred at 15°C for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added and extracted, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (12.2 mg, 16.8%).

[0393] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.56 - 6.86 (m, 2H), 6.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 3.73 (d, J = 6.8 Hz, 2H), 1.76 (s, 6H), 1.18 - 1.22 (m, 1H), 0.45 - 0.71 (m, 2H), 0.17 - 0.37 (m, 2H); MS (ESI): m / z 314.1 [M+H]+

[0394] Manufacturing Example M18-5: 2-Bromo-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine {2-bromo-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine}

[0395]

[0396] Example 46 was treated in the same manner as in Manufacturing Examples M17-1 and M18-4 to obtain the title compound as a yellow oil (350 mg, 99%).

[0397] Manufacturing Example M18-6-a: tert-butyl 3-chloro-9,9-dimethyl-6-(2-morpholinoethoxy)acridine-10(9H)-carboxylate {tert-butyl 3-chloro-9,9-dimethyl-6-(2-morpholinoethoxy)acridine-10(9H)-carboxylate}

[0398]

[0399] Example 23 After obtaining the above starting materials through Manufacturing Examples M17-1 and M4, the title compound was obtained as a yellow oil by treating in the same manner as Manufacturing Example M18-4 using 2-morpholinoethanol-1-ol.

[0400] Manufacturing Example M18-6-b: tert-butyl 3-(ethoxymethyl)-9,9-dimethyl-6-(2-morpholinoethoxy)acridine-10(9H)-carboxylate {tert-butyl 3-(ethoxymethyl)-9,9-dimethyl-6-(2-morpholinoethoxy)acridine-10(9H)-carboxylate}

[0401]

[0402] Manufacturing Example M18-6-a was treated in the same manner as Manufacturing Example M13-3 to obtain the title compound as a yellow oil.

[0403] Manufacturing Example M18-7-a: 1-((7-bromo-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-2-methylpropan-2-ol {1-((7-bromo-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-2-methylpropan-2-ol}

[0404]

[0405] Example 46 The starting material (300 mg, 1.0 eq.) obtained through Manufacturing Example M17-1 was dissolved in DMF (6 mL), and K2CO3 (272 mg, 2 eq.) was added and 50 o After stirring for 1 hour, add 2,2-dimethyloxirane (711 mg, 10 eq.) and 100 o C was stirred for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (460 mg, crude).

[0406] Manufacturing Example M18-7-b: 2-bromo-6-(2-methoxy-2-methylpropoxy)-9,9-dimethyl-9,10-dihydroacridine {2-bromo-6-(2-methoxy-2-methylpropoxy)-9,9-dimethyl-9,10-dihydroacridine}

[0407]

[0408] Manufacturing Example M18-7-a (140 mg, 1 eq.) was added to THF (3 mL) and 0 o Add NaH (60%, 28 mg, 2.4 eq.) to C and 20 o After stirring for 30 minutes, MeI (125 mg, 3 eq.) was added and stirred at 30°C under nitrogen for 12 hours. After confirming the reaction by LCMS, the mixture was filtered with Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (90 mg, 62%).

[0409] Manufacturing Example M18-8-a: tert-butyl 2-bromo-9,9-dimethyl-6-(2-oxopropoxy)acridine-10(9H)-carboxylate {tert-butyl 2-bromo-9,9-dimethyl-6-(2-oxopropoxy)acridine-10(9H)-carboxylate}

[0410]

[0411] Example 46 The starting material (790 mg, 1.0 eq.) obtained through Manufacturing Examples M17-1 and M4 was dissolved in acetone (18 mL), and then K2CO3 (810 mg, 3 eq.) and KI (65 mg, 0.2 eq.) were added and 70 o After stirring for 30 minutes, 1-chloropropan-2-one (307 mg, 1.7 eq.) was added and 70 oC was stirred for 2 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.9 g, crude).

[0412] Manufacturing Example M18-8-b: tert-butyl 2-bromo-6-((2-((tert-butyldimethylsilyl)oxy)allyl)oxy)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-bromo-6-((2-((tert-butyldimethylsilyl)oxy)allyl)oxy)-9,9-dimethylacridine-10(9H)-carboxylate}

[0413]

[0414] Manufacturing Example M18-8-a (0.9 g, 1.0 eq.) was dissolved in DCM (12 mL) and 0 o Add TEA (395 mg, 2 eq.) and TBSOTf (620 mg, 1.2 eq.) to C and 25 o C was stirred for 12 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.55 g, 48%).

[0415] Manufacturing Example M18-8-c: tert-butyl 2-bromo-6-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-bromo-6-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate}

[0416]

[0417] Manufacturing Example M18-8-b (1.28 g, 1.0 eq.) was dissolved in DCM (150 mL) and 0 o Add diiodomethane (2.33 g, 4 eq.) and diethylzinc (1 M, 8.7 mL, 4 eq.) to C and then 25 o C was stirred for 1 hour. After confirming the reaction by LCMS, the reaction was terminated by pouring a saturated NH4Cl aqueous solution, and DCM was added for extraction. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (320 mg, 25%).

[0418] Manufacturing Example M18-8-d: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate}

[0419]

[0420] Manufacturing Example M18-8-c (200 mg, 1.0 eq.) was treated in the same manner as Manufacturing Example M13-2 to obtain the title compound as a yellow oil (180 mg, 74%).

[0421] Manufacturing Example M18-8-e: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-hydroxycyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-hydroxycyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate}

[0422]

[0423] Manufacturing Example M18-8-d (180 mg, 1.0 eq.) was added to THF (4 mL), then TBAF (1 M, 508 uL, 2 eq.) was added and 25 o C was stirred for 1 hour. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (110 mg, 72%).

[0424] Manufacturing Example M18-8-f: tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-methoxycyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate {tert-butyl 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-6-((1-methoxycyclopropyl)methoxy)-9,9-dimethylacridine-10(9H)-carboxylate}

[0425]

[0426] Manufacturing Example M18-8-e (260 mg, 1.0 eq.) was treated in the same manner as Manufacturing Example M18-7-b to obtain the title compound as a yellow oil (146 mg, 54%).

[0427]

[0428] Synthetic Route IV

[0429] Manufacturing Example M19: 9,9-dimethyl-9,10-dihydroacridine-2-carboxylic acid {9,9-dimethyl-9,10-dihydroacridine-2-carboxylic acid}

[0430]

[0431] Manufacturing Example M3-19 (130 mg, 1 eq.) was added to THF (2 mL) and MeOH (1 mL), and anhydrous lithium hydroxide (116 mg, 6 eq.) was added, followed by 60 o C was stirred for 2 hours. After confirming the reaction by LCMS, 1N HCl was added to adjust the pH to 1-2, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a gray solid (120 mg, crude).

[0432] 1 H NMR (400 MHz, DMSO-d6) δ12.2 (br s, 1H), 9.3 (br s, 1H), 7.83 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.98 - 7.01 (m, 1H), 6.71 - 6.81 (m, 3H), 1.42 (s, 6H);

[0433] Manufacturing Example M20: tert-butyl 4-(9,9-dimethyl-9,10-dihydroacridine-2-carbonyl)piperazine-1-carboxylate {tert-butyl 4-(9,9-dimethyl-9,10-dihydroacridine-2-carbonyl)piperazine-1-carboxylate}

[0434]

[0435] Manufacturing Example M19 (120 mg, 1 eq.) was added to DCM (4 mL), EDCI (136 mg, 1.5 eq.), HOBt (6.4 mg, 0.1 eq), DIEA (122 mg, 2 eq.), tert-butyl piperazine-1-carboxylate (88 mg, 1 eq.) was added, and then 20 o C was stirred for 12 hours. After confirming the reaction by LCMS, water was added to terminate the reaction, EA was added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow oil (160 mg, 80%).

[0436] 1 H NMR (400 MHz, CDCl3) δ7.10 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.03 - 7.07 (m, 1H), 6.85 - 6.90 (m, 1H), 6.60 - 6.66 (m, 2H),6.33 (br s, 1H), 3.50 - 3.59 (m, 4H), 3.34 - 3.43 (m, 4H), 1.50 (s, 6H), 1.40 (s, 9H);

[0437] Manufacturing Example M21 (Example 16): (9,9-dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone {(9,9-dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone}

[0438]

[0439] Manufacturing Example M20 (80 mg, 1 eq.) was treated in the same manner as Manufacturing Example M7 to obtain the title compound as a white solid (26 mg, 43%).

[0440] 1H NMR (400 MHz, DMSO-d6) δ9.12 (s, 1 H), 7.32 - 7.41 (m, 2 H), 7.12 (br d, J= 8.4 Hz, 1 H) 7.07 (t, J= 7.6 Hz, 1 H), 6.77 - 6.88 (m, 3 H) 3.42 (br s, 4 H) 2.69 (br s, 4 H) 1.50 (s, 6 H); MS (ESI): m / z 322.1 [M+H]+

[0441] Synthetic methods other than general synthetic routes

[0442] Manufacturing Example M22: 1-(2-(phenylamino)phenyl)cyclopentan-1-ol {1-(2-(phenylamino)phenyl)cyclopentan-1-ol}

[0443]

[0444] 2-Bromo-N-phenylaniline (1 g, 1 eq.) was dissolved in THF (20 mL), n-BuLi (2.5 M, 4.84 mL, 3 eq.) was added, and the mixture was stirred for 30 minutes under nitrogen conditions at -60°C. A solution of cyclopentanone (1.70 g, 5 eq.) in THF (5 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours under nitrogen conditions at -60°C. After confirming the reaction by LCMS, water was added to terminate the reaction, and EA was added for extraction. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a brown oil (803 mg, crude).

[0445] 1H NMR (400 MHz, DMSO-d6) δ 8.06 (br s, 1H), 7.26 - 7.32 (m, 2H), 7.18 - 7.23 (m, 3H), 6.98 (d, J = 8.4 Hz, 2H), 6.86 (t, J = 7.6 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 5.50 (s, 1H), 1.96 - 2.05 (m, 2H), 1.80 - 1.88 (m, 2H), 1.71 - 7.78 (m, 2H), 1.61 - 1.68 (m, 2H);

[0446] Manufacturing Example M23: 10H-spiro[acridine-9,1'-cyclopentane] {10H-spiro[acridine-9,1'-cyclopentane]}

[0447]

[0448] Manufacturing Example M22 Compound (400 mg, 1 eq) was added to H3PO4 (4 mL) and stirred at 100°C for 2 hours. After confirming the reaction by LCMS, saturated aqueous NaHCO3 solution was added to adjust the pH to 8-9, water and EA were added to extract, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a white solid (153 mg, 41.1%).

[0449] 1 H NMR (400 MHz, DMSO-d6) δ8.85 (br s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.78 - 6.83 (m, 4H), 1.94 - 1.99 (m, 4H), 1.80 - 1.84 (m, 4H);

[0450] Example 17: 2-bromo-10H-spiro[acridine-9,1'-cyclopentane] {2-bromo-10H-spiro[acridine-9,1'-cyclopentane]}

[0451]

[0452] Manufacturing Example M23 Compound (112 mg, 1 eq.) was dissolved in DMF (5 mL), and NBS (80.47 mg, 0.95 eq.) was added at 0°C, followed by stirring at 15°C for 1 hour. After confirming the reaction by LCMS, water was added to terminate the reaction, and EA was added to extract. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a brown solid (87.4 mg, 58.1%).

[0453] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (br s, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.19 -7.23 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.76 - 6.85 (m, 3H), 1.94 - 2.01 (m, 4H), 1.79 - 1.83 (m, 4H);

[0454] Example 18: 3-ethoxy-10H-spiro[acridine-9,1'-cyclopentane] {3-ethoxy-10H-spiro[acridine-9,1'-cyclopentane]}

[0455]

[0456] After reaction and treatment in the same manner as in Preparation Example M1 using 3-ethoxyaniline and (2-bromophenyl)boronic acid, the title compound was obtained as a white solid by reaction and treatment in the same manner as in Preparation Examples M19 and M20.

[0457] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (br s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91 - 7.02 (m, 2H), 6.72 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 4.04 (q, J = 7.2 Hz, 1H), 2.37 - 2.43 (m, 2H), 2.03 - 2.11 (m, 2H), 1.93-2.01 (m, 2H), 1.82 - 1.91 (m, 2H), 1.38 (t, J = 6.8 Hz, 3H); MS (ESI): m / z 280.2 [M+H]+

[0458] Example 19: N,N-dimethyl-1-(10H-spiro[acridine-9,1'-cyclopentan]-2-yl)methanamine {N,N-dimethyl-1-(10H-spiro[acridine-9,1'-cyclopentan]-2-yl)methanamine}

[0459]

[0460] Example 17 was reacted and treated in the same manner as Manufacturing Example M13-1 to obtain the title compound as a white solid.

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (br s, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 - 7.21 (m, 1H), 7.04 - 7.10 (m, 1H), 6.80 - 6.88 (m, 3H), 4.15 (d, J = 5.2 Hz, 2H), 2.62 - 2.69 (m, 6H), 1.96 - 2.05 (m, 4H), 1.79 - 1.90 (m, 4H);

[0462] Example 20: Cyclopropyl(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone {cyclopropyl(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone}

[0463]

[0464] Example 2 (50 mg, 1 eq.) was dissolved in DMF (2 mL), and HOBt (24 mg, 1.2 eq.), EDCI (34.1 mg, 1.2 eq.), and cyclopropanecarboxylic acid (15.3 mg, 1.2 eq.) were added, followed by stirring at 25°C for 1 hour. After confirming the reaction by LCMS, saturated aqueous NaHCO3 solution was poured to adjust the pH to 8, and water and EA were added to extract. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC to obtain the title compound as a white solid (24 mg, 33.3%).

[0465] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (br s, 1H), 7.19 - 7.25 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.35 - 6.40 (m, 1H), 6.31 (d, J = 2.0 Hz, 1H), 3.69 (s, 3H), 3.60 - 3.65 (m, 2H), 3.41 - 3.44 (m, 2H), 3.39 (s, 2H), 2.24 - 2.41 (m, 4H), 1.88 - 1.97 (m, 1H), 1.44 (s, 6H), 0.62 - 0.75 (m, 4H); MS (ESI): m / z 428.2 [M+H]+

[0466]

[0467] Examples Compounds 1 to 285 can be prepared by following the synthetic methods of Preparation Examples M1 to M21 and Preparation Examples M22 and M23 of the general synthetic routes 1, 2, and 3 above. Specific examples of the preparation of the examples compounds are as follows.

[0468]

[0469] Example 21: 6-(tert-butyl)-9,9-dimethyl-2-(trifluoromethyl)-9,10-dihydroacridine {6-(tert-butyl)-9,9-dimethyl-2-(trifluoromethyl)-9,10-dihydroacridine}

[0470]

[0471] The title compound was obtained as a white solid by reacting and treating with methyl 2-amino-4-(tert-butyl)benzoate and (4-(trifluoromethyl)phenyl)boronic acid in the same manner as in Preparation Examples M1, M2 and M3-1.

[0472] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 7.58 (s, 1H), 7.25 - 7.40 (m, 2H), 6.77 - 6.96 (m, 3H), 1.50 (s, 6H), 1.26 (s, 9H); MS (ESI): m / z 334.2 [M+H]+

[0473] Example 22: 9,9-diethyl-3-methoxy-9,10-dihydroacridine {9,9-diethyl-3-methoxy-9,10-dihydroacridine}

[0474]

[0475] In Manufacturing Example M1 step, methyl 2-amino-4-methoxybenzoate and phenylboronic acid were reacted and treated in the same manner as in Manufacturing Examples M1, M2 and M3-1 using ethylgriniard reagent in Manufacturing Example M2 step, to obtain the title compound as a white solid.

[0476] 1 H NMR (400 MHz, DMSO-d6) δ8.61 (br s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 3.70 (s, 3H), 1.75 - 1.87 (m, 4H), 0.48 (t, J = 7.2 Hz, 6H); MS (ESI): m / z 268.1 [M+H]+

[0477] The example compounds in Table 2 below were prepared in a similar manner to Examples 21 and 22 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 2.

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] <Preparation of Example Compounds According to Synthetic Route II-a-1>

[0486] Example 67: 2-methoxy-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine {2-methoxy-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine}

[0487]

[0488] Example 31 was reacted and treated in the same manner as Preparation Examples M4, M5, M6 and M7 to obtain the title compound as a yellow solid.

[0489] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (br s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 10.4, 2.0 Hz, 1H), 6.92 (brs, 1H), 6.66 - 6.76 (m, 3H), 3.70 (s, 3H), 3.40 (s, 2H), 2.90 - 2.94 (m, 4H), 2.41 - 2.46 (m, 4H), 1.48 (s, 6H); MS (ESI): m / z 317.0 [M+H]+

[0490] The example compounds in Table 3 below were prepared in a similar manner to Example 67 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 3.

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498] <Preparation of Example Compounds According to Synthetic Route II-a-2>

[0499] Example 108: 2-((4-benzylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine {2-((4-benzylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine}

[0500]

[0501] Example 2 and benzaldehyde were reacted and treated in the same manner as in Preparation Example M8-1 to obtain the title compound as a white solid.

[0502] 1H NMR (400 MHz, DMSO-d6) δ8.76 (br s, 1H), 7.17 - 7.33 (m, 7H), 6.90 - 7.01. (m, 1H), 6.63 - 6.72 (m, 1H), 6.35 - 6.45 (m, 1H), 6.25 - 6.30 (m, 1H), 3.69 (s, 3H), 3.43 (s, 2H), 3.35 - 3.37 (m, 2H), 2.32 - 2.38 (m, 8H), 1.43 (s, 6H); MS (ESI): m / z 428.3 [M+H]+

[0503] The example compounds in Table 4 below were prepared in a similar manner to Example 108 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 4.

[0504]

[0505]

[0506]

[0507]

[0508] <Preparation of Example Compounds According to Synthetic Route II-b>

[0509] Example 129: 2-cyclopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine {2-cyclopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine}

[0510]

[0511] Example 42 was reacted and treated in the same manner as Preparation Examples M4, M9-1 and M10 to obtain the title compound as a white solid.

[0512] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 1H), 7.36 - 7.43 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.08 - 7.16 (m, 2H), 7.00 - 7.06 (m, 2H), 6.67 - 6.74 (m, 1H), 6.58 - 6.62 (m, 1H), 6.46 (s, 1H), 6.29 - 6.34 (m, 1H), 1.71 - 1.92 (m, 1H), 1.44 - 1.48 (m, 6H), 0.82 - 0.87 (m, 2H), 0.52 - 0.61 (m, 2H); MS (ESI): m / z 342.1 [M+H]+

[0513] The example compounds in Table 5 below were prepared in a similar manner to Example 129 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 5.

[0514]

[0515]

[0516] <Preparation of Example Compounds According to Synthetic Route II-c>

[0517] Example 143: 2-isopropyl-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine {2-isopropyl-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine}

[0518]

[0519] Manufacturing Example M3-3 Compound and tert-butyl piperazine-1-carboxylate were reacted and treated in the same manner as Manufacturing Examples M4, M11-1 and M12 to obtain the title compound as a yellow solid.

[0520] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (br s, 1H), 8.31 (br s, 1H), 7.15 (d, J = 1.6 Hz, 1H), 6.86 - 6.97 (m, 2H), 6.63 - 6.72 (m, 3H), 2.96 - 3.02 (m, 8H), 2.76 - 2.83 (m, 1H), 1.47 (s, 6H), 1.16 (d, J = 6.8 Hz, 6H); MS (ESI): m / z 336.2 [M+H]+

[0521] The example compounds in Table 6 below were prepared in a similar manner to Example 143 above. The chemical structural formula, compound name, NMR, and LCMS analysis results of each example compound are shown in Table 6.

[0522]

[0523]

[0524]

[0525] <Preparation of Example Compounds According to Synthetic Route II-d-1>

[0526] Example 165: 1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine {1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine}

[0527]

[0528] Example 38 was reacted and treated in the same manner as Preparation Examples M4, M13-1 and M14 to obtain the title compound as a white solid.

[0529] 1H NMR (400 MHz, DMSO-d6) δ 8.97 (br s, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.14 - 7.23 (m, 2H), 6.98 - 7.05 (m, 1H), 6.70 - 6.80 (m, 3H), 4.12 (d, J = 4.8 Hz, 2H), 2.61 (s, 2H), 2.60 - 2.64 (m, 2H), 2.48 - 2.51 (m, 2H), 1.80 - 1.90 (m, 4H), 0.49 (t, J = 7.2 Hz, 6H); MS (ESI): m / z 295.0 [M+H]+

[0530] The example compounds in Table 7 below were prepared in a similar manner to Example 165 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 7.

[0531]

[0532]

[0533]

[0534]

[0535] <Preparation of Example Compounds According to Synthetic Route II-d-2>

[0536] Example 187: 6-((2-methoxyethoxy)methyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine {6-((2-methoxyethoxy)methyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine}

[0537]

[0538] Example 30 was reacted and treated in the same manner as in Preparation Example M4, and then commercially available M15-R3 was used to react and treat in the same manner as in Preparation Examples M15-1 and M16, to obtain the title compound as a white solid.

[0539] 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (br s, 1H), 8.99 (br s, 1H), 7.63 -7.70 (m, 1H), 7.32 - 7.44 (m, 2H), 6.72 - 6.85 (m, 3H), 4.44(s, 2H), 4.35 (s, 2H), 3.48 - 3.58 (m, 8H), 3.25 (s, 3H), 3.01 - 3.22 (m, 4H), 1.28 (s, 6H); MS (ESI): m / z 396.1 [M+H]+

[0540] The example compounds of Table 8 below were prepared in a similar manner to Example 187 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 8.

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551] <Preparation of the example compound according to Manufacturing Example M17-1>

[0552] Example 238: 7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol {7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol}

[0553]

[0554] Example 33 was reacted and treated in the same manner as Manufacturing Example M17-1 to obtain the title compound as a white solid.

[0555] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 8.56 (br s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.02 - 7.11 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.15 - 6.21 (m, 2H), 1.43 (s, 6H), 1.25 (s, 9H); MS (ESI): m / z 282.0 [M+H]+

[0556] The example compounds in Table 9 below were prepared in a similar manner to Example 238 above. The chemical structures, compound names, NMR, and LCMS analysis results of each example compound are shown in Table 9.

[0557]

[0558] <Preparation of Example Compounds According to Synthetic Route III>

[0559] Example 243: 3-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine {3-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine}

[0560]

[0561] Example 239 was reacted and treated in the same manner as Preparation Example M18-1 to obtain the title compound as a white solid.

[0562] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (br s, 1H), 7.16 - 7.27 (m, 2H), 6.79 - 6.86 (m, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.32 - 6.36 (m, 1H), 6.26 - 6.29 (m, 1H), 3.94 (q, J = 7.2 Hz, 2H), 1.43 (s, 6H), 1.30 (t, J = 7.2 Hz, 3H), 1.25 (s, 9H); MS (ESI): m / z 310.2 [M+H]+

[0563] The example compounds of Table 10 below were prepared in a similar manner to Example 243 above. The chemical structural formula, compound name, NMR, and LCMS analysis results of each example compound are shown in Table 10.

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] <Preparation of Example Compounds According to Synthetic Route IV>

[0571] The example compounds in Table 11 below were prepared in a similar manner to the above manufacturing examples M19 to M21 (Example 16). The chemical structural formula, compound name, NMR, and LCMS analysis results of each example compound are shown in Table 11.

[0572]

[0573] Experimental Example 1: Cell Culture

[0574] The cell line media composition and culture conditions used in the following experimental examples were prepared as follows. Each cell line was cultured at 37°C in a 5% CO2 incubator. Furthermore, the cell lines were cultured free of microbial contamination, such as Mycoplasma. Table 12 shows the media composition used for culturing each cell line.

[0575]

[0576] Table 12: Media composition used for culturing each cell line

[0577] Cell lineCell typeMedia compositionH9C2Cardiac cellsDMEM, 10% FBS, 1%PSSMLE-12Lung epithelial cellsDMEM / F-12, 10% FBS, 1%PS, 0.1%Insulin-Transferrin-Selenium (ITS), 10 nM Hydrocortisone, 10 nM β10 mM HEPES, 2 mM L-GlutaMaxARPE-19Retinal epithelial cellsDMEM / F-12, 10% FBS, 1%PSPC-12Adrenal medullary cellsDMEM, 10% FBS, 1%PSHT-22Hippocampal neuronsDMEM, 10% FBS, 1%PSSHK-2Renal proximal tubule epithelial cellsDMEM / F-12, 10% FBS, 1%PSNIH / 3T3Fibroblast cellsDMEM, 10% FBS, 1%PS

[0578] Experimental Example 2: Measurement of the protective effect against apoptosis in cardiac cells (H9C2)

[0579] To confirm the protective effect on heart cells, 1.5 X 10 H9C2 cells 4Each well was seeded into a 96-well plate and cultured for 24 hours. The final concentration of the compound was diluted to 0.001, 0.01, 0.03, 0.1, 0.3, 1,3, 3, 10, and 30 μM, treated to each well, and cultured for 15 to 20 minutes. t-BHP (tert-Butyl hydroperoxide) was treated to a final concentration of 400 μM, and cultured for 2 to 3 hours. To confirm the cell death protection effect of each compound, the degree of extracellular secretion of lactate dehydrogenase (LDH) was measured using the Cytotoxicity LDH assay kit [Dojindo; CK12]. Briefly, 2 to 3 hours after t-BHP treatment, 70 μL of the supernatant was taken from the 96-well plate containing the cells and transferred to a new 96-well plate. Add 70 μL / well of assay buffer (same amount as sample) included in the kit, wrap with foil, block light, and react at room temperature for 15 minutes. Observe the changed color of the sample, add 35 μL / well of stop solution, and measure the absorbance value at a wavelength of 490 nm using an iD3 spectrophotometer to determine the EC. 50　 The values ​​were calculated. The preferred EC of the example compound 50 is 1.0 μM or less, and more preferably 0.2 μM or less. Table 13 shows the protective effect of the example compound against t-BHP, an apoptosis-inducing substance.

[0580]

[0581] Table 13: t-BHP-induced apoptosis protection in cardiac cells (H9C2)

[0582] Example EC 50 Example EC 50 Example EC 50 Example EC 5050 ≤ 0.2 μM, B indicates 0.2 μM < EC 50 ≤ 1 μM,C indicates EC 50 >1.0 μM

[0583] Experimental Example 3: Apoptosis protection effect on cardiac cells (H9C2), lung epithelial cells (MLE-12), retinal epithelial cells (ARPE-19), adrenal medullary cells (PC-12), hippocampal neurons (HT-22), renal proximal tubular epithelial cells (HK-2), and fibroblasts (NIH / 3T3).

[0584] To determine the apoptotic protective effect on cardiac cells, adrenal medullary cells, retinal epithelial cells, lung epithelial cells, renal proximal tubular epithelial cells, hippocampal neurons and fibroblasts, 4 x 10 per well were seeded for each cell type. 3 ~ 1.5 X 10 4The cells were seeded in 96-well plates and cultured for 18 to 24 hours. The final concentration of the example compounds was diluted to 0.01 to 1.0 μM and treated to each well, and cultured for 15 to 20 minutes. RSL3 was treated to 0.3 to 3 μM for each cell as shown in Table 13 and cultured for 24 hours. To confirm the cell death protection effect of the example compounds, the degree of extracellular secretion of LDH was measured using the Cytotoxicity LDH assay kit [Dojindo; CK12]. Briefly, at the end of 24-hour treatment with RSL3 for each cell, 70 μL of the supernatant containing the cells was taken and transferred to a new 96-well plate. 70 μL / well (same amount as the sample) of the assay buffer included in the kit was added, and the plate was covered with foil to block light and reacted at room temperature for 15 to 20 minutes. The color of the changed sample was observed, 35 μL / well of Stop solution was added, and the absorbance value at a wavelength of 490 nm was measured using an iD3 spectrophotometer to calculate the % inhibition value. Tables 14 and 15 show the cell death reduction rate according to each concentration of the example compound for RSL3, a ferroptosis-inducing substance.

[0585]

[0586] Table 14: Apoptotic protective effects of RSL3 on cardiac cells (H9C2), lung epithelial cells (MLE-12), retinal epithelial cells (ARPE-19), adrenal medullary cells (PC-12), hippocampal neurons (HT-22), renal proximal tubular epithelial cells (HK-2), and fibroblasts (NIH / 3T3).

[0587] Cell line H9C2MLE-12ARPE-19PC-12RSL3 Concentration (νM) 0.5 1.0 1.0 0.3 Compound concentration (νM) 0.0 2 0.2 0.0 3 0.3 0.0 1 0.1 0.0 3 0.3 Example Inhibition (%)Fer-179983210018977696151001008199761009898211810009919100369633100991009810010097966798999697841009 2937394100N / TN / TN / TN / T9899749898N / TN / TN / TN / T98997710098991007697959679N / TN / T6010019100N / TN / T86100016118 9458991990159677959692100368410928698109541001181895699916710095100100921009795168N / TN / T99100100100N / TN / T18894997985489897992461009882829494969624796978989939598992489910010010088999899250981002610026985997

[0588] Cell line HT-22HK-2NIH / 3T3RSL3 Concentration (νM) 1.0 0.75 3.0 Compound concentration (νM) 0.0 2 0.2 0.0 3 0.3 0.0 3 0.3 Example Inhibition (%) Fer-1 100 100 37 100 5 100 15 100 100 9 100 0 100 219 4 100 31 100 319 33 100 100 100 100 9 4 100 67 100 100 100 100 100 100 7 30 100 N / TN / TN / TN / T7 4 0 100 N / TN / TN / TN / T7 7 100 100 100 100 102 100 79 N / TN / T5 6 100 5 100 8 6 0 5 13 2 11 0 109 41001003110011009610010026100010010910010022100010016710010099100100100168N / TN / T9610051001 8810010069100110024610010010010020100247100100100100610024810010099100110025010010024100191

[0589] In Tables 14 and 15 above, the comparative compound Fer-1 and the example compounds exhibited different ferroptosis inhibition abilities for each cell type. It was confirmed that the example compounds exhibited similar or more effective ferroptosis inhibition abilities than the comparative compound Fer-1 for each cell type.

[0590]

[0591] Experimental Example 4: Inhibitory Effect on Intracellular Lipid Reactive Oxygen Species (Lipid-ROS) Accumulation in Lung Epithelial Cells, Retinal Epithelial Cells, and Hippocampal Neurons

[0592] Experimental Example 4-1: To confirm the inhibitory effect on the accumulation of intracellular lipid reactive oxygen species in lung epithelial cells, 2 X 10 MLE-12 cells were seeded in a 12-well plate. 5 Each well was divided into 10 wells and cultured for 18 to 24 hours. The final concentrations of the example compounds 46, 71, 85, 88, 123 and the comparative example compound Fer-1 were diluted to 0.01, 0.1 and 1 μM and treated in each well and cultured for 10 minutes. After that, the final concentration of RSL3 was treated to 1 μM and cultured for 2 hours. In order to confirm the inhibitory effect on intracellular lipid reactive oxygen species, BODIPY™ 581 / 591 C11 (Lipid Peroxidation Sensor) [Invitrogen] TM; D3861] was used. According to the manufacturer's experimental method, BODIPY™ 581 / 591 C11 was diluted in cell culture medium to a final concentration of 5 μM and treated, and fluorescent staining was performed after reaction for 30 minutes. MLE-12 cells fluorescently stained with BODIPY™ 581 / 591 C11 were detached from the 12-well plate using 0.25% trypsin-EDTA and transferred to a microtube, and fluorescence (Ex / Em 500~650 nm / 510~665 nm) was measured using BD FACSLyric™ to calculate the change ratio compared to the control group. The results are shown in Fig. 1.

[0593] Figure 1 shows the inhibitory effects of the Example compounds 15, 77, 96, 188, 246 and the Comparative example compound Fer-1 according to each concentration, as a ratio to the control group, when the accumulation of intracellular lipid reactive oxygen species was induced by RSL3, a ferroptosis-inducing substance. When MLE-12 cells were treated with 1 μM RSL3, intracellular lipid reactive oxygen species significantly increased compared to the control group (RSL3-untreated group), and it can be confirmed that lipid reactive oxygen species decreased as the concentration increased when treated with the Example compounds 15, 77, 96, 188, 246 and the Comparative example compound Fer-1. Therefore, it was confirmed that the intracellular lipid reactive oxygen species increased by RSL3 treatment were effectively suppressed when treated with the Example compounds 15, 77, 96, 188 and 246.

[0594] Experimental Example 4-2: The inhibitory effect on lipid reactive oxygen species was confirmed in ARPE-19 cells using the same method as Experimental Example 4-1, but with different conditions as shown in Table 16 below, and the results are shown in Figure 2.

[0595] Figure 2 shows that intracellular lipid reactive oxygen species significantly increased upon treatment with RSL3 (1.0 μM) in ARPE-19 cells and decreased upon treatment with Example Compounds 15, 77, 96, 188, and 246. In particular, Example Compounds 15 and 246 showed some inhibitory effects on the accumulation of lipid reactive oxygen species even at the lowest concentration of 0.01 μM.

[0596] Experimental Example 4-3: The inhibitory effect on lipid reactive oxygen species was confirmed for HT-22 cells using the same method as Experimental Example 4-1, but with different conditions as shown in Table 16 below, and the results are shown in Figure 3.

[0597] Figure 3 shows that intracellular lipid reactive oxygen species significantly increased upon treatment with RSL3 (1.0 μM) in HT-22 cells and decreased upon treatment with Example Compounds 15, 73, 74, 77, 188 and 246. Example Compounds 15, 73, 74, 77 and 246 showed some inhibitory effects on the accumulation of lipid reactive oxygen species even at the lowest concentration of 0.01 μM. Example Compound 188 was found to inhibit the accumulation of lipid reactive oxygen species similar to Fer-1 in the concentration range used in the experiment.

[0598]

[0599]

[0600] Experimental Example 5: Inhibitory effect on intracellular ferrous ion accumulation in retinal epithelial cells and lung epithelial cells.

[0601] Experimental Example 5-1: To confirm the inhibitory effect on intracellular iron ion accumulation in retinal epithelial cells, ARPE-19 cells were seeded in a 6-well plate at 3 x 10 5Each well was divided into individual cells and cultured for 18-24 hours. The final concentrations of the example compounds 15, 77, 96, 188, 246 and the comparative example compound Fer-1 were diluted to 0.01, 0.1 and 1 μM and treated to each well and cultured for 20 minutes. After that, the final concentration of RSL3 was treated to 1 μM and cultured for 4 hours. FerroOrange [DOJINDO; F374] was used to confirm the inhibitory effect on intracellular iron ion accumulation. According to the manufacturer's experimental method, FerroOrange was diluted in the cell culture medium to a final concentration of 1 μM and treated, and the reaction was performed for 30 minutes and fluorescent staining was performed. ARPE-19 cells fluorescently stained with FerroOrange were detached from 6-well plates using 0.25% trypsin-EDTA and transferred to microtubes. Fluorescence (Ex / Em 580 nm / 543 nm) was measured using BD FACSLyric™, and the change in percentage compared to the control group (RSL3-untreated group) was calculated. The results are shown in Fig. 4.

[0602] Figure 4 shows the inhibitory effects of Example Compounds 15, 77, 96, 188, 246 and Comparative Example Compound Fer-1 according to their concentrations, as a ratio to the control group, when intracellular iron ion accumulation was induced by treatment with RSL3, a ferroptosis-inducing substance. When ARPE-19 cells were treated with 1 μM RSL3, intracellular iron ion accumulation significantly increased compared to the control group, and when Example Compounds 15, 77, 96, 188, 246 and Comparative Example Compound Fer-1 were treated, it was shown to decrease in a concentration-dependent manner. In particular, Example Compounds 15, 77 and 246 showed significant inhibitory effects on intracellular iron ion accumulation even at a lower concentration range (0.1 μM) than Fer-1. In conclusion, it was confirmed that the intracellular iron ion increased by RSL3 treatment was effectively inhibited by Example Compounds 15, 77, 96, 188 and 246.

[0603] Experimental Example 5-2: The inhibitory effect on intracellular iron ion accumulation in MLE-12 cells was confirmed using the same method as Experimental Example 5-1, but with different conditions as shown in Table 16 below, and the results are shown in Figure 5.

[0604] Figure 5 shows that intracellular iron ion accumulation in MLE-12 cells significantly increased compared to the control group when treated with RSL3 (1.0 μM) and decreased by treatment with examples compounds 15, 77, 96, 188, and 246.

[0605]

[0606]

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 are each independently hydrogen, halogen, -OC 1-4 Haloalkyl, -NH-C 3-6 Cycloalkyl, or -O-5 to 10-membered aryl, R 2 is hydrogen, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Alkylene-OH, -C 1-8 Alkoxy, -C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, - C 1-8 Alkylene-C 1-8 Alkoxy, or -L 1 -W 1 And, L 1 is a direct bond, or -O-, -O-(CH 2 ) m -, or -(CH 2 ) m - and m is an integer from 1 to 4, W 1 Silver -NR 8 R 9 , -C 3-8 Cycloalkyl, -5 to 11-membered heterocycloalkyl or -5 to 10-membered aryl, wherein the aryl of 5 to 10 atoms is halogen, -C 1-4 Alkoxy and -OC 1-4 It may be substituted with one or more selected from the group consisting of haloalkyl, R 8 and R 9 are each independently hydrogen or -C 1-6 It is alkyl, R 3 is hydrogen, halogen, -C 1-8 Alkylene-OH, or -L 2 -X 1 And, L 2 -C(=O)-, -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH 2 ) n - and n is an integer from 1 to 4, X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl, X 1 Heterocycloalkyl of -5 to 11 atoms is -C 1-4 Alkyl, -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NH-C 1-4 Alkyl, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 10-membered heterocycloalkyl, -C(=O)-5 to 10-membered aryl, -C(=O)-5 to 10-membered heteroaryl, and -(CH 2 ) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the aryl having 5 to 10 atoms or the heteroaryl having 5 to 10 atoms may be substituted with halogen, o is an integer from 1 to 4, R 4 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-4 Haloalkyl, -C 1-3 Alkylene-C 1-4 Alkoxy, -C 2-6 Alkenyl, -C 1-4 Alkoxy, -C 1-4 Alkylene-OH, -C 3-8 Cycloalkyl, -5 to 10-membered aryl, or -O-5 to 10-membered aryl, wherein aryl is -CN, -C(=O)NR 8 R 9 , -NHS(=O) 2 R 9 or -S(=O) 2 R 9 is unsubstituted or substituted with one or more substituents selected from the group consisting of R 5 is hydrogen, halogen, -CN, -C 1-8 Alkyl, -(OC 1-4 alkylene) p -Alkoxy, -(C 1-4 alkylene-O) p -R 9 , -C 1-4 Alkylene-OC 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -C 1-4 Alkoxy, or -L 3 -Z 1 , p is an integer from 1 to 4, and R 5 can be substituted with -OH, L 3 is a direct bond, or -NH-, -C 1-4 Alkylene-, -O-(C 1-4 alkylene)-, or -(C 1-4 alkylene)-O-, Z 1 is -C 3-8 Cycloalkyl, -5 to 11-membered heterocycloalkyl, -5 to 10-membered aryl or -5 to 10-membered heteroaryl, Z 1 Silver -C(=O)NR 8 R 9 , -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-4 may be substituted with one or more substituents selected from the group consisting of alkoxy, and -CN, R 6 and R 7 are each independently -C 1-6 Alkyl or R 6 And R 7 are connected to each other -C 3-6 Forming cycloalkyl, R 1 Inland R 3 At least one of them is not hydrogen, and R 4 and R 5 At least one of them is not hydrogen.

2. In paragraph 1, R 1 and R 4 is hydrogen, R 2 is hydrogen, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, - C 1-8 Alkylene-C 1-8 Alkoxy, or -L 1 -W 1 And, L 1 is a direct bond, or -O-, -O-(CH 2 ) m -, or -(CH 2 ) m - and m is an integer from 1 to 4, W 1 Silver -NR 8 R 9 , -C 3-8 Cycloalkyl, -5 to 11-membered heterocycloalkyl or -5 to 10-membered aryl, wherein the aryl of 5 to 10 atoms is halogen, -C 1-4 Alkoxy and -OC 1-4 It may be substituted with one or more selected from the group consisting of haloalkyl, R 3 is hydrogen, halogen, -C 1-8 Alkylene-OH, or -L 2 -X 1 And, L 2 is -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH 2 ) n - and n is an integer from 1 to 4, X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl, X 1 Heterocycloalkyl of -5 to 11 atoms is -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 11-membered heterocycloalkyl, and -(CH 2 ) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the heteroaryl having 5 to 10 atoms is unsubstituted, and o is an integer from 1 to 4, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

3. In any one of paragraphs 1 to 2, R 1 , R 2 and R 4 is hydrogen, R 3 is hydrogen, halogen, -C 1-8 Alkylene-OH, or -L 2 -X 1 And, L 2 is -C(=O)NH-, -C(=O)NH-C 1-4 Alkylene- or -(CH 2 ) n - and n is an integer from 1 to 4, X 1 Silver -NR 8 R 9 , or -5 to 11-membered heterocycloalkyl, X 1 Heterocycloalkyl of -5 to 11 atoms is -C 3-8 Cycloalkyl, -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, -OC 1-4 Alkylene-NH-C 1-4 Alkylene-OH, -5 to 11-membered heterocycloalkyl, and -(CH 2 ) o - is unsubstituted or substituted with at least one substituent selected from the group consisting of heteroaryl having 5 to 10 atoms, wherein the heteroaryl having 5 to 10 atoms is unsubstituted, and o is an integer from 1 to 4, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

4. In any one of paragraphs 1 to 3, R 1 , R 2 , and R 4 is hydrogen, R 3 is -L 2 -X 1 And, L 2 is -C(=O)NH-C 1-4 Alkylene- or -(CH 2 ) n - and n is an integer from 1 to 4, X 1 is morpholinyl, piperidinyl or piperazinyl, X 1 Silver -C 1-6 Alkylene-OH, -(OC 1-4 alkylene) o -OH, -NR 9 -C 1-6 Alkyl-OH, -NH-C 1-4 Alkylene-OC 1-4 Alkylene-OH, and -OC 1-4 Alkylene-NH-C 1-4 is unsubstituted or substituted with at least one substituent selected from the group consisting of alkylene-OH, and p is an integer from 1 to 4, R 5 is -(OC 1-4 alkylene) p -Alkoxy, -(C 1-4 alkylene-O) p -R 9 , -C 1-4 Alkylene-OC 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -C 1-4 Alkoxy, or -L 3 -Z 1 , p is an integer from 1 to 4, and R 5 can be substituted with -OH, L 3 is a direct bond, or -C 1-4 Alkylene-, -O-(C 1-4 alkylene)-, or -(C 1-4 alkylene)-O-, Z 1 is -C 3-8 Cycloalkyl, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, piperidine, piperazine, oxazepaine, pyrazole, imidazole or pyridine, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, R 1 , R 2 and R 5 is hydrogen, R 4 is -C 1-6 Alkyl, -OC 1-4 Haloalkyl, -C 1-3 Alkylene-C 1-4 Alkoxy, -C 2-6 Alkenyl, -C 1-4 Alkoxy, -C 1-4 Alkylene-OH, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R 3 If R is not hydrogen, 1 and R 2 is hydrogen, or R 6 and R 7 These ethyl groups or are linked to each other -C 3-6 When forming a cycloalkyl, R 4 and R 5 are all hydrogen, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

7. In any one of paragraphs 1 to 5, R 6 and R 7 are each independently -CH 3 or -CH 2 CH 3 person, A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, A compound of the above chemical formula 1, characterized in that it is one selected from the following group of compounds, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof: <1> 2-Bromo-7,9,9-trimethyl-9,10-dihydroacridine; <2> 6-Methoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <3> 6-Methoxy-9,9-dimethyl-2-((4-(oxetan-3-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <4> 2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethan-1-ol; <5> 2-((2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethyl)amino)ethan-1-ol; <6> 2-Isopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <7> 2-Cyclopropyl-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <8> 2-(tert-butyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <9> 1-(6-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <10> 3-(Ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <11> 8-Bromo-9,9-dimethyl-9,10-dihydroacridin-3-ol; <12> 1-Bromo-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <13> 6-(Difluoromethoxy)-2-isopropyl-9,9-dimethyl-9,10-dihydroacridine; <14> 2-Isopropyl-9,9-dimethyl-6-(2,2,2-trifluoroethoxy)-9,10-dihydroacridine; <15> 1-Chloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine; <16> (9,9-Dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone; <17> 2-Bromo-10H-spiro[acridine-9,1'-cyclopentane]; <18> 3-Ethoxy-10H-spiro[acridine-9,1'-cyclopentane]; <19> N,N-Dimethyl-1-(10H-spiro[acridin-9,1'-cyclopentan]-2-yl)methanamine;<20> Cyclopropyl(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone; <21> 6-(tert-butyl)-9,9-dimethyl-2-(trifluoromethyl)-9,10-dihydroacridine; <22> 9,9-Diethyl-3-methoxy-9,10-dihydroacridine; <23> 3-Chloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <24> 1-Chloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <25> 3-Chloro-6,9,9-trimethyl-9,10-dihydroacridine; <26> 2-Chloro-6,9,9-trimethyl-9,10-dihydroacridine; <27> 1-Chloro-6,9,9-trimethyl-9,10-dihydroacridine; <28> 7-Bromo-1-chloro-9,9-dimethyl-9,10-dihydroacridine; <29> 5-Chloro-3-methoxy-9,9-dimethyl-9,10-dihydroacridine; <30> 2-Bromo-6-chloro-9,9-dimethyl-9,10-dihydroacridine; <31> 2-Bromo-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <32> 2-Bromo-6-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridine; <33> 2-(tert-butyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <34> 3-(tert-butyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <35> 2-Bromo-7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridine; <36> 3-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <37> 1-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <38> 2-Bromo-9,9-diethyl-9,10-dihydroacridine; <39> 6-(tert-butyl)-2-fluoro-9,9-dimethyl-9,10-dihydroacridine; <40> 6-(tert-butyl)-2-chloro-9,9-dimethyl-9,10-dihydroacridine; <41> 2-(tert-butyl)-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <42> 2-Bromo-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine;<43> 2-Bromo-6-fluoro-9,9-dimethyl-9,10-dihydroacridine; <44> 2-Bromo-6,9,9-trimethyl-9,10-dihydroacridine; <45> 7-Bromo-1-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <46> 2-Bromo-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <47> 2-Isopropyl-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <48> 7-Bromo-3-chloro-1,9,9-trimethyl-9,10-dihydroacridine; <49> 7-Bromo-1-chloro-3,9,9-trimethyl-9,10-dihydroacridine; <50> 1-Chloro-6-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <51> 3-Chloro-6-methoxy-1,9,9-trimethyl-9,10-dihydroacridine; <52> 1,3-Dichloro-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <53> 1-Chloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <54> 3-Chloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <55> 1,3-Dichloro-9,9-dimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <56> 1,3-Dichloro-9,9-dimethyl-8-(trifluoromethoxy)-9,10-dihydroacridine; <57> 2-Bromo-6-chloro-9,9-diethyl-9,10-dihydroacridine; <58> 2,9,9-Trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <59> 1,9,9-Trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <60> 3,9,9-Trimethyl-6-(trifluoromethoxy)-9,10-dihydroacridine; <61> 6-(tert-butyl)-1-chloro-9,9-dimethyl-9,10-dihydroacridine; <62> 1-Chloro-6-isopropyl-9,9-dimethyl-9,10-dihydroacridine; <63> 2-(8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)propan-2-ol; <64> 1-Chloro-6-cyclopropyl-9,9-dimethyl-9,10-dihydroacridine;<65> 1-Chloro-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <66> 1-Chloro-9,9-dimethyl-8-phenoxy-9,10-dihydroacridine; <67> 2-Methoxy-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <68> 1-(7-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <69> 6-(tert-butyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <70> 1-(8-chloro-9,9-dimethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <71> 2-(tert-butyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <72> 1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N-methylmethanamine; <73> 9,9-Diethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <74> 2-(piperazin-1-ylmethyl)-10H-spiro[acridine-9,1'-cyclopentane]; <75> 2-((2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <76> 2-((2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <77> 2-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <78> 2-((3,5-dimethylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <79> 2-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <80> 2-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <81> 2-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine;<82> 2-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <83> 2,9,9-Trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <84> 2-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-7-methoxy-9,9-dimethyl-9,10-dihydroacridine; <85> 2-((3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <86> 6-Fluoro-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <87> 6,9,9-Trimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <88> 6-Methoxy-9,9-dimethyl-2-((4-phenylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <89> 2-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <90> 2-((4-(4-chlorobenzyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <91> 6-Methoxy-9,9-dimethyl-2-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <92> (4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)(phenyl)methanone; <93> (4-chlorophenyl)(4-((6-methoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)methanone; <94> 6-Methoxy-9,9-dimethyl-2-((4-phenethylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <95> 6-Methoxy-9,9-dimethyl-2-((4-propylpiperazin-1-yl)methyl)-9,10-dihydroacridine; <96> 2-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <97> 6-Methoxy-9,9-dimethyl-2-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine;<98> 2-((4-cyclopropylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <99> 6-Methoxy-9,9-dimethyl-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <100> 7-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-1-methoxy-3,9,9-trimethyl-9,10-dihydroacridine; <101> 4-((7,9,9-trimethyl-9,10-dihydroacridin-3-yl)methyl)morpholine; <102> 2,9,9-Trimethyl-6-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <103> 4-((7,9,9-trimethyl-9,10-dihydroacridin-3-yl)methyl)thiomorpholine 1,1-dioxide; <104> 6-(Ethoxymethyl)-9,9-dimethyl-2-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <105> 4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)thiomorpholine; <106> 4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)thiomorpholine 1,1-dioxide; <107> 6-(Ethoxymethyl)-9,9-dimethyl-2-(pyrrolidin-1-ylmethyl)-9,10-dihydroacridine; <108> 2-((4-benzylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <109> 6-Methoxy-9,9-dimethyl-2-((4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <110> 6-Methoxy-9,9-dimethyl-2-((4-oxetan-3-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <111> 2-((4-cyclopentylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <112> 2-((4-(cyclopentylmethyl)piperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <113> 6-Methoxy-9,9-dimethyl-2-((4-(tetrahydrofuran-3-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine;<114> 2-((4-cyclohexylpiperazin-1-yl)methyl)-6-methoxy-9,9-dimethyl-9,10-dihydroacridine; <115> 6-Methoxy-9,9-dimethyl-2-((4-(oxepan-4-yl)piperazin-1-yl)methyl)-9,10-dihydroacridine; <116> 2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethan-1-ol; <117> 2-(2-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethoxy)ethan-1-ol; <118> 2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol; <119> 3-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)propan-1-ol; <120> 4-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)-2-methylbutan-2-ol; <121> 5-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)pentan-1-ol; <122> 2-(2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethoxy)ethan-1-ol; <123> N-(2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)propan-1-amine; <124> 2-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)(methyl)amino)ethan-1-ol; <125> 1-((2-(4-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)-2-methylpropan-2-ol; <126> 2-((2-(4-((9,9-dimethyl-6-morpholino-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol;<127> 2-(2-(4-((6-ethoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethoxy)ethan-1-ol; <128> 2-((2-(4-((6-ethoxy-9,9-dimethyl-9,10-dihydroacridin-2-yl)methyl)piperazin-1-yl)ethyl)amino)ethan-1-ol; <129> 2-Cyclopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <130> 2-Isopropyl-9,9-dimethyl-6-phenoxy-9,10-dihydroacridine; <131> 2,9,9-Trimethyl-6-phenoxy-9,10-dihydroacridine; <132> 9,9-Dimethyl-6-phenoxy-2-(prop-1-en-2-yl)-9,10-dihydroacridine; <133> 1-Chloro-9,9-dimethyl-6-phenyl-9,10-dihydroacridine; <134> 1-Chloro-6-ethyl-9,9-dimethyl-9,10-dihydroacridine; <135> 1-Chloro-9,9-dimethyl-6-propyl-9,10-dihydroacridine; <136> 3,9,9-Trimethyl-6-(2,2,2-trifluoroethyl)-9,10-dihydroacridine; <137> 1-Chloro-9,9-dimethyl-6-(2,2,2-trifluoroethyl)-9,10-dihydroacridine; <138> 1,3-Dichloro-9,9-dimethyl-6-phenyl-9,10-dihydroacridine; <139> 1,3-Dichloro-6-(4-chlorophenyl)-9,9-dimethyl-9,10-dihydroacridine; <140> 1,3-Dichloro-6-(4-methoxyphenyl)-9,9-dimethyl-9,10-dihydroacridine; <141> 1,3-Dichloro-9,9-dimethyl-6-(4-(trifluoromethoxy)phenyl)-9,10-dihydroacridine; <142> 6-(2-ethoxyethyl)-2,9,9-trimethyl-9,10-dihydroacridine; <143> 2-Isopropyl-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <144> 4-(7-isopropyl-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <145> 2-Isopropyl-9,9-dimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <146> 2,9,9-Trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine;<147> 4-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <148> 2,9,9-Trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <149> 1,9,9-Trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <150> 3,9,9-Trimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <151> 4-(8,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <152> 4-(6,9,9-trimethyl-9,10-dihydroacridin-3-yl)morpholine; <153> 1,9,9-Trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <154> 3,9,9-Trimethyl-6-(piperidin-1-yl)-9,10-dihydroacridine; <155> 4-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)thiomorpholine 1,1-dioxide; <156> 1,3-Dichloro-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <157> 4-(6,8-dichloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <158> 4-(2-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)ethyl)morpholine; <159> 2,9,9-Trimethyl-6-(2-(piperidin-1-yl)ethyl)-9,10-dihydroacridine; <160> 2,9,9-Trimethyl-6-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine; <161> 4-(2-(7,9,9-trimethyl-9,10-dihydroacridin-3-yl)ethyl)thiomorpholine 1,1-dioxide; <162> 4-(7-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-3-yl)morpholine; <163> 2-(Ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-yl)-9,10-dihydroacridine; <164> 4-(2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)ethyl)morpholine; <165> 1-(9,9-diethyl-9,10-dihydroacridin-2-yl)-N,N-dimethylmethanamine; <166> 6-Chloro-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine;<167> 3-Methoxy-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <168> 9,9-Dimethyl-6-phenoxy-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <169> 1,9,9-Trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <170> 1-Methoxy-3,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <171> (9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methanol; <172> (9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)methanol; <173> 1-Chloro-3,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <174> 3-Chloro-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <175> 1-Chloro-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <176> 1-Chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <177> 2-Chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <178> 3-Chloro-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <179> 6-(Ethoxymethyl)-1,9,9-trimethyl-9,10-dihydroacridine; <180> 1-Chloro-6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridine; <181> 1,3-Dichloro-6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridine; <182> 1-Chloro-6-(ethoxymethyl)-3,9,9-trimethyl-9,10-dihydroacridine; <183> 3-Chloro-6-(ethoxymethyl)-1,9,9-trimethyl-9,10-dihydroacridine; <184> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-((trifluoromethoxy)methyl)-9,10-dihydroacridine; <185> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(trifluoromethoxy)-9,10-dihydroacridine;<186> 9,9-Dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine-3-carbonitrile; <187> 6-((2-methoxyethoxy)methyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <188> 6-(Ethoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <189> 2-(Ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <190> 1-Chloro-3-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <191> 3-Chloro-1-(ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <192> 9,9-Dimethyl-6-(phenoxymethyl)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <193> 2-(Ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <194> 6-(Ethoxymethyl)-9,9-diethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <195> 3-Chloro-1-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <196> 6-(Butoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <197> 3-(Ethoxymethyl)-1,9,9-trimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <198> 1-Chloro-3-(ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <199> 6-(Ethoxymethyl)-2-(piperazin-1-ylmethyl)-10H-spiro[acridine-9,1'-cyclopentane]; <200> 9,9-Dimethyl-6-phenyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <201> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-N,N-dimethylbenzamide; <202> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-N-methylbenzamide;<203> 9,9-Dimethyl-2-phenyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <204> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N,N-dimethylbenzamide; <205> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <206> 1-(Ethoxymethyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <207> 1-(Ethoxymethyl)-9,9-dimethyl-6-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <208> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)propan-2-ol; <209> 6-(methoxymethyl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <210> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(1H-pyrazol-5-yl)-9,10-dihydroacridine; <211> 6-(1H-imidazol-1-yl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <212> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(pyridin-2-yl)-9,10-dihydroacridine; <213> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-1-ylmethyl)-9,10-dihydroacridine; <214> 4-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methyl)morpholine; <215> 6-(1H-imidazol-2-yl)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <216> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-1-yl)-9,10-dihydroacridine; <217> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)morpholine; <218> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)thiomorpholine; <219> 2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methoxy)ethan-1-ol;<220> 3-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <221> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)-N-methylbenzamide; <222> N-(4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)phenyl)methanesulfonamide; <223> 2-(2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)methoxy)ethoxy)ethan-1-ol; <224> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)thiomorpholine 1,1-dioxide; <225> 9,9-Dimethyl-6-(piperazin-1-yl)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <226> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)-1,4-oxazepaine; <227> 9,9-Dimethyl-N-phenyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <228> 4-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)benzonitrile; <229> 2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)benzonitrile; <230> 9,9-Dimethyl-2-(4-(methylsulfonyl)phenyl)-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <231> 9,9-Dimethyl-2-(2-(methylsulfonyl)phenyl)-7-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <232> N-(2-(9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-2-yl)phenyl)methanesulfonamide; <233> 4-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide; <234> 3-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide; <235> 2-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)amino)-N-methylbenzamide;<236> N-(4-(ethoxymethyl)phenyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <237> N-(2-(ethoxymethyl)phenyl)-9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-amine; <238> 7-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol; <239> 6-(tert-butyl)-9,9-dimethyl-9,10-dihydroacridin-3-ol; <240> 9,9-Diethyl-9,10-dihydroacridin-3-ol; <241> 6,8-Dichloro-9,9-dimethyl-9,10-dihydroacridin-3-ol; <242> 8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-ol; <243> 3-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <244> 2-(tert-butyl)-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <245> 3-Ethoxy-9,9-diethyl-9,10-dihydroacridine; <246> 1-Chloro-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <247> 3-Chloro-6-ethoxy-1,9,9-trimethyl-9,10-dihydroacridine; <248> 1-Chloro-6-ethoxy-3,9,9-trimethyl-9,10-dihydroacridine; <249> 1-Chloro-6-(difluoromethoxy)-9,9-dimethyl-9,10-dihydroacridine; <250> 1,3-Dichloro-6-(difluoromethoxy)-9,9-dimethyl-9,10-dihydroacridine; <251> 1,3-Dichloro-6-(cyclopropylmethoxy)-9,9-dimethyl-9,10-dihydroacridine; <252> 1,3-Dichloro-6-ethoxy-9,9-dimethyl-9,10-dihydroacridine; <253> 6-(Difluoromethoxy)-2,9,9-trimethyl-9,10-dihydroacridine; <254> 6-Ethoxy-1,9,9-trimethyl-9,10-dihydroacridine; <255> 1-Chloro-9,9-dimethyl-6-(2-(piperidin-1-yl)ethoxy)-9,10-dihydroacridine; <256> 4-(2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine;<257> 1-Chloro-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <258> 4-(2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)thiomorpholine 1,1-dioxide; <259> 2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-N-methylethan-1-amine; <260> 2-((8-chloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)-N,N-dimethylethan-1-amine; <261> 6-Ethoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <262> 6-(Cyclohexylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <263> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-9,10-dihydroacridine; <264> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-(piperidin-4-ylmethoxy)-9,10-dihydroacridine; <265> 6-(Cyclopropylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <266> 4-(2-((6,8-dichloro-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine; <267> 1,3-Dichloro-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <268> 4-(2-((6-(ethoxymethyl)-9,9-dimethyl-9,10-dihydroacridin-3-yl)oxy)ethyl)morpholine; <269> 6-Isopropoxy-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <270> 9,9-Dimethyl-2-(piperazin-1-ylmethyl)-6-propoxy-9,10-dihydroacridine; <271> 9,9-Dimethyl-6-(neopentyloxy)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <272> 6-(Cyclobutylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <273> 6-(2-methoxyethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine;<274> 3-(Ethoxymethyl)-9,9-dimethyl-6-(2-(piperazin-1-yl)ethoxy)-9,10-dihydroacridine; <275> 9,9-Dimethyl-6-(oxetan-3-ylmethoxy)-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <276> 1-((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)oxy)-2-methylpropan-2-ol; <277> 6-(azetidine-3-ylmethoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <278> 6-(2-methoxy-2-methylpropoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <279> 1-(((9,9-dimethyl-7-(piperazin-1-ylmethyl)-9,10-dihydroacridin-3-yl)oxy)methyl)cyclopropan-1-ol; <280> 6-((1-methoxycyclopropyl)methoxy)-9,9-dimethyl-2-(piperazin-1-ylmethyl)-9,10-dihydroacridine; <281> 9,9-Dimethyl-N-(2-(methylamino)ethyl)-9,10-dihydroacridine-2-carboxamide; <282> 9,9-Dimethyl-N-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine-2-carboxamide; <283> (4-(cyclopentylamino)-9,9-dimethyl-9,10-dihydroacridin-2-yl)(piperazin-1-yl)methanone; <284> 4-(Cyclopentylamino)-9,9-dimethyl-N-(2-(methylamino)ethyl)-9,10-dihydroacridine-2-carboxamide and <285> 4-(Cyclopentylamino)-9,9-dimethyl-N-(2-(piperazin-1-yl)ethyl)-9,10-dihydroacridine-2-carboxamide.; 9. A pharmaceutical composition for the prevention or treatment of at least one disease selected from the following group, comprising a compound of the chemical formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient; and a pharmaceutically acceptable carrier: Acute or chronic liver disease, including hepatitis, fibrosis or cirrhosis; neurodegenerative diseases, including dementia, including Alzheimer's disease and vascular dementia, Parkinson's disease, epilepsy, dementia with Lewy bodies or Huntington's disease; ischemic diseases, including ischemic heart disease, reperfusion injury, ischemic stroke or ischemic injury; pancreatitis, bacterial or viral sepsis, diabetes or diabetic complications, diabetic vascular disease; Necrotizing proctitis, cystic fibrosis, rheumatoid arthritis, osteoarthritis, nephrotic syndrome, bacterial infections, viral infections including SARS-CoV or HIV, multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, asphyxia, tuberculosis, endometriosis, vascular insufficiency, psoriasis, frostbite, course / complication of steroid injections, vibrio sepsis, tenderness, hemoglobinuria, burns, hyperpyrexia, Crohn's disease, celiac disease, compartment syndrome, spinal cord injury, glomerulonephritis, renal failure, muscular dystrophy, inherited metabolic disorders, mycoplasma infection, anthrax, Anderson's disease, Fabry disease, congenital mitochondrial diseases, phenylketonuria, placental infarction, syphilis, and aseptic necrosis; alcoholism and cocaine addiction; Necrosis associated with exposure to or administration or self-administration of antibiotics, anticancer agents, drugs including Doxorubicin, Puromycin, Bleomycin, nonsteroidal anti-inflammatory drugs (NSAIDs), or Cyclosporine, chemical toxins including carbon tetrachloride, cyanide, methanol, or ethylene glycol, toxic gases, pesticides, or heavy metals including lead, mercury, or cadmium; damage caused by exposure to radiation or ultraviolet light and cell necrosis associated therewith;Acute or chronic kidney disease, traumatic brain injury, necrotizing enterocolitis, skin diseases including psoriasis and allergic dermatitis; organ preservation or transplantation; chronic inflammatory pulmonary disease including acute respiratory distress syndrome or acute lung disease, pneumonia, tuberculosis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis; demyelinating diseases including demyelination and amyotrophic lateral sclerosis (ALS); high blood pressure including pulmonary hypertension; psychiatric diseases including stroke, prion disease, epilepsy, ataxia, migraine, memory and cognitive decline, seizures, tremors, or depression; Spinocerebellar degeneration including Friedreich's ataxia; dyslipidemia including insulin resistance and hyperlipidemia; atherosclerosis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis; various cancers and cancer metastases; diseases related to visual impairment including macular degeneration, retinitis pigmentosa, cataracts and glaucoma;Anemia, cholestasis, hypoparathyroidism, pancytopenia, pancreatic disorders, lactic acidosis, lactic acidemia, hearing loss, short stature, ileus, cardiac conduction defects including arrhythmias, cardiomyopathy, myocardial infarction, ischemia-reperfusion heart injury, heart failure, endometriosis, infertility, premature menopause; muscular dystrophy including limb-girdle muscular dystrophy (LGMD), Becker muscular dystrophy (BMD), and Duchenne muscular dystrophy (DMD); aging and age-related diseases; Neuropathic pain; Mucositis including oral mucositis and gastrointestinal mucositis; 10. A pharmaceutical composition for preventing or treating a degenerative neurological disease, liver disease, kidney disease, stroke, myocardial infarction, ocular disease, or lung disease, comprising a compound of chemical formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient; and a pharmaceutically acceptable carrier.

11. In paragraph 10, A pharmaceutical composition wherein the above-mentioned neurodegenerative disease is at least one selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, Epilepsy, Huntington's Disease, Amyotrophic lateral sclerosis, Friedreich's ataxia, Multiple sclerosis, Charcot-Marie-Tooth (CMT) disease, Dementia with Lewy Bodies, and Traumatic Brain Injury.

12. In any one of paragraphs 9 to 11, A pharmaceutical composition, wherein the compound of the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof inhibits cell necrosis or ferroptosis.

13. A method for preventing or treating a disease related to cell necrosis or ferroptosis, comprising a step of administering a compound of formula 1 according to paragraph 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, in a pharmaceutically effective amount to a subject in need thereof.

14. A method for inhibiting ferroptosis, comprising administering to a subject in need thereof a compound of formula 1 according to paragraph 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, in a pharmaceutically effective amount.

15. A method for inhibiting reactive oxygen species (ROS) in a cell, comprising the step of contacting a cell with a compound of formula 1 according to claim 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

16. Use of a compound of formula 1 according to claim 1, or a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention or treatment of diseases related to cell necrosis or ferroptosis.

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