Quinone reductase 2 inhibitor compounds and uses thereof

Abstract

To provide additional aminoquinoline quinone reductase 2 (QR2) inhibitors that exhibit diminished lysosomal accumulation to reduce toxicity.SOLUTION: According to some embodiments, provided herein is a compound of a formula (I), or a pharmaceutically acceptable salt or prodrug thereof. Compositions comprising the compound, and uses thereof for inhibiting the activity of quinone reductase-2, as well as in methods of treatment, are also provided.SELECTED DRAWING: Figure 1A

Description

[Background technology]

[0001] The prototype contains chloroquine (CQ) and hydroxychloroquine (HQ). Minoquinoline is a quinone reductase 2 (QR2) inhibitor, which was originally developed to treat It was originally developed to treat atherosclerosis, but has since been used to treat a variety of conditions, particularly autoimmune diseases, such as systemic lupus erythema. It is also effective in treating other indications, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It has been found that. Singer et al., “Update on immune function.” nosuppressive therapy,” Curr. Opin. Rheu matol. 1998, 10:169-173; se of chloroquine and hydroxychloroquine for non-infectious conditions other tha n rheumatoid arthritis or lupus: a cruci al review,” Lupus 1996, 5 Suppl 1:S59-64 In SLE and RA, aminoquinolines are the mainstay of first-line therapy and are used in combination with other drugs. Aminoquinolines are used to treat the signs and symptoms of SLE and RA. Not only does it improve the condition of the blood, but it also has a beneficial effect on lipid metabolism, reducing the incidence of thrombosis. Similar benefits have been observed in patients with inflammatory or erosive osteoarthritis. It has also been shown to be effective when used as adjuvant therapy in graft-versus-host disease, cancer, and HIV. The effectiveness of this treatment has been shown. Savarino et al., “Effects of chloroquine on viral infections: an old drug against today's diseases?” Lancet I nfect. Dis. 2003, 3(11):722-7; Savarino et al., “Risks and benefits of chloroqui ne use in anticancer strategies,” Lancet Oncol. 2006, 7(10):792-3; Sotelo et al. , ”Adding chloroquine to conventional tr eating for glioblastoma multiforme: ar andomized, double-blind, placebo-control led trial,” Ann. Intern. Med. 2006, 144( 5):337-43.

[0002] The potential of chloroquine (CQ) in neuroprotection has been investigated in the past in stroke, excitotoxicity and Although it has been tested in preclinical models of trauma and trauma, the therapeutic mechanisms remain elusive. CQ increased the number of microglia transported to the site of brain injury in a permanent MCA occlusion model. and dramatically limit PMN migration and reduce reactive astrogliosis and angiogenesis This reduces stroke volume by 60%. Giulian et al., "The ole of mononuclear phagocytes in wound h ealing after traumatic injury to adult m ammalian brain,” J. Neurosci. 1989, 9:44 16-4429; Ivanova et al., “Cerebral ische mia enhances polyamine oxidation: identi fication of enzymatically formed 3-amino propanal as an endogenous mediator of ne uronal and glial cell death,” J. Exp. Me d. 1998, 188:327-340. CQ inhibits the microglia response to various stimuli. It also reduces cytokine production by inflammatory bowel disease cells in vitro. Giulian, ”Microglia and the immune pathology of Alzheimer disease,” Am. J. Hum. Genet. 1 999, 65:13-18.

[0003] As some malaria strains are resistant to CQ, derivative compounds are also being investigated. U.S. Patent Application Publication No. 2006 / 0074105 to Are et al. discloses a method for treating malaria and autoimmune diseases. Certain quinoline and quinazoline derivatives are said to be useful in the treatment of autoimmune diseases. The conductor is described.

[0004] CQ and HQ are often used clinically as first-line therapy for autoimmune disorders. However, its effectiveness is limited by serious side effects. The drug is retinal toxic and unless dosing is limited, long-term use can lead to "target maculopathy" and loss of vision. Cardiac toxicity, although rare, can also occur, resulting in conduction disturbances (e.g. This may manifest as either a myocardial infarction (e.g., bundle branch block) and / or cardiomyopathy associated with congestive heart failure. Electron microscopy of cardiac and retinal biopsies after long-term CQ or HQ therapy has shown This directly results in high drug accumulation in endothelial cells (as well as in melanosomes in the retina and skin). Characteristic cytoplasmic inclusions that are believed to be the result of the endothelial cell death were identified. During therapeutic administration, CQ can accumulate at mM concentrations in skin, retina, kidney and liver cells. , plasma concentrations remain <1 μM.

[0005] In particular, further aminoquinoline quinolone derivatives, which also reduce lysosomal storage and reduce toxicity, are There remains a need for the development of nonreductase 2 (QR2) inhibitors. Summary of the Invention

[0006] According to some embodiments, the compound of formula (I): [ka] (Wherein, R1 is a nitrogen-containing heterocyclo or nitrogen-containing heteroaryl.) or a pharma- ceutically acceptable salt or prodrug thereof, The compound is fluoromethyl, difluoromethyl or trifluoromethyl once, twice is optionally substituted once or three times; Such compounds are provided herein.

[0007] In some embodiments, R1 is [ka] (wherein D1, D2, D3 and D4 are hydrogen, halo, alkyl, acyl, alkoxy, Aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol, sulfo each independently selected from the group consisting of aryl, sulfoxide, nitrile, nitro, and haloalkyl; or D1 and D2, D2 and D3 or D3 and D4 are optionally substituted. Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring). or a pharma- ceutically acceptable salt or prodrug thereof, The compound (including R1) may be fluoromethyl, difluoromethyl or trifluoromethyl. It may be optionally substituted once, twice or three times with methyl.

[0008] In some embodiments, D1, D2, D3 and D4 are each hydrogen.

[0009] In some embodiments, the compound is a compound of formula (I)(a)(1) or formula (I) Compound (a)(2) [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0010] In some embodiments, the compound has formula (I)(a)(2): [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0011] In some embodiments, the compound is a compound of formula (I)(a)(2) [ka] or a pharma- ceutically acceptable salt or prodrug thereof.

[0012] In some embodiments, R1 is [ka] (In the formula, X1, X2 and X3 are each independently selected from the group consisting of carbon, nitrogen and oxygen.) And, D5, D6, D7 and D8, when present, are hydrogen, halo, alkyl, acyl, aryl, koxy, aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol , sulfone, sulfoxide, nitrile, nitro and haloalkyl; Selected for the position or Two of D5, D6, D7 and D8 are optionally substituted fused rings (e.g. For example, cyclohexane or cyclohexene fused rings are formed together. or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0013] In some embodiments, the compound is a compound of formula (I)(b)(1) [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0014] In some embodiments, R1 is [ka] (In the formula, X4, X5, X6, X7 and X8 are each selected from the group consisting of carbon, nitrogen and oxygen.) and at least two of X4, X5, X6, X7 and X8 are independently selected. has at least three carbons, D9, D 10 , D 11 , D 12 , D 13 and D. 14 When present, it is hydrogen, halo, Alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, Hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D9, D 10 , D 11 , D 12 , D 13 and D. 14 Two of them are optional. fused rings (e.g., cyclohexane or cyclohexene rings) together to form (Complete. or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0015] In some embodiments, R1 is [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0016] In some embodiments, R1 is [ka] (In the formula, X9, 10 , X 11 and X 12 each selected from the group consisting of carbon, nitrogen and oxygen are independently selected, 10 , X 11 and X 12 At least two of them are charcoal It is raw, D 15 , D 16 , D 17 , D 18 and D. 19 When present, it is hydrogen, halo, alkyl, or aryl. aryl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, hydro From xyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D 15 , D 16 , D 17 , D 18 and D. 19 Two of the are optionally substituted. Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring). .) or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0017] In some embodiments, R1 is [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The compound is reacted once with fluoromethyl, difluoromethyl or trifluoromethyl, Optionally substituted two or three times.

[0018] In some embodiments, the compound has a positive LogD value at about pH 4 to pH 5.

[0019] Also included are compounds described herein and a carrier (e.g., a pharma- ceutically acceptable carrier). Compositions are also provided.

[0020] Also, quinone reductase 2 (QR2) and the compounds or compositions taught herein. A method for inhibiting the activity of QR2, comprising contacting in v The method is further provided wherein the contacting is performed in vitro or the contacting is performed in vivo. It will be offered.

[0021] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. There is also provided a method of treating malaria in a subject comprising administering to an elephant. Further provided is a compound or composition as taught herein for use in the treatment of Use of the compounds taught herein for the preparation of a medicament for the treatment of malaria. is further provided.

[0022] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method of treating an immune disorder in a subject comprising administering to said subject a therapeutically effective amount of the compound. Further provided is a compound or composition as taught herein for use in the treatment of Use of the compounds taught herein for the preparation of a medicament for the treatment of an immune disorder. is further provided.

[0023] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method of treating acute neurological injury in a subject comprising administering to said subject a therapeutically effective amount of The compounds or compositions taught herein for use in treating nerve injury are further The present invention provides a method for preparing a medicament for treating acute nerve injury, comprising administering to said patient a therapeutically effective amount of the compound taught herein. Uses of the compounds are further provided.

[0024] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. administering to an elephant a chronic neurological disorder (e.g., Parkinson's disease) in said subject. Methods for treating chronic neurological disorders (such as Alzheimer's disease) are also provided. Further provided is a compound or composition as taught herein for use in treating chronic neurological disorders. The present invention further provides a method for the preparation of a medicament for the treatment of a chronic obstructive pulmonary disease (COPD) or a pulmonary artery disease (PAH). Provided.

[0025] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method of treating lupus in a subject comprising administering to said subject a therapeutically effective amount of the compound. Further provided is a compound or composition as taught herein for use in the treatment of Use of the compounds taught herein for the preparation of a medicament for the treatment of lupus is further provided.

[0026] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method of treating an infection in a subject comprising administering to said subject a therapeutically effective amount of the compound. Further provided are compounds or compositions taught herein for use in the treatment of Further disclosed is the use of the compounds taught herein for the preparation of a medicament for the treatment of an infectious disease. will be provided.

[0027] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method for treating cancer in a subject, comprising administering to said subject a compound comprising the steps of: Further provided is a compound or composition as taught herein for use in treating cancer. Further provided is the use of a compound taught herein for the preparation of a medicament for the treatment of .

[0028] The compounds or compositions taught herein can also be administered to a subject in need thereof in a therapeutically effective amount. Also provided is a method of treating CNS lupus in a subject, comprising administering to said subject a therapeutically effective amount of the compound. A compound or composition as taught herein for use in the treatment of NS lupus Further provided herein are methods for preparing a medicament for the treatment of CNS lupus. Further provided are uses of the compounds.

[0029] The compounds or compositions taught herein can also be administered in therapeutically effective amounts to reduce the risk of cerebrovascular disease. Also provided is a method for treating a subject at high risk of cerebrovascular disease, comprising administering to said subject The compounds or compositions taught herein for use in treating subjects with high blood pressure Further provided is a method for preparing a medicament for treating a subject at high risk for cerebrovascular disease. Further provided are uses of the compounds taught herein.

[0030] In some embodiments of the above-described methods or uses, the administration is chronic administration (e.g., for several months). (over months or years).

[0031] In some embodiments of the above methods or uses, administration occurs once a day. [Brief description of the drawings]

[0032] [Figure 1A] FIG. 1A is a graph showing the LogD of chloroquine versus pH. [Figure 1B] Figure 1B is a graph showing the LogD of QR2I-44 versus pH. The LogD of QR2I-44 above about pH 4 is positive, indicating that membrane permeability is maintained in the lysosomal pH range. Unlike CQ, QR2I-44 is not trapped in lysosomes. [Figure 2A] FIG. 2A is a graph showing 5-day rotarod results of QR2I-44 versus vehicle. [Figure 2B] Figure 2B is a graph showing 5-day rotarod results of QR2I-44 versus chloroquine (CQ). The results show that QR2I-44 is neuroprotective after TBI and is therapeutically superior to CQ. [Diagram 3] FIG. 1 is a graph showing the results of a comparative study of chloroquine (CQ), Compound 1, Compound 2 and QR2I-44 in a 7-day rotarod test, confirming the initial durability of neuroprotection of QR2I-44. [Figure 4] FIG. 1 is a graph showing rotarod latency versus time after traumatic brain injury (TBI) for chloroquine (CQ), Compound 1, Compound 2, and QR2I-44 in a 28-day rotarod test, demonstrating the persistence of therapeutic effect of QR2I-44 nearly one month after TBI. [Figure 5A] FIG. 5A is a graph showing the speed of administration of QR2I-44 in the Morris Water Maze (MWM) test versus days after traumatic brain injury (TBI). [Figure 5B] The results indicate that the effect seen in FIG. 5B (i.e., faster learning with QR2I-44 administration) is not compromised by differences in motor performance. P value=0.0165, significance level=5%. [Figure 6A]FIG. 6A is an image showing a representative high-resolution coronal MRI of a mouse brain with a hippocampal ROI overlay for volumetric analysis. [Figure 6B] FIG. 6B is a graph showing hippocampal volume in normal, treated and untreated groups, demonstrating a statistically significant improvement in volume in mice treated with QR2I-44 versus vehicle control. [Figure 7A] Figure 7A is a representative MRI with template overlay ROIs of important subcortical brain structures, including the corpus callosum / external capsule (CC / EC). [Figure 7B] Figure 7B is a graph showing diffusion anisotropy (FA) of CC / EC in normal, treated, and untreated groups after TBI, demonstrating improvement in FA of these large white matter tracts after QR2I-44 therapy. FA is a common measure of tract integrity using a high-resolution MRI technique called diffusion-weighted imaging (DTI). [Figure 8A] Figure 8A is a graph showing the results of inflammatory microparticle (MP) release from RAW264.7 cells following stimulation with TOLL-like receptor ligands and treatment with QR2I-44. TOLL-like receptor ligands: PIC = polyinosinic:polycytidylic acid (TLR3); CpG = CpG oligodeoxynucleotide DNA (TLR9). [Figure 8B] Figure 8B is a graph showing the results of TNF-alpha release from RAW264.7 cells following stimulation with TOLL-like receptor ligands and treatment with QR2I-44. TOLL-like receptor ligands: PIC = polyinosinic:polycytidylic acid (TLR3); CpG = CpG oligodeoxynucleotide DNA (TLR9). [Figure 8C] Figure 8C is a graph showing the results of TNF-alpha release from RAW264.7 cells following stimulation with TOLL-like receptor ligands and treatment with QR2I-44. TOLL-like receptor ligands: PIC = polyinosinic:polycytidylic acid (TLR3); CpG = CpG oligodeoxynucleotide DNA (TLR9). [Figure 9]1 is a graph showing the results of QR2I-44 treatment on anti-cDNA antibody production in a mouse model of human systemic lupus erythematosus (LPR / mrl) at 1 week and 3 weeks after initiation of therapy. [Figure 10] FIG. 1 is a graph providing data showing prevention of menadione-induced loss of membrane potential by QR2 inhibitors. All QR2 inhibitors were able to prevent menadione-induced loss of membrane potential as detected by tetramethylrhodamine ethyl ester (TMRE, a fluorescent dye sequestered by live and active mitochondria). Wild-type HEK293 cells were pretreated with QR2 inhibitors (CDL-1, CDL-2 and QR2i-44) for 1 hour, then exposed to menadione for 4 hours and assayed for membrane potential. QR2i-44 significantly prevented menadione-induced loss of membrane potential. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Provided herein are compounds useful as inhibitors of quinone reductase 2, as well as formulations thereof. In some embodiments, the compounds are used to treat infectious diseases, cancer, immune disorders, and the like. Treatment of subjects at high risk for neurological injury, acute neurological injury and chronic neurological disorders, and cerebrovascular disease It is useful in.

[0034] The disclosures of all patent references cited herein are incorporated by reference in their entirety to the extent that they are consistent with the disclosures set forth herein. The present invention is described in detail below with reference to the accompanying drawings, in which: As used herein in the appended claims, the singular forms "a" and "an" and "the" include the plural forms as well, unless the context clearly indicates otherwise. As used herein in the description of the invention and in the appended claims, The singular forms "a" and "an" and "the" are used unless the context clearly indicates otherwise. Insofar as the term is used herein, the plural forms are intended to be included as well. "About" and "approximately" refer to a measurable value, e.g., an amount of a compound, When referring to dose, time, temperature, etc., 20%, 10%, 5%, 1%, 0.5% of the specified amount or even 0.1% variation. "And / or" and " / " mean one or more of the associated listed items. " or " shall be interpreted as being in the optional and all possible combinations and alternatives of When used in combination, it refers to and includes the absence of a combination.

[0035] [I.Definition] The following definitions are used herein:

[0036] As known in the art, "H" refers to a hydrogen atom. "C" refers to a carbon atom. " refers to a nitrogen atom. "O" refers to an oxygen atom.

[0037] "Halo" refers to F, Cl, Br or I. "Cl" is chloro and "I" is iodine. "F" is fluoro, and "Br" is bromo.

[0038] "Acyl" refers to a -C(O)R group, where R is a suitable substituent, e.g., an acetyl group, a butyl group, a benzoyl group, or an alkylbenzoyl group. do.

[0039] As used herein, "alkyl" refers to an alkyl group having 1 or 2 to 10 or 20 or more carbon atoms. Straight or branched chain saturated hydrocarbons containing 1,2-dichlorophenyl ether (e.g., C2, C3, C4, C5, C6 , C7, C8, C9, C10, C11, C12, C13, C14, C15, etc. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, o-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- Pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- Dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl In some embodiments, alkyl includes 1 to 3, 4 or 5 aryl groups. is a "lower alkyl" having carbon atoms.

[0040] As used herein, "alkenyl" refers to a straight or branched chain alkyl group having one or more double bonds. is an unsaturated hydrocarbon group.

[0041] As used herein, "alkynyl" refers to a straight or branched chain alkynyl group having one or more triple bonds. is an unsaturated hydrocarbon group.

[0042] As used herein, "amino" refers to the -NH2 group. As used herein, "amide" refers to This refers to an organic functional group that has a carbonyl group (C=O) bonded to (N).

[0043] As used herein, "alkoxy" refers to an oxygen atom (-O-), as defined herein. Representative examples of alkoxy include, but are not limited to, the following: However, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy Examples of alkoxy include oxy, pentyloxy, hexyloxy, and the like.

[0044] As used herein, "aryl" refers to a ring system having one or more aromatic rings. Representative examples are azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydro Includes naphthyl, etc.

[0045] As used herein, "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms is halo (F, Cl). , Br or I), 1 or 2 to 10 or 20 or more Carbon atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C1 Refers to straight or branched chain hydrocarbons containing C1, C12, C13, C14, C15, etc. Representative examples of "haloalkyl" include, but are not limited to, fluoroalkyl (e.g., For example, fluoromethyl (-CH2F), difluoromethyl (-CHF2) or trifluoromethyl (-CHF2). Contains methyl (-CF3).

[0046] As used herein, a "heterocyclo" refers to a ring structure having at least one heterocyclic ring selected from O, N, and S. A monocyclic, bicyclic or tricyclic ring system containing a hetero atom. A monocyclic heterocyclic ring system is one containing O, containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N and S; The five-membered ring has 0 to 2 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, However, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane , dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole , isothiazolidine, isoxazole, isoxazoline, isoxox Sazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, Oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyran pyridine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyridine pyrrolidine, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydrofuran Din, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole , thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, These include sulfoxides, thiopyrans, triazines, triazoles, trithianes, etc. Bicyclic rings The system may comprise an aryl group as defined herein, a cycloalkyl group as defined herein, or any of the above monocyclic ring systems fused to another monocyclic ring system as defined herein Representative examples of bicyclic ring systems include, but are not limited to, benzyl, phenyl ... Benzoimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran Ran, benzodioxin, 1,3-benzodioxole, cinnoline, indazole, isopropyl alcohol Indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiamine Ophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridin quinolidine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, Examples of nitrogen-containing heterocyclos include: Examples of the aryl group include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. etc.

[0047] "Heteroaryl" refers to an alkyl group in which one or more carbon atoms are selected from the group consisting of O, N and S. Heteroaryl means a cyclic aromatic hydrocarbon substituted with independently selected atoms. Examples of alkyl groups are pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl. , pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, Isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl Quinolyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxa Preferred heteroaryl groups include thienyl, isothiazolyl and benzo[b]thienyl. is a 5-membered or 6-membered ring, and is 1 to 3 independently selected from the group consisting of O, N and S. Each heteroatom-containing heteroaryl group may be unsubstituted or and, if chemically feasible, may be substituted with 1 to 4 suitable substituents. For example, the heteroatom S may be substituted with one or two oxo groups, which may be represented as =O. Examples of nitrogen-containing heteroaryls include, but are not limited to, pyridinyl. , pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, thi Azolyl, triazolyl, isothiazolyl, indolyl, benzimidazolyl, benzoyl Xazolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl, carbazole , azepinyl, 1,4-diazepinyl, purinyl, pteridinyl, phthalazinyl, etc. .

[0048] The aryl, heteroaryl and heterocyclo groups of the present invention are those which are chemically feasible. In some cases, alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxy oxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl Sulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylthio oxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, Cyano, formyl, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalky Kyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, NR'R'' (wherein R' and R'' are each independently hydrogen, alkyl, alkylcarbonyl, aryl, arylaryl, or the like. and —C(O)NR′R″, where R ' and R'' are hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. It may be substituted 4 or 5 times.

[0049] "Hydroxyl" and "hydroxy" refer to the --OH group.

[0050] "Nitrile" refers to the group --CN.

[0051] "Nitro" refers to the -NO2 group.

[0052] "Sulfone" refers to a sulfonyl functional group -SO2R, where R is an optionally covalently bonded It refers to an atom (or atoms).

[0053] "Sulfoxide" refers to the radical -S(O)R, where R is an optionally covalently bonded atom(s). It is possible.)

[0054] "Thiol" or "mercapto" refers to the group -SH or its tautomer: =S.

[0055] As used herein, a "fused ring" refers to a ring that is connected to two substituents of the formula provided herein. The ring systems that can be formed by the above-mentioned methods (e.g., "heterocyclo", "aryl" or "heteroaryl" ring systems) Each of the two substituents may be independently selected from C, O, N, or S. As the fused ring I or fused ring II such as R2 and R3, a part of the ring system exemplified below is used together. The carbons contained in the fused ring II may be independently selected from the group consisting of O, N and S. Each heteroatom-containing fused ring system, if present, may be substituted with any of the heteroatoms. In the latter case, it may be unsubstituted or, if chemically feasible, may have 1 to 4 suitable substitutions. It may be substituted with a group.

[0056] [ka]

[0057] "Pharmaceutically acceptable salts" refer to salts that possess the biological effectiveness of the free acids and bases of a specified compound. Salts that are pharma- ceutically acceptable and that do not exhibit any biological or other undesirable properties. Examples of acceptable salts are sulfates, pyrosulfates, bisulfates, sulfites, hydrogen sulfites, and phosphates. , monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide Umide, acetate, propionate, decanoate, caprylate, acrylate, formate, Isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, Succinate, suberate, sebacate, fumarate, maleate, butyne-1,4 -dionate, hexyne-1,6-dionate, benzoate, chlorobenzoate, methyl Benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates Acid salts, sulfonates, xylene sulfonates, phenylacetates, phenylpropionates , phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate salts, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, Phthalene-2-sulfonate, and mandelate.

[0058] A "prodrug" is known in the art and is a compound that is substituted with a specified pharma- ceutical active compound. A compound that can be converted under physiological conditions, by lytic degradation, or metabolically into a compound that is A thorough discussion is given in T. Higuchi and V. Stella, Prodr ugs as Novel delivery Systems, Vol. 14 o f the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers i n Drug Design, American Pharmaceutical A ssociation and Pergamon Press, 1987 All of the above references are incorporated herein by reference in their entirety. See also U.S. Patent No. 6,680,299. Examples include the activation of the subject as described herein. The compounds include prodrugs that are metabolized in vivo, and prodrugs include alcohols. or carboxylic acid groups are present in the compound, either as esters of such groups or as alkoxy groups. When a choline group is present in the compound, it is an acetal or ketal of such a group. Alternatively, if amine groups are present in the compound, the N-Mannich base or isopropyl group of such groups may be used. If a amine or carbonyl group is present in the compound, the Schiff salt of such a group group, oxime, acetal, enol ester, oxazolidine or thiazolidine For example, see U.S. Pat. No. 6,680,324 and U.S. Pat. No. 6,680,322. It is being done.

[0059] As is understood in the art, the term "optionally substituted" refers to any group that is A group can be unsubstituted or substituted with one or more suitable substituents. In addition, the "substituent" is a hydrogen atom on the parent organic molecule. It is an alternative group.

[0060] [II. Active Compounds] Compounds of formula (I) [ka] (wherein R1 is a nitrogen-containing heterocyclo or nitrogen-containing heteroaryl). or a pharma- ceutically acceptable salt or prodrug thereof is herein referred to as an active compound. In some embodiments, the compound is fluoromethyl, difluoromethyl or or trifluoromethyl. It's fine.

[0061] In some embodiments, R1 is [ka] (wherein D1, D2, D3 and D4 are hydrogen, halo, alkyl, acyl, alkoxy, Aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol, sulfo each independently selected from the group consisting of aryl, sulfoxide, nitrile, nitro, and haloalkyl; or D1 and D2, D2 and D3 or D3 and D4 are optionally substituted. Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring) or a pharma- ceutically acceptable salt or prodrug thereof. The compounds of formula (I) may be fluoromethyl, difluoromethyl or trifluoromethyl. It may be substituted one, two or three times with any independently selected suitable group. In an embodiment, D1, D2, D3 and D4 are each hydrogen.

[0062] In some embodiments, the compound is a compound of formula (I)(a)(1) or formula (I) Compound (a)(2) [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. The alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of aryl, aryl, aryl and aryl groups.

[0063] In some embodiments, the compound is a compound of formula (I)(a)(1) [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. The alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of aryl, aryl, aryl and aryl groups.

[0064] In some embodiments, the compound is a compound of formula (I)(a)(2) [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. The alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of aryl, aryl, aryl and aryl groups.

[0065] In some embodiments of formula (I), R1 is [ka] (In the formula, X1, X2 and X3 are each independently selected from the group consisting of carbon, nitrogen and oxygen.) And, D5, D6, D7 and D8, when present, are hydrogen, halo, alkyl, acyl, aryl, koxy, aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol , sulfone, sulfoxide, nitrile, nitro and haloalkyl; Selected for the position or Two of D5, D6, D7 and D8 are optionally substituted fused rings (e.g. For example, cyclohexane or cyclohexene fused rings are formed together. or a pharma- ceutically acceptable salt or prodrug thereof. The compound may be selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl. In some embodiments, the aryl group is substituted 1, 2, or 3 times with Two of D5, D6, D7 and D8 together form a fused ring.

[0066] In some embodiments, the compound is a compound of formula (I)(b)(1) [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. The alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of aryl, aryl, aryl and aryl.

[0067] In some embodiments of Formula (I), R1 is [ka] (In the formula, X4, X5, X6, X7 and X8 are each selected from the group consisting of carbon, nitrogen and oxygen.) and at least two of X4, X5, X6, X7 and X8 are independently selected. has at least three carbons, D9, D 10 , D 11 , D 12 , D 13 and D. 14 When present, it is hydrogen, halo, Alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, Hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D9, D 10 , D 11 , D 12 , D 13 and D. 14 Two of them are optional. fused rings (e.g., cyclohexane or cyclohexene rings) together to form (to be completed) or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. In some embodiments, the alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of: D9, D on adjacent atoms 10 , D 11 , D 12 , D 13 and D. 14 Two of them are shrinking Together they form a fused ring.

[0068] In some embodiments of formula (I), R1 is [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compound may be independently selected from fluoromethyl, difluoromethyl, or trifluoromethyl. It may be substituted one, two or three times with suitable selected groups.

[0069] In some embodiments of Formula (I), R1 is [ka] (In the formula, X9, 10 , X 11 and X 12 each selected from the group consisting of carbon, nitrogen and oxygen are independently selected, 10 , X 11 and X 12 At least two of them are charcoal It is raw, D 15 , D 16 , D 17 , D 18 and D. 19 When present, it is hydrogen, halo, alkyl, or aryl. aryl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, hydro From xyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D 15 , D 16 , D 17 , D 18 and D. 19 Two of the are optionally substituted. Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring). .) or a pharma- ceutically acceptable salt or prodrug thereof. The compounds are independently selected from fluoromethyl, difluoromethyl, and trifluoromethyl. In some embodiments, the alkyl group may be substituted one, two or three times with a suitable group selected from the group consisting of: D on adjacent atoms 15 , D 16 , D 17 , D 18 and D. 19 Two of them have fused rings. Form together.

[0070] In some embodiments of formula (I), R1 is [ka] or a pharma- ceutically acceptable salt or prodrug thereof. The compound may be independently selected from fluoromethyl, difluoromethyl, or trifluoromethyl. It may be substituted one, two or three times with suitable selected groups.

[0071] In some embodiments, the compound has a positive LogD value between about pH 4 and pH 5.

[0072] Unless otherwise stated, structures depicted herein represent all enantiomers of that structure. , diastereomers and geometric (or conformational) forms, e.g., R and S configurations at each asymmetric center. (Z) and (E) double bond isomers, and (Z) and (E) stereoisomers. Thus, single stereochemical isomers of the compounds are also intended to be included. Thiomers, diastereomers and geometric (or conformational) mixtures are also within the scope of the invention. Additionally, unless otherwise stated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. The tautomeric forms include keto-enol tautomers of the compounds. Unless otherwise stated, all rotamer forms of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, structures depicted herein may be extinguished with one or more isotopes. It is also intended to include compounds which differ only in the presence of an enriched atom. For example, deuterium or or replacement of hydrogen by tritium, or 13 C or 14 Carbon from C-enriched carbon Compounds having the structures of the present invention, except for the substitutions, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. .

[0073] [III. How to use] As noted above, the active compounds taught herein are useful as QR2 inhibitors. Such active compounds are useful in treating infectious diseases, cancer, immune disorders, acute nerve injury and chronic neurological disorders. The active compounds may also be useful in treating subjects at high risk for chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). may also be useful in the treatment of disorders associated with mitochondrial dysfunction.

[0074] Infectious diseases include, but are not limited to, parasitic infections, such as malaria and amphibian infections. infections, bacterial infections, e.g., Lyme disease, as well as viral infections, e.g., human immunodeficiency virus infections. All viruses (HIV), Ebola virus, Chikungunya virus, Dengue virus, Zika virus Includes infectious diseases such as viruses.

[0075] Cancer treatments include, but are not limited to, radiosensitization of cancer, chemosensitization of cancer, or the like. The cancer to be treated may include, but is not limited to, glioblastoma.

[0076] Immune disorders include, but are not limited to, autoimmune diseases. Diseases include, but are not limited to, lupus (systemic lupus erythematosus (SLE) and and lupus nephritis); autoimmune myopathy; psoriasis; scleroderma; CREST syndrome; inflammatory myositis ;Sjogren's syndrome;Mixed connective tissue disease;Rheumatoid arthritis;Psoriatic arthritis;Relapsing rheumatoid arthritis Urine; Eosinophilic fasciitis; Dermatomyositis; Juvenile chronic arthritis, erosive osteoarthritis; Pyrophosphate Calcium deposition disease; multiple sclerosis; inflammatory bowel disease; colitis; Crohn's disease; acute respiratory distress syndrome Pulmonary inflammation; idiopathic pulmonary fibrosis; osteoporosis; delayed type hypersensitivity; autoimmune thyroiditis; pontine Main disease; Graves' disease; Asthma; Primary biliary cirrhosis; Idiopathic thrombocytopenic purpura; Diabetes mellitus ;Leukopenia;Opportunistic infections;Thrombosis;Arteriosclerosis;Therapy-induced diseases, e.g., antibiotics Substance allergy, gene vector hypersensitivity and chemotherapy Lupus-related autoimmune myopathy is typically characterized by induction of human anti-mouse antibodies. The primary manifestation is proximal muscle weakness and muscle pain. There is also involvement of the peripheral nervous system (PNS) in the psoriasis.

[0077] Acute neurological injuries include, but are not limited to, traumatic brain injury and non-traumatic acute brain injury. Traumatic brain injuries as known in the art include injuries caused by blunt force due to sudden acceleration or deceleration. Brain damage caused by single or repeated external mechanical forces such as sheer force Traumatic brain injuries include, but are not limited to, concussion, Other acute injuries include contusions, and hemorrhages, including parenchymal, subdural, epidural and subarachnoid hemorrhages. Neuropathic neuronal damage may be due to hypoxic or ischemic brain damage, e.g., arterial stroke (focal, comprehensive) This includes attacks due to venous infarction, infection, etc.

[0078] Chronic neurological disorders include, but are not limited to, primary dementia, e.g., Alzheimer's disease, Immersion, vascular, Lewy body dementia, frontotemporal, progressive supranuclear palsy, corticobasal ganglia dementia dementia, as well as secondary dementias associated with chronic inflammatory conditions, e.g., Behçet's disease, multifocal dementia, Sclerosis, SLE (CNS lupus), celiac disease and non-celiac gluten sensitivity; Movement disorders, such as dystonia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease; and epilepsy. CNS lupus, especially, can cause acute confusion, fatigue, headaches, and pain, subtle cognitive impairment, delirium, coma, dementia, sensory / motor / autonomic deficits and / or are clinically manifested as attacks (the latter occurring more frequently in lupus patients than in the general population). CNS lupus may also be manifested as a psychiatric disorder, e.g., depression, mania, and / or psychosis. More focal neurological deficits may also occur, secondary to lupus-related embolic, hematologic, and It can cause thrombotic or vasculitic cerebral and spinal infarction and cranial nerve damage. The pathophysiological mechanisms of encephalitis include encephalitis, transverse myelitis, neuritis and stroke of the brain or spinal cord. (embolic, thrombotic or vasculitic).

[0079] Subjects at high risk for cerebrovascular disease are those with documented prior ischemic stroke or microbleeds; Modifiable vascular risk factors, e.g., diabetes, hypercoagulability condition, hypertension; subjects with non-modifiable risk factors, e.g., age, race, family history, etc. include.

[0080] Antimalarial Hydroxychloroquine Reduces Cerebrovascular Disease in Patients at High Risk for Stroke There is evidence that it can reduce the incidence of droxychloroquine use is associated with incident cardiovascular events in rheumatoid arthritis patients,” J.A. mer. Heart Assoc. 2016;5:e002867; Jung e t al., ”The protective effect of antimal arial drugs on thrombovascular events in systemic lupus erythrematosus,” Arthrit is Rheum. 2010, 62(3):863-8; Wallace et al., ”The relevance of antimalarial ther apy with regard to thrombosis, hyperchol esterolemia and cytokines in SLE,” Lupus See 1993, Suppl 1:S13-5.

[0081] Disorders known to be associated with mitochondrial dysfunction include, but are not limited to, , neurodegenerative diseases, e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, muscle atrophy lateral sclerosis and Friedreich's ataxia; cardiovascular diseases, e.g., atherosclerotic arteries Sclerosis, and other cardiac and vascular conditions; diabetes and metabolic syndrome; autoimmune diseases Autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus and type 1 diabetes; activity and psychiatric disorders, e.g., autism, schizophrenia, bipolar disorder and mood disorders; gastrointestinal disorders Fatigue disorders, e.g., chronic fatigue syndrome and Gulf War illness; musculoskeletal disorders, e.g., fibromyalgia These include: skeletal muscle hypertrophy / atrophy; cancer; chronic infections; etc. Overview by "Mitochondrial Dysfunction and Chron ic Disease: Treatment With Natural Supplement elements,” Integrative Medicine, vol. 13, no. 4, 35-43 (2014).

[0082] As used herein, the term "treat" refers to treating an individual who is at risk for an injury, disease, or disorder. Benefit to the patient (e.g., one or more symptoms such as cognitive and / or motor dysfunction) The role of the agent is to provide a therapeutic effect, such as improving or reducing the risk of developing a disease, or slowing the progression of damage or symptoms. This refers to any type of treatment.

[0083] In some embodiments, the treatment is for an infectious disease, cancer, an immune disorder, acute nerve injury, or chronic nerve injury. Preventing, reducing the risk of developing, or reducing the severity or progression of a medical disorder and preventive treatment (i.e., treatment to prevent onset) of cerebrovascular disease in subjects at high risk of cerebrovascular disease. In some embodiments, the treatment, e.g., the method taught herein, is The compound may be administered daily or otherwise chronically to the subject.

[0084] Although the present invention is primarily directed to the treatment of human subjects, the invention also encompasses the treatment of animal subjects, particularly mammalian subjects. For veterinary purposes on subjects, e.g. mice, rats, dogs, cats, livestock and horses. and / or for drug screening and / or drug development purposes. obtain.

[0085] IV. Formulations In some embodiments, the active compound(s) is provided in a pharma- ceutically acceptable carrier. The carrier must be compatible with any other ingredients of the formulation and not deleterious to the recipient thereof. In some embodiments, the compound is pharma- ceutically acceptable. The carrier should be sterile (e.g., endotoxin-free water, pyrogen-free water or endotoxin-free water). (oxin-free saline or pyrogen-free saline).

[0086] The formulations of the present invention are suitable for short-term, rapid-onset, rapid-offset t), controlled release, sustained release, delayed release and pulsed release formulations, as described herein. The present invention provides formulations that achieve administration of the compounds described in the above. Remington's Pharmaceuticals S sciences (18th ed.; Mack Publishing Compa. NY, Eaton, Pa., 1990).

[0087] The pharmaceutical preparation of the present invention can be administered orally, parenterally (including intravenously, intramuscularly, subcutaneously, intradermally and transdermally). Suitable for a variety of modes of delivery, including intravenous, topical (cutaneous, buccal and sublingual) and rectal administration. could be.

[0088] The invention is explained in more detail in the following non-limiting examples. EXAMPLES

[0089] [Example 1] (Development of non-lysosomotropic aminoquinoline inhibitors of QR2) Chloroquine and hydroxychloroquine are lysosome antagonists that preferentially accumulate in the lysosomes of cells. It is a lysosomotropic drug. For chloroquine, the p-amino acid of the tertiary amine nitrogen The Ka of the quinoline nitrogen is 10.32 and the pKa of the quinoline nitrogen is 7.29. At pH 4-5.5, nearly 100% of chloroquine is doubly protonated, resulting in a 2+ charge. It becomes a strongly hydrophilic membrane impermeant molecule and is thus trapped in acidic organelles. do.

[0090] A quantitative treatment of such trapping phenomena involves the determination of the relative distribution of all forms of the compound at various pH levels. The partitioning properties can be obtained by examining the octanol-water partition coefficient, LogD, of the drug. Compounds with a positive LogD for a given pH are relatively lipophilic and membrane permeable. Compounds with high but negative LogD are hydrophilic and have low membrane permeability.

[0091] Figures 1A-1B show the LogD of chloroquine and QR2I-44. The regions depicted represent the likely range of lysosomal pH encountered in vivo. At lysosomal pH, the LogD of chloroquine is negative, and these molecules at these pHs This reflects accumulated charges and loss of membrane permeability. For this reason, LogD remains positive over the range of lysosomal pH and thus The lipophilicity and therefore membrane permeability of the glycerol derivatives are maintained to a certain degree.

[0092] Lysosomal storage is associated with 4- This is believed to be the primary mechanism responsible for the major toxicity of aminoquinolines (retina, heart). Using gP and LogD calculations and LiPE analysis, the inhibitory properties of QR2 and its lysosomal Candidate compounds were determined with the aim of combining low likelihood of accumulation.

[0093] From these analyses, the compound 7-methoxy-4-(pyridin-3-yl)methylaminoxidase was Nolin (referred to herein as "QR2I-44", "QR2i-44" or "I-44" ) (the structure is shown in Example 3 below) was found. The LogD value of this compound remained positive. and the compounds remain lipophilic (and therefore membrane permeable) at pH 4–5 in the lysosome. As mentioned above, Figures 1A-1B show that chloroquine (Figure 1A) and QR The LogD of 2I-44 (Figure 1B) is shown.

[0094] The 4-aminoquinoline scaffold has been used since the initial discovery of chloroquine and hydroxychloroquine. Although it has been investigated by several groups, this particular compound has not been investigated to date. Previous studies have not demonstrated the efficacy of 7-aminoquinolines for antimalarial activity. The extensive literature already available that considers the necessity of halogen substitution at the 4-aminoxyloxy group has led to the We consciously avoided extending the Norrin scaffold to include compounds with methoxy at the 7-position. It is possible that the structure-activity relationship vity relationships in 4-aminoquinoline a tiplasmodials,” J. Med. Chem. 2002, 45: 3531-3539; Shreekant and Bhimanna, ”4-am inoquinolines: An Overview of Antimalari al Chemotherapy,” Med. Chem. 2016, 6:001 -011.)

[0095] The 7-halo substituted derivatives were initially shown to be more active than the unsubstituted analogues (Fol ey and Tilley, “Quinoline antimalarials: mechanisms of action and resistance prospects for new agents,” Pharmacol. Her. 1998, 79: 55-87). Several other groups have used 7-chloro is indeed essential for the inhibition of B-hematin formation (e.g., Vippagunta e t al., “Structural specificity of chloro quine-hematin binding related to inhibit ion of hematin polymerization and parasi te growth,” J. Med. Chem. 1999, 42: 4630 ), 7-chloro group and NH2 and OCH3 (methoxy), etc. Replacement of the β-hematin group with other electron donor groups inhibits B-hematin formation and therefore antimalarial activity. The report more specifically stated that the objective of the present invention is to substantially weaken or eliminate the

[0096] Egan TJ (2006) Interactions of quinolin e antimalarials with hematin in solution J Inorg Biochem 100: 916-926; Nsumiwa, S.; Kuter, D.; Wittlin, S.; Chibale, K. ; Egan, TJ Bioorg. Med. Chem. 2013, 2 1, 3738); Egan, T.J.; Hunter, R.; Kasch ula, CH; Marques, HM; Misplon, A.; Walden, JC, J. Med. Chem. 2000, 43, 283; Kaschula, CH; Egan, TJ; Hunte r, R.; Basilico, N.; Parapini, S.; Taram elli, D.; Pasini, E.; Monti, DJ Med. See also Chem. 2002, 45, 3531.

[0097] [Example 2] Synthesis and characterization of QR2 inhibitors

[0098] [ka] 4,7-Dimethylpyrrolidone in aqueous methylamine (40%, 20 mL 260 mmol, 26 equiv.) A suspension of roloquinoline (2.0 g, 10.2 mmol) was placed in a microwave oven at 90°C ( Heat at 150W (initial power setting) for 2 hours. TLC (2% MeO in CH2Cl2 Analysis of the reaction mixture by H) showed complete consumption of the starting material. The filter cake was washed with HO and concentrated under vacuum. Air drying gave the pure product as a white microcrystalline solid (1.8 g, 92%). 1 H NMR ( DMSO-d6, 300 MHz) δ 8.40 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.77 (s , 1H), 6.38 (d, J = 5.4 Hz, 1H), 2.86 (d, J = 5.4 Hz, 3H). ESIMS: m / z = 193 [(M+ H) + ].

[0099] [ka]

[0100] General procedure for 7-substituted-4-(pyridin-3-yl)-methylaminoquinolines 7-Substituted-4-chloroquinoline (5.1 mmol), 3-aminomethylpyridine (0. A mixture of 1-butanol (5 mL) and 70 g of 1-propanol (6.2 mmol, 1.2 equiv.) was The mixture was heated in a closed, thick-walled pressure vessel (12 mL) at 130°C (bath temperature) for 24 hours. The vessel was then cooled to room temperature. The mixture was cooled to rt and the contents were diluted with Et2O (150 mL). The insoluble material was removed in vacuo. Filtered. The cake was dissolved in a minimum amount of MeOH and the resulting solution was added to silica gel (approximately 3 g). The mixture was concentrated to dryness under reduced pressure. diSepR f SiO2(40g), 100%CH2Cl2→75%(90:10, C H2Cl2:10% NH3 in MeOH) gave the desired product. X=OCH3 (pale off yellow solid, 0.60g, 44%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1H), 8.42 (m, 1H), 8.21 (d, J = 5.6 Hz, 1 H), 8.14 (d, J = 9.2 Hz, 1H), 7.79-7.72 (m, 2H), 7.32-7.29 (m, 1H), 7.14 (m, 1H) , 7.06 (dd, 2.4 Hz, 8.8 Hz, 1H), 6.25 (d, J = 5.4 Hz, 1H), 4.52 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H). ESIMS: m / z 266 [(M+H) + ]. X=Cl (white solid, 0.92g, 67%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 8.42 (s, 1H), 8.27 (m, 2H), 8.00 (s, 1H), 7.75 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.31 (m, 3H), 6.39 (d, J = 5.4 Hz, 1H), 4.55 (d, J = 5.4 Hz, 2H). ESIMS: m / z = 270 [(M+H) + ].

[0101] [Example 3] (Comparative study of QR2 inhibitors)

[0102] [ka]

[0103] [Table 1]

[0104] Neuroprotective potential of QR2I-44 in a mouse model of closed head injury (TBI) (Laskowitz et al., “Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improve d functional outcomes in a traumatic bra in injury murine model”, Sci. Rep. 2017 Apr 21;7:46461; Laskowitz, et al. atic brain injury worsens neurodegen erative pathology: improvement with an a polipoprotein E-based therapeutic.” Jour nal of Neurotrauma 2010m 27:1983-1995). closed The chain head impact model induces selective vulnerability of neurons in the cortex, basal ganglia, and hippocampus. It causes damage, induces diffuse axonal injury, and produces measurable vestibular motor deficits and long-term neurological deficits. The TBI model is a single-arm MRI designed to avoid skull fractures. The damage is mainly caused by acceleration / deceleration forces. The therapeutic compound was delivered intraperitoneally 4 hours after TBI and then weekly thereafter for the duration of the experiment. This was terminated after 28 days with assessment of spatial learning and memory.

[0105] Figures 2, 3 and 4 show the therapeutic effect of QR2I-44 and similar inhibitory properties (7- chloro-N-methylquinolin-4-amine), and both are weak QR2 inhibitors. Compound 2 (7-chloro-N-(pyridin-3-yl)quinolin-4-amine) and CQ Treatment with three other 4-aminoquinoline compounds that inhibit QR2, consisting of (chloroquine) The results of the assessment of vestibular motor function after TBI are summarized in Table 1. The subjects were subjected to the rotarod test for 5 consecutive days after TBI, then on the 7th and 28th days. Figure 2A-B shows that after 5 days, locomotion was observed in mice treated with QR2i-44 compared to vehicle. Almost 300% improvement in rotor latency (time to fall off the rotor rod) compared to CQ Figures 3 and 4 show that QR2I-44 is 1 hour away from TBI, showing an improvement of almost 200%. Results: After 1 and 4 weeks, the study produced sustained improvements in vestibular motor function compared to other QR2 inhibitors This indicates that.

[0106] FIG. 5A-B shows a harpoon for testing the ability of a mouse to find a submerged platform. We summarize the results of spatial learning and memory assessment using the mouse water maze 4 weeks after TBI. The subjects were given 4 trials per day for 4 consecutive days (intertrial interval = 30 min). The latency to find was recorded and averaged over four trials per day. Mice were then cultured for 28–31 days after injury. Mice were examined on the day of surgery (n = 11-12 mice per group). Standard control studies were also performed. Figure 5B shows the effect of QR2I-44 on the inflammatory bowel function in animals treated with QR2I-44 compared to vehicle. showed a 30-35% improvement in learning and memory in the control group, and Figure 5A shows that this improvement in function was This indicates that the results are not confounded by differences in motor function (i.e., swimming speed).

[0107] Figures 6-7 show the volume and axis distribution of brain subregions using high-resolution ex vivo MRI. Results of quantitative measurements of the integrity of the tract are outlined. A total of 15 mice (postnatal age 10–14 days) were Normal n=3; Vehicle n=6; QR2I-44 n=6. BI and treatment followed the same protocol as for vestibular motor and learning / memory assessment. After fixation, the rats were sacrificed and perfused 6 weeks after TBI. After fixation, the brains were removed from the skull and perfused with 0.5% Pr The tissue was stored in formalin supplemented with oHance to facilitate high-resolution MRI.

[0108] The MRI protocol consisted of: (1) a 3D T1-weighted FLASH® sequence V = 1.8cm x 1.8cm x 1.8cm; matrix = 256 x 256 x 256; solution Image resolution = 70 x 70 x 70 μm / pixel; TE / TR = 6 / 30 ms; average = 16; Lip angle = 34; scan time = 6 hours 33 minutes; (2) 3D DTI-based high resolution Spin echo FOV=1.8cm×1.8cm×1.8cm; matrix=128× 128×128; resolution=141×141×141μm / pixel; TE / TR=25 / 250 ms; diffusion directions = 60; Ao images = 5; B value per direction = 1500 sec / mm 2; scan time = 73 h 30 min. For post-processing, mouse brains were incubated at 4°C for 1 h at 4°C for 1 h at 4°C. Reference templates from the Forest University mouse database were registered. The DTI parameters were recorded using TrackV and segmented using ITK-SNAP. Calculations were performed using IS software.

[0109] Figure 6A-B shows that hippocampal volume loss after TBI was reduced by QR2I-4 compared to vehicle controls. 7A-B show that the fibromyalgia was substantially alleviated in animals receiving 4 treatment. DTI parameters such as diffusion anisotropy (FA), a measure of tract integrity, were significantly improved compared to controls. In large white matter tract regions such as the corpus callosum / external capsule (CC / EC), significant increases were observed after QR2I-44 treatment. It shows that there will be improvements.

[0110] Figure 8A-C outlines the results of investigating the potential of QR2I-44 for the treatment of lupus. FIG. 8A shows the TOLL-like receptor ligand CpG oligodeoxynucleotide DNase. After stimulation with A(CpG), microparticles (M This shows the effectiveness of QR2I-44 in reducing the release of phospholipase A (MP). These particles are small membrane-bound vesicles that arise from activated and dead cells. They are in the 0.0 micron size range and contain nuclear, cytoplasmic and membrane components. MPs have diverse biological functions, as shown in ro and in vivo experiments. Its activities may also mediate inflammation, thrombosis, and intercellular communication, among others. MP has been shown to be effective in treating lupus erythematosus in both physiological and pathophysiological settings. (Spencer et al., “The Proper ies of Microparticles from RAW 264.7 Mac rophage Cells Undergoing in vitro Activa tion or Apoptosis” 2014, 20(3): 239-248 ).

[0111] FIG. 8B-C shows RAW26 cells after stimulation with TOLL-like receptor ligands CpG and PIC. 4.7 Inhibits release of inflammatory cytokine TNF-alpha from mouse macrophage cells These results demonstrate the ability of QR2I-44 to inhibit the release of β-lactamase inhibitors. In both cases, the inhibition of release was dose-dependent. do.

[0112] Fig. 9 MRL / lpr mice have an autoimmune disease similar to human systemic lupus erythematosus. MRL / lpr is a well-established mouse model. Figure 9 shows some of the biomarkers found in QR2I-44. Anti-cDNA autoantibody production in MRL / lpr mice 1 and 3 weeks after initiation of therapy. The comparative figures show the gradual therapeutic inhibition of autoantibodies in this model. Harm is evident and is also dose-dependent.

[0113] Drug-like properties, cardiotoxicity, mutagenicity, hepatocyte stability and cytochrome P450 of compound QR2I-44 An initial screen for mAb P450 inhibition and induction was performed. Not a potent inhibitor of the hERG ion channel (IC50>10μM), but an improved It is not mutagenic in the mutagenic assay and is highly soluble in aqueous solution (water solubility >60 μg / ml) and showed high membrane permeability in Caco2 cells (effective permeability >20×10-6c m / sec) and is not a P-glycoprotein substrate or inhibitor (efflux ratio <0.5; 10 μM elacridar-insensitive), low to moderate mouse and human plasma protein binding (Approximately 50-70% binding by ultracentrifugation) and demonstrates adequate mouse and human hepatocyte stability (>90% remaining at 1 hour) and is not an inducer or inhibitor of CYP3A4 or 2D6. , and found it to be likely to be orally bioavailable and CNS penetrant.

[0114] [Example 4] Absorption and brain penetration of QR2i-44 In mice, QR2i-44 was administered intravenously (IV), intraperitoneally (IP) and orally (P All of the administration methods, including those listed below, were found to be sufficiently absorbed and to have brain permeability. Results of PO delivery of 25 mg / kg QR2i-44 in mouse plasma and brain samples Shows.

[0115] [Table 2]

[0116] [Example 5] (Confirmation of binding to QR2 by the crystal structure of QR2i-44) Molecular replacement was used to form a complex with FADH and QR2i-44 at 1.60 Å resolution. We have determined the crystal structure of reduced QR2, which forms the enzyme. We have examined the effect of redox state on the enzyme structure. To clarify the structure of the oxidized complex, we also determined the structure at 1.40 Å. Using the ribosomal protein as a model, the structure was easily phased by molecular replacement. The quaternary structure is similarly consistent with the established constitutive functional homodimer. r).

[0117] The crystal structure indicates that QR2i-44 and related compounds with planar ring structures bind to natural substrates such as cyclic arylsuccinates. It was confirmed that it binds to QR2 and FADH in a manner similar to that of non. Furthermore, the crystal structure QR2i-44 penetrates the substrate-binding site and binds the planar aromatic functional group and the FAD isoalloxane. Its ability to achieve optimal stacking with Sajin gives it an advantage over other QR2 inhibitors. This shows that it is possible.

[0118] [Example 6] (QR2 Inhibition for the Treatment of Mitochondrial Dysfunction) Parkinson's disease (PD) is the most common motor neurodegenerative disorder. There is an unmet medical need for innovative treatments that can prevent or stop cancer treatments. There is a great need for more treatment options that currently do not exist. PD is characterized by progressive neurodegeneration. The clinical symptoms are non-motor features such as motor impairment and cognitive decline. The exact mechanism underlying the pathogenesis of PD is still unclear. Mitochondrial dysfunction is an important factor contributing to the pathogenesis of both sporadic and familial PD. It is known that mitochondrial complex I activity is one of the factors that contribute to PD. Inhibitors of complex I, e.g., mitochondrial toxins, are used to treat the brain and whole body of subjects with Rotenone has been shown to reduce the behavioral and pathological symptoms of PD when administered to rodents and non-human primates. It mimics many of the underlying clinical features and characteristics of PD. Many of the genes reported to increase mitochondrial function were related to the mitochondrial pathway.

[0119] The quinone reductase 2 (QR2) enzyme can contribute to mitochondrial oxidative damage. In vivo inhibition of this enzyme revealed P, which is indicative of mitochondrial dysfunction and oxidative stress. Blockade of QR2 activity has been shown to suppress neurotoxic effects in PD models, and blockade of QR2 activity has been shown to suppress neurotoxic effects in PD models, In the context of neurodegenerative diseases, mitochondrial function can be protected and restored.

[0120] Interestingly, an association between polymorphisms in QR2 and the risk of developing PD in humans was observed. Some of these polymorphisms result in increased QR2 expression, high enzyme activity, and increased expression in the presence of dopamine. It has been shown that increased ROS production occurs (Harada et al., "An ssociation between idiopathic Parkinson' s disease and polymorphisms of phase II detoxification enzymes: glutathione S-tr ansferase M1 and quinone oxidoreductase 1 and 2,” Biochem Biophys Res Commun. 20 01;288(4):887-92; Wang et al. ion of NRH:quinone oxidoreductase 2 gene promoter polymorphism with higher genes expression and increased susceptibility to Parkinson's disease,” J Gerontol A Bi ol Sci Med Sci. 2008;63(2):127-34).

[0121] Consistent with pathological QR2 activity, previous studies have shown that drugs (e.g., chloroquine and Inhibition of QR2 with riboflavin and resveratrol has been shown to be effective in various animal models of neurological injury, including PD. It has been shown to be neuroprotective in mice (Boutin et al., "Qui none Reductase 2 Inhibitor: Main Biochem ical and Cellular Characterization,” Mol Pharmacol. 2019;95(3):269-859-11; Janda et al., “The antidote effect of quinone oxidoreductase 2 inhibitor against para quat-induced toxicity in vitro and in vi vo,” Br J Pharmacol. 2013;168(1):46-59; Janda et al., “Parkinsonian toxin-induce d oxidative stress inhibits basal autoph agy in astrocytes via NQO2 / quinone oxide reductase 2: Implications for neuroprote ction,” Autophagy. 2015;11(7):1063-80). For example, QR2 inhibition abrogates paraquat-induced toxicity associated with PD (Janda et al. (see above). Furthermore, QR2 inhibition inhibits the PD-associated toxin MPP + Induced neurotoxicity (Boutin et al., supra). In summary, PD The role of oxidative stress, mitochondrial dysfunction, QR2 pathophysiology, and QR in The report that 2 inhibition could mediate protection against neurotoxicity by reducing ROS levels suggests that This supports the rationale for developing QR2 inhibitors as a treatment strategy for D (Cassagn es et al., “Oxidative stress and neurode generation: The possible contribution of quinone reductase 2,” Free Radic Biol M ed. 2018;120:56-61).

[0122] Complex I dysfunction, mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of PD. (Sanders et al., "Oxidative damage" age to macromolecules in human Parkinson disease and the rotenone model,” Free R adic Biol Med. 2013;62:111-20). Rotenone and paraquat, which cause mitochondrial dysfunction and oxidative stress Environmental toxicants are associated with an increased risk of developing human PD (Tanner et al. l., “Rotenone, paraquat, and Parkinson’s disease,” Environ Health Perspect. 2011 ;119(6):866-72). Thus, toxic exposures associated with PD may be involved in mitochondrial dysfunction. A cellular and in vivo model for endogenous dysfunction and oxidative stress This is the method.

[0123] Wild-type HEK293 cells were cultured with QR2 inhibitors (CDL-1, CDL-2 or QR2i- 44) for 1 hour and exposed to menadione or vehicle for 4 hours. The membrane potential was measured.

[0124] Results: As shown in Figure 10, all QR2 inhibitors were tetramethylrhodamine ethyl esters. Detected by Stere (a fluorescent dye sequestered by live and active mitochondria) QR2i-44 was able to prevent the menadione-induced loss of membrane potential, which was previously thought to be caused by menadione. significantly prevented menadione-induced loss of membrane potential and prevented menadione-induced mitochondrial depolarization. I was able to stop it.

[0125] What has been described above is illustrative of the present invention and is not to be construed as limiting thereof. The present invention is limited to the scope of the claims, including any equivalents thereof. is defined as

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, R １ is a nitrogen-containing heterocyclo or nitrogen-containing heteroaryl. or a pharma- ceutically acceptable salt or prodrug thereof, the compound is substituted once with fluoromethyl, difluoromethyl or trifluoromethyl, Compounds which are optionally substituted twice or three times.

2. R １ but, 【Chemistry 2】 [In the formula, D １ , D ２ , D ３ and D. ４ is hydrogen, halo, alkyl, acyl, alkoxy, Aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol, sulfo each independently selected from the group consisting of aryl, sulfoxide, nitrile, nitro, and haloalkyl; or D １ and D. ２ , D ２ and D. ３ Or D ３ and D. ４ is optionally substituted Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring). or a pharma- ceutically acceptable salt or prodrug thereof. 。

3. D １ , D ２ , D ３ and D. ４ The compound of claim 2 , wherein each is hydrogen.

4. A compound of formula (I)(a)(1) or a compound of formula (I)(a)(2) 【Chemistry 3】 or a pharma- ceutically acceptable salt or prodrug thereof, Fluoromethyl, difluoromethyl or trifluoromethyl once, twice or three times The compound of claim 3 which is optionally substituted.

5. A compound of formula (I)(a)(2), 【Chemistry 4】 or a pharma- ceutically acceptable salt or prodrug thereof, Fluoromethyl, difluoromethyl or trifluoromethyl once, twice or three times The compound of claim 3 which is optionally substituted.

6. Compound of formula (I)(a)(2) 【Chemistry 5】 or a pharma- ceutically acceptable salt or prodrug thereof. 。

7. R １ but, 【Chemistry 6】 [In the formula, X １ , X ２ and X ３ are each independently selected from the group consisting of carbon, nitrogen and oxygen. And, D ５ , D ６ , D ７ and D. ８ When present, represents hydrogen, halo, alkyl, acyl, aryl, koxy, aryl, heteroaryl, amino, amido, nitro, hydroxyl, thiol , sulfone, sulfoxide, nitrile, nitro and haloalkyl; Selected for the position or D ５ , D ６ , D ７ and D. ８ Two of the rings are optionally substituted fused rings (e.g. For example, cyclohexane or cyclohexene fused rings are formed together. or a pharma- ceutically acceptable salt or prodrug thereof, the compound is substituted once with fluoromethyl, difluoromethyl or trifluoromethyl, 2. The compound of claim 1, which is optionally substituted two or three times.

8. A compound of formula (I)(b)(1), 【Chemistry 7】 or a pharma- ceutically acceptable salt or prodrug thereof, Fluoromethyl, difluoromethyl or trifluoromethyl once, twice or three times 8. The compound of claim 7 which is optionally substituted.

9. R １ but, 【Chemistry 8】 (In the formula, X ４ , X ５ , X ６ , X ７ and X ８ each selected from the group consisting of carbon, nitrogen and oxygen are independently selected, ４ , X ５ , X ６ , X ７ and X ８ At least two of has at least three carbons, D ９ , D １０ , D １１ , D １２ , D １３ and D. １４ When present, it is hydrogen, halo, Alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, Hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D ９ , D １０ , D １１ , D １２ , D １３ and D. １４ Two of them are optional. fused rings (e.g., cyclohexane or cyclohexene rings) that are substituted together to form (Complete.) or a pharma- ceutically acceptable salt or prodrug thereof. 。

10. R １ but, 【Chemistry 9】 or a pharma- ceutically acceptable salt or prodrug thereof. 。

11. R １ but, 【Chemistry 10】 [In the formula, X ９ , X １０ , X １１ and X １２ each selected from the group consisting of carbon, nitrogen and oxygen are independently selected, ９ , X １０ , X １１ and X １２ At least two of them are charcoal It is raw, D １５ , D １６ , D １７ , D １８ and D. １９ When present, it is hydrogen, halo, alkyl, or aryl. aryl, acyl, alkoxy, aryl, heteroaryl, amino, amido, nitro, hydro From xyl, thiol, sulfone, sulfoxide, nitrile, nitro and haloalkyl or D １５ , D １６ , D １７ , D １８ and D. １９ Two of the are optionally substituted. Together they form a fused ring (e.g., a cyclohexane or cyclohexene fused ring). 。］ or a pharma- ceutically acceptable salt or prodrug thereof, The compound is fluoromethyl, difluoromethyl or trifluoromethyl once, twice 2. The compound of claim 1, which is optionally substituted once or three times.

12. R １ but, 【Chemistry 11】 or a pharma- ceutically acceptable salt or prodrug thereof, the compound is substituted once with fluoromethyl, difluoromethyl or trifluoromethyl, 12. The compound of claim 11, optionally substituted two or three times.

13. The compound according to any one of claims 1 to 12, having a positive LogD value of about pH 4 to 5. thing.

14. A composition comprising a compound according to any one of claims 1 to 13 and a carrier.

15. The composition of claim 14, wherein the carrier is a pharma- ceutically acceptable carrier.

16. Quinone reductase 2 (QR2) and a compound according to any one of claims 1 to 13, or A method for inhibiting the activity of QR2 comprising contacting a subject with the composition of claim 14 or 15. How to harm.

17. The method of claim 16 , wherein the contacting is performed in vitro.

18. The method of claim 16 , wherein the contacting is performed in vivo.

19. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. How to treat malaria.

20. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. A method for treating immune disorders.

21. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. How to treat acute nerve injury.

22. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. A method for treating chronic neurological disorders.

23. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. How to treat lupus.

24. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. How to treat an infection.

25. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. A method for treating cancer.

26. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. Methods for treating CNS lupus.

27. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject at high risk of cerebrovascular disease. Treatment methods.

28. A compound according to any one of claims 1 to 13 or a compound according to claim 14 or 15. administering a therapeutically effective amount of the composition to a subject in need thereof. Methods for treating disorders associated with mitochondrial dysfunction.

29. 29. The method of claim 16, wherein the administration comprises chronic administration (e.g., over months or years).

2. The method according to claim 1 .

30. The method of any one of claims 16 to 29, wherein the administration occurs once daily.

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