NOX inhibitors for use in the treatment of Alport syndrome

Abstract

The present invention relates to a novel medical use of a NOX inhibitor. In particular, the present invention relates to the use of such an inhibitor in the treatment of Alport syndrome. Furthermore, the present invention relates to a novel pharmaceutical combination. In particular, the present invention also relates to a combination product comprising a NOX inhibitor and an ACE inhibitor.

Description

Technical Field

[0001] The present invention relates to a new medical use of NOX inhibitors. In particular, the present invention relates to the use of such inhibitors in the treatment of Alport syndrome. Furthermore, the present invention relates to novel pharmaceutical combinations.

Background Art

[0002] Alport syndrome is a hereditary disorder of the basement membrane that leads to glomerulonephritis causing renal failure. Progressive hearing loss and eye abnormalities may also occur (Mochizuki et al. Nat. Genet. 1994, 8, p. 77-82, Colville et al. Ophthalmic Genet. 1997, 18, p. 119-128).

[0003] The symptoms typically begin in childhood, and the first sign of this condition is usually the presence of blood in the urine (hematuria). Other symptoms of kidney disease may include having protein in the urine (proteinuria). Over time, affected individuals may experience swelling (edema), weakening of the bones, and joint pain (bone dystrophy). Without treatment, affected individuals will experience end-stage renal failure.

[0004] Patients with Alport syndrome have been reported to show mutations in the collagen IV genes (Mochizuki et al., supra, Lemmink et al. Hum. Mol. Genet. 1994, 3(8), p. 1269-1273, and Lemmink et al. Mutat. 1997, 9(6), p. 477-99, Gubler et al. Kidney Int. 1995, 47, p. 1142-1147). Approximately 85% of Alport syndrome cases are X-linked and are associated with mutations in the Col4a5 gene. Without treatment, 90% of males will develop renal failure by the age of 40. Females have a lower frequency of developing renal failure and a slower progression. Approximately 14% are autosomal recessive genotypes, which are caused by mutations in the Col4a3 and Col4a4 genes and occur when both parents have the abnormal gene and the abnormal gene is inherited from both parents by the child. To cause autosomal recessive Alport syndrome, both copies of the abnormal gene are required. Autosomal dominant genotypes are rare (van der Loop et al., Kidney Int. 2000, 58(5), p. 1870-1875) and occur when one parent has the disease and the abnormal gene is inherited by the child.

[0005] There is no specific treatment for Alport syndrome, and the aim of current treatment is to monitor and control the progression of the disease and treat the symptoms. To keep the kidneys as healthy as possible, it is very important to control the patient's blood pressure. Studies have suggested that ACE inhibitors, angiotensin receptor blockers, and statins may help reduce proteinuria and the progression of kidney disease. However, treatment for chronic renal failure is often required and may include dietary therapy and fluid restriction.

[0006] In Alport syndrome, treatment can delay the progression of kidney disease, but there is no treatment for the disease, and at present, no treatment has been shown to completely halt the decline in renal function. The rate of progression of renal function decline in individuals with Alport syndrome is highly variable. In many affected individuals, renal function eventually deteriorates to the point where dialysis or kidney transplantation is required.

[0007] Accordingly, there is a true clinical need for more effective treatments for Alport syndrome, and the inventors have surprisingly found that administration of a NOX inhibitor to a mouse model of Alport syndrome, which is a collagen type IV alpha 3 chain (Col4a3) double knockout mouse, results in a decrease in the ratio of albumin to creatinine in the urine of the mouse. Further studies have also shown that blood urea nitrogen (BUN) and cystatin C levels in the plasma of the double knockout mice decrease after administration of the NOX inhibitor. These findings suggest that NOX inhibitors may be useful for the treatment of Alport syndrome.

[0008] The listing or discussion of a document that has clearly been previously published herein should not necessarily be construed as an admission that the document is part of the prior art or common general knowledge.

Mode for Carrying Out the Invention

[0009] Medical Use According to a first aspect of the present invention, there is provided a NOX inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alport syndrome, which use is hereinafter referred to as "use according to the present invention".

[0010] As used herein, the expression "NOX inhibitor" refers to any substance that can inhibit, block, attenuate, or interfere with nicotinamide adenine dinucleotide phosphate oxidase (NADPH), particularly nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and / or nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), either wholly or in part. This term can be defined as a compound that can affect the enzyme activity of the enzyme, its cellular localization, the stability of the protein, and / or the expression of messenger RNA or protein. Preferably, the NOX4 / NOX1 inhibitor should be able to reduce enzyme activity and reactive oxygen species (ROS) production in a cell-free assay using a membrane that expresses only the NOX isoform NOX4 / 1 protein, such as recombinant protein NOX4 / 1. Thus, when referring to a NOX inhibitor, the term "inhibitor" is intended to include, but is not limited to, molecules that inhibit the activity of NOX4 and / or NOX1, either completely or in part.

[0011] The NOX inhibitor for use in the present invention can be a NOX4 inhibitor, a NOX4 / 1 inhibitor, or a NOX1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] For example, the NOX inhibitor can be a pyrazolopyridine NOX4 or NOX4 / 1 inhibitor, a pyrazolidinedione NOX4 or NOX4 / 1 inhibitor, an amidothiazole NOX1 or NOX4 / 1 inhibitor, or an indole NOX4 / 1 inhibitor, or a pharmaceutically acceptable salt thereof. Alternatively, the NOX inhibitor can be a 2,5-disubstituted benzoxazole or a benzothiazole NOX4 inhibitor, or a pharmaceutically acceptable salt thereof.

[0013] The NOX4 / 1 inhibitor is selective for NOX4 and / or NOX1, and thus has a greater NOX inhibitory activity against NOX4 and / or NOX1 compared to other NOX proteins, such as NOX2 and / or NOX3 / 5. According to certain embodiments, the NOX4 / 1 inhibitor has a greater NOX inhibitory activity against NOX4 / 1 that is higher than that of other NOX proteins. For example, NOX4 / 1 inhibitors include small molecules, peptides, peptidomimetics, chimeric proteins, natural or non-natural proteins, nucleic acid-derived polymers (e.g., DNA and RNA aptamers, siRNA, shRNA, PNA, or LNA, etc.), fusion proteins having NOX4 / 1 antagonistic activity, antibody antagonists such as neutralizing anti-NOX4 / 1 antibodies, or gene therapy vectors that drive the expression of such NOX4 / 1 antagonists.

[0014] In particular, a NOX4 / 1 inhibitor is an agent that exhibits an inhibition constant Ki of less than 5 millimolars in a functional ROS production assay, such as those described in Gaggini et al. Bioorg. Med. Chem. 2011, 19(23), p. 6989-6999. For example, a NOX4 / 1 inhibitor is an agent that inhibits ROS production in a cell-free assay using a membrane that expresses only the NOX isoform NOX4, or the NOX1 protein, such as recombinant protein NOX4, or NOX1, in a range of less than about 1 μM, such as between about 30 nM and 300 nM. The term "siRNA" refers to short interfering RNA, which is double-stranded RNA (about 19-23 nucleotides) capable of knocking down or silencing target mRNA from a target gene. Artificial siRNA may be chemically synthesized as oligonucleotides or cloned as short hairpin RNA into plasmid or viral vectors (adenovirus, retrovirus, lentivirus) to generate transient or stable transfection in any type of cell (Martin et al. Ann. Rev. Genomics Hum. Genet. 2007, 8, p. 81-108, Huang et al. Expert. Opin. Ther. Targets 2008, 12(5), p. 637-645).

[0015] Unless otherwise specified, the relevant NOX inhibitors and their pharmaceutically acceptable salts may be referred to herein as "the compounds of the present invention", and specific compounds are outlined in the sections of the same heading below.

[0016] Pharmaceutically acceptable salts referred to within the scope of the present invention include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one equivalent or more of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or the medium using standard techniques (e.g., under reduced pressure, by lyophilization or filtration). Salts can also be prepared, for example, by exchanging the counterion of a component of the present invention in salt form with another counterion using a suitable ion exchange resin.

[0017] Examples of acid addition salts that may be mentioned include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprinate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hypoxanthine salt, phthalate or terephthalate), halide salts (e.g., chloride salt, bromide salt, or iodide salt), sulfonate salts (e.g., benzenesulfonate, methyl-, bromo-, or chloro-benzenesulfonate, methyl-, bromo-, or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxy-ethanesulfonate, 1- or 2-naphthalenesulfonate, or 1,5-naphthalenedisulfonate), or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, or nitrate, etc.

[0018] Examples of base addition salts that may be mentioned include salts formed with alkali metals (for example, Na salts and K salts), alkaline earth metals (for example, Mg salts and Ca salts), organic bases (for example, ethanolamine, diethanolamine, triethanolamine, tromethamine), or inorganic bases (ammonia, aluminum hydroxide). More specifically, examples of base addition salts that may be mentioned include Mg salts, Ca salts, and most specifically, K salts and Na salts.

[0019] Examples of specific pharmaceutically acceptable salts that may be mentioned include base addition salts, such as salts formed with alkali metals (for example, salts formed with Na or K), and acid addition salts, such as halide salts (for example, chloride salts, bromide salts, or iodide salts), and sulfonate salts (for example, benzenesulfonate salts, methyl-, bromo-, or chloro-benzenesulfonate salts, xylenesulfonate salts, methanesulfonate salts, ethanesulfonate salts, propanesulfonate salts, hydroxy-ethanesulfonate salts, 1- or 2-naphthalenesulfonate salts, or 1,5-naphthalenedisulfonate salts).

[0020] In another aspect of the present invention, a method for treating Alport syndrome is provided, the method comprising administering to a patient in need thereof an effective amount of a NOX inhibitor or a pharmaceutically acceptable salt thereof.

[0021] In a further aspect of the present invention, there is provided the use of a NOX inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Alport syndrome.

[0022] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0023] Specific features and embodiments described in connection with a given aspect of the invention are to be regarded as disclosed in combination with any other specific features and embodiments of that aspect of the invention, unless the context indicates otherwise.

[0024] It is shown herein that the compounds of the invention are adapted for the treatment of Alport syndrome. Those skilled in the art will understand that reference to the "treatment" of a condition (or, equivalently, "treating" that condition) has its ordinary meaning in the medical arts. In particular, the term can refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition.

[0025] The term "treatment" may also refer herein to the "prevention" of a particular condition (and equivalently, "preventing" or "prophylaxis" of that condition), all of which also have their ordinary meaning in the art (i.e., achieving a reduction in the likelihood of developing the associated condition, or symptoms associated with the associated condition), but the compounds of the invention are preferably adapted for the therapeutic treatment of Alport syndrome.

[0026] As used herein, the term "effective amount" refers to the amount of a compound that provides a desired therapeutic effect (i.e., the desired treatment as described herein) to a subject of treatment. Such an effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject exhibits signs of and / or feels the effect).

[0027] As used herein, reference to a "patient" refers to a living subject being treated, including mammalian (particularly human) patients, and such a "patient" is also referred to as a "subject" and vice versa. Reference to a "patient" (and thus to a "subject") should also be considered to refer to an individual who does not exhibit symptoms of the relevant disease.

[0028] In a preferred embodiment of the present invention, the NOX inhibitor is for use in combination with an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof. The inventors have surprisingly found that in a mouse model of Alport syndrome with type IV collagen α3 chain (Col4a3) double knockout mice, the combined administration of a NOX inhibitor and an ACE inhibitor is more potent in reducing the ratio of albumin to creatinine in the urine of mice, and there are also studies indicating a synergistic effect. That is, the administration of the NOX inhibitor alone and the ACE inhibitor alone reduces the ratio of albumin to creatinine in the urine of mice, but when these are administered in combination, the effect of reducing the ratio of albumin to creatinine becomes higher than additive. Furthermore, looking at the urinary albumin level in mice, the hypothesis that the combined use of the NOX inhibitor and the ACE inhibitor shows a longer-lasting effect of maintaining normal renal function compared to when the inhibitors are administered separately was supported.

[0029] As used herein, the expression "ACE inhibitor" refers to a substance that can inhibit, block, attenuate, or interfere with angiotensin-converting enzyme (ACE) either wholly or in part. This term can also be defined such that this compound affects the enzyme activity of the enzyme, its cellular localization, protein stability, messenger RNA or protein expression.

[0030] Preferably, the ACE inhibitor should be able to reduce enzyme activity, particularly the ability to convert angiotensin I to angiotensin II. Thus, when referring to an ACE inhibitor, the term "inhibitor" is intended to include, but is not limited to, molecules that inhibit the activity of ACE either completely or in part.

[0031] ACE inhibitors have a large ACE inhibitory activity component against ACE as compared to other ACE proteins. For example, ACE inhibitors include small molecules, peptides, peptidomimetics, chimeric proteins, natural or non-natural proteins, nucleic acid-derived polymers (such as DNA and RNA aptamers, siRNA, shRNA, PNA, or LNA), fusion proteins having ACE antagonistic activity, antibody antagonists such as neutralizing anti-ACE antibodies, or gene therapy vectors that drive the expression of such ACE antagonists.

[0032] ACE inhibitors for use in combination with NOX inhibitors include ramipril, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, trandolapril. Preferably, the ACE inhibitor for use in combination with the NOX inhibitor is ramipril.

[0033] In another aspect of the present invention, the NOX inhibitor is for use in combination with an angiotensin receptor antagonist (ARB) or a pharmaceutically acceptable salt thereof.

[0034] In a further aspect of the present invention, the NOX inhibitor is for use in combination with an ARB or a pharmaceutically acceptable salt thereof and an ACE inhibitor or a pharmaceutically acceptable salt thereof.

[0035] As used herein, the expression "angiotensin receptor antagonist (ARB)" refers to a substance that can wholly or partially inhibit, block, attenuate or interfere with angiotensin II receptor type 1 (AT 1 ). This term can be defined such that a compound affects the activity of a hormone, cellular localization, protein stability, and / or the expression of messenger RNA or protein.

[0036] Preferably, the ARB is angiotensin II AT 1It should be able to inhibit the activation and result in vasodilation of the patient, a decrease in the secretion of the patient's vasopressin, and / or a decrease in the production and secretion of aldosterone. Accordingly, the term "antagonist" is intended to include, but is not limited to, molecules that completely or partially inhibit the activity of angiotensin II receptor type 1.

[0037] An angiotensin receptor antagonist has greater inhibitory activity against angiotensin II receptor type 1 compared to other angiotensin II receptor type 1 proteins. For example, angiotensin receptor antagonists include fusion proteins having angiotensin II receptor type 1 antagonistic activity, such as small molecules, peptides, peptidomimetics, chimeric proteins, natural or non-natural proteins, polymers derived from nucleic acids (such as DNA and RNA aptamers, siRNA, shRNA, PNA, or LNA), antibody antagonists such as neutralizing anti-angiotensin II receptor type 1 antibodies, or gene therapy vectors that drive the expression of such angiotensin II receptor type 1 antagonists.

[0038] Examples of angiotensin receptor antagonists for use in combination with a NOX inhibitor include azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan.

[0039] The compounds of the present invention Compounds according to formula (I) Specific NOX inhibitors that may be included in the use of the present invention include those of formula (I)

Chemical formula

[0040] Compounds according to formula (II) Further NOX inhibitors that may be included in the use of the present invention include those of formula (II)

Chemical formula

[0041] Compounds according to formula (III) Further NOX inhibitors that may be included in the use of the present invention include those according to formula (III)

Chemical formula

[0042] The compound according to formula (IV) Alternative NOX inhibitors that may be included in the use of the present invention include those of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0043] In certain embodiments, the compound according to formula (IV) is of formula (IVa)

Chemical formula

[0044] In certain embodiments, the compound according to formula (IV) is of formula (IVb)

Chemical formula

[0045] In certain embodiments, the compound according to formula (IV) is of formula (IVc)

Chemical formula

[0046] Compounds according to formula (V) Alternative NOX inhibitors that may be included in the use of the present invention include those of formula (V)

Chemical formula

[0047] Further compounds In one embodiment of the invention, the compounds of the invention can form compounds as described, for example, in WO2017 / 192304, WO2016 / 207785, WO2019 / 215291, or WO2018 / 203298, which are hereby incorporated by reference herein.

[0048] Definition of Substituents To avoid any ambiguity, the compounds of the present invention may exist as solids, and accordingly the scope of the present invention includes all its amorphous, crystalline, and semicrystalline forms. When the compounds of the present invention exist in crystalline and semicrystalline forms, such forms may include solvates, which are also included within the scope of the present invention. The compounds of the present invention may also exist in solution.

[0049] The present invention also encompasses isotopically labeled compounds of the present invention where one or more atoms are actually replaced by atoms having an atomic mass, or mass number, different from that which is usually found in nature (or most abundantly found in nature), but which are identical to those described herein. All isotopes of any particular atom or element specified herein are intended to be within the scope of the compounds of the present invention. Accordingly, reference to a compound of the present invention also includes deuterated compounds, i.e., compounds of the present invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0050] The term "alkyl", when used alone or in combination with other terms, refers to a monovalent alkyl group containing straight-chain or branched-chain C 1 ~C 20 alkyl and having 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl, n-eicosanyl, etc. Preferably, the term "alkyl" refers to C 1 ~C 9Alkyl, more preferably, C 1 ~C 6 alkyl, particularly preferably, C 1 ~C 4 alkyl, and these, by analogy, each refer to a monovalent alkyl group having 1 to 9 carbon atoms, a monovalent alkyl group having 1 to 6 carbon atoms, and a monovalent alkyl group having 1 to 4 carbon atoms, respectively.

[0051] The term "alkenyl", when used alone or in combination with other terms, includes linear or branched C 2 ~C 20 alkenyl. The alkenyl may have a number of double bonds at available positions, and the configuration of the double bond may be in the (E) configuration or the (Z) configuration. This term is exemplified by vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1-eicosenyl, 3,7,11,15-tetramethyl-1-hexadecenyl, etc. Preferably, the term "alkenyl" refers to C 2 ~C 8 alkenyl, more preferably, C 2 ~C 6 alkenyl. Particularly preferred are vinyl or ethenyl (-CH=CH 2 ), n-2-propenyl (allyl, -CH 2 CH=CH 2 ), isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and 3-methyl-2-butenyl.

[0052] The term "alkynyl", when used alone or in combination with other terms, includes linear or branched C 2 ~C20 It contains alkynyl. The alkynyl may have a triple bond at an available position and in an available number. This term refers to groups such as ethynyl (-C≡CH), 1-propynyl, 2-propynyl (propargyl: -CH 2 C≡CH), 2-butynyl, 2-penten-4-ynyl, etc., alkynyl groups having 2 to 20 carbon atoms and optionally having a double bond. In particular, these include C 2 ~C 8 alkynyl, more preferably C 2 ~C 6 alkynyl is included. Preferably, these include C 2 ~C 6 alkynyl is included, which refers to a group having 2 to 6 carbon atoms and at least 1 or 2 alkynyl unsaturated sites.

[0053] The term "heteroalkyl" refers to C 1 ~C 12 -alkyl in which at least one carbon is substituted with a heteroatom selected from O, N, or S, preferably C 1 ~C 6 -alkyl. A particularly preferred heteroalkyl is 2-methoxyethyl.

[0054] The term "aryl" refers to an unsaturated aromatic carbocyclic group having 6 to 14 carbon atoms with a single ring (e.g., phenyl) or multiple fused rings (e.g., indenyl, naphthyl), and this term includes phenyl, naphthyl, anthryl, phenanthrenyl.

[0055] "C 1 ~C 6 alkylaryl" refers to an aryl group having a C 1 ~C 6 alkyl substituent, including methylphenyl, ethylphenyl.

[0056] "arylC 1 ~C 6 alkyl" refers to a C 1 ~C6 Refers to an alkyl group, including 3-phenylpropyl and benzyl.

[0057] The term "heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or tricyclic fused-ring heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolidinyl, quinazolinyl, pteridinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, and benzquinolyl.

[0058] 「C 1 ~C 6 The term "alkylheteroaryl" refers to a heteroaryl group having a C 1 ~C 6 alkyl substituent, including methylfuryl.

[0059] 「heteroarylC 1 ~C 6 The term "heteroarylC 1 ~C 6 alkyl" refers to a C

[0060] "C 2 ~C 6 The term "alkenylaryl" refers to an aryl group having an alkenyl substituent, including vinylphenyl, of C 2 ~C 6 "

[0061] The term "arylC 2 ~C 6 alkenyl" refers to a C 2 ~C 6 alkenyl group having an aryl substituent, including phenylvinyl."

[0062] The term "C 2 ~C 6 alkenylheteroaryl" refers to a heteroaryl group having an alkenyl substituent, including vinylpyridinyl, of C 2 ~C 6 "

[0063] The term "heteroarylC 2 ~C 6 alkenyl" refers to a C 2 ~C 6 alkenyl group having a heteroaryl substituent, including pyridinylvinyl."

[0064] The term "C 3 ~C 8 cycloalkyl" refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a monocyclic ring (e.g., cyclohexyl) or a plurality of fused rings (e.g., norbornyl). C 3 ~C 8 Cycloalkyl includes cyclopentyl, cyclohexyl, and norbornyl."

[0065] The term "heterocycloalkyl" refers to a C 3 ~C 8 cycloalkyl group as defined above, wherein up to 3 carbon atoms are substituted with heteroatoms selected from the group consisting of O, S, and NR, and R is defined as hydrogen or methyl, of C 3 ~C 8Refers to a cycloalkyl group. The term "heterocycloalkyl" includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl.

[0066] "C 1 ~C 6 alkyl C 3 ~C 8 The term "cycloalkyl" refers to a C 1 ~C 6 alkyl-substituted C 3 ~C 8 cycloalkyl group.

[0067] "C 3 ~C 8 cycloalkyl C 1 ~C 6 The term "alkyl" refers to a C 3 ~C 8 -cycloalkyl-substituted C 1 ~C 6 alkyl group.

[0068] "C 1 ~C 6 The term "alkylheterocycloalkyl" refers to a C 1 ~C 6 heterocycloalkyl group having an alkyl substituent.

[0069] "Heterocycloalkyl C 1 ~C 6 The term "alkyl" refers to a C 1 ~C 6 alkyl group having a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl)methyl.

[0070] The term "carboxy" refers to the -C(O)OH group.

[0071] "Carboxy C 1 ~C 6The term "alkyl" refers to a C alkyl group having a carboxy substituent, including 2-carboxyethyl. 1 ~C 6 alkyl group.

[0072] The term "acyl" refers to a -C(O)R group, where R is H, C 1 ~C 6 alkyl, aryl, heteroaryl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl C 1 ~C 6 alkyl, heteroaryl C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl C 1 ~C 6 alkyl, and heterocycloalkyl C 1 ~C 6 alkyl selected from the list consisting of, a -C(O)R group, including acetyl. Preferably, R is C 1 ~C 6 alkyl.

[0073] The term "acyl C 1 ~C 6 alkyl" refers to a C alkyl group having an acyl substituent, including 2-acetylethyl. 1 ~C 6 alkyl group.

[0074] The term "acylaryl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl.

[0075] The term "acyloxy" refers to a -OC(O)R group, where R is H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C1 ~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, aryl C 2 ~C 6 Alkenyl, heteroaryl C 2 ~C 6 Alkenyl, aryl C 2 ~C 6 Alkynyl, heteroaryl C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 Refers to a -OC(O)R group selected from the list consisting of alkyl and includes acetyloxy.

[0076] "Acyl-oxy C 1 ~C 6 The term "alkyl" refers to a C 1 ~C 6 alkyl group having an acyl-oxy substituent and includes 2-(ethylcarbonyloxy)ethyl.

[0077] The term "alkoxy" is a -O-R group in which R is C 1 ~C 6 alkyl, aryl, heteroaryl, aryl C 1 ~C 6 alkyl and heteroaryl C 1 ~C 6 Refers to a -O-R group selected from the list consisting of alkyl. Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy.

[0078] "Alkoxy C 1 ~C 6 The term "alkyl" refers to a C 1 ~C 6 alkyl group having an alkoxy substituent and includes methoxyethyl.

[0079] The term "alkoxycarbonyl" refers to a -C(O)OR group, where R is C 1 ~C 6 alkyl, aryl, heteroaryl, arylC 1 ~C 6 alkyl, heteroarylC 1 ~C 6 alkyl, and heteroalkyl.

[0080] The term "alkoxycarbonylC 1 ~C 6 alkyl" refers to an alkyl group having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl. 1 ~C 6 alkyl group, including 2-(dimethylaminocarbonyl)ethyl, N-ethylacetamidyl, N,N-diethylacetamidyl, etc.

[0081] The term "aminocarbonyl" refers to a -C(O)NRR′ group, where R and R′ are independently selected from the list consisting of H, C 1 ~C 6 alkyl, aryl, heteroaryl, arylC 1 ~C 6 alkyl, and heteroarylC 1 ~C 6 alkyl, and includes N-phenylcarbonyl.

[0082] The term "aminocarbonyl" refers to a -C(O)NRR′ group, where R and R′ are independently selected from the list consisting of H, C 1 ~C 6 alkyl, aryl, heteroaryl, arylC 1 ~C 6 alkyl, and heteroarylC 1 ~C 6 alkyl, and includes N-phenylcarbonyl.

[0083] The term "aminocarbonylC 1 ~C 6 alkyl" refers to an alkyl group having an aminocarbonyl substituent, such as 2-(dimethylaminocarbonyl)ethyl, N-ethylacetamidyl, N,N-diethylacetamidyl, etc.

[0084] The term "acylamino" refers to a -NRC(O)R' group, wherein R and R' are independently selected from the list consisting of H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, arylheteroaryl, arylC 1 ~C 6 alkyl, heteroarylC 1 ~C 6 alkyl, arylC 2 ~C 6 alkenyl, heteroarylC 2 ~C 6 alkenyl, arylC 2 ~C 6 alkynyl, heteroarylC 2 ~C 6 alkynyl, cycloalkylC 1 ~C 6 alkyl, and heterocycloalkylC 1 ~C 6 and is selected independently from the list consisting of alkyl and includes acetylamino.

[0085] The term "acylaminoC 1 ~C 6 alkyl" refers to a C 1 ~C 6 alkyl group having an acylamino substituent and includes 2-(propionylamino)ethyl.

[0086] The term "ureido" refers to a -NRC(O)NR'R'' group, wherein R, R', and R'' are independently selected from the list consisting of H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC 1~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, aryl C 2 ~C 6 Alkenyl, heteroaryl C 2 ~C 6 Alkenyl, aryl C 2 ~C 6 Alkynyl, heteroaryl C 2 ~C 6 Alkynyl, cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 Independently selected from the list consisting of alkyl, wherein R′ and R′′, together with the nitrogen atom to which they are attached, may optionally form a 3- to 8-membered heterocycloalkyl ring.

[0087] "Ureido C 1 ~C 6 The term "alkyl" refers to a C having a ureido substituent 1 ~C 6 alkyl group, including 2-(N′-methylureido)ethyl,

[0088] The term "carbamate" refers to a -NRC(O)OR′ group, wherein R and R′ are C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 alkylaryl, heteroaryl C 1 ~C 6 alkyl, aryl C 2 ~C 6 alkenyl, heteroaryl C 2 ~C 6 alkenyl, aryl C 2 ~C 6 alkynyl, heteroaryl C2 ~C 6 Alkynyl, cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 Independently selected from the list consisting of alkyl, wherein R can also be hydrogen.

[0089] The term "amino" refers to a -NRR' group, wherein R and R' are H, C 1 ~C 6 Alkyl, aryl, heteroaryl, C 1 ~C 6 Alkylaryl, C1 - C 6 Independently selected from the list consisting of alkylheteroaryl, cycloalkyl, and heterocycloalkyl, wherein R and R' together with the nitrogen atom to which they are attached can optionally form a 3 - 8 membered heterocycloalkyl ring.

[0090] The term "aminoalkyl" refers to an alkyl group having an amino substituent and includes 2-(1 - pyrrolidinyl)ethyl.

[0091] The term "ammonium" refers to a positively charged -N + RR'R'' group, wherein R, R', and R'' are C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylaryl, C 1 ~C 6 Independently selected from the list consisting of alkylheteroaryl, cycloalkyl, and heterocycloalkyl, wherein R and R' together with the nitrogen atom to which they are attached can optionally form a 3 - 8 membered heterocycloalkyl ring.

[0092] The term "ammoniumalkyl" refers to an alkyl group having an ammonium substituent and includes 1 - ethylpyrrolidinium.

[0093] "Halogen" refers to fluoro, chloro, bromo, and iodo atoms.

[0094] The term "sulfonyloxy" refers to a -OSO 2 -R group, where R is C 1 ~C 6 alkyl, C substituted with halogen 1 ~C 6 alkyl, for example, -OSO 2 -CF 3 group, C 2 ~C 6 alkenyl, alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 alkyl, heteroaryl C 1 ~C 6 alkyl, aryl C 2 ~C 6 alkenyl, heteroaryl C 2 ~C 6 alkenyl, aryl C 2 ~C 6 alkynyl, heteroaryl C 2 ~C 6 alkynyl, cycloalkyl C 1 ~C 6 alkyl, and heterocycloalkylalkyl selected from the group consisting of.

[0095] The term "sulfonyloxy C 1 ~C 6 alkyl" refers to an alkyl group having a sulfonyloxy substituent and includes 2-(methylsulfonyloxy)ethyl.

[0096] The term "sulfonyl" refers to a "-SO 2 -R" group, where R is aryl, heteroaryl, C 1 ~C 6 alkyl, C substituted with halogen 1 ~C 6 alkyl (for example, -SO 2 -CF 3 group), C2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, aryl C 2 ~C 6 Alkenyl, heteroaryl C 2 ~C 6 Alkenyl, aryl C 2 ~C 6 Alkynyl, heteroaryl C 2 ~C 6 Alkynyl, cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 It is selected from the group consisting of alkyl.

[0097] "Sulfonyl C 1 ~C 6 The term "alkyl" refers to an alkyl group having a sulfonyl substituent and includes 2-(methylsulfonyl)ethyl.

[0098] The term "sulfinyl" refers to a group of "-S(O)-R", wherein R is alkyl, alkyl substituted with halogen (e.g., -SO-CF 3 group), C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, aryl C 2 ~C 6 Alkenyl, heteroaryl C 2 ~C 6Alkenyl, aryl C 2 ~C 6 Alkynyl, heteroaryl C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 It is selected from the group consisting of alkyl.

[0099] The term "sulfinylalkyl" refers to an alkyl group having a sulfinyl substituent and includes 2-(methylsulfinyl)ethyl.

[0100] The term "sulfanyl" refers to a -S-R group, wherein R is H, C 1 ~C 6 Alkyl, C substituted with halogen 1 ~C 6 Alkyl (e.g., -S-CF 3 group), C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, aryl C 2 ~C 6 Alkenyl, heteroaryl C 2 ~C 6 Alkenyl, aryl C 2 ~C 6 Alkynyl, alkynylheteroaryl, cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 It is selected from the group consisting of alkyl. Preferred sulfanyl groups include methylsulfanyl and ethylsulfanyl.

[0101] "Sulfanyl C 1 ~C 6 alkyl" refers to a C 1 ~C 5 -alkyl group, including 2-(ethylsulfanyl)ethyl.

[0102] The term "sulfonylamino" refers to a -NRSO 2 -R′ group, where R and R′ are C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 3 ~C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 alkyl, heteroaryl C 1 ~C 6 alkyl, aryl C 2 ~C 6 alkenyl, heteroaryl C 2 ~C 6 alkenyl, aryl C 2 ~C 6 alkynyl, heteroaryl C 2 ~C 6 alkynyl, C 3 ~C 8 -cycloalkyl C 1 ~C 6 alkyl, and heterocycloalkyl C 1 ~C 6 are independently selected from the group consisting of.

[0103] The term "sulfonylamino C 1 ~C 6 alkyl" refers to an alkyl group having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl.

[0104] The term "aminosulfonyl" refers to a -SO 2 -NRR′ group, where R and R′ are H, C1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl C 1 ~C 6 Alkyl, heteroaryl C 1 ~C 6 Alkyl, arylalkenylheteroaryl C 2 ~C 6 Alkenyl, aryl C 2 ~C 6 Alkynyl, heteroaryl C 2 ~C 6 Alkynyl, C 3 ~C 8 -Cycloalkyl C 1 ~C 6 Alkyl, and heterocycloalkyl C 1 ~C 6 Independently selected from the group consisting of alkyl, wherein R and R′, together with the nitrogen atom to which they are attached, may optionally form a 3- to 8-membered heterocycloalkyl ring. Examples of the aminosulfonyl group include cyclohexylaminosulfonyl and piperidinylsulfonyl.

[0105] "Aminosulfonyl C 1 ~C 6 Alkyl" refers to a C 1 ~C 6 alkyl group having an aminosulfonyl substituent and includes 2-(cyclohexylaminosulfonyl)ethyl.

[0106] Unless otherwise restricted in the definition of each substituent, it should be understood that all of the above substituents are optionally substituted.

[0107] Unless otherwise restricted by the definition of each substituent, the term "substituted" means C 1 ~C 6 Alkyl, C 2 ~C6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 Cycloalkyl, heterocycloalkyl, C 1 ~C 6 Alkylaryl, C 1 ~C 6 Alkylheteroaryl, C 1 ~C 6 Alkylcycloalkyl, C 1 ~C 6 Alkylheterocycloalkyl, cycloalkyl C 1 ~C 6 Alkyl, heterocycloalkyl C 1 ~C 6 Alkyl, amino, alkylamino, aminosulfonyl, ammonium, alkoxy, acyl, acylamino, aminocarbonyl, aryl, aryl C 1 ~C 6 Alkyl, heteroaryl, heteroaryl C 1 ~C 6 Groups substituted with 1 to 5 substituents selected from the group consisting of alkyl, sulfinyl, sulfonyl, sulfonamide, alkoxy, alkoxycarbonyl, carbamate, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro.

[0108] Specific NOX inhibitors that can be used in the use of the present invention include those selected from the group consisting of the following. 2-(2-Chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 2-(2-Chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 4-(2-Fluoro-4-methoxyphenyl)-2-(2-methoxyphenyl)-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, (R)-3-Methoxy-4-(2-morpholino-1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, 10-Benzoyl-2-(2-chlorophenyl)-2,3,8,9,10,11-hexahydro-1H-pyrazolo[4′,3′:3,4]pyrido[1,2-a][1,4]diazepine-1,5(7H)-dione, (S)-3-Methoxy-4-(1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, (R)-4-(2-Hydroxy-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, and (R)-4-(2-(Dimethylamino)-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide.

[0109] The specific compounds of the present invention Further specific NOX inhibitors that can be used in the use of the present invention include those selected from the group consisting of the following. 5-(2-Methylpyridin-4-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 2,5-Bis(2-methylpyridin-4-yl)-1H-indole, 4-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine, 5-(5-Fluoropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Chloropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Isopropoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, N,N-Dimethyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-3-amine, 5-(6-Methylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 2-(2-Methylpyridin-4-yl)-5-(pyrimidin-5-yl)-1H-indole, 2-Methyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)-1H-benzo[d]imidazole, 2-(2-(Azetidin-1-yl)pyridin-4-yl)-5-(5-methylpyridin-3-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(2-methoxypyridin-4-yl)-1H-indole, 2-(2,6-Dimethylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(2-methylpyrimidin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-1H-indole, 4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)-2-methylthiazole, 2-(2-Cyclopropylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-(4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-ol, 1-(4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 2-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 4-(4-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 2-(5-Fluoropyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(6-methoxypyridin-3-yl)-1H-indole, 4-(5-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 5-(5-Methoxypyridin-3-yl)-2-(6-(oxetan-3-yl)pyridin-3-yl)-1H-indole, 1-(5-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, N,N-Dimethyl-5-(5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-amine, 4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, N,N-Dimethyl-4-(5-(quinolin-4-yl)-1H-indol-2-yl)pyridin-2-amine, 1-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 1-(4-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 1-(4-(6-Chloro-5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro [3.3]heptane, 6-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane, 2-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-7-oxa-2-azaspiro[3.5]nonane, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-3-methylazetidin-3-ol, 6-chloro-2-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxylic acid, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxamide, (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-yl)methanol, 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl)-1H-indole, N-(1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-3-yl)methanesulfonamide, (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-2-yl)methanol, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-2-one, 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-3-fluoropyridin-2-yl)morpholine, 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-1H-indole, 6-Chloro-2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide, 6-Chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-1-methylpiperazin-2-one, 3′-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methyl-5′H-spiro[azetidine-3,7′-furo[3,4-b]pyridine], 7-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, (5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)(oxetan-3-yl)methanol, 6-Chloro-2-(6-(methoxy(oxetan-3-yl)methyl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)propan-1-ol, 5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one, 4-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-cyclopropylmethyl)pyridin-2(1H)-one, 4-(5-(7-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(4,6-Difluoro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(5-chloropyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 6-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 4-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 6-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-4-methyl-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-6-methyl-2-(2-methylpyridin-4-yl)-1H-indole, 4-Methyl-2,5-di(pyridin-4-yl)-1H-indole, 6-Methyl-2,5-di(pyridin-4-yl)-1H-indole, 4-(5-(4-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-Chloro-2,5-di(pyridin-4-yl)-1H-indole, 6-Chloro-2,5-di(pyridin-4-yl)-1H-indole, N,N-Dimethyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine 5-(6-Cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(6-Methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(6-(Methoxymethyl)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(5-Ethoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(5-Cyclopropoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(5-(Cyclopropylmethoxy)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 5-(5-Cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole 7-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine 3-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)quinoline N-Methyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine 4-(4-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-yl)morpholine 5-(6-Chloro-2-(6-morpholinopyridin-3-yl)-1H-indol-5-yl)quinolin-2-ol 4-(5-(6-Chloro-5-(thieno[2,3-c]pyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine 4-(5-(6-Chloro-5-(6-fluoroquinolin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine 4-(5-(6-Chloro-5-(2-methoxyquinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Fluoroquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, 4-(5-(Isoquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, N,N-Dimethyl-4-(5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-amine, 3-Chloro-2,5-di(pyridin-4-yl)-1H-indole, 2-(2-Methylpyridin-4-yl)-5-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-3-yl)-1H-indole, 4-(2-(Pyridin-4-yl)-1H-indol-5-yl)quinoline, 4-(2-(Pyridin-3-yl)-1H-indol-5-yl)quinoline, 2,5-Di(pyridin-4-yl)-1H-indole, 2-(Pyridin-3-yl)-5-(pyridin-4-yl)-1H-indole, 2,5-Di(pyridin-3-yl)-1H-indole, 2-(1-Methyl-1H-pyrazol-5-yl)-5-(pyridin-4-yl)-1H-indole, 5-(2-(4-Methylpiperidin-1-yl)pyridin-4-yl)-2-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-2-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyrimidin-4-yl)-1H-indole, 2-(3-Fluoropyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-Isopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 4-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)pyridin-2-yl)morpholine, 1-(2-Methoxyethyl)-2,5-di(pyridin-4-yl)-1H-indole, 1-(2-Methoxyethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Methyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Ethyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-(Cyclopropylmethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-(Benzyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 7-(4-Chloro-5-(5-methoxypyridin-3-yl)-l-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 7-(6-Chloro-5-(5-methoxypyridin-3-yl)-l-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 1-Cyclopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Methyl-2,5-di(pyridin-4-yl)-1H-indole, and 5-(5-Methoxypyridin-3-yl)-2-(3-methylpyridin-4-yl)-1H-indole.

[0110] A particularly preferred NOX inhibitor for use in the treatment of Alport syndrome is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, which is also generally known as cetanaxib and is referred to herein as cetanaxib.

[0111] The structure (non-salt form) of cetanaxib is shown below.

Chemical formula

[0112] Pharmaceutical Compositions and Dosage Forms One of ordinary skill in the art will recognize that, when used in the uses and methods described herein, the compounds of the invention can be administered either alone or in combination with an ACE inhibitor and / or an ARB in a manner that permits systemic absorption, which can occur via several possible routes. For example, the compounds of the invention can be administered orally, intravenously or intraarterially, intramuscularly, intradermally, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, transdermally, nasally, pulmonary (e.g., by inhalation, tracheal, or bronchial administration), or by any other parenteral route, in the form of a pharmaceutical formulation comprising the compound in a pharmaceutically acceptable dosage form. In particular, the compounds of the invention can be administered orally, rectally, or intravenously (e.g., by intravenous infusion).

[0113] The compounds of the present invention are generally administered in the form of one or more pharmaceutical formulations, mixed with pharmaceutically acceptable excipients, which can be selected taking into account the intended route of administration and standard pharmaceutical practices. Such pharmaceutically acceptable excipients can be chemically inert with respect to the active compound and can have no adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable excipients can also impart immediate release (e.g., rapid release) or modified release (e.g., delayed release) of the compounds of the present invention.

[0114] Suitable pharmaceutical formulations are commercially available or, alternatively, are described in the literature (e.g., Lachman et al, ‘The Theory and Practice of Industrial Pharmacy’, CBS, 4 th edition (2015), ‘Remington: The Science and Practice of Pharmacy’, Troy (ed.), Elsevier, 23 rd edition (2020), and / or ‘Aulton’s Pharmaceutics: The Design and Manufacture of Medicines’, Taylor and Aulton (eds.), Elsevier, 5 th edition, 2017). The relevant disclosures of all these documents are incorporated herein by reference. Otherwise, the preparation of suitable formulations can be achieved non-inventively by a person skilled in the art using routine techniques.

[0115] As described herein, pharmaceutical formulations can be prepared in a manner suitable for the desired route of administration using techniques and materials known to those skilled in the art. In particular, pharmaceutical formulations can take the form of oral formulations or intravenous formulations (or formulations suitable for use in the preparation of intravenous formulations, e.g., concentrated formulations).

[0116] For example, when intended for oral administration, the pharmaceutical formulation containing the compound of the present invention can be provided in the form of tablets, or oral powders or solutions, each optionally containing suitable excipients, which can be prepared using techniques known to those skilled in the art. Similarly, when intended for intravenous (I.V.) administration, the pharmaceutical formulation containing the compound of the present invention can be provided in the form of a solution suitable for I.V. administration, or as a solution suitable for the preparation of a solution suitable for I.V. administration, which can be prepared using techniques known to those skilled in the art. Similarly, when intended for rectal administration, the pharmaceutical formulation containing the compound of the present invention can be provided in the form of tablets (e.g., suppositories), or powders or solutions, each optionally containing suitable excipients, which can be prepared using techniques known to those skilled in the art.

[0117] Depending on the patient being treated, the route of administration, and the severity of the condition (e.g., the level of pain and the severity of its effects), the compound of the present invention can be administered in various therapeutically effective amounts to the relevant patient in need thereof. Appropriate dosages can be determined by those skilled in the art using routine techniques such as routine dosage escalation studies.

[0118] Similarly, the amount of the compound of the present invention included in the relevant pharmaceutical formulation can be determined based on the desired dosage of the compound of the present invention, the ease of formulation, and the route of administration (which can, in turn, determine the availability of the compound of the present invention for systemic absorption).

[0119] Suitable dosages of the compound of the present invention can include dosages (e.g., for I.V. administration) in the range of about 0.05 to about 300 mg / kg, such as about 0.5 to about 200 mg / kg (e.g., about 1 to about 100 mg / kg, such as about 30 mg / kg or about 90 mg / kg). In particular, such dosages can be administered by I.V. infusion over a fixed period of time such as about 1 hour. Furthermore, such administration can be repeated as necessary, in the form of regular, sequential infusions, which can reduce the dosage.

[0120] To avoid ambiguity, in this specification, for example, when the term "about" is used in the context of an amount (e.g., the dosage of an active ingredient), such a variable is approximate, and thus it will be understood that the numerical values defined herein can vary by ±10%, for example, ±5%, preferably ±2% (e.g., ±1%). For example, "10 ± 10%" means 9 to 11.

[0121] To avoid ambiguity, one of ordinary skill in the art will understand that the dosage of the compounds of the present invention administered (e.g., to a human) should be sufficient to provide the desired therapeutic response or effect within a reasonable time frame (and over the time frame). For example, the compounds of the present invention can be provided in a form suitable for rapid (i.e., quick or immediate) release of the active ingredient(s), such as in the form of rapidly disintegrating tablets, and such tablets can be formulated using techniques and materials known to one of ordinary skill in the art.

[0122] In any case, one of ordinary skill in the art will be able to routinely determine the most suitable actual dosage for an individual patient. The above dosages are exemplary of standard cases, and of course, there can be individual cases where higher or lower dosage ranges are appropriate, and such cases are within the scope of the present invention.

[0123] The administration of the compounds of the present invention can be continuous (e.g., by continuous I.V. infusion) or intermittent (e.g., by bolus injection or by periodic administration of tablets or solutions), or can be provided in the form of a single administration (e.g., by injection or by administration of tablets or solutions). The dosage form is also determined by the timing and frequency of administration, and vice versa.

[0124] Combination products and related part kits As outlined above, in the uses and methods described herein, the compounds of the present invention can also be used in combination with an ACE inhibitor and / or an ARB for the treatment of Alport syndrome.

[0125] Accordingly, according to a further aspect of the present invention, there is provided a combination product comprising the following. (a) a NOX inhibitor, or a pharmaceutically acceptable salt thereof, and (b) an ACE inhibitor, or a pharmaceutically acceptable salt thereof and / or an ARB, or a pharmaceutically acceptable salt thereof. These combination products are hereinafter referred to as "combination products according to the present invention".

[0126] The NOX inhibitor, ACE inhibitor, and ARB may be any of the NOX inhibitor, ACE inhibitor, and ARB as disclosed herein.

[0127] For example, specific ACE inhibitors include ramipril, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, trandolapril, and combinations thereof. Preferably, the ACE inhibitor used in combination with the NOX inhibitor is ramipril.

[0128] Specific ARBs include azilsartan, candesartan, eprosartan, sparsentan, irbesartan, losartan, olmesartan, telmisartan, valsartan, and combinations thereof.

[0129] Preferably, the combination product comprises the following. (a) a NOX inhibitor, or a pharmaceutically acceptable salt thereof, and (b) an ACE inhibitor, or a pharmaceutically acceptable salt thereof.

[0130] More preferably, the combination product comprises the following. (a) cetirizine, or a pharmaceutically acceptable salt thereof, and (b) ramipril, or a pharmaceutically acceptable salt thereof.

[0131] To avoid ambiguity, the ACE inhibitor ramipril may also be referred to by its IUPAC name (2S,3aS,6aS)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrole-2-carboxylic acid. The structure of this compound (in the non-salt state) is shown below. [Chemical Formula]

[0132] The combination products according to the present invention are for administering a NOX inhibitor as defined herein in combination with an ACE inhibitor and / or an ARB as defined herein. Thus, at least one of their formulations contains a NOX inhibitor and at least one contains an ACE inhibitor and / or an ARB, presented as separate formulations or presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a NOX inhibitor and an ACE inhibitor or an ARB).

[0133] In fact, the combination products can be presented as three separate formulations, at least one of which contains a NOX inhibitor, another contains an ACE inhibitor, and another contains an ARB.

[0134] Thus, there is further provided a combination product according to the present invention, comprising a parts kit containing the following components: (A) A pharmaceutical preparation containing a NOX inhibitor as defined herein or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier, and (B) A pharmaceutical preparation containing an ACE inhibitor as defined herein or a pharmaceutically acceptable salt thereof and / or an ARB as defined herein or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier, Components (A) and (B) are provided in forms suitable for administration together with each other.

[0135] According to a further aspect of the present invention, there is provided a method of making a parts kit as defined above, the method comprising associating a component (A) as defined above with a component (B) as defined above, and thus rendering the two components suitable for administration in combination with each other.

[0136] By “associating” the two components with each other, the components (A) and (B) of the parts kit are (i) provided as separate formulations (i.e., independently of each other), and may then be brought together for use in combination with each other in combination therapy, or (ii) may be packaged and presented together as separate components of a “combination pack” for use in combination with each other in combination therapy.

[0137] Thus, (I) one of the components (A) and (B) as defined herein, (II) is provided in a kit of parts together with instructions for using that component in combination with the other of the two components.

[0138] The parts kit described herein may comprise two or more formulations comprising an appropriate amount / dosage of a NOX inhibitor / salt / solvate, and / or two or more formulations comprising an appropriate amount / dosage of an ACE inhibitor / salt / solvate, and / or an ARB / salt / solvate to provide repeated dosing. Where two or more formulations (comprising any active compound) are present, such formulations may be the same or different with respect to the dosage, chemical composition(s), and / or physical form(s) of any compound.

[0139] The combination product according to the present invention has utility in the treatment of Alport syndrome.

[0140] According to a further aspect of the present invention, there is provided a method of treating Alport syndrome, the method comprising administering to a patient in need of such treatment a combination product according to the present invention.

[0141] With respect to the parts kit described herein, "administered in combination with" includes that each formulation comprising a NOX inhibitor (or a salt / solvate thereof), and an ACE inhibitor (or a salt / solvate thereof), and / or an ARB (or a salt / solvate thereof) is administered continuously, separately, and / or simultaneously over the course of treating the relevant condition.

[0142] Thus, with respect to the combination product according to the present invention, the term "administered in combination with" means that the two components of the combination product (NOX inhibitor, and ACE inhibitor, and / or ARB) are administered together or in sufficiently close temporal proximity (optionally, repeatedly) such that either the formulation comprising the NOX inhibitor, or the formulation comprising the ACE inhibitor, and / or ARB, when administered alone (optionally, repeatedly) over the same treatment course in the absence of the other component(s), enables a greater beneficial effect for the patient over the course of treating the relevant condition. The determination as to whether the combination provides a greater beneficial effect for the treatment of a particular condition and over the course of that treatment depends on the condition being treated or prevented, but can be routinely achieved by one of ordinary skill in the art.

[0143] Furthermore, in the context of the parts kit according to the present invention, the term "in conjunction with" includes that one or the other of the two formulations can be administered (optionally, repeatedly) before, after, and / or simultaneously with the other component(s). As used in this context, the terms "administered simultaneously" and "administered concurrently with" include that individual dosages of the NOX inhibitor, and the ACE inhibitor, and / or ARB are administered within 48 hours (e.g., 24 hours) of each other.

[0144] Preparation of Compounds and Formulations The compounds of the present invention can be obtained commercially or can be prepared using techniques known to those skilled in the art, such as those described in the disclosures referenced herein. For example, cetanaxib can be prepared according to the procedure described in Example 62 (Scheme 2) of WO2010 / 035221, the content of which (in particular, the procedures described in the examples provided therein) is incorporated herein by reference.

[0145] As described herein, pharmaceutical formulations (including those containing two or more active ingredients as described in the third aspect of the present invention) can be prepared using techniques known to those skilled in the art. Similarly, parts kits (as described herein) can be prepared using techniques known to those skilled in the art.

[0146] According to a further aspect of the present invention, the following are provided. - A method for preparing a pharmaceutical formulation as described above, comprising mixing components (a) and (b) as previously described herein in connection with related aspects of the present invention, optionally together with one or more pharmaceutically acceptable excipients (i.e., making them into the same formulation), and - A method for preparing a parts kit as described herein, comprising correlating components (A) and (B) as described herein in connection with related aspects of the present invention.

[0147] To avoid doubt, by "correlating the components with each other", components (A) and (B) of the parts kit described herein are hereinafter - provided as separate formulations (i.e., independently of each other) and can then be brought together for use in combination therapy with each other, or - included that they can be packaged and presented together as separate components of a "combination pack" for use in combination therapy with each other.

[0148] When used in accordance with the uses and methods described herein, the compounds of the present invention are more convenient, more effective, less toxic, have a broader range of activity, are more potent, cause fewer side effects, and may have other useful pharmacological properties for physicians and / or patients than similar treatments (or conservative treatments) known in the prior art in the treatment of Alport syndrome.

Examples

[0149] The present invention is further illustrated by, but not limited to, the following examples and the accompanying drawings.

Brief Description of the Drawings

[0150]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

[0151] Example 1 Test Using Col4A3 Alport Mouse Model Overview The purpose of this test was to investigate the effect of cetnarib, an inhibitor of NOX (e.g., NOX1 / 4), in a mouse model of Alport syndrome in Col4a3 ko / ko mice.

[0152] This test was conducted repeatedly, and each test is referred to herein as the first experiment and the second experiment.

[0153] Mice homozygous for the Col4a3 ko / ko target mutation are a model of autosomal recessive Alport syndrome (Cosgrove et al. Kidney Int. 2007, 71(7), p. 615 - 618). Animals bred on a 129 / SvJ background develop glomerulonephritis and die at approximately 8.5 weeks of age (Jackson Laboratory strain: #002908). Gross et al. (Kidney Int. 2003, 63(2), p. 438 - 446) reported an average survival period of 10 weeks. Since homozygous Col4a3 ko / ko mice reflect the main features of Alport syndrome, this mouse model is useful for testing drug candidates.

[0154] Forty homozygous Col4a3 ko / ko mice were assigned to four groups (vehicle, cetirizine, ramipril, cetirizine + ramipril combination), with n = 10 mice per group, and used in this study. The animals were treated with vehicle and / or compound by daily oral gavage starting at 4 weeks of age for 4 weeks. The reference compound, ramipril, was administered via drinking water, prepared weekly and replaced at the latest after 4 days. Additionally, a wild-type control group (Col4A3+ / +) without any treatment was added to this study as one group (n = 6 mice).

[0155] Clinical signs and end points were monitored daily as needed from 8 weeks of age until tissue collection.

[0156] Urine samples were collected at three time points (baseline (at 4 weeks of age), 6 weeks of age, and 8 weeks of age, after 2 weeks and 4 weeks of treatment, respectively). Albumin and creatinine levels were evaluated by ELISA in 8 urine samples per treatment group.

[0157] After the test, the animals were euthanized by i.p. injection of pentobarbital, and terminal blood was collected by cardiac puncture into EDTA-coated tubes. Plasma was collected by centrifugation (3000×g, room temperature, for 10 minutes), and 50 μL plasma aliquots were transferred to 1.5 mL tubes, frozen in dry ice, and stored at -80°C.

[0158] Treatment Forty homozygous Col4a3 ko / ko mice were assigned to four groups, with n = 10 mice per group, and used in this study. The animals were treated with vehicle or compound by daily oral gavage starting at 4 weeks of age for 4 weeks. The reference compound, ramipril, was administered via drinking water, prepared weekly and replaced at the latest after 4 days. Additionally, a wild-type control group (Col4A3+ / +) without any treatment was added to this study as one group (n = 6 mice). The treatment groups are summarized in the following table.

[0159]

Table 1

[0160] Urine sampling Urine samples were collected from all animals in groups A - D by directly extracting the urine produced using a pipette at the baseline before treatment initiation, at 6 weeks of age, and at 8 weeks of age, respectively. If no urine was excreted during the fixation process, abdominal massage was permitted. Urine was collected into Eppendorf tubes, centrifuged at 800×g for 10 minutes at room temperature, and the supernatant was transferred to a new tube and stored frozen at -20°C until use.

[0161] Chemical substances The creatinine and albumin concentrations in the urine supernatants collected from 8 animals in each of groups A - D at 3 time points: baseline, 6 weeks of age, and 8 weeks of age were analyzed (n = 96).

[0162] Creatinine level measurement The creatinine levels in urine samples from all animals (n = 8 per group, 4 groups, 3 time points, total n = 96) were analyzed. For this purpose, the enzymatic assay (DZ072B) of Diazyme (registered trademark) was used. The analysis was performed with some modifications for use in 96 - well plates and reading with a standard plate photometer (Cytation 5, Biotek) according to the manufacturer's protocol.

[0163] Albumin level measurement The albumin levels (total n = 96) in the urine supernatants collected from each animal at 3 time points in each group were analyzed using an albumin mouse ELISA kit (ab108792; Abcam) according to the manufacturer's protocol.

[0164] Briefly, the urine sample was centrifuged at 800×g for 10 minutes and diluted with diluent N. 50 μL of albumin standard or sample was added per well and incubated for 2 hours. After the washing step, 50 μL of biotinylated albumin antibody was added to each well and incubated for 1 hour. After washing the microplate, 50 μL of streptavidin-peroxidase conjugate was added per well and incubated for 30 minutes. Then, the microplate was washed again and incubated with 50 μL of chromogenic substrate per well for 15 minutes. The reaction was stopped by adding 50 μL of stop solution per well. The albumin concentration was measured by reading the absorbance at 450 nm immediately after adding the stop solution.

[0165] Plasma sample After confirming deep anesthesia, the chest was opened and blood was collected by puncturing the heart with a 23-gauge needle. The needle was removed and the blood was transferred to a sample tube (MiniCollect® K2EDTA (potassium ethylenediaminetetraacetate)). The tube had to be inverted thoroughly to promote uniform distribution of EDTA and prevent coagulation. The blood sample was centrifuged at 3000×g for 10 minutes at room temperature (22°C). The plasma was transferred to a pre-labeled 1.5 ml LoBind Eppendorf tube (50 μL aliquot + remainder), frozen with dry ice, and stored at -80°C.

[0166] Colorimetric detection of blood urea nitrogen (BUN) The BUN plasma levels of all animals at the end of the test were analyzed. For this purpose, an assay from Invitrogen® (catalog number: EIABUN) was used. The analysis was performed according to the manufacturer's protocol.

[0167] Quantitative detection of mouse cystatin C The cystatin C plasma levels of all animals at the end of the test were analyzed. For this purpose, an ELISA kit from Abcam® (catalog number: ab119590) was used. The analysis was performed according to the manufacturer's protocol.

[0168] Result Albumin level When the albumin levels in the urine of homozygous Col4a3 ko / ko mice were evaluated, an increase over time was shown in both the first and second experiments, and the results are seen in Figures 1 and 6. At 4 weeks of age (baseline), similar albumin levels were observed in all groups. In the secukinumab-administered group (Group B), at 6 weeks of age, there was a tendency for the albumin level to increase compared to the vehicle-administered group, but in the ramipril-administered group (Group C), in the first experiment, the amount of urinary albumin slightly decreased, and in the second experiment, the albumin level in the urine decreased more significantly. Interestingly, in both experiments, the combination of ramipril and secukinumab (Group D) decreased the albumin concentration compared to vehicle-administered mice. At 8 weeks of age, after administering ramipril and secukinumab to homozygous Col4a3 ko / ko mice (Group D), the albumin concentration significantly decreased compared to control mice (Group A), and a decrease in the mean albumin concentration was shown with secukinumab alone.

[0169] Creatinine level When the creatinine levels in the urine were analyzed, there were no significant differences between the groups at all test time points in both the first and second experiments. The results can be shown in Figures 2 and 7.

[0170] Albumin / creatinine ratio When calculating the albumin / creatinine ratio, as shown in detail in Figures 3 and 8, in the urine of 6-week-old Col4a3 ko / ko mice (Group B), after secukinumab administration, there was a tendency to increase compared to vehicle-administered animals (Group A) in both the first and second experiments. In contrast, ramipril administration (Group C) decreased the albumin / creatinine ratio, but in the first experiment, it did not reach a significant difference (it reached a significant difference in the second experiment). The combined treatment (ramipril + secukinumab) further decreased the ratio, and in the first experiment, it became significant as a result of statistical analysis by unpaired t-test. At 8 weeks of age, when ramipril was administered alone (Group C) or secukinumab was administered in combination (Group D) to Col4a3 ko / ko mice, the albumin / creatinine ratio significantly decreased compared to the vehicle-administered group, and secukinumab alone showed an average decrease (Group B).

[0171] BUN and cystatin C levels in plasma samples The test results of blood urea nitrogen (BUN) and cystatin C in plasma samples for the first experiment are shown in Figures 4 and 5, respectively. The test results of blood urea nitrogen (BUN) in plasma samples for the second experiment are shown in Figure 9.

[0172] In the first experiment, secukinumab alone, ramipril alone, and the combined administration of both showed a significant decrease in the plasma concentrations of BUN and cystatin C compared to vehicle alone. This decrease was the same in all treatment groups. In the second experiment, the combined use of ramipril and secukinumab showed a significant decrease in BUN.

Claims

1. A NOX inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alport syndrome.

2. The NOX inhibitor according to claim 1 for use, wherein the NOX inhibitor is a NOX4 inhibitor, a NOX4 / 1 inhibitor, or a NOX1 inhibitor, or a pharmaceutically acceptable salt thereof.

3. The NOX inhibitor according to claim 1 or claim 2 for use, wherein the NOX inhibitor is a pyrazolopyridine NOX4 or NOX4 / 1 inhibitor, a pyrazolidinedione NOX4 or NOX4 / 1 inhibitor, an amidothiazole NOX1 or NOX4 / 1 inhibitor, or an indole NOX4 / 1 inhibitor, or a pharmaceutically acceptable salt thereof.

4. The NOX inhibitor according to any one of claims 1 to 3 for use, wherein the NOX inhibitor is a 2,5-disubstituted benzoxazole or benzothiazole NOX4 inhibitor, or a pharmaceutically acceptable salt thereof.

5. A NOX inhibitor according to any one of claims 1 to 3 for use, wherein the NOX inhibitor has the formula (I) 【Chemical 1】 wherein, in the formula, G １ is selected from the group consisting of: H, optionally substituted alkyl, for example, aminocarbonylalkyl (for example, phenylacetamide), Optionally substituted C ３ to C ８ -cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, arylalkyl, for example, phenylalkyl, for example, phenylmethyl, or 3-methylphenylmethyl, substituted arylalkyl, for example, substituted phenylalkyl, for example, substituted phenylmethyl (for example, 4-fluorobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-methylbenzyl, or 4-bromobenzyl), heteroarylalkyl, and substituted heteroarylalkyl, for example, substituted pyridinealkyl, for example, pyridin-2-ylmethyl, G ２ is selected from the group consisting of: H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, for example, phenyl (for example, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-chlorophenyl, 2-methylphenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 2,5-difluorophenyl, or 2-methoxyphenyl), optionally substituted alkylaryl, optionally substituted arylalkyl, Heteroaryl, for example, benzothiazolyl, or pyridinyl, Substituted heteroaryl, for example, substituted benzothiazolyl (e.g., 1,3 - benzothiazol - 2 - yl), or substituted pyridinyl (e.g., pyridin - 2 - yl), Optionally substituted alkylheteroaryl, Optionally substituted heteroarylalkyl, Optionally substituted alkenylaryl, Optionally substituted arylalkenyl, Optionally substituted alkenylheteroaryl, Optionally substituted heteroarylalkenyl, Optionally substituted C ３ ~C ８ -cycloalkyl, Optionally substituted heterocycloalkyl, Optionally substituted alkyl C ３ -C ８ -cycloalkyl, Optionally substituted C ３ ~C ８ -cycloalkylalkyl, Optionally substituted alkylheterocycloalkyl, and Optionally substituted heterocycloalkylalkyl, G ３ is selected from the group consisting of: H, Optionally substituted alkyl, for example, optionally substituted methyl, or optionally substituted ethyl, Optionally substituted alkenyl, Optionally substituted alkynyl, Optionally substituted aryl, for example, optionally substituted phenyl, Optionally substituted alkylaryl, Optionally substituted arylalkyl, Optionally substituted heteroaryl, Optionally substituted alkylheteroaryl, Optionally substituted heteroarylalkyl, Optionally substituted alkenylaryl, Optionally substituted arylalkenyl, Optionally substituted alkenylheteroaryl, Optionally substituted heteroarylalkenyl, Optionally substituted C ３ to C ８ -cycloalkyl, Optionally substituted heterocycloalkyl, Optionally substituted alkyl C ３ ~C ８ -cycloalkyl, Optionally substituted C ３ to C ８ -cycloalkylalkyl, Optionally substituted alkylheterocycloalkyl, and Optionally substituted heterocycloalkylalkyl, G ４ is selected from the group consisting of: H, Optionally substituted alkyl, for example, optionally substituted pentyl (e.g., isopentyl), Optionally substituted heteroalkyl, Optionally substituted alkoxy, for example, optionally substituted methoxy (e.g., 2 - methoxyethyl), Optionally substituted alkenyl, Optionally substituted alkynyl, Optionally substituted aryl, Optionally substituted alkylaryl, Arylalkyl, for example, benzyl, or phenylethyl (e.g., 2 - phenylethyl), A substituted arylalkyl, for example, a substituted benzyl (e.g., methyl benzoate), or a substituted phenylethyl (e.g., 4-methoxyphenylethyl), An optionally substituted heteroaryl, An optionally substituted alkylheteroaryl, An optionally substituted heteroarylalkyl, for example, an optionally substituted thiophenylalkyl (e.g., an optionally substituted thiophenylmethyl, e.g., thiophen-2-ylmethyl), an optionally substituted imidazolylalkyl (e.g., an optionally substituted imidazolylethyl, e.g., imidazol-4-ylethyl), an optionally substituted indolylalkyl (e.g., an optionally substituted indolylethyl, e.g., indol-3-ylethyl), an optionally substituted furanylalkyl (e.g., an optionally substituted furanylmethyl, e.g., furan-2-ylmethyl), an optionally substituted benzodioxolylalkyl (e.g., an optionally substituted benzodioxolylmethyl, e.g., 1,3-benzodioxol-5-ylmethyl), or an optionally substituted pyridinylmethyl (e.g., pyridin-3-ylmethyl, or pyridin-2-ylmethyl), An optionally substituted alkenylaryl, An optionally substituted arylalkenyl, An optionally substituted alkenylheteroaryl, An optionally substituted heteroarylalkenyl, Optionally substituted C ３ ~C ８ -cycloalkyl, A heterocycloalkyl, for example, morpholinyl (e.g., 5-morpholin-4-yl), piperazinyl (e.g., 4-methylpiperazinyl), or piperidinyl (e.g., 4-methylbenzyl) piperidin-4-yl), A substituted heterocycloalkyl, for example, a substituted morpholinyl (e.g., 5-morpholin-4-yl), a substituted piperazinyl (e.g., 4-methylpiperazinyl), or a substituted piperidinyl (e.g., 4-methylbenzyl) piperidin-4-yl), Optionally substituted alkyl C ３ -C ８ -cycloalkyl, Optionally substituted C ３ ~C ８ -cycloalkylalkyl, An optionally substituted alkylheterocycloalkyl, Heterocycloalkylalkyl, such as morpholinylalkyl (e.g., morpholinylethyl, or morpholinylpropyl, in particular, 2-morpholin-4-yl-ethyl, or 3-(morpholin-4-yl)propyl), piperazinylalkyl (e.g., piperazinylethyl, e.g., 2-(4-acetylpiperazin-1-yl)ethyl, or 2-(4-hexanoylpiperazin-1-yl)ethyl), or pyrrolidinylalkyl (e.g., pyrrolidinylpropyl, e.g., 3-(2-oxopyrrolidin-L-yl)propyl), or tetrahydrofuranylalkyl (e.g., tetrahydrofuranylmethyl, e.g., tetrahydrofuran-2-ylmethyl), and substituted heterocycloalkylalkyl, such as substituted morpholinylalkyl (e.g., substituted morpholinylethyl, or substituted morpholinylpropyl, in particular, substituted 2-morpholin-4-yl ethyl, or substituted 3-(morpholin-4-yl)propyl), substituted piperazinylalkyl (e.g., substituted piperazinylethyl, e.g., substituted 2-(4-acetylpiperazin-1-yl)ethyl, or substituted 2-(4-hexanoylpiperazin-1-yl)ethyl), or substituted pyrrolidinylalkyl (e.g., substituted pyrrolidinylpropyl, e.g., substituted 3-(2-oxopyrrolidin-L-yl)propyl), or substituted tetrahydrofuranylalkyl (e.g., substituted tetrahydrofuranylmethyl, e.g., substituted tetrahydrofuran-2-ylmethyl), G ５ is selected from the group consisting of: H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, optionally substituted heteroarylalkyl, optionally substituted alkenylaryl, optionally substituted arylalkenyl, optionally substituted alkenylheteroaryl, optionally substituted heteroarylalkenyl, Optionally substituted C ３ to C ８ -cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted alkyl C ３ ~C ８ -cycloalkyl, Optionally substituted C ３ ~C ８ -cycloalkylalkyl, optionally substituted alkylheterocycloalkyl, and optionally substituted heterocycloalkylalkyl, Formula (I) and its pharmaceutically acceptable salts The NOX inhibitor according to [[ID=]].

6. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor has the formula (II): 【Chemical 2】 wherein in the formula Ar １ is selected from the list consisting of: phenyl, Phenyl substituted by a halogen, for example, chloro (e.g., Ar １ is 2-chlorophenyl), and phenyl substituted by alkoxy, for example, methoxy, G １ and G ５ is H, G ３ is selected from the group consisting of: Optionally substituted C １ ~C ６ alkyl, for example, optionally substituted methyl, phenyl, phenyl substituted by halogen, amino, alkylamino, or alkoxy, for example, phenyl is 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 3-dimethylaminophenyl, 2-trimethylaminophenyl, 3-methylaminophenyl, 3-aminophenyl or 4-methoxyphenyl, G ４ is selected from the list consisting of the following: H, C １ to C ６ alkyl, for example, methyl, Replacement C １ ~C ６ Alkyl, for example, substituted methyl, optionally, C １ ~C ６ The alkyl is substituted by alkoxy, for example, substituted C １ ~C ６ The alkyl is methoxy, cyethyl, for example, 2-methoxyethyl, Heteroaryl C １ -C ６ alkyl, for example, pyridinyl C １ -C ６ alkyl (for example, pyridinylmethyl, in particular, pyridin-2-ylmethyl, pyridin-3-ylmethyl, 6-methoxypyridin-3-ylmethyl, 2-methoxypyridin-4-ylmethyl), or pyrazinyl C １ -C ６ alkyl, for example, pyrazin-2-ylmethyl, Replacement heteroaryl C １ -C ６ alkyl, for example, substituted pyridinyl C １ -C ６ alkyl (for example, substituted pyridinylmethyl, especially, substituted pyridin-2-ylmethyl, substituted pyridin-3-ylmethyl, substituted 6-methoxypyridin-3-ylmethyl, substituted 2-methoxypyridin-4-ylmethyl), or substituted pyrazinyl C １ -C ６ alkyl, for example, substituted pyrazin-2-ylmethyl, Alkoxy C １ ~C ６ alkyl, for example, methoxyethyl (e.g., 2-methoxyethyl), and Replacement C １ ~C ６ alkyl, for example, substituted methoxyethyl (e.g., substituted 2-methoxyethyl), or G ３ and G ４ combine together to form an optionally substituted 7-membered heterocycloalkyl ring containing two nitrogen atoms, with the two nitrogens being linked via an optionally substituted C １ to C ３ alkyl moiety formula (II) and its tautomers, geometric isomers, optically active forms, and pharmaceutically acceptable salts thereof The NOX inhibitor according to [[ID=]].

7. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor has the formula (III) [Chemical Formula 3] wherein in the formula Ar １ , G １ , and G ５ is as defined in claim 5 or claim 6, G ６ selected from the group consisting of: C １ ~C ６ alkyl, Replacement C １ ~C ６ alkyl, Aryl C １ ~C ６ alkyl, for example, benzyl, Replacement aryl C １ ~C ６ alkyl, for example, substituted phenyl C １ ~C ６ alkyl, for example, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl), Heteroaryl C １ ~C ６ alkyl, for example, pyridinyl C １ ~C ６ alkyl, for example, pyridinylmethyl (for example, pyridin-2-ylmethyl, or pyridin-3-ylmethyl), or furanyl C １ ~C ６ alkyl, for example, furanylmethyl (for example, furan-3-ylmethyl), Replacement heteroaryl C １ -C ６ alkyl, for example, substituted pyridinyl C １ -C ６ alkyl, for example, substituted pyridinylmethyl (for example, substituted pyridin-2-ylmethyl, or substituted pyridin-3-ylmethyl), or substituted furanyl C １ -C ６ alkyl, for example, substituted furanylmethyl (for example, substituted furan-3-ylmethyl), formula (III) and its tautomers, geometric isomers, optically active forms, and pharmaceutically acceptable salts thereof The NOX inhibitor according to [[ID=]].

8. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor has the formula (IV) 【Chemical Formula 4】 wherein in the formula A １ 、 A ２ 、 and A ３ are independently selected from the list consisting of: hydrogen, halogen, CN, CF ３ , CHF ２ 、 Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted carboxy, and optionally substituted alkoxycarbonyl, and R ｉ is selected from the group consisting of: hydrogen, halogen, CN, CF ３ 、 CHF ２ , Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, and optionally substituted carboxy, R ｉｉ is selected from a list consisting of: hydrogen, Optionally substituted C １ ~C ６ alkyl, C ３ - C ８ cycloalkyl, Optionally substituted halo C １ -C ６ alkyl, Optionally substituted halo C ３ -C ８ Cycloalkyl, Optionally substituted aryl C １ -C ６ alkyl, Optionally substituted heteroaryl C １ ~C ６ alkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, substituted heterocycloalkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted hydroxy C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted alkoxycarbonyl C １ ~C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted aryl C ３ -C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, and Optionally substituted halo C ３ -C ８ Cycloalkyl, Ar ３ is selected from the following: 【Chemical Formula 5】 R １ 、 and R ４ is independently selected from the list consisting of: hydrogen, halogen, CN, CF ３ , CHF ２ 、 NH ２ , Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, alkoxy, amino, optionally substituted heterocycloalkyl, carboxy, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted aminoheterocycloalkyl C １ -C ６ alkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, and Optionally substituted aminocarbonyl C １ -C ６ alkyl, R ２ is selected from the list consisting of: hydrogen, halogen, CF ３ 、 CHF ２ 、 NH ２ , Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted alkoxy, amino, optionally substituted heterocycloalkyl, carboxy, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted amino C ３ ~C ８ Cycloalkyl, Optionally substituted aminoheterocycloalkyl C １ -C ６ alkyl, Optionally substituted C ３ -C ８ carboxycycloalkyl, and Optionally substituted aminocarbonyl C １ -C ６ alkyl, R ３ is selected from the list consisting of: hydrogen, halogen, CF ３ 、 CHF ２ , NH ２ 、 Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted alkoxy, amino, optionally substituted heterocycloalkyl, carboxy, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted alkoxy C ３ ~C ８ cycloalkyl, Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted aminoheterocycloalkyl C １ -C ６ alkyl, Optionally substituted C ３ ~C ８ Carboxycycloalkyl, and Optionally substituted aminocarbonyl C １ -C ６ alkyl, R ５ is selected from the group consisting of: hydrogen, halogen, CF ３ 、 CHF ２ 、 NH ２ 、 Optionally substituted C １ - C ６ alkyl, Optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted alkoxy, amino, optionally substituted heterocycloalkyl, carboxy, Optionally substituted alkoxy C １ ~C ６ alkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted amino C ３ ~C ８ Cycloalkyl, Optionally substituted aminoheterocycloalkyl C １ -C ６ alkyl, Optionally substituted C ３ -C ８ carboxycycloalkyl, and Optionally substituted aminocarbonyl C １ -C ６ alkyl, Wherein, R １ , R ２ , R ３ , and R ４ is not H, and the others are H or R １ , R ２ , R ３ , R ４、 and R ５ may combine together to form an optionally substituted bicyclic heteroaryl, Ar ３ which is also optionally substituted bicyclic heteroaryl, in particular selected from the group consisting of: 【Chemical Formula 6】 wherein, R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , and R １３ are each independently selected from the list consisting of: hydrogen, halogen, hydroxy, CN, CF ３ 、 CHF ２ , NH ２ 、 alkoxy, amino, carboxy, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ - C ８ Cycloalkyl C １ - C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ -C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ ~C ８ Cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, acylamino, ureido, sulfonyl, and sulfonylamino, R １４ is selected from the list consisting of: hydrogen, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ ~C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Aryl C ３ ~C ８ Cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, and Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, Ar ２ is selected from the following group: 【Chemical Formula 7】 wherein, R １５ , R １６ , and R １９ are independently selected from the list consisting of: hydrogen, halogen, hydroxy, CN, CF ３ 、 CHF ２ 、 NH ２ , alkoxy, amino, carboxy, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted alkenyl, alkynyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Aminocarbonyl C １ ~C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ -C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, acylamino, ureido, and sulfonyl, or In the formula, R １５ , R １６ , and R １９ may further be selected from the following groups: 【Chemical 8】 wherein y, w, z, and t are each independently an integer in the range of 1 to 3, wherein h is an integer in the range of 0 to 3, wherein n is an integer in the range of 0 to 4, wherein G is selected from the list consisting of: N-R ２３ , O, S, and SO ２ 、 wherein J is selected from the list consisting of: C(B)n, and N-R ２３ , wherein L is selected from the list consisting of: C-(B)n, N-R ２３ , O, S, and SO ２ 、 wherein, R ２３ is selected from the list consisting of: hydrogen, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C ３ - C ８ Cycloalkyl C １ - C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Alkoxy C １ ~C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ - C ８ Cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ - C ８ cycloalkyl, and aminosulfonyl, wherein B is selected from the group consisting of: hydrogen, halogen, hydroxy, CN, CF ３ 、 CHF ２ 、 NH ２ , alkoxy, amino, carboxy, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ ~C ８ Cycloalkyl C １ ~C ６ Alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ ~C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ -C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ ~C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, acylamino, Ureido, sulfonyl, and sulfonylamino, wherein, R １７ , and R １８ are independently selected from the list consisting of: hydrogen, halogen, CN, CF ３ 、 CHF ２ 、 alkoxy, amino, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, Optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, acylamino, ureido, sulfonyl, aminosulfonyl, and sulfonylamino, wherein, R ２０ , and R ２２ are independently selected from the list consisting of: hydrogen, halogen, CN, CF ３ , CHF ２ 、 alkoxy, amino, Optionally substituted C １ -C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, Optionally substituted C ３ - C ８ Cycloalkyl C １ - C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, and optionally substituted amino C ３ -C ８ cycloalkyl, wherein, R ２１ is selected from the list consisting of: hydrogen, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ Alkylaryl C １ -C ６ Alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ -C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ ~C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, and Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, wherein R １５ and R １６ together combine to form an optionally substituted bicyclic heteroaryl having the following formula: 【Chemical Formula 9】 wherein X, Y, and Z are each independently selected from the list consisting of: C(R ２４ R ２５ ), CH ２ C(R ２４ R ２５ ), C(=O), O, and N-R ２６ , wherein, R ２４ , and R ２５ are each independently selected from the list consisting of: hydrogen, halogen, hydroxy, CN, CF ３ 、 CHF ２ 、 NH ２ , alkoxy, amino, carboxy, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ ~C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted amino C １ -C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ -C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ -C ８ cycloalkyl, Optionally substituted amino C ３ -C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, acylamino, ureido, sulfonyl, and sulfonylamino, In the formula, R ２４ , and R ２５ together combine to form an optionally substituted C ３ -C ８ cycloalkyl or an optionally substituted heterocycloalkyl, wherein, R ２６ is selected from the group consisting of: hydrogen, aminocarbonyl, alkoxycarbonyl, Optionally substituted C １ - C ６ alkyl, Optionally substituted C ３ -C ８ cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted C ３ ~C ８ Cycloalkyl C １ ~C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, Optionally substituted aryl C １ ~C ６ alkyl, Optionally substituted heteroaryl C １ -C ６ alkyl, Optionally substituted alkoxy C １ -C ６ alkyl, Amino C １ ~C ６ alkyl, Optionally substituted carboxy C １ -C ６ alkyl, Optionally substituted aminocarbonyl C １ ~C ６ alkyl, Optionally substituted heterocycloalkyl C ３ -C ８ cycloalkyl, Optionally substituted aryl C ３ ~C ８ cycloalkyl, Optionally substituted heteroaryl C ３ -C ８ cycloalkyl, Optionally substituted alkoxy C ３ ~C ８ cycloalkyl, Optionally substituted amino C ３ - C ８ cycloalkyl, Optionally substituted carboxy C ３ -C ８ cycloalkyl, Optionally substituted aminocarbonyl C ３ -C ８ cycloalkyl, and aminosulfonyl, wherein R １５ and R １９ may combine together to form an optionally substituted bicyclic heteroaryl, In the formula, R １５ , and R ２１ may combine together to form an optionally substituted bicyclic heteroaryl, In the formula, R １７ , and R ２１ may combine together to form an optionally substituted bicyclic heteroaryl, In the formula, R ２０ , and R ２１ may combine together to form a bicyclic heteroaryl optionally substituted Formula (IV) and its tautomers, geometric isomers, optically active forms, and pharmaceutically acceptable salts thereof is a NOX inhibitor, a NOX inhibitor by

9. A NOX inhibitor for use according to any one of Claims 1 to 3, wherein the NOX inhibitor is of formula (V) 【Chemical 10】 wherein in the formula X ｉ is selected from a list consisting of CR ２７ and N Y ｉ is selected from the list consisting of C, H, and N, A ４ is selected from the list consisting of: -OCHR ３１ -, -NR ３０ -CHR ３１ -、 -CH ２ NR ３０ -, and -CH ２ -O-, wherein, R ２７ is selected from the list consisting of: H, halogen, and optionally substituted C １ - C ６ alkyl, wherein, R ２８ is selected from the list consisting of: H, halogen (e.g., chloro, fluoro), optionally substituted alkoxy, e.g., optionally substituted methoxy (e.g., methoxy, (tetrahydro-2H-pyran-4-yl)methoxy, piperidin-4-ylmethoxy), or optionally substituted ethoxy (e.g., 2-(dimethylamino)ethoxy, 2-hydroxyethoxy, 1-phenylethoxy, 2-methoxyethoxy), Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted C １ -C ６ alkyl, for example, optionally substituted methyl, Optionally selected substituted amino, for example, optionally substituted C １ -C ６ alkylamino (e.g., methylamino, tetrahydro-2H-pyran-4-yl)methyl)amino, (1-methylpiperidin-4-yl)methyl)amino, dimethylamino, optionally substituted ethylamino, for example, 2-morpholinoethylamino, or 2-(dimethylamino)ethylamino, or methoxyethylamino, optionally substituted methylamino, for example, 1-methyl-1H-imidazol-4-ylmethylamino, or 2-hydroxyethyl)amino, optionally substituted propylamino, for example, dimethylaminopropylamino), Optionally substituted heterocycloalkyl, for example, optionally substituted piperazine (e.g., methylpiperazin-1-yl), Optionally substituted C １ -C ６ Alkylheterocycloalkyl, e.g., optionally substituted C １ -C ６ Alkylpiperazine (e.g., methylpiperazin-1-yl), Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted alkoxy C １ ~C ６ alkyl, -O-R ３４ and -NR ３５ R ３６ 、 In the formula, R ２９ is a group of the formula -(CHR ３２ )n-A ５ or R ２９ is, from A ４ portion CHR ３１ together with, optionally substituted aryl, for example, optionally substituted phenyl (e.g., phenyl, or phenyl substituted with halogen, e.g., fluorophenyl substituted with alkoxy, e.g., substituted with methoxy), and optionally substituted heteroaryl, for example, 1,3-dihydro-1H-indenyl (e.g., 1-(dimethylamino)-2,3-dihydro-1H-indenyl-2-yl, 2,3-dihydro-1H-indenyl-2-yl, 2,3-dihydro-1H-indenyl-1-yl), or optionally substituted 6,7-dihydro-5H-cyclopenta[b]pyridinyl (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl, 2-methylpyridin-3-yl, 5-methylpyridin-2-yl), or optionally substituted 1,2,3,4-tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalen-1-yl), or optionally substituted 2,3-dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-3-yl, 2,3-dihydro-1H-inden-1-yl), or optionally substituted thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), or optionally substituted isoxazolyl (e.g., 5-methylisoxazol-3-yl), or optionally substituted pyrazolyl (e.g., 1-methyl-1H-pyrazol-3-yl), or optionally substituted imidazolyl (e.g., 1-methyl-1H-imidazol-2-yl) selected from, form an optionally substituted ring, or R ２９ is, together with the moiety NR ４ from A ３０ forms an optionally substituted ring selected from optionally substituted aryl and optionally substituted heteroaryl, such as optionally substituted isoindolinyl (e.g., isoindolin-2-yl, 1H-indol-1-yl), and wherein n is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4), In the formula, R ３０ is selected from H and optionally substituted alkyl, for example, optionally substituted methyl, In the formula, A ５ is an optionally substituted aryl, for example, optionally substituted phenyl (e.g., methoxyphenyl, fluorophenyl, chlorophenyl), optionally substituted heteroaryl, for example, optionally substituted pyridine (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-3-yl, 5-methylpyridin-2-yl), or optionally substituted pyrazolyl (e.g., 1,3-dimethyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-3-yl), or optionally substituted thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), or optionally substituted imidazolyl (e.g., 1H-imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-5-yl), or optionally substituted 1,2,4-triazolyl (e.g., 1-methyl-1H-1,2,4-triazol-5-yl), or optionally substituted isoxazolyl (e.g., 1-cyclopropylisoxazol-3-yl), or optionally substituted oxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol-3-yl), or optionally substituted pyrimidinyl (e.g., pyrimidin-2-yl), and is an optionally substituted ring selected from wherein, R ３１ is selected from the list consisting of: Η, Optionally substituted C １ ~C ６ alkyl, for example, optionally substituted methyl (e.g., methoxymethyl, 3,3-difluoropyrrolidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, hydroxymethyl), or optionally substituted ethyl, or optionally substituted propyl (e.g., methyl, hydroxymethyl, hydroxyethyl, 2-propanolyl, hydroxylisopropyl), Optionally substituted amino C １ ~C ６ alkyl, for example, optionally substituted aminomethyl (e.g., dimethylaminomethyl, methylaminomethyl), Optionally substituted alkoxy C １ -C ６ alkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, for example, optionally substituted heterocycloalkylmethyl, for example, optionally substituted pyrrolidine C １ -C ６ alkyl (for example, 3,3-difluoropyrrolidin-1-ylmethyl), or substituted piperazine C １ -C ６ alkyl (for example, 4-methylpiperazin-1-ylmethyl), or heterocycloalkylethyl, for example, optionally substituted morpholino C １ -C ６ alkyl (for example, morpholinomethyl, morpholinoethyl), or optionally substituted pyrrolidine C １ -C ６ alkyl (for example, pyrrolidinomethyl, pyrrolidinoethyl), Optionally substituted aminocarbonyl (e.g., dimethylaminocarbonyl), Optionally substituted C ２ - C ８ cycloalkyl, e.g., optionally substituted cyclopropyl, and Optionally substituted amino C １ ~C ６ alkyl, for example, optionally substituted aminoethyl (e.g., dimethylaminoethyl), or optionally substituted aminomethyl (e.g., dimethylaminomethyl), wherein, R ３２ is selected from the list consisting of: Η, Optionally substituted C １ -C ６ alkyl, e.g., optionally substituted methyl, Optionally substituted amino, Optionally substituted C １ -C ６ alkylamino (e.g., dimethylamino), and hydroxy, and wherein R ３２ groups are independently selected for each repeating unit (CHR ３２ ), wherein, R ３３ is selected from the list consisting of: H, halogen (e.g., fluoro), and Optionally substituted C １ ~C ６ alkyl, for example, methyl, wherein, R ３４ is selected from the group consisting of: H, Optionally substituted C １ -C ６ alkyl, for example, optionally substituted methyl, or optionally substituted ethyl (e.g., methoxyethyl, 2-(dimethylamino)ethyl, hydroxyethyl), Optionally substituted amino C １ ~C ６ alkyl, Optionally substituted heterocycloalkyl, Optionally substituted C ２ -C ８ cycloalkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, e.g., optionally substituted heterocycloalkylmethyl, e.g., optionally substituted tetrahydropyran C １ -C ６ alkyl (e.g., tetrahydro-2H-pyran-4-yl), or optionally substituted piperidinealkyl (e.g., 1-methylpiperidin-4-yl), Optionally substituted C ２ -C ８ Cycloalkyl C １ -C ６ Alkyl, Optionally substituted alkoxy, Optionally substituted amino C １ -C ６ alkyl, for example, optionally substituted aminoethyl (e.g., 2-(dimethylamino)ethyl), Optionally substituted aryl C １ -C ６ alkyl, and Optionally substituted heteroaryl C １ -C ６ alkyl, wherein, R ３５ , and R ３６ are independently selected from the list consisting of: H, Optionally substituted C １ -C6 alkyl, for example, optionally substituted methyl (e.g., 1-methyl-1H-imidazol-4-yl)methyl), or optionally substituted ethyl (e.g., 2-methoxyethyl), Optionally substituted amino C １ -C ６ alkyl, for example, optionally substituted aminoethyl (e.g., dimethylaminoethyl), or optionally substituted aminopropyl (e.g., dimethylamino) propyl), Optionally substituted heterocycloalkyl, for example, optionally substituted piperidine (e.g., 1-methylpiperidine), Optionally substituted C ２ - C ８ cycloalkyl, Optionally substituted heterocycloalkyl C １ -C ６ alkyl, e.g., optionally substituted heterocycloalkylethyl, e.g., optionally substituted morpholino C １ -C ６ alkyl (e.g., 2-morpholinoethyl), or optionally substituted heterocycloalkylmethyl, e.g., optionally substituted tetrahydrofuran C １ -C ６ alkyl (e.g., tetrahydro-2H-pyran-4-ylmethyl), or piperidine C １ -C ６ alkyl (e.g., 1-methylpiperidin-4-yl)methyl, or optionally substituted imidazolyl C １ -C ６ alkyl (e.g., 1-methyl-1H-imidazol-4-yl)methyl), optionally substituted C ２ -C ８ cycloalkyl C １～ C ６ alkyl, Optionally substituted alkoxy, Optionally substituted alkoxy C １ -C ６ alkyl, for example, optionally substituted alkoxyethyl (e.g., 2-methoxyethyl), Optionally substituted aryl C １ -C ６ alkyl, and Optionally substituted heteroaryl C １ ~C ６ alkyl, e.g., heteroaryl C １ ~C ６ alkylmethyl, e.g., optionally substituted imidazolyl C １ ~C ６ alkyl (e.g., 1-methyl-1H-imidazol-4-ylmethyl), optionally substituted amino C １ ~C ６ alkyl, e.g., optionally substituted aminoethyl, or optionally substituted aminopropyl (e.g., 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl), Formula (V) and its tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives is a NOX inhibitor, a NOX inhibitor according to.

10. The NOX inhibitor is selected from the group consisting of the following: the NOX inhibitor for use according to any one of claims 1 to 3: 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 4-(2-fluoro-4-methoxyphenyl)-2-(2-methoxyphenyl)-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, (R)-3-methoxy-4-(2-morpholino-1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, 10-benzoyl-2-(2~chlorophenyl)-2,3,8,9,10,11---hexahydro-1H-pyrazolo[4′,3′:3,4]pyrido[1,2-a][1,4]diazepine 1,5(7H)-dione, (S)-3-methoxy-4-(1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, (R)-4-(2-hydroxy-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide, and (R)-4-(2-(dimethylamino)-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide.

11. The NOX inhibitor according to claim 8, wherein the NOX inhibitor is selected from the group consisting of: 5-(2-methylpyridin-4-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 2,5-bis(2-methylpyridin-4-yl)-1H-indole, 4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine, 5-(5-fluoropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-chloropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-isopropoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, N,N-dimethyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-3-amine, 5-(6-methylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 2-(2-methylpyridin-4-yl)-5-(pyrimidin-5-yl)-1H-indole, 2-methyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)-1H-benzo[d]imidazole, 2-(2-(azetidin-1-yl)pyridin-4-yl)-5-(5-methylpyridin-3-yl)-1H-indole, 5-(5-methoxypyridin-3-yl)-2-(2-methoxypyridin-4-yl)-1H-indole, 2-(2,6-dimethylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 5-(5-methoxypyridin-3-yl)-2-(2-methylpyrimidin-4-yl)-1H-indole, 5-(5-methoxypyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-1H-indole, 4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-2-methylthiazole, 2-(2-cyclopropylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-(4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-ol, 1-(4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 2-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 4-(4-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 2-(5-Fluoropyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(6-methoxypyridin-3-yl)-1H-indole, 4-(5-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 5-(5-Methoxypyridin-3-yl)-2-(6-(oxetan-3-yl)pyridin-3-yl)-1H-indole, 1-(5-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, N,N-Dimethyl-5-(5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-amine, 4-(5-(5-Methoxypyridin-3-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, N,N-Dimethyl-4-(5-(quinolin-4-yl)-1H-indol-2-yl)pyridin-2-amine, 1-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 1-(4-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane, 1-(4-(6-Chloro-5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro [3.3]heptane, 6-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane, 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-7-oxa-2-azaspiro[3.5]nonane, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-3-methylazetidin-3-ol, 6-chloro-2-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxylic acid, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxamide, ((1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-yl)methanol, 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl)-1H-indole, N-(1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-3-yl)methanesulfonamide, ((1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-2-yl)methanol, 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-2-one, 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-3-fluoropyridin-2-yl)morpholine, 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-1H-indole, 6-Chloro-2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 4-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide, 6-Chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 4-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-1-methylpiperazin-2-one, 3′-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methyl-5′H-spiro[azetidine e-3,7′-furo[3,4-b]pyridine], 7-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, (5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)(oxetan-3-yl)methanol, 6-Chloro-2-(6-(methoxy(oxetan-3-yl)methyl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 2-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)propan-1-ol, 5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one, 4-(6-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-cyclopropylmethyl)pyridin-2(1H)-one, 4-(5-(7-Chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(4,6-Difluoro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-chloro-5-(5-chloropyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 6-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 4-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 6-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-4-methyl-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-6-methyl-2-(2-methylpyridin-4-yl)-1H-indole, 4-Methyl-2,5-di(pyridin-4-yl)-1H-indole, 6-Methyl-2,5-di(pyridin-4-yl)-1H-indole, 4-(5-(4-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-Chloro-2,5-di(pyridin-4-yl)-1H-indole, 6-Chloro-2,5-di(pyridin-4-yl)-1H-indole, N,N-Dimethyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine, 5-(6-Cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(6-Methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(6-(Methoxymethyl)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Ethoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Cyclopropoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-(Cyclopropylmethoxy)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 7-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 3-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)quinoline, N-Methyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine, 4-(4-(2-(2-Methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-yl)morpholine, 5-(6-Chloro-2-(6-morpholinopyridin-3-yl)-1H-indol-5-yl)quinolin-2-ol, 4-(5-(6-Chloro-5-(thieno[2,3-c]pyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(6-fluoroquinolin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Chloro-5-(2-methoxyquinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine, 4-(5-(6-Fluoroquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, 4-(5-(Isoquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine, N,N-Dimethyl-4-(5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-amine, 3-Chloro-2,5-di(pyridin-4-yl)-1H-indole, 2-(2-Methylpyridin-4-yl)-5-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-3-yl)-1H-indole, 4-(2-(Pyridin-4-yl)-1H-indol-5-yl)quinoline, 4-(2-(Pyridin-3-yl)-1H-indol-5-yl)quinoline, 2,5-Di(pyridin-4-yl)-1H-indole, 2-(Pyridin-3-yl)-5-(pyridin-4-yl)-1H-indole, 2,5-Di(pyridin-3-yl)-1H-indole, 2-(1-Methyl-1H-pyrazol-5-yl)-5-(pyridin-4-yl)-1H-indole, 5-(2-(4-Methylpiperidin-1-yl)pyridin-4-yl)-2-(pyridin-4-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyridin-2-yl)-1H-indole, 5-(5-Methoxypyridin-3-yl)-2-(pyrimidin-4-yl)-1H-indole, 2-(3-Fluoropyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole, 1-Isopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 4-(5-(6-Chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)pyridin-2-yl)morpholine, 1-(2-Methoxyethyl)-2,5-di(pyridin-4-yl)-1H-indole, 1-(2-Methoxyethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Methyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Ethyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-(Cyclopropylmethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-(Benzyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 7-(4-Chloro-5-(5-methoxypyridin-3-yl)-l-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 7-(6-Chloro-5-(5-methoxypyridin-3-yl)-l-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 1-Cyclopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole, 1-Methyl-2,5-di(pyridin-4-yl)-1H-indole, and 5-(5-Methoxypyridin-3-yl)-2-(3-methylpyridin-4-yl)-1H-indole.

12. The NOX inhibitor is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, and the NOX inhibitor for use according to any one of claims 1 to 3.

13. The following: (a) A NOX inhibitor, optionally, the NOX inhibitor is as defined in any one of claims 2 to 12, a NOX inhibitor, or a pharmaceutically acceptable salt thereof, and (b) A combination product comprising an ACE inhibitor, or a pharmaceutically acceptable salt thereof, and / or an ARB, or a pharmaceutically acceptable salt thereof, A combination product for use in the treatment of Alport syndrome.

14. A combination product for use according to claim 13, comprising a pharmaceutical preparation comprising a NOX inhibitor, an ACE inhibitor, and / or an ARB, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

15. The combination product for use as defined in claim 13 or claim 14, wherein the ACE inhibitor is selected from the list consisting of ramipril, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, and trandolapril.

16. The combination product is as follows: (a) 2-(2-Chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, or a pharmaceutically acceptable salt thereof, and (b) Ramipril, or a pharmaceutically acceptable salt thereof A combination product for use as defined in any one of claims 13 to 15.

17. The combination product for use as described in claim 13 or claim 14, wherein the ARB is selected from the list consisting of azilsartan, candesartan, eprosartan, sparsentan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

18. The following components: A pharmaceutical preparation comprising a NOX inhibitor, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, optionally wherein the NOX inhibitor is as defined in any one of claims 2 to 12, and A parts kit comprising a pharmaceutical preparation comprising an ACE inhibitor, or a pharmaceutically acceptable salt thereof, and / or an ARB, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A combination product for use as defined in any one of claims 13 to 17, wherein components (A) and (B) are provided in a form suitable for administration together with each other.

19. A parts kit comprising: (I) One of components (A) and (B) as defined in claim 18, (II) The component, together with instructions for use in combination with the other of the two components.

20. A method for treating Alport syndrome, comprising administering to a patient in need of such treatment a NOX inhibitor as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

21. Use of a NOX inhibitor as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alport syndrome.

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