NOX inhibitors for treatment of olbaud syndrome

Abstract

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

Description

Technical Field

[0001] The present invention relates to novel medical uses of NOX inhibitors. In particular, the present invention relates to the use of such inhibitors in the treatment of Alport syndrome. In addition, the present invention relates to a novel pharmaceutical composition. Background Art

[0002] Allport syndrome is an inherited basement membrane disorder that causes glomerular nephropathy and subsequent renal failure. Progressive deafness and eye abnormalities may also occur (Mochizuki et al. Nat. Genet. 1994, 8, pp. 77-82; Colville et al. Ophthalmic Genet. 1997, 18, pp. 119-128).

[0003] Symptoms usually begin in childhood, and the first sign of the condition is usually the presence of blood in the urine (hematuria). Other symptoms of nephropathy may include protein in the urine (proteinuria). Over time, the affected individual may experience swelling (edema), osteoporosis, and joint pain (osteodystrophy). Without treatment, the affected individual will experience end-stage renal disease.

[0004] Patients with Alport syndrome have been reported to show mutations in the collagen IV gene (Mochizuki et al., supra; Lemmink et al. Hum. Mol. Genet. 1994, 3(8), pp. 1269-1273 and Lemmink et al. Hum. Mutat. 1997, 9(6), pp. 477-99; Gubler et al. Kidney Int. 1995, 47, pp. 1142-1147). Approximately 85% of cases of Alport syndrome are X-linked and are associated with mutations in the Col4a5 gene. Without treatment, 90% of males develop renal failure by age 40. Females develop renal failure less frequently and more slowly. About 14% are autosomal recessive forms caused by mutations in the Col4a3 and Col4a4 genes, which is when both parents carry the abnormal gene and both parents pass the abnormal gene on to their children. Both copies of the abnormal gene are required to cause the autosomal recessive type of Alport syndrome. Autosomal dominant inheritance is rare (van der Loop et al., Kidney Int. 2000, 58(5), pp. 1870-1875) and occurs when one parent has the disease and passes the abnormal gene to the child.

[0005] There is no one specific treatment for Alport syndrome and current treatment goals include monitoring and controlling disease progression and treating symptoms. In order to keep the kidneys as healthy as possible, it is very important to control the patient's blood pressure. Studies have shown that ACE inhibitors, angiotensin receptor blockers, and statins can help reduce proteinuria and kidney disease progression. However, treatment of chronic renal failure is often necessary and may include dietary modifications and fluid restrictions.

[0006] Although treatment can slow the progression of kidney disease in Alport syndrome, the condition is incurable and no treatment to date has been shown to completely stop kidney decline. The rate of progression of kidney decline in individuals with Alport syndrome varies widely. In many affected individuals, kidney function eventually deteriorates to the point where dialysis or a kidney transplant is required.

[0007] Therefore, there is a real clinical need for more effective treatment of Alport syndrome, and the inventors have surprisingly found that in the Alport syndrome mouse model of collagen type IV α3 chain (Col4a3) double knockout mice, the administration of NOX inhibitors reduces the ratio of albumin to creatine in the mouse urine. Further studies also show that after the administration of NOX inhibitors, the blood urea nitrogen (BUN) and cystatin C levels in the plasma of double knockout mice are reduced. These findings may make NOX inhibitors potentially useful for the treatment of Alport syndrome.

[0008] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an admission that the document is part of the current state of the art or is common general knowledge. Summary of the invention

[0009] Medical Uses

[0010] According to a first aspect of the present invention, there is provided a NOX inhibitor or a pharmaceutically acceptable salt thereof for treating Alport syndrome, and the use thereof is hereinafter referred to as "the use of the present invention".

[0011] As used herein, the expression "NOX inhibitor" refers to any substance that can completely or partially inhibit, block, weaken or interfere with nicotinamide adenine dinucleotide phosphate oxidase (NADPH), especially nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and / or nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1). The term can be defined as a compound that affects the enzyme activity, cellular localization, protein stability and / or expression of messenger RNA or protein of the enzyme. 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 expressing only the NOX isoform NOX4 / 1 protein (e.g., recombinant protein NOX4 / 1). Therefore, when referring to NOX inhibitors, the term "inhibitor" is intended to include, but is not limited to, molecules that completely or partially inhibit the activity of NOX4 and / or NOX1.

[0012] The NOX inhibitor used in the present invention is a NOX4 inhibitor, a NOX4 / 1 inhibitor or a NOX1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0013] For example, the NOX inhibitor may be a pyrazolopyridine NOX4 or NOX4 / 1 inhibitor, a pyrazolidinedione NOX4 or NOX4 / 1 inhibitor, an amidethiazole NOX1 or NOX4 / 1 inhibitor or an indole NOX4 / 1 inhibitor, or a pharmaceutically acceptable salt thereof. Alternatively, the NOX inhibitor may be a 2,5-disubstituted benzoxazole or benzothiazole NOX4 inhibitor, or a pharmaceutically acceptable salt thereof.

[0014] The NOX4 / 1 inhibitor is selective for NOX4 and / or NOX1 and thus has a primary NOX inhibitory activity against NOX4 and / or NOX1 compared to other NOX proteins, such as NOX2 and / or NOX3 / 5. According to a specific embodiment, the NOX4 / 1 inhibitor has a higher primary NOX inhibitory activity against NOX4 / 1 than against other NOX proteins. For example, the NOX4 / 1 inhibitor includes a small molecule, a peptide, a peptide mimetic, a chimeric protein, a natural or non-natural protein, a nucleic acid-derived polymer (e.g., DNA and RNA aptamers, siRNA, shRNA, PNA or LNA), a fusion protein with NOX4 / 1 antagonistic activity, an antibody antagonist, such as a neutralizing anti-NOX4 / 1 antibody, or a gene therapy vector that drives the expression of such a NOX4 / 1 antagonist.

[0015] In particular, NOX4 / 1 inhibitors are agents that exhibit an inhibition constant Ki of less than 5 micromolar in a functional ROS production assay, such as those described in Gaggini et al. Bioorg. Med. Chem. 2011, 19 (23), pp. 6989-6999. For example, NOX4 / 1 inhibitors are agents that inhibit ROS production in a cell-free assay using only NOX isoforms NOX4 or NOX1 proteins, such as recombinant protein NOX4 or NOX1 membranes, in a range of about less than 1 μM, such as between about 30 and 300 nM. The term "siRNA" refers to small interfering RNA, which is a double-stranded RNA (about 19 to 23 nucleotides) that can attenuate or silence a targeted mRNA from a target gene. Artificial siRNAs can be chemically synthesized as oligonucleotides or cloned into plasmids or viral vectors (adenovirus, retrovirus or lentivirus) as short hairpin RNAs to produce transient or stable transfections in any type of cell (Martin et al. Ann. Rev. Genomics Hum. Genet. 2007, 8, pp. 81-108; Huang et al. Expert. Opin. Ther. Targets 2008, 12(5), pp. 637-645).

[0016] Unless otherwise specified, the related NOX inhibitors and their pharmaceutically acceptable salts may be referred to herein as "compounds of the invention," and specific compounds are summarized below in sections having the same headings.

[0017] The pharmaceutically acceptable salts mentioned within the scope of the present invention include acid addition salts and base addition salts. Such salts can be formed in a conventional manner, for example, by reacting the free acid or free base form of the compound of the present invention with one or more appropriate acid or base equivalents, optionally in a solvent or in a medium in which the salt is insoluble, followed by standard techniques (e.g., under reduced pressure, by freeze drying or by filtering) to remove the solvent or the medium. Salts can also be prepared by, for example, exchanging the counter ions of the compounds of the present invention in the form of a salt with another counter ion using a suitable ion exchange resin.

[0018] Acid addition salts that may be mentioned include carboxylates (e.g. formates, acetates, trifluoroacetates, propionates, isobutyrates, heptanoates, decanoates, octanoates, stearates, acrylates, caproates, propiolates, ascorbates, citrates, glucuronates, glutamates, glycolates, α-hydroxybutyrates, lactates, tartrates, phenylacetates, mandelates, phenylpropionates, phenylbutyrates, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates, methoxybenzoates, dinitrobenzoates, o-acetoxybenzoates, salicylates, nicotinates, isonicotinates, cinnamates, oxalates, malonates, succinates, salts, such as bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-, 3-bis(2-amino-3-yl)-1-propenesulfonate, bis(2-

[0019] Base addition salts that may be mentioned include salts formed by alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminum hydroxide). More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most particularly, K salts and Na salts.

[0020] Particular pharmaceutically acceptable salts that may be mentioned include base addition salts, such as those formed with alkali metals (for example salts formed with Na or K); and acid addition salts, such as halide salts (for example chloride, bromide or iodide salts) and sulfonates (for example benzenesulfonate, methylbenzenesulfonate, bromobenzenesulfonate or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, isethionate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenedisulfonate).

[0021] In an alternative aspect of the present invention, there is provided a method of treating Alport syndrome, the method comprising administering to a patient in need thereof an effective amount of a NOX inhibitor or a pharmaceutically acceptable salt thereof.

[0022] In another aspect of the present invention, there is provided use of a NOX inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating Alport syndrome.

[0023] Unless defined otherwise, 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.

[0024] Unless the context indicates otherwise, particular features and embodiments described in relation to a given aspect of the invention are considered to be disclosed in combination with any and all other particular features and embodiments of that aspect of the invention.

[0025] It is indicated herein that the compounds of the invention are useful for treating Alport syndrome. One skilled in the art will appreciate that references herein to treatment of a condition (or analogous to "treating" the condition) employ their standard meaning in the medical arts. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition.

[0026] Although the term treatment may also refer herein to "prevention" of a particular condition (and, similarly, to "prevention" or "prophylaxis" of such a condition), both of which are also used in their normal meaning in the art (i.e., achieving a reduction in the likelihood of developing the relevant condition or symptoms associated with the relevant condition), the compounds of the present invention are preferably indicated for the therapeutic treatment of Alport syndrome.

[0027] As used herein, the term "effective amount" will refer to the amount of a compound that confers the desired therapeutic effect on the treated subject (i.e., the desired treatment as described herein). The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the effect and / or feels the effect).

[0028] As used herein, reference to a "patient" shall refer to a living subject, including a mammalian (especially human) patient, to be treated, and thus a "patient" may also be referred to as a "subject," and vice versa. Reference to a "patient" (and thus also to a "subject") shall also be deemed to refer to an individual who does not display symptoms of the relevant condition.

[0029] In a preferred aspect of the present invention, NOX inhibitors are used in combination with angiotensin converting enzyme (ACE) inhibitors or pharmaceutically acceptable salts thereof. The inventors have surprisingly found that in the Alport syndrome mouse model of collagen type IV α3 chain (Col4a3) double gene knockout mice, the combined administration of NOX inhibitors and ACE inhibitors more effectively reduces the ratio of albumin to creatine in mouse urine, and some studies point out the presence of a synergistic effect. In other words, the administration of a single NOX inhibitor and a single ACE inhibitor reduces the ratio of albumin to creatine in mouse urine, but the combined administration of these has a greater than additive effect on reducing the ratio of albumin to creatine. In addition, when observing albumin and urine levels in mice, the results support the following hypothesis: compared with the administration of inhibitors separately from each other, the combination of NOX inhibitors and ACE inhibitors shows a long-term effect in maintaining normal renal function.

[0030] As used herein, the expression "ACE inhibitor" refers to any substance that is capable of completely or partially inhibiting, blocking, attenuating or interfering with angiotensin converting enzyme (ACE). The term may also be defined as a compound that affects the enzyme activity, cellular localization, protein stability, expression of messenger RNA or protein of the enzyme.

[0031] Preferably, an ACE inhibitor should be able to reduce the activity of the enzyme and in particular its 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 fully or partially inhibit the activity of ACE.

[0032] Compared with other ACE proteins, ACE inhibitors have a major ACE inhibitory active component against ACE. For example, ACE inhibitors include small molecules, peptides, peptide mimetics, chimeric proteins, natural or non-natural proteins, nucleic acid-derived polymers (e.g., DNA and RNA aptamers, siRNA, shRNA, PNA or LNA), fusion proteins with ACE antagonistic activity, antibody antagonists, such as neutralizing anti-ACE antibodies, or gene therapy vectors that drive the expression of such ACE antagonists.

[0033] Specific ACE inhibitors used in combination with NOX inhibitors include ramipril, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril and trandolapril. Preferably, the ACE inhibitor used in combination with a NOX inhibitor is ramipril.

[0034] In another aspect of the present invention, a NOX inhibitor is used in combination with an angiotensin-receptor blocker (ARB) or a pharmaceutically acceptable salt thereof.

[0035] In another aspect of the present invention, a NOX inhibitor is used in combination with an ARB or a pharmaceutically acceptable salt thereof and an ACE inhibitor or a pharmaceutically acceptable salt thereof.

[0036] As used herein, the expression "angiotensin-receptor blocker (ARB)" refers to any substance that is capable of fully or partially inhibiting, blocking, attenuating or interfering with angiotensin II receptor type 1 (AT1). The term can be defined as a compound that affects the activity, cellular localization, protein stability and / or expression of messenger RNA or protein of a hormone.

[0037] Preferably, the ARB should be able to block the activation of angiotensin II AT1 to cause vasodilation in the patient, reduce vasopressin secretion in the patient, and / or reduce the production and secretion of aldosterone. Therefore, the term "blocker" is intended to include, but is not limited to, molecules that fully or partially inhibit the activity of angiotensin II receptor type 1.

[0038] Angiotensin-receptor blockers have a primary angiotensin II receptor type 1 inhibitory activity on angiotensin II receptor type 1 as compared to other angiotensin II receptor type 1 proteins. For example, angiotensin-receptor blockers include small molecules, peptides, peptide mimetics, chimeric proteins, natural or non-natural proteins, nucleic acid-derived polymers (e.g., DNA and RNA aptamers, siRNA, shRNA, PNA or LNA), fusion proteins with angiotensin II receptor type 1 antagonist activity, 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.

[0039] Specific angiotensin-receptor blockers used in combination with NOX inhibitors include azilsartan, candesartan, eprosartan, irbesartan, losartan, Olmesartan, telmisartan, and valsartan.

[0040] Compounds of the present invention

[0041] Compounds according to formula (I)

[0042] Specific NOX inhibitors that may be included in the uses of the present invention include NOX inhibitors according to formula (I):

[0043]

[0044] in:

[0045] G 1 Selected from the group consisting of:

[0046] H;

[0047] Optionally substituted alkyl, such as aminocarbonylalkyl (eg, phenylacetamide);

[0048] Optionally substituted C3-C8-cycloalkylalkyl;

[0049] optionally substituted heterocycloalkylalkyl;

[0050] Arylalkyl, for example phenylalkyl, for example phenylmethyl or 3-methylphenylmethyl;

[0051] substituted arylalkyl, for example substituted phenylalkyl, for example substituted phenylmethyl (eg 4-fluorobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 4-bromobenzyl);

[0052] heteroarylalkyl; and

[0053] substituted heteroarylalkyl, for example substituted pyridinylalkyl, for example pyridin-2-ylmethyl;

[0054] G 2 Selected from the group consisting of:

[0055] H;

[0056] optionally substituted alkyl;

[0057] optionally substituted alkenyl;

[0058] optionally substituted alkynyl;

[0059] optionally substituted aryl, for example phenyl (eg, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-chlorophenyl, 2-methylphenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 2,5-difluorophenyl or 2-methoxyphenyl);

[0060] optionally substituted alkylaryl;

[0061] optionally substituted arylalkyl;

[0062] heteroaryl, such as benzothiazolyl or pyridinyl;

[0063] substituted heteroaryl, for example substituted benzothiazolyl (eg 1,3-benzothiazol-2-yl) or substituted pyridinyl (eg pyridin-2-yl);

[0064] optionally substituted alkylheteroaryl;

[0065] optionally substituted heteroarylalkyl;

[0066] optionally substituted alkenylaryl;

[0067] optionally substituted arylalkenyl;

[0068] optionally substituted alkenylheteroaryl;

[0069] optionally substituted heteroarylalkenyl;

[0070] Optionally substituted C3-C8-cycloalkyl;

[0071] optionally substituted heterocycloalkyl;

[0072] Optionally substituted alkyl C3-C8-cycloalkyl;

[0073] Optionally substituted C3-C8-cycloalkylalkyl;

[0074] Optionally substituted alkylheterocycloalkyl; and

[0075] optionally substituted heterocycloalkylalkyl;

[0076] G 3 Selected from the group consisting of:

[0077] H;

[0078] optionally substituted alkyl, such as optionally substituted methyl or optionally substituted ethyl;

[0079] optionally substituted alkenyl;

[0080] optionally substituted alkynyl;

[0081] optionally substituted aryl, for example optionally substituted phenyl;

[0082] optionally substituted alkylaryl;

[0083] optionally substituted arylalkyl;

[0084] optionally substituted heteroaryl;

[0085] optionally substituted alkylheteroaryl;

[0086] optionally substituted heteroarylalkyl;

[0087] optionally substituted alkenylaryl;

[0088] optionally substituted arylalkenyl;

[0089] optionally substituted alkenylheteroaryl;

[0090] optionally substituted heteroarylalkenyl;

[0091] Optionally substituted C3-C8-cycloalkyl;

[0092] optionally substituted heterocycloalkyl;

[0093] Optionally substituted alkyl C3-C8-cycloalkyl;

[0094] Optionally substituted C3-C8-cycloalkylalkyl;

[0095] Optionally substituted alkylheterocycloalkyl; and

[0096] optionally substituted heterocycloalkylalkyl;

[0097] G 4 Selected from the group consisting of:

[0098] H;

[0099] optionally substituted alkyl, such as optionally substituted pentyl (eg, isopentyl);

[0100] optionally substituted heteroalkyl;

[0101] Optionally substituted alkoxy, such as optionally substituted methoxy; (eg 2-methoxyethyl);

[0102] optionally substituted alkenyl;

[0103] optionally substituted alkynyl;

[0104] optionally substituted aryl;

[0105] optionally substituted alkylaryl;

[0106] Arylalkyl, such as benzyl or phenylethyl (eg 2-phenylethyl);

[0107] substituted arylalkyl, for example substituted benzyl (eg benzoic acid methyl) or substituted phenylethyl (eg 4-methoxyphenylethyl);

[0108] optionally substituted heteroaryl;

[0109] optionally substituted alkylheteroaryl;

[0110] optionally substituted heteroarylalkyl, for example optionally substituted thienylalkyl (for example optionally substituted thienylmethyl, for example thien-2-ylmethyl), optionally substituted imidazolylalkyl (for example optionally substituted imidazolylethyl, for example imidazo-4-ylethyl), optionally substituted indolylalkyl (for example optionally substituted indolylethyl, for example indol-3-ylethyl), optionally substituted furanylalkyl (for example optionally substituted furanylmethyl, for example furan-2-ylmethyl), optionally substituted benzodioxolylalkyl (for example optionally substituted benzodioxolylmethyl, for example 1,3-benzodioxol-5-ylmethyl), or optionally substituted pyridinylmethyl (for example pyridin-3-ylmethyl or pyridin-2-ylmethyl);

[0111] optionally substituted alkenylaryl;

[0112] optionally substituted arylalkenyl;

[0113] optionally substituted alkenylheteroaryl;

[0114] optionally substituted heteroarylalkenyl;

[0115] Optionally substituted C3-C8-cycloalkyl;

[0116] heterocycloalkyl, such as morpholinyl (e.g., 5-morpholin-4-yl), piperazinyl (e.g., 4-methylpiperazinyl), or piperidinyl (e.g., 4-methylbenzyl)piperidin-4-yl);

[0117] substituted heterocycloalkyl, such as substituted morpholinyl (e.g. 5-morpholin-4-yl), substituted piperazinyl (e.g. 4-methylpiperazinyl) or substituted piperidinyl (e.g. 4-methylbenzyl)piperidin-4-yl);

[0118] Optionally substituted alkyl C3-C8-cycloalkyl;

[0119] Optionally substituted C3-C8-cycloalkylalkyl;

[0120] optionally substituted alkylheterocycloalkyl;

[0121] heterocycloalkylalkyl, for example morpholinylalkyl (for example morpholinylethyl or morpholinylpropyl, in particular 2-morpholin-4-yl-ethyl or 3-(morpholin-4-yl)propyl), piperazinylalkyl (for example piperazinylethyl, for example 2-(4-acetylpiperazin-1-yl)ethyl or 2-(4-hexanoylpiperazin-1-yl)ethyl), or pyrrolidinylalkyl (for example pyrrolidinylpropyl, for example 3-(2-oxopyrrolidin-1-yl)propyl), or tetrahydrofuranylalkyl (for example tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl); and

[0122] substituted heterocycloalkylalkyl, for example 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, for example substituted 2-(4-acetylpiperazin-1-yl)ethyl or substituted 2-(4-hexanoylpiperazin-1-yl)ethyl), or substituted pyrrolidinylalkyl (e.g. substituted pyrrolidinylpropyl, for example substituted 3-(2-oxopyrrolidin-1-yl)propyl), or substituted tetrahydrofuranylalkyl (e.g. substituted tetrahydrofuranylmethyl, for example substituted tetrahydrofuran-2-ylmethyl);

[0123] G 5 Selected from the group consisting of:

[0124] H;

[0125] optionally substituted alkyl;

[0126] optionally substituted alkenyl;

[0127] optionally substituted alkynyl;

[0128] optionally substituted aryl;

[0129] optionally substituted alkylaryl;

[0130] optionally substituted arylalkyl;

[0131] optionally substituted heteroaryl;

[0132] optionally substituted alkylheteroaryl;

[0133] optionally substituted heteroarylalkyl;

[0134] optionally substituted alkenylaryl;

[0135] optionally substituted arylalkenyl;

[0136] optionally substituted alkenylheteroaryl;

[0137] optionally substituted heteroarylalkenyl;

[0138] Optionally substituted C3-C8-cycloalkyl;

[0139] optionally substituted heterocycloalkyl;

[0140] Optionally substituted alkyl C3-C8-cycloalkyl;

[0141] Optionally substituted C3-C8-cycloalkylalkyl;

[0142] Optionally substituted alkylheterocycloalkyl; and

[0143] optionally substituted heterocycloalkylalkyl;

[0144] and pharmaceutically acceptable salts thereof.

[0145] Compounds according to formula (II)

[0146] Other NOX inhibitors that may be included in the use of the present invention include NOX inhibitors according to formula (II):

[0147]

[0148] in:

[0149] Ar 1 Select from the list consisting of:

[0150] Phenyl;

[0151] Phenyl substituted with halogen such as chlorine (for example, wherein Ar 1 is 2-chlorophenyl); and

[0152] Phenyl substituted with an alkoxy group such as methoxy

[0153] G 1 and G 5 is H;

[0154] G 3 Select from the list consisting of:

[0155] Optionally substituted C1-C6 alkyl, for example optionally substituted methyl;

[0156] Phenyl;

[0157] phenyl substituted by halogen, amino, alkylamino or alkoxy, for example, wherein the phenyl is 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 3-dimethylaminophenyl, 2-tri-methylaminophenyl, 3-methylaminophenyl, 3-aminophenyl or 4-methoxyphenyl;

[0158] G 4 Select from the list consisting of:

[0159] H;

[0160] C1-C6 alkyl, such as methyl,

[0161] Substituted C1-C6 alkyl, such as substituted methyl, optionally wherein the C1-C6 alkyl is substituted with alkoxy, for example wherein the substituted C1-C6 alkyl is methoxyethyl, such as 2-methoxyethyl;

[0162] heteroaryl C1-C6alkyl, for example pyridyl C1-C6alkyl (for example pyridylmethyl, especially pyridyl-2-ylmethyl, pyridyl-3-ylmethyl, 6-methoxypyridin-3-ylmethyl, 2-methoxypyridin-4-ylmethyl) or pyrazinyl C1-C6alkyl, for example pyrazin-2-ylmethyl;

[0163] Substituted heteroaryl C1-C6 alkyl, for example substituted pyridyl C1-C6 alkyl (for example substituted pyridylmethyl, in particular substituted pyridyl-2-ylmethyl, substituted pyridyl-3-ylmethyl, substituted 6-methoxypyridin-3-ylmethyl, substituted 2-methoxypyridin-4-ylmethyl) or substituted pyrazinyl C1-C6 alkyl, for example substituted pyrazin-2-ylmethyl;

[0164] Alkoxy C1-C6 alkyl, such as methoxyethyl (eg 2-methoxyethyl); and

[0165] Substituted C1-C6 alkyl, such as substituted methoxyethyl (such as substituted 2-methoxyethyl)

[0166] or G 3 and G 4 together form an optionally substituted 7-membered heterocycloalkyl ring comprising two nitrogen atoms, and wherein the two nitrogens are linked via an optionally substituted C1-C3 alkyl moiety,

[0167] and tautomers, geometric isomers, optically active forms and pharmaceutically acceptable salts thereof.

[0168] Compounds according to formula (III)

[0169] Other NOX inhibitors that may be included in the use of the present invention include NOX inhibitors according to formula (III):

[0170]

[0171] in:

[0172] Ar 1 , G 1 and G 5 As defined above for compound (I) or compound (II);

[0173] G 6 Selected from the group consisting of:

[0174] C1-C6 alkyl;

[0175] Substituted C1-C6 alkyl;

[0176] Aryl C1-C6 alkyl, for example benzyl;

[0177] Substituted aryl C1-C6 alkyl, for example substituted phenyl C1-C6 alkyl, for example 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl;

[0178] heteroaryl C1-C6 alkyl, for example pyridyl C1-C6 alkyl, for example pyridylmethyl (for example pyridyl-2-ylmethyl or pyridyl-3-ylmethyl) or furanyl C1-C6 alkyl, for example furanylmethyl (for example furan-3-ylmethyl);

[0179] Substituted heteroaryl C1-C6 alkyl, for example substituted pyridyl C1-C6 alkyl, for example substituted pyridylmethyl (for example substituted pyridyl-2-ylmethyl or substituted pyridyl-3-ylmethyl) or substituted furanyl C1-C6 alkyl, for example substituted furanylmethyl (for example substituted furan-3-ylmethyl);

[0180] and tautomers, geometric isomers, optically active forms and pharmaceutically acceptable salts and / or derivatives thereof.

[0181] Compounds according to formula (IV)

[0182] Alternative NOX inhibitors that may be included in the use of the present invention include NOX inhibitors according to formula (IV):

[0183]

[0184] in:

[0185] A 1 , A 2 and A 3 independently selected from the list consisting of: hydrogen;

[0186] halogen;

[0187] CN;

[0188] CF3;

[0189] CHF2;

[0190] Optionally substituted C1-C6 alkyl;

[0191] Optionally substituted C3-C8 cycloalkyl;

[0192] optionally substituted heteroalkyl;

[0193] optionally substituted heterocycloalkyl;

[0194] optionally substituted alkoxy;

[0195] an optionally substituted amino group;

[0196] optionally substituted carboxyl; and

[0197] optionally substituted alkoxycarbonyl; and R i Selected from the group consisting of:

[0198] hydrogen;

[0199] halogen;

[0200] CN;

[0201] CF3;

[0202] CHF2;

[0203] Optionally substituted C1-C6 alkyl;

[0204] Optionally substituted C3-C8 cycloalkyl;

[0205] optionally substituted heteroalkyl;

[0206] Optionally substituted heterocycloalkyl; and

[0207] optionally substituted carboxyl;

[0208] R ii Select from the list consisting of:

[0209] hydrogen;

[0210] Optionally substituted C1-C6 alkyl;

[0211] C3-C8 cycloalkyl;

[0212] Optionally substituted haloC1-C6 alkyl;

[0213] Optionally substituted haloC3-C8 cycloalkyl;

[0214] Optionally substituted aryl C1-C6 alkyl;

[0215] Optionally substituted heteroaryl C1-C6 alkyl;

[0216] optionally substituted heteroalkyl;

[0217] optionally substituted heterocycloalkyl;

[0218] substituted heterocycloalkyl;

[0219] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0220] Optionally substituted hydroxy C1-C6 alkyl;

[0221] Optionally substituted alkoxy C1-C6 alkyl;

[0222] Optionally substituted alkoxycarbonyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl;

[0223] Optionally substituted aryl C3-C8 cycloalkyl;

[0224] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0225] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0226] Optionally substituted amino C3-C8 cycloalkyl; and optionally substituted halo C3-C8 cycloalkyl;

[0227] Ar 3 Selected from:

[0228]

[0229] R 1 and R 4 independently selected from the list consisting of: hydrogen;

[0230] halogen;

[0231] CN;

[0232] CF3;

[0233] CHF2;

[0234] NH2;

[0235] Optionally substituted C1-C6 alkyl;

[0236] Optionally substituted C3-C8 cycloalkyl;

[0237] Alkoxy;

[0238] Amino;

[0239] optionally substituted heterocycloalkyl;

[0240] carboxyl;

[0241] Optionally substituted alkoxy C1-C6 alkyl;

[0242] Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C1-C6 alkyl;

[0243] Optionally substituted aminoC3-C8cycloalkyl;

[0244] Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; and Optionally substituted aminocarbonyl C1-C6 alkyl;

[0245] R 2 Select from the list consisting of:

[0246] hydrogen;

[0247] halogen;

[0248] CF3;

[0249] CHF2;

[0250] NH2;

[0251] Optionally substituted C1-C6 alkyl;

[0252] Optionally substituted C3-C8 cycloalkyl;

[0253] optionally substituted alkoxy;

[0254] Amino;

[0255] optionally substituted heterocycloalkyl;

[0256] carboxyl;

[0257] Optionally substituted alkoxy C1-C6 alkyl;

[0258] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0259] Optionally substituted amino C1-C6 alkyl;

[0260] Optionally substituted aminoC3-C8cycloalkyl;

[0261] Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted C3-C8 carboxycycloalkyl; and Optionally substituted aminocarbonyl C1-C6 alkyl;

[0262] R 3 Select from the list consisting of:

[0263] hydrogen;

[0264] halogen;

[0265] CF3;

[0266] CHF2;

[0267] NH2;

[0268] Optionally substituted C1-C6 alkyl;

[0269] Optionally substituted C3-C8 cycloalkyl;

[0270] optionally substituted alkoxy;

[0271] Amino;

[0272] optionally substituted heterocycloalkyl;

[0273] carboxyl;

[0274] Optionally substituted alkoxy C1-C6 alkyl;

[0275] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0276] Optionally substituted amino C1-C6 alkyl;

[0277] Optionally substituted aminoC3-C8cycloalkyl;

[0278] Optionally substituted aminoheterocycloalkyl C1-C6 alkyl;

[0279] Optionally substituted C3-C8 carboxycycloalkyl; and

[0280] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0281] R 5 Selected from the group consisting of:

[0282] hydrogen;

[0283] halogen;

[0284] CF3;

[0285] CHF2;

[0286] NH2;

[0287] Optionally substituted C1-C6 alkyl;

[0288] Optionally substituted C3-C8 cycloalkyl;

[0289] optionally substituted alkoxy;

[0290] Amino;

[0291] optionally substituted heterocycloalkyl;

[0292] carboxyl;

[0293] Optionally substituted alkoxy C1-C6 alkyl;

[0294] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0295] Optionally substituted amino C1-C6 alkyl;

[0296] Optionally substituted aminoC3-C8cycloalkyl;

[0297] Optionally substituted aminoheterocycloalkyl C1-C6 alkyl;

[0298] Optionally substituted C3-C8 carboxycycloalkyl; and

[0299] optionally substituted aminocarbonyl C1-C6 alkyl,

[0300] When R 1 , R 2 , R 3 and R 4 When one of the groups is not H, the other of the group is H or R 1 , R 2 , R 3 , R 4 and R 5 Any of can be linked together to form an optionally substituted bicyclic heteroaryl;

[0301] Ar 3 Also selected from optionally substituted bicyclic heteroaryl, in particular selected from the group consisting of:

[0302]

[0303] Where R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 each independently selected from the list consisting of: hydrogen;

[0304] halogen;

[0305] Hydroxyl;

[0306] CN;

[0307] CF3;

[0308] CHF2;

[0309] NH2;

[0310] Alkoxy;

[0311] Amino;

[0312] carboxyl;

[0313] aminocarbonyl;

[0314] Alkoxycarbonyl;

[0315] Optionally substituted C1-C6 alkyl;

[0316] Optionally substituted C3-C8 cycloalkyl;

[0317] optionally substituted haloalkyl;

[0318] optionally substituted heteroalkyl;

[0319] optionally substituted heterocycloalkyl;

[0320] optionally substituted aryl;

[0321] optionally substituted heteroaryl;

[0322] Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0323] Optionally substituted aryl C1-C6 alkyl;

[0324] Optionally substituted heteroaryl C1-C6 alkyl;

[0325] Optionally substituted alkoxy C1-C6 alkyl;

[0326] Optionally substituted amino C1-C6 alkyl;

[0327] Optionally substituted carboxyl C1-C6 alkyl;

[0328] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0329] Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl;

[0330] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0331] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0332] Optionally substituted aminoC3-C8cycloalkyl;

[0333] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0334] Optionally substituted aminocarbonyl C3-C8 cycloalkyl; acylamino;

[0335] Urea group;

[0336] Sulfonyl; and

[0337] Sulfonylamino;

[0338] R 14 Select from the list consisting of:

[0339] hydrogen;

[0340] aminocarbonyl;

[0341] Alkoxycarbonyl;

[0342] Optionally substituted C1-C6 alkyl;

[0343] Optionally substituted C3-C8 cycloalkyl;

[0344] optionally substituted haloalkyl;

[0345] optionally substituted heteroalkyl;

[0346] optionally substituted heterocycloalkyl;

[0347] optionally substituted aryl;

[0348] optionally substituted heteroaryl;

[0349] Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0350] Optionally substituted aryl C1-C6 alkyl;

[0351] Optionally substituted heteroaryl C1-C6 alkyl;

[0352] Optionally substituted alkoxy C1-C6 alkyl;

[0353] Optionally substituted amino C1-C6 alkyl,

[0354] Carboxyl C1-C6 alkyl;

[0355] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0356] Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; aryl C3-C8 cycloalkyl;

[0357] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0358] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0359] Optionally substituted aminoC3-C8cycloalkyl;

[0360] Optionally substituted carboxyl C3-C8 cycloalkyl, and optionally substituted aminocarbonyl C3-C8 cycloalkyl; Ar 2 Selected from the following groups:

[0361]

[0362]

[0363] Where R 15 , R 16 and R 19 independently selected from the list consisting of: hydrogen;

[0364] halogen;

[0365] Hydroxyl;

[0366] CN;

[0367] CF3;

[0368] CHF2;

[0369] NH2;

[0370] Alkoxy;

[0371] Amino;

[0372] carboxyl;

[0373] aminocarbonyl;

[0374] Alkoxycarbonyl;

[0375] Optionally substituted C1-C6 alkyl;

[0376] Optionally substituted C3-C8 cycloalkyl;

[0377] optionally substituted alkenyl;

[0378] Alkynyl;

[0379] optionally substituted haloalkyl;

[0380] optionally substituted heteroalkyl;

[0381] optionally substituted heterocycloalkyl;

[0382] optionally substituted aryl;

[0383] optionally substituted heteroaryl;

[0384] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0385] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0386] Optionally substituted aryl C1-C6 alkyl;

[0387] Optionally substituted heteroaryl C1-C6 alkyl;

[0388] Optionally substituted alkoxy C1-C6 alkyl;

[0389] Optionally substituted amino C1-C6 alkyl;

[0390] Optionally substituted carboxyl C1-C6 alkyl;

[0391] Aminocarbonyl C1-C6 alkyl;

[0392] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0393] Optionally substituted aryl C3-C8 cycloalkyl;

[0394] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0395] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0396] Optionally substituted aminoC3-C8cycloalkyl;

[0397] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0398] Optionally substituted aminocarbonyl C3-C8 cycloalkyl;

[0399] Acylamino;

[0400] urea groups; and

[0401] sulfonyl; or

[0402] Where R 15 , R 16 and R 19 They may also be independently selected from the following groups:

[0403]

[0404] wherein y, w, z and t are independently: an integer in the range of 1 to 3;

[0405] Wherein h is: an integer in the range of 0 to 3;

[0406] Where n is: an integer in the range of 0 to 4;

[0407] Wherein G is selected from the list consisting of: NR 23 ;

[0408] O;

[0409] S; and

[0410] SO2;

[0411] wherein J is selected from the list consisting of: C(B)n; and

[0412] NR 23 ;

[0413] wherein L is selected from the list consisting of: C-(B)n;

[0414] NR 23 ;

[0415] O;

[0416] S; and

[0417] SO2;

[0418] Where R 23 Select from the list consisting of:

[0419] hydrogen;

[0420] aminocarbonyl;

[0421] Alkoxycarbonyl;

[0422] Optionally substituted C1-C6 alkyl;

[0423] Optionally substituted C3-C8 cycloalkyl;

[0424] optionally substituted haloalkyl;

[0425] optionally substituted heteroalkyl;

[0426] optionally substituted heterocycloalkyl;

[0427] optionally substituted aryl;

[0428] optionally substituted heteroaryl;

[0429] C3-C8 cycloalkylC1-C6 alkyl;

[0430] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0431] Optionally substituted aryl C1-C6 alkyl;

[0432] Optionally substituted heteroaryl C1-C6 alkyl;

[0433] Alkoxy C1-C6 alkyl;

[0434] Optionally substituted amino C1-C6 alkyl;

[0435] Optionally substituted carboxyl C1-C6 alkyl;

[0436] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0437] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0438] Optionally substituted aryl C3-C8 cycloalkyl;

[0439] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0440] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0441] Optionally substituted aminoC3-C8cycloalkyl;

[0442] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0443] Optionally substituted aminocarbonyl C3-C8 cycloalkyl; and aminosulfonyl;

[0444] Wherein B is selected from the group consisting of:

[0445] hydrogen;

[0446] halogen;

[0447] Hydroxyl;

[0448] CN;

[0449] CF3;

[0450] CHF2;

[0451] NH2;

[0452] Alkoxy;

[0453] Amino;

[0454] carboxyl;

[0455] aminocarbonyl;

[0456] Alkoxycarbonyl;

[0457] Optionally substituted C1-C6 alkyl;

[0458] Optionally substituted C3-C8 cycloalkyl;

[0459] optionally substituted haloalkyl;

[0460] optionally substituted heteroalkyl;

[0461] optionally substituted heterocycloalkyl;

[0462] optionally substituted aryl;

[0463] optionally substituted heteroaryl;

[0464] Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0465] Optionally substituted aryl C1-C6 alkyl;

[0466] Optionally substituted heteroaryl C1-C6 alkyl;

[0467] Optionally substituted alkoxy C1-C6 alkyl;

[0468] Optionally substituted amino C1-C6 alkyl;

[0469] Optionally substituted carboxyl C1-C6 alkyl;

[0470] Aminocarbonyl C1-C6 alkyl;

[0471] Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl;

[0472] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0473] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0474] Optionally substituted aminoC3-C8cycloalkyl;

[0475] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0476] Optionally substituted aminocarbonyl C3-C8 cycloalkyl; acylamino;

[0477] Urea group;

[0478] Sulfonyl; and

[0479] Sulfonylamino;

[0480] Where R 17 and R 18 independently selected from the list consisting of: hydrogen;

[0481] halogen;

[0482] CN;

[0483] CF3;

[0484] CHF2;

[0485] Alkoxy;

[0486] Amino;

[0487] Optionally substituted C1-C6 alkyl;

[0488] Optionally substituted C3-C8 cycloalkyl;

[0489] optionally substituted haloalkyl;

[0490] optionally substituted heteroalkyl;

[0491] optionally substituted heterocycloalkyl;

[0492] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0493] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0494] Optionally substituted alkoxy C1-C6 alkyl;

[0495] Optionally substituted amino C1-C6 alkyl;

[0496] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0497] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0498] Optionally substituted aminoC3-C8cycloalkyl;

[0499] Acylamino;

[0500] Urea group;

[0501] Sulfonyl;

[0502] aminosulfonyl; and

[0503] Sulfonylamino;

[0504] Where R 20 and R 22 independently selected from the list consisting of: hydrogen;

[0505] halogen;

[0506] CN;

[0507] CF3;

[0508] CHF2;

[0509] Alkoxy;

[0510] Amino;

[0511] Optionally substituted C1-C6 alkyl;

[0512] Optionally substituted C3-C8 cycloalkyl;

[0513] optionally substituted haloalkyl;

[0514] optionally substituted heteroalkyl;

[0515] optionally substituted heterocycloalkyl;

[0516] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0517] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0518] Optionally substituted alkoxy C1-C6 alkyl;

[0519] Optionally substituted amino C1-C6 alkyl;

[0520] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0521] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0522] and optionally substituted aminoC3-C8cycloalkyl;

[0523] Where R 21 Select from the list consisting of:

[0524] hydrogen;

[0525] aminocarbonyl;

[0526] Alkoxycarbonyl;

[0527] Optionally substituted C1-C6 alkyl;

[0528] Optionally substituted C3-C8 cycloalkyl;

[0529] optionally substituted haloalkyl;

[0530] optionally substituted heteroalkyl;

[0531] Heterocycloalkyl;

[0532] optionally substituted aryl;

[0533] optionally substituted heteroaryl;

[0534] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0535] Optionally substituted heterocycloalkyl C1-C6 alkylaryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl;

[0536] Optionally substituted alkoxy C1-C6 alkyl;

[0537] Optionally substituted amino C1-C6 alkyl;

[0538] Optionally substituted carboxyl C1-C6 alkyl;

[0539] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0540] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0541] Optionally substituted aryl C3-C8 cycloalkyl;

[0542] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0543] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0544] Optionally substituted aminoC3-C8cycloalkyl;

[0545] Optionally substituted carboxyl C3-C8 cycloalkyl; and

[0546] Optionally substituted aminocarbonyl C3-C8 cycloalkyl;

[0547] Where R 15 and R 16 may be linked together to form an optionally substituted bicyclic heteroaryl group having the formula:

[0548]

[0549] wherein X, Y and Z are each independently selected from the list consisting of:

[0550] C(R 24 R 25 );

[0551] CH2C(R 24 R 25 );

[0552] C(=O);

[0553] O; and

[0554] NR 26 ;

[0555] Where R 24 and R25 Each independently selected from the list consisting of:

[0556] hydrogen;

[0557] halogen;

[0558] Hydroxyl;

[0559] CN;

[0560] CF3;

[0561] CHF2;

[0562] NH2;

[0563] Alkoxy;

[0564] Amino;

[0565] carboxyl;

[0566] aminocarbonyl;

[0567] Alkoxycarbonyl;

[0568] Optionally substituted C1-C6 alkyl;

[0569] Optionally substituted C3-C8 cycloalkyl;

[0570] optionally substituted haloalkyl;

[0571] optionally substituted heteroalkyl;

[0572] optionally substituted heterocycloalkyl;

[0573] optionally substituted aryl;

[0574] optionally substituted heteroaryl;

[0575] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0576] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0577] Optionally substituted aryl C1-C6 alkyl;

[0578] Optionally substituted heteroaryl C1-C6 alkyl;

[0579] Optionally substituted alkoxy C1-C6 alkyl;

[0580] Optionally substituted amino C1-C6 alkyl;

[0581] Optionally substituted carboxyl C1-C6 alkyl;

[0582] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0583] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0584] Optionally substituted aryl C3-C8 cycloalkyl;

[0585] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0586] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0587] Optionally substituted aminoC3-C8cycloalkyl;

[0588] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0589] Optionally substituted aminocarbonyl C3-C8 cycloalkyl;

[0590] Acylamino;

[0591] Urea group;

[0592] Sulfonyl; and

[0593] Sulfonylamino;

[0594] Where R 24 and R 25 can be linked together to form an optionally substituted C 3- C8 cycloalkyl or optionally substituted heterocycloalkyl;

[0595] Where R 26 Selected from the group consisting of:

[0596] hydrogen;

[0597] aminocarbonyl;

[0598] Alkoxycarbonyl;

[0599] Optionally substituted C1-C6 alkyl;

[0600] Optionally substituted C3-C8 cycloalkyl;

[0601] optionally substituted haloalkyl;

[0602] optionally substituted heteroalkyl;

[0603] optionally substituted heterocycloalkyl;

[0604] optionally substituted aryl;

[0605] optionally substituted heteroaryl;

[0606] Optionally substituted C3-C8 cycloalkylC1-C6 alkyl;

[0607] Optionally substituted heterocycloalkyl C1-C6 alkyl;

[0608] Optionally substituted aryl C1-C6 alkyl;

[0609] Optionally substituted heteroaryl C1-C6 alkyl;

[0610] Optionally substituted alkoxy C1-C6 alkyl;

[0611] Amino C1-C6 alkyl;

[0612] Optionally substituted carboxyl C1-C6 alkyl;

[0613] Optionally substituted aminocarbonyl C1-C6 alkyl;

[0614] Optionally substituted heterocycloalkyl C3-C8cycloalkyl;

[0615] Optionally substituted aryl C3-C8 cycloalkyl;

[0616] Optionally substituted heteroaryl C3-C8 cycloalkyl;

[0617] Optionally substituted alkoxy C3-C8 cycloalkyl;

[0618] Optionally substituted aminoC3-C8cycloalkyl;

[0619] Optionally substituted carboxyl C3-C8 cycloalkyl;

[0620] Optionally substituted aminocarbonyl C3-C8 cycloalkyl; and

[0621] aminosulfonyl;

[0622] Where R 15 and R 19 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 15 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 17 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 20 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; and tautomers, geometric isomers, optically active forms, and pharmaceutically acceptable salts thereof.

[0623] In a particular embodiment, the compound according to formula (IV) is a compound of formula (IVa):

[0624]

[0625] Among them, Ar 2 ,Ar 3 , R i ; R ii , A 1 and A 2 As defined above, wherein at least one of A1 and A2 is not H. In a particular embodiment, the compound according to formula (IV) is a compound according to formula (IVb):

[0626]

[0627] Among them, Ar 2 ,Ar 3 , R ii , A 1 and A 2 As defined above.

[0628] In a particular embodiment, the compound according to formula (IV) is a compound of formula (IVc):

[0629]

[0630] Among them, Ar 2 ,Ar 3 , R ii and A 2 As defined above.

[0631] Compounds according to formula (V)

[0632] Alternative NOX inhibitors that may be included in the use of the present invention include NOX inhibitors according to formula (V):

[0633]

[0634] in:

[0635] X i Selected by CR 27 and N are a list;

[0636] Y i selected from the list consisting of CH and N;

[0637] A4 is selected from the list consisting of:

[0638] -OCHR 31 -;

[0639] -NR 30 -CHR 31 -;

[0640] -CH2NR 30 -;as well as

[0641] -CH2-O-;

[0642] Where R 27 Select from the list consisting of:

[0643] H;

[0644] halogen;

[0645] and optionally substituted C1-C6 alkyl;

[0646] Where R 28 Select from the list consisting of:

[0647] H;

[0648] Halogens (e.g. chlorine, fluorine);

[0649] optionally substituted alkoxy, for example 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);

[0650] Optionally substituted alkoxy C1-C6 alkyl;

[0651] Optionally substituted C1-C6 alkyl, for example optionally substituted methyl;

[0652] Optionally substituted amino, for example optionally substituted C1-C6 alkylamino (for example 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);

[0653] Optionally substituted heterocycloalkyl, for example optionally substituted piperazine (eg methylpiperazin-1-yl);

[0654] Optionally substituted C1-C6 alkylheterocycloalkyl, for example optionally substituted C1-C6 alkylpiperazine (eg methylpiperazin-1-yl);

[0655] Optionally substituted amino C1-C6 alkyl;

[0656] Optionally substituted alkoxy C1-C6 alkyl;

[0657] -OR 34 ;as well as

[0658] -NR 35 R 36 ;

[0659] Where R 29 The formula is -(CHR 32 )n-A5; or

[0660] R 29 With part of the CHR from A4 31 The optionally substituted aryl radicals form an optionally substituted ring selected from the group consisting of optionally substituted aryl radicals, such as optionally substituted phenyl radicals (e.g., phenyl radicals or phenyl radicals substituted with halogen radicals, such as fluoro radicals, phenyl radicals substituted with alkoxy radicals, such as methoxy radicals), and optionally substituted heteroaryl radicals, such as optionally substituted 1,3-dihydro-1H-indenyl radicals (e.g., 1-(dimethylamino)-2,3-dihydro-1H-inden-2-yl radicals, 2,3-dihydro-1H-inden-2-yl radicals, 2,3-dihydro-1H-inden-1-yl radicals), or optionally substituted 6,7-dihydro-5H-cyclopentapyridinyl radicals (e.g., 6,7-dihydro-5H-cyclopentapyridinyl radicals [b]pyridin-5-yl radicals, 2-methylpyridin- or optionally substituted 1,2,3,4-tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydronaphthyl) 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); or

[0661] R 29 With some NR from A4 30 forming an optionally substituted ring selected from the list consisting of optionally substituted aryl and optionally substituted heteroaryl, such as optionally substituted isoindolyl (e.g., isoindolin-2-yl, 1H-indol-1-yl);

[0662] wherein n is an integer from 0 to 4 (e.g., 0, 1, 2, 3 or 4);

[0663] Where R 30 is selected from H and optionally substituted alkyl, such as optionally substituted methyl;

[0664] wherein A5 is an optionally substituted ring selected from 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. pyrimidinyl-2-yl);

[0665] Where R 31 Select from the list consisting of:

[0666] Η;

[0667] Optionally substituted C1-C6 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-propanol, hydroxyisopropyl);

[0668] Optionally substituted aminoC1-C6 alkyl, for example optionally substituted aminomethyl (eg dimethylaminomethyl, methylaminomethyl);

[0669] Optionally substituted alkoxy C1-C6 alkyl;

[0670] Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylmethyl, for example optionally substituted pyrrolidine C1-C6 alkyl (for example 3,3-difluoropyrrolidin-1-ylmethyl) or substituted piperazine C1-C6 alkyl (for example 4-methylpiperazin-1-ylmethyl) or heterocycloalkylethyl, for example optionally substituted morpholino C1-C6 alkyl (for example morpholinomethyl, morpholinoethyl) or optionally substituted pyrrolidine C1-C6 alkyl (for example pyrrolidinemethyl, pyrrolidineethyl);

[0671] Optionally substituted aminocarbonyl (eg dimethylaminocarbonyl);

[0672] Optionally substituted C2-C8 cycloalkyl, such as optionally substituted cyclopropyl; and

[0673] Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (eg dimethylaminoethyl) or optionally substituted aminomethyl (eg dimethylaminomethyl);

[0674] R 32 Select from the list consisting of:

[0675] Η;

[0676] Optionally substituted C1-C6 alkyl, for example optionally substituted methyl;

[0677] an optionally substituted amino group;

[0678] Optionally substituted C1-C6 alkylamino (eg, dimethylamino); and

[0679] hydroxyl group; and

[0680] For each repeating unit (CHR 32 ), R 32 The groups are independently selected;

[0681] Where R 33 Select from the list consisting of:

[0682] H;

[0683] Halogens (such as fluorine); and

[0684] Optionally substituted C1-C6 alkyl, for example methyl;

[0685] Where R 34 Selected from the group consisting of:

[0686] H;

[0687] Optionally substituted C1-C6 alkyl, for example optionally substituted methyl or optionally substituted ethyl (eg methoxyethyl, 2-(dimethylamino)ethyl, hydroxyethyl);

[0688] Optionally substituted amino C1-C6 alkyl;

[0689] optionally substituted heterocycloalkyl;

[0690] Optionally substituted C2-C8 cycloalkyl;

[0691] Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylmethyl, for example optionally substituted tetrahydropyranyl C1-C6 alkyl (for example tetrahydro-2H-pyran-4-yl) or optionally substituted piperidinylalkyl (for example 1-methylpiperidin-4-yl);

[0692] Optionally substituted C2-C8 cycloalkylC1-C6 alkyl;

[0693] optionally substituted alkoxy;

[0694] Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (eg 2-(dimethylamino)ethyl);

[0695] Optionally substituted aryl C1-C6 alkyl; and

[0696] Optionally substituted heteroaryl C1-C6 alkyl;

[0697] R 35 and R 36 Independently selected from the list consisting of:

[0698] H;

[0699] Optionally substituted C1-C6 alkyl, for example optionally substituted methyl (for example (1-methyl-1H-imidazol-4-yl)methyl) or optionally substituted ethyl (for example 2-methoxyethyl);

[0700] Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (for example dimethylaminoethyl) or for example optionally substituted aminopropyl (for example dimethylamino)propyl);

[0701] optionally substituted heterocycloalkyl, such as optionally substituted piperidine (eg 1-methylpiperidine);

[0702] Optionally substituted C2-C8 cycloalkyl;

[0703] Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylethyl, for example optionally substituted morpholino C1-C6 alkyl (for example 2-morpholinoethyl) or optionally substituted heterocycloalkylmethyl, for example optionally substituted tetrahydrofuran C1-C6 alkyl (for example tetrahydro-2H-pyran-4-ylmethyl) or piperidine C1-C6 alkyl (for example 1-methylpiperidin-4-yl)methyl or optionally substituted imidazolyl C1-C6 alkyl (for example (1-methyl-1H-imidazol-4-yl)methyl) optionally substituted C2-C8 cycloalkyl C1-C6 alkyl;

[0704] optionally substituted alkoxy;

[0705] Optionally substituted alkoxy C1-C6 alkyl, for example optionally substituted alkoxyethyl (eg 2-methoxyethyl);

[0706] Optionally substituted aryl C1-C6 alkyl; and

[0707] Optionally substituted heteroaryl C1-C6 alkyl, for example heteroaryl C1-C6 alkylmethyl, for example optionally substituted imidazolyl C1-C6 alkyl (for example 1-methyl-1H-imidazol-4-ylmethyl), optionally substituted amino C1-C6 alkyl, for example optionally substituted aminoethyl or optionally substituted aminopropyl (for example 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl)); and tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts and pharmaceutically active derivatives thereof.

[0708] Other compounds

[0709] In one aspect of the invention, the compounds of the invention may form compounds incorporated herein by reference, such as those described in WO 2017 / 192304, WO 2016 / 207785, WO 2019 / 215291 or WO 2018 / 203298.

[0710] Substituent Definition

[0711] For the avoidance of doubt, the compound of the present invention can exist in solid form, and therefore the scope of the present invention includes all amorphous, crystallized and partially crystalline forms thereof. When the compound of the present invention exists in crystallized and partially crystalline forms, such forms may include solvates, which are included in the scope of the present invention. The compound of the present invention may also be present in a solution.

[0712] The present invention also encompasses isotopically labeled compounds of the present invention, which are identical but in fact have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are encompassed within the scope of the compounds of the present invention. Thus, reference to compounds of the present invention also includes deuterated compounds, i.e., compounds in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0713] The term "alkyl" when used alone or in combination with other terms includes straight or branched C1-C 20Alkyl refers to a monovalent alkyl group having 1 to 20 carbon atoms. This term is exemplified by the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-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 and n-eicosyl. Preferably, the term "alkyl" refers to a C1-C9 alkyl group, more preferably a C1-C6 alkyl group, particularly preferably a C1-C4 alkyl group, and so on, which respectively 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.

[0714] The term "alkenyl" when used alone or in combination with other terms includes straight or branched C2-C 20 Alkenyl. It can have any available number of double bonds in any available position, and the configuration of the double bonds can be (E) or (Z) configuration. This term is exemplified by the following groups, for example: 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-eicosene and 3,7,11,15-tetramethyl-1-hexadecenyl, etc. Preferably, the term "alkenyl" refers to C2-C8 alkenyl, more preferably C2-C6 alkenyl. Particularly preferred are vinyl (vinyl or ethenyl) (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2), isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and 3-methyl-2-butenyl.

[0715] The term "alkynyl" when used alone or in combination with other terms includes straight or branched C2-C 20Alkynyl. It can have any available number of triple bonds in any available position. This term is exemplified by, for example, an alkynyl group, which can have a carbon number of 2 to 20 and optionally has a double bond, such as ethynyl (-C≡CH), 1-propynyl, 2-propynyl (propargyl:-CH2C≡CH), 2-butynyl and 2-pentene-4-ynyl. Specifically, it includes C2-C8 alkynyl, and more preferably C2-C6 alkynyl. Preferably, the group includes C2-C6 alkynyl, which refers to a group having 2 to 6 carbon atoms and having at least 1 or 2 alkynyl unsaturated sites.

[0716] The term "heteroalkyl" refers to a C1-C 12 -alkyl, preferably C1-C6-alkyl, in which at least one carbon has been replaced by a heteroatom selected from O, N or S. A particularly preferred heteroalkyl is 2-methoxyethyl.

[0717] The term "aryl" refers to an unsaturated aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, indenyl, naphthyl), and includes phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0718] The term "C1-C6 alkylaryl" refers to an aryl group having a C1-C6 alkyl substituent, including methylphenyl and ethylphenyl.

[0719] The term "aryl C1-C6 alkyl" refers to a C1-C6 alkyl group having an aryl substituent, including 3-phenylpropyl and benzyl.

[0720] The term "heteroaryl" refers to a monocyclic heteroaromatic group, or a bicyclic or tricyclic fused ring heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furanyl, 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, benzofuranyl, [2,3-dihydro]benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl , isobenzothiophenyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthene and benzoquinolyl.

[0721] The term "C1-C6 alkylheteroaryl" refers to a heteroaryl group having a C1-C6 alkyl substituent, including methylfuranyl.

[0722] The term "heteroaryl C1-C6 alkyl" refers to a C1-C6 alkyl group having a heteroaryl substituent, including furanylmethyl.

[0723] The term "C2-C6 alkenylaryl" refers to an aryl group having a C2-C6 alkenyl substituent, including vinylphenyl.

[0724] The term "aryl C2-C6 alkenyl" refers to a C2-C6 alkenyl group having an aryl substituent, including phenylvinyl.

[0725] The term "C2-C6 alkenylheteroaryl" refers to a heteroaryl group having a C2-C6 alkenyl substituent, including vinylpyridyl.

[0726] The term "heteroaryl C2-C6 alkenyl" refers to a C2-C6 alkenyl group having a heteroaryl substituent, including pyridylvinyl.

[0727] The term "C3-C8 cycloalkyl" refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). C3-C8 cycloalkyl includes cyclopentyl, cyclohexyl, and norbornyl.

[0728] The term "heterocycloalkyl" refers to a C3-C8 cycloalkyl group according to the above definition, wherein up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, and R is defined as hydrogen or methyl. The term "heterocycloalkyl" includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydrofuranyl.

[0729] The term "C1-C6 alkyl C3-C8 cycloalkyl" refers to a C3-C8 cycloalkyl group having a C1-C6 alkyl substituent, including methylcyclopentyl.

[0730] The term "C3-C8 cycloalkyl C1-C6 alkyl" refers to a C1-C6 alkyl group having a C3-C8 cycloalkyl substituent, including 3-cyclopentylpropyl.

[0731] The term "C1-C6 alkylheterocycloalkyl" refers to a heterocycloalkyl group having a C1-C6 alkyl substituent, including 4-methylpiperidinyl.

[0732] The term "heterocycloalkyl C1-C6 alkyl" refers to a C1-C6 alkyl group having a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl)methyl.

[0733] The term "carboxy" refers to the group -C(O)-OH.

[0734] The term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group having a carboxyl substituent, including 2-carboxyethyl.

[0735] The term "acyl" refers to a group -C(O)R, wherein R is selected from the list consisting of H, C1-C6 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, including acetyl. Preferably, R is C1-C6 alkyl.

[0736] The term "acyl C1-C6 alkyl" refers to a C1-C6 alkyl group having an acyl substituent, including 2-acetylethyl.

[0737] The term "acylaryl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl.

[0738] The term "acyloxy" refers to the group -OC(O)R, wherein R is selected from the list consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, C3-C8-cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, including acetoxy.

[0739] The term "acyloxy C1-C6 alkyl" refers to a C1-C6 alkyl group having an acyloxy substituent, including 2-(ethylcarbonyloxy)ethyl.

[0740] The term "alkoxy" refers to a group -OR, wherein R is selected from the list consisting of C1-C6 alkyl, aryl, heteroaryl, arylC1-C6 alkyl and heteroarylC1-C6 alkyl. Preferred alkoxy groups include, for example, methoxy, ethoxy and phenoxy.

[0741] The term "alkoxy C1-C6 alkyl" refers to a C1-C6 alkyl group having an alkoxy substituent, including methoxyethyl.

[0742] The term "alkoxycarbonyl" refers to the group -C(O)OR, where R includes C1-C6 alkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, and heteroalkyl.

[0743] The term "alkoxycarbonyl C1-C6 alkyl" refers to a C1-C6 alkyl group having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl.

[0744] The term "aminocarbonyl" refers to the group -C(O)NRR', wherein R and R' are independently selected from the list consisting of H, C1-C6 alkyl, aryl, heteroaryl, arylC1-C6 alkyl and heteroarylC1-C6 alkyl, including N-phenylcarbonyl.

[0745] The term "aminocarbonyl C1-C6 alkyl" refers to an alkyl group having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl, N-ethylacetylamino and N,N-diethyl-acetylamino.

[0746] The term "amido" refers to the group -NRC(O)R', wherein R and R' are independently selected from the list consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, including acetamido.

[0747] The term "amido C1-C6 alkyl" refers to a C1-C6 alkyl group having an acylamino substituent, including 2-(propionylamino)ethyl.

[0748] The term "urea" refers to the group -NRC(O)NR'R", wherein R, R' and R" are independently selected from the list consisting of H, C1-C6 alkyl, C2-C6 alkenyl, alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, and wherein R' and R" together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

[0749] The term "ureido C1-C6 alkyl" refers to a C1-C6 alkyl group having a ureido substituent, including 2-(N'-methylureido)ethyl.

[0750] The term "carbamate" refers to the group -NRC(O)OR', wherein R and R' are independently selected from the list consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylaryl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, and wherein R may also be hydrogen.

[0751] The term "amino" refers to the group -NRR', wherein R and R' are independently selected from the list consisting of H, C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, cycloalkyl and heterocycloalkyl, and wherein R and R' together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

[0752] The term "aminoalkyl" refers to an alkyl group having an amino substituent, including 2-(1-pyrrolidinyl)ethyl.

[0753] The term "ammonium" refers to a positively charged group -N + RR'R", wherein R, R' and R" are independently selected from the list consisting of C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, cycloalkyl and heterocycloalkyl, and wherein R and R' together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

[0754] The term "ammoniumalkyl" refers to an alkyl group having an ammonium substituent, including 1-ethylpyrrolidinium.

[0755] The term "halogen" refers to fluorine, chlorine, bromine and iodine atoms.

[0756] The term "sulfonyloxy" refers to the group -OSO2-R, wherein R is selected from the group consisting of C1-C6 alkyl, halogen-substituted C1-C6 alkyl, such as an -OSO2-CF3 group, C2-C6 alkenyl, alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, cycloalkylC1-C6 alkyl and heterocycloalkylalkyl.

[0757] The term "sulfonyloxy C1-C6 alkyl" refers to an alkyl group having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl.

[0758] The term "sulfonyl" refers to the group "-SO2-R", wherein R is selected from the group consisting of aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkyl substituted with halogen (e.g. -OSO2-CF3 group), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl.

[0759] The term "sulfonyl C1-C6 alkyl" refers to an alkyl group having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl.

[0760] The term "sulfinyl" refers to the group "-S(O)-R", wherein R is selected from the group consisting of alkyl, halogen-substituted alkyl (e.g., a -SO-CF3 group), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, C3-C8-cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl.

[0761] The term "sulfinylalkyl" refers to an alkyl group having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl.

[0762] The term "sulfhydryl" refers to a group -SR, wherein R is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkyl substituted with halogen (e.g., -S-CF3 group), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, alkynylheteroaryl, cycloalkylC1-C6 alkyl, and heterocycloalkylC1-C6 alkyl. Preferred sulfhydryls include methylsulfhydryl and ethylsulfhydryl.

[0763] The term "mercapto C1-C6 alkyl" refers to a C1-C5-alkyl group having a mercapto substituent, including 2-(ethylthio)ethyl.

[0764] The term "sulfonylamino" refers to the group -NRSO2-R', wherein R and R' are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylC2-C6 alkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, C3-C8-cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl.

[0765] The term "sulfonylamino C1-C6 alkyl" refers to an alkyl group having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl.

[0766] The term "aminosulfonyl" refers to the group -SO2-NRR', wherein R and R' are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylalkenyl, heteroarylC2-C6 alkenyl, arylC2-C6 alkynyl, heteroarylC2-C6 alkynyl, C3-C8-cycloalkylC1-C6 alkyl and heterocycloalkylC1-C6 alkyl, and wherein R' and R" with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring. Aminosulfonyl includes cyclohexylaminosulfonyl and piperidinylsulfonyl.

[0767] The term "aminosulfonyl C1-C6 alkyl" refers to a C1-C6 alkyl group having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl.

[0768] Unless otherwise limited by the definition of an individual substituent, all of the above substituents are to be understood as being all optionally substituted.

[0769] Unless otherwise limited by the definition of individual substituents, the term "substituted" refers to a group substituted with 1 to 5 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, cycloalkylC1-C6 alkyl, heterocycloalkylC1-C6 alkyl, amino, alkylamino, aminosulfonyl, ammonium, alkoxy, acyl, acylamino, aminocarbonyl, aryl, arylC1-C6 alkyl, heteroaryl, heteroarylC1-C6 alkyl, sulfinyl, sulfonyl, sulfonamide, alkoxy, alkoxycarbonyl, carbamate, sulfhydryl, halogen, carboxyl, trihalomethyl, cyano, hydroxyl, mercapto and nitro.

[0770] Specific NOX inhibitors useful in the use of the present invention include those selected from the group consisting of:

[0771] 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

[0772] 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

[0773] 4-(2-Fluoro-4-methoxyphenyl)-2-(2-methoxyphenyl)-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

[0774] (R)-3-methoxy-4-(2-morpholino-1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide;

[0775] 10-Benzyl-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;

[0776] (S)-3-methoxy-4-(1-phenylethoxy)-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide;

[0777] (R)-4-(2-hydroxy-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide; and

[0778] (R)-4-(2-(Dimethylamino)-1-phenylethoxy)-3-methoxy-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)benzamide.

[0779] Specific compounds of the present invention

[0780] Other specific NOX inhibitors that can be used in the use of the present invention include those selected from the group consisting of:

[0781] 5-(2-methoxypyridin-4-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0782] 2,5-Bis(2-methylpyridin-4-yl)-1H-indole;

[0783] 4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine;

[0784] 5-(5-fluoropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0785] 5-(5-chloropyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0786] 5-(5-isopropoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0787] N,N-dimethyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-3-amine;

[0788] 5-(6-methylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0789] 2-(2-methylpyridin-4-yl)-5-(pyrimidin-5-yl)-1H-indole;

[0790] 2-methyl-5-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)-1H-benzo[d]imidazole;

[0791] 2-(2-(azetidin-1-yl)pyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0792] 5-(5-methoxypyridin-3-yl)-2-(2-methoxypyridin-4-yl)-1H-indole;

[0793] 2-(2,6-dimethylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0794] 5-(5-methoxypyridin-3-yl)-2-(2-methylpyrimidin-4-yl)-1H-indole;

[0795] 5-(5-methoxypyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-1H-indole;

[0796] 4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-2-methylthiazole;

[0797] 2-(2-cyclopropylpyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0798] 1-(4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-ol;

[0799] 1-(4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane;

[0800] 2-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0801] 4-(4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0802] 2-(5-fluoropyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0803] 5-(5-methoxypyridin-3-yl)-2-(6-methoxypyridin-3-yl)-1H-indole;

[0804] 4-(5-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0805] 5-(5-methoxypyridin-3-yl)-2-(6-(oxetan-3-yl)pyridin-3-yl)-1H-indole;

[0806] 1-(5-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane;

[0807] N,N-dimethyl-5-(5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-amine;

[0808] 4-(5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine;

[0809] N,N-dimethyl-4-(5-(quinolin-4-yl)-1H-indol-2-yl)pyridin-2-amine;

[0810] 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane;

[0811] 1-(4-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane;

[0812] 1-(4-(6-chloro-5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane;

[0813] 6-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0814] 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-7-oxa-2-azaspiro[3.5]nonane;

[0815] 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-3-methylazetidin-3-ol;

[0816] 6-Chloro-2-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0817] 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxylic acid;

[0818] 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxamide;

[0819] (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-yl)methanol;

[0820] 6-Chloro-5-(5-methoxypyridin-3-yl)-2-(6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl)-1H-indole;

[0821] N-(1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-3-yl)methanesulfonamide;

[0822] (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-2-yl)methanol;

[0823] 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-2-one;

[0824] 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-3-fluoropyridin-2-yl)morpholine;

[0825] 6-Chloro-5-(5-methoxypyridin-3-yl)-2-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-1H-indole;

[0826] 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;

[0827] 6-Chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0828] 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-1-methylpiperazin-2-one;

[0829] 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];

[0830] 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;

[0831] (5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)(oxetan-3-yl)methanol;

[0832] 6-chloro-2-(6-(methoxy(oxetan-3-yl)methyl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0833] 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)propan-1-ol;

[0834] 5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one;

[0835] 4-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-cyclopropylmethyl)pyridin-2(1H)-one;

[0836] 4-(5-(7-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0837] 4-(5-(4,6-difluoro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0838] 4-(5-(6-chloro-5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0839] 4-(5-(6-chloro-5-(5-chloropyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0840] 4-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0841] 6-Fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0842] 4-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0843] 6-Chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0844] 5-(5-methoxypyridin-3-yl)-4-methyl-2-(2-methylpyridin-4-yl)-1H-indole;

[0845] 5-(5-methoxypyridin-3-yl)-6-methyl-2-(2-methylpyridin-4-yl)-1H-indole;

[0846] 4-Methyl-2,5-di(pyridin-4-yl)-1H-indole;

[0847] 6-methyl-2,5-di(pyridin-4-yl)-1H-indole;

[0848] 4-(5-(4-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0849] 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0850] 4-Chloro-2,5-di(pyridin-4-yl)-1H-indole

[0851] 6-Chloro-2,5-di(pyridin-4-yl)-1H-indole;

[0852] N,N-dimethyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine;

[0853] 5-(6-cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0854] 5-(6-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0855] 5-(6-(Methoxymethyl)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0856] 5-(5-ethoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0857] 5-(5-cyclopropyloxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0858] 5-(5-(Cyclopropylmethoxy)pyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0859] 5-(5-cyclopropylpyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0860] 7-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine;

[0861] 3-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)quinoline;

[0862] N-methyl-4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-amine;

[0863] 4-(4-(2-(2-methylpyridin-4-yl)-1H-indol-5-yl)pyridin-2-yl)morpholine;

[0864] 5-(6-chloro-2-(6-morpholinopyridin-3-yl)-1H-indol-5-yl)quinolin-2-ol;

[0865] 4-(5-(6-chloro-5-(thieno[2,3-c]pyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0866] 4-(5-(6-chloro-5-(6-fluoroquinolin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0867] 4-(5-(6-chloro-5-(2-methoxyquinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0868] 4-(5-(6-Fluoroquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine;

[0869] 4-(5-(isoquinolin-4-yl)-1H-indol-2-yl)-N,N-dimethylpyridin-2-amine;

[0870] N,N-dimethyl-4-(5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-amine;

[0871] 3-Chloro-2,5-di(pyridin-4-yl)-1H-indole;

[0872] 2-(2-methylpyridin-4-yl)-5-(pyridin-4-yl)-1H-indole;

[0873] 5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0874] 5-(5-methoxypyridin-3-yl)-2-(pyridin-4-yl)-1H-indole;

[0875] 5-(5-methoxypyridin-3-yl)-2-(pyridin-3-yl)-1H-indole;

[0876] 4-(2-(Pyridin-4-yl)-1H-indol-5-yl)quinoline;

[0877] 4-(2-(Pyridin-3-yl)-1H-indol-5-yl)quinoline;

[0878] 2,5-Bis(pyridin-4-yl)-1H-indole;

[0879] 2-(Pyridin-3-yl)-5-(pyridin-4-yl)-1H-indole;

[0880] 2,5-Bis(pyridin-3-yl)-1H-indole;

[0881] 2-(1-methyl-1H-pyrazol-5-yl)-5-(pyridin-4-yl)-1H-indole;

[0882] 5-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-2-(pyridin-4-yl)-1H-indole;

[0883] 5-(5-methoxypyridin-3-yl)-2-(pyridin-2-yl)-1H-indole;

[0884] 5-(5-methoxypyridin-3-yl)-2-(pyrimidin-4-yl)-1H-indole;

[0885] 2-(3-fluoropyridin-4-yl)-5-(5-methoxypyridin-3-yl)-1H-indole;

[0886] 1-isopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0887] 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)pyridin-2-yl)morpholine;

[0888] 1-(2-methoxyethyl)-2,5-di(pyridin-4-yl)-1H-indole;

[0889] 1-(2-methoxyethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0890] 1-methyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0891] 1-ethyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0892] 1-(Cyclopropylmethyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0893] 1-(Benzyl)-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0894] 7-(4-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine;

[0895] 7-(6-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine;

[0896] 1-cyclopropyl-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole;

[0897] 1-methyl-2,5-di(pyridin-4-yl)-1H-indole; and

[0898] 5-(5-methoxypyridin-3-yl)-2-(3-methylpyridin-4-yl)-1H-indole.

[0899] A particularly preferred NOX inhibitor for treating 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 commonly known and referred to herein as setanaxib.

[0900] The structure of setanerxib (in non-salt form) is shown below.

[0901]

[0902] Drug composition and dosage

[0903] Those skilled in the art will appreciate that when used for the purposes and methods described herein, the compounds of the invention, alone or in combination with ACE inhibitors and / or ARBs, can be administered in a manner that allows systemic absorption, which can occur via many possible routes; for example, the compounds of the invention can be administered orally, intravenously or intraarterially, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g., sublingually or intrabuccally), rectally, transdermally, nasally, transpulmonary (e.g., by inhalation, trachea or bronchus), or by any other parenteral route in the form of a pharmaceutical preparation 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).

[0904] The compounds of the present invention will generally be administered in the form of one or more pharmaceutical formulations mixed with a pharmaceutically acceptable excipient, which may be selected according to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable excipients may be chemically inert to the active compound and have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable excipients may also impart immediate (e.g., rapid) or regulated (e.g., delayed) release to the compounds of the present invention.

[0905] Suitable pharmaceutical preparations may be commercially available or otherwise described in the literature (see, e.g., Lachman et al., "The Theory and Practice of Industrial Pharmacy", CBS, 4th edition (2015); "Remington: The Science and Practice of Pharmacy", Troy (ed.), Elsevier, 23rd edition (2020); and / or "Aulton's Pharmaceutics: The Design and Manufacture of Medicines", Taylor and Aulton (ed.), Elsevier, 5th edition, 2017), all of which are incorporated herein by reference. Otherwise, preparations suitable for use may be obtained by those skilled in the art using conventional techniques in a non-inventive manner.

[0906] As described herein, pharmaceutical preparations 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 preparations can be in the form of oral preparations or intravenous preparations (or preparations suitable for preparing intravenous preparations, such as concentrated preparations).

[0907] For example, when intended for oral administration, pharmaceutical preparations comprising the compounds of the invention can be provided in the form of tablets or oral powders or solutions, each of which optionally includes a suitable excipient, which can be prepared using techniques known to those skilled in the art. Similarly, when intended for intravenous (IV) administration, pharmaceutical preparations comprising the compounds of the invention can be provided in the form of solutions suitable for IV administration or in the form of solutions suitable for IV administration, which can be prepared using techniques known to those skilled in the art. Similarly, when intended for rectal administration, pharmaceutical preparations comprising the compounds of the invention can be provided in the form of tablets (e.g., suppositories) or powders or solutions each optionally including a suitable excipient, which can be prepared using techniques known to those skilled in the art.

[0908] Depending on the patient to be treated, the route of administration and the severity of the condition (e.g., the severity of the pain level and its effects), the compounds of the present invention can be administered at different therapeutically effective doses (to relevant patients in need thereof). Suitable doses can be determined by those skilled in the art using conventional techniques, such as by conventional dose titration studies, etc.

[0909] Similarly, the amount of a compound of the invention included in a relevant pharmaceutical formulation can be determined based on the desired dosage of the compound of the invention, ease of formulation, and route of administration (which in turn can determine the availability of the compound of the invention for systemic absorption).

[0910] Suitable doses of the compounds of the invention may include doses (e.g., IV administration) ranging from about 0.05 to 300 mg / kg, e.g., about 0.5 to about 200 mg / kg (e.g., about 1 to about 100 mg / kg, e.g., about 30 mg / kg or about 90 mg / kg). In particular, such doses may be administered by IV over a period of time, e.g., about one hour. In addition, such doses may be repeated, e.g., in a periodic, continuous infusion, which may be a reduced dose, if necessary.

[0911] For the avoidance of doubt, when the word "about" is used herein, for example in the context of an amount (e.g., a dose of an active ingredient), it is understood that such variables are approximate and may therefore vary by ±10%, such as ±5% and preferably ±2% (e.g., ±1%) relative to the number specified herein. For example, "10 ± 10%" means 9 to 11.

[0912] For the avoidance of doubt, it will be appreciated by those skilled in the art that the dose of the compounds of the invention administered (e.g., to humans) should be sufficient to achieve the desired therapeutic response or effect within a reasonable time frame (and beyond). For example, the compounds of the invention may be provided in a form suitable for rapid (i.e., quick or immediate) release of the active ingredient, such as in the form of a fast disintegrating tablet, which may be formulated using techniques and materials known to those skilled in the art.

[0913] In any case, those skilled in the art will be able to routinely determine the actual dosage that will be most suitable for individual patients. Although the dosages mentioned above are examples of average cases; of course, there may be individual instances where higher or lower dosage ranges are described, and such dosages are within the scope of the present invention.

[0914] Administration of the compounds of the invention may be continuous (e.g., by continuous IV infusion) or intermittent (e.g., by bolus or via periodic administration of tablets or solutions), or may be provided in the form of a single dose (e.g., by injection or via administration of tablets or solutions). The dosage form may also be determined by the timing and frequency of administration, and vice versa.

[0915] Combination Products and Related Kits

[0916] As outlined above, the compounds of the invention may also be used in combination with an ACE inhibitor and / or an ARB for the treatment of Alport syndrome in the uses and methods described herein.

[0917] Therefore, according to another aspect of the present invention, there is provided a combination product comprising:

[0918] (a) a NOX inhibitor or a pharmaceutically acceptable salt thereof; and

[0919] (b) ACE inhibitors or pharmaceutically acceptable salts thereof, and / or ARBs or pharmaceutically acceptable salts thereof.

[0920] Said combination product is hereinafter referred to as "the combination product of the invention".

[0921] The NOX inhibitor, ACE inhibitor and ARB can be any NOX inhibitor, ACE inhibitor and ARB disclosed herein.

[0922] 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.

[0923] Specific ARBs include azilsartan, candesartan, eprosartan, sparsentan, irbesartan, losartan, olmesartan, telmisartan, valsartan, and combinations thereof.

[0924] Preferably, the combination product comprises:

[0925] (a) a NOX inhibitor or a pharmaceutically acceptable salt thereof; and

[0926] (b) an ACE inhibitor or a pharmaceutically acceptable salt thereof.

[0927] Even more preferably, the combination product comprises:

[0928] (a) setanerxib or a pharmaceutically acceptable salt thereof; and

[0929] (b) ramipril or a pharmaceutically acceptable salt thereof.

[0930] For the avoidance of doubt, 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 the compound (in non-salt form) is shown below.

[0931]

[0932] The combination products of the present invention provide for the combined administration of a NOX inhibitor as defined above and an ACE inhibitor and / or an ARB as defined above, and may therefore be presented as separate formulations, wherein at least one of those formulations comprises a NOX inhibitor and at least one comprises an ACE inhibitor and / or an ARB, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation comprising a NOX inhibitor and an ACE inhibitor or an ARB).

[0933] Indeed, the combination product may be presented in three separate formulations, wherein at least one of those formulations comprises a NOX inhibitor, another comprises an ACE inhibitor and another comprises an ARB.

[0934] Therefore, there is further provided a combination product according to the invention comprising a kit of parts comprising:

[0935] (A) a pharmaceutical preparation comprising a NOX inhibitor as defined above or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; and

[0936] (B) a pharmaceutical preparation comprising an ACE inhibitor or a pharmaceutically acceptable salt thereof, and / or an ARB or a pharmaceutically acceptable salt thereof as defined above, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

[0937] The components (A) and (B) are each provided in a form suitable for administration in combination with the other component.

[0938] According to another aspect of the present invention, there is provided a method of preparing a kit of parts as defined above, said method comprising combining component (A) as defined above with component (B) as defined above, such that both components are suitable for administration in combination with each other.

[0939] By "associating" the two components with each other, we include components (A) and (B) of the kit of parts which may be:

[0940] (i) are provided as separate preparations (i.e. separate from each other) which are subsequently combined together for use in combination with each other in a combination therapy; or

[0941] (ii) The separate components are packaged and presented together as a "combination package" for use in conjunction with each other in a combination therapy.

[0942] Therefore, a kit is also provided, comprising:

[0943] (I) one of components (A) and (B) as defined herein; and

[0944] (II) instructions for using the component in combination with the other of the two components.

[0945] The kits described herein may contain more than one formulation including an appropriate amount / dose of a NOX inhibitor / salt / solvate, and / or more than one formulation including an appropriate amount / dose of an ACE inhibitor / salt / solvate and / or an ARB / salt / solvate to provide for repeated administration. If there is more than one formulation (comprising any active compound), such formulations may be the same, or may differ in terms of the dose, chemical composition, and / or physical form of any compound.

[0946] The combination product according to the invention may be used to treat Alport's syndrome.

[0947] According to another aspect of the present invention there is provided a method of treating Alport's syndrome, said method comprising administering a combination product according to the present invention to a patient in need of such treatment.

[0948] In the context of the kit of parts described herein, by "combined administration" we include the sequential, separate and / or simultaneous administration of the respective formulations 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) during the treatment of the relevant condition.

[0949] Thus, with respect to the combination products of the present invention, the term "combined administration" includes the administration of the two components of the combination product (NOX inhibitor and ACE inhibitor and / or ARB) together or sufficiently close in time (optionally repeated administration) to enable the patient to obtain a beneficial effect during the treatment of the relevant condition than the formulation containing the NOX inhibitor or the formulation containing the ACE inhibitor and / or ARB in the absence of the other components when administered alone (optionally repeated administration) during the same treatment. The determination of whether the combination provides a better beneficial effect in the treatment of a particular condition and during the treatment will depend on the condition to be treated or prevented, but can be routinely accomplished by a person skilled in the art.

[0950] In addition, in the context of a kit of parts according to the invention, the term "combination" includes that one or the other of the two preparations can be administered before, after and / or simultaneously with the administration of the other component (optionally repeated administration). When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of the NOX inhibitor and the ACE inhibitor and / or ARB are administered within 48 hours (e.g., 24 hours) of each other.

[0951] Preparation of compounds and formulations

[0952] The compounds of the present invention are commercially available or can be prepared using techniques known to those skilled in the art, such as those described in the disclosure referenced herein. For example, setanerxib can be prepared according to the procedures described in Example 62 (Scheme 2) of WO 2010 / 035221, the contents of which (particularly, the procedures described in the examples provided therein) are incorporated herein by reference.

[0953] As described herein, pharmaceutical preparations (including preparations containing more than one active ingredient as described in the third aspect of the present invention) can be prepared using techniques known to those skilled in the art. Similarly, kits (as described herein) can be prepared using techniques known to those skilled in the art in the art.

[0954] According to other aspects of the present invention, there is provided:

[0955] - a process for preparing a pharmaceutical formulation as described above, said process comprising mixing (i.e. into the same formulation) components (a) and (b) as described above in relation to the related aspects of the invention, optionally with one or more pharmaceutically acceptable excipients; and

[0956] - A method of preparing a kit of parts as described above, said method comprising combining components (A) and (B) as described above in relation to the relevant aspects of the invention.

[0957] For the avoidance of doubt, by referring to the components as "associated" with each other we include that components (A) and (B) of the kit as described above may be:

[0958] - are provided as separate preparations (ie separate from each other) which are subsequently combined together for use in combination with each other in a combination therapy; or

[0959] -The individual components are packaged and presented together as a "combination pack" for use in conjunction with each other in a combination therapy.

[0960] When used in the uses and methods described herein, the compounds of the invention may have the following advantages: in the treatment of Alport syndrome, they may be more convenient for the physician and / or the patient, more effective, less toxic, have a broader spectrum of activity, be more effective, produce fewer side effects, or may have other useful pharmacological properties compared to similar treatments (or preventive measures) known in the prior art.

[0961] Examples

[0962] The present invention is further illustrated but not limited by the following examples and drawings, in which:

[0963] Figure 1 Depicted are the results of a first experiment analyzing the amount of albumin in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (group B; represented by the term "compound" in the figure), ramipril alone (group C), and a combination of setacanib and ramipril (group D), compared to a control group (group A; represented by the term "vehicle" in the figure);

[0964] Figure 2 Depicted are the results of a first experiment analyzing the creatinine content in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (group B; represented by the term "compound" in the figure), ramipril alone (group C), and a combination of setacanib and ramipril (group D), compared to a control group (group A; represented by the term "vehicle" in the figure);

[0965] Figure 3 Depicted are the results of a first experiment analyzing the albumin / creatinine ratio in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D) compared to a control group (Group A; represented by the term "Vehicle" in the Figure);

[0966] Figure 4 Depicted are the results of a first experiment analyzing blood urea nitrogen (BUN) ratios in plasma samples of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D) compared to a control group (Group A; represented by the term "Vehicle" in the Figure);

[0967] Figure 5 Depicted are the results of analyzing cystatin C in plasma samples of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D) compared to a control group (Group A; represented by the term "Vehicle" in the Figure);

[0968] Figure 6 Depicted are the results of a second experiment analyzing the amount of albumin in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D), compared to a control group (Group A; represented by the term "Vehicle" in the Figure);

[0969] Figure 7Depicted are the results of a second experiment analyzing the creatinine levels in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D), compared to a control group (Group A; represented by the term "Vehicle" in the Figure);

[0970] Figure 8 depicts the results of a second experiment analyzing the albumin / creatinine ratio in the urine of homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D), compared to a control group (Group A; represented by the term "Vehicle" in the Figure); and

[0971] Fig. 9 Depicted are the results of a second experiment analyzing blood urea nitrogen (BUN) ratios in plasma samples from homozygous Col4a3 ko / ko mice treated with setacanib alone (Group B; represented by the term "Compound" in the Figure), ramipril alone (Group C), and a combination of setacanib and ramipril (Group D), compared to a control group (Group A; represented by the term "Vehicle" in the Figure).

[0972] Example 1

[0973] Study on Col4A3 Alport Mouse Model

[0974] Summarize

[0975] The aim of the study was to examine the effects of setanerxib, a NOX (eg, NOX1 / 4) inhibitor, on the Alport syndrome mouse model in Col4a3 ko / ko mice.

[0976] The studies were repeated and each study is referred to herein as the first experiment and the second experiment.

[0977] Col4a3 ko / ko targeted mutation homozygous mice are a model of autosomal recessive Alport syndrome (Cosgrove et al. Kidney Int. 2007, 71(7), pp. 615-618). Animals raised 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), pp. 438-446) report an average survival of 10 weeks. Because homozygous Col4a3 ko / ko mice reflect the key features of Alport syndrome, this mouse model can be used to test potential drug candidates.

[0978] The study used 40 homozygous Col4a3 ko / ko mice, divided into 4 groups (vehicle, stancoxib, ramipril and stancoxib + ramipril combination), n = 10 animals per group. Starting from 4 weeks of age, animals were treated with vehicle and / or compound by oral gavage every day for 4 weeks. The reference compound ramipril was administered via drinking water, prepared once a week, but replaced after 4 days at the latest. In addition, a wild-type control group (Col4A3+ / +) without any treatment was included in the study, with n = 6 animals.

[0979] Beginning at 8 weeks of age, clinical signs and termination criteria were monitored daily as needed until tissue collection.

[0980] Urine samples were collected at 3 time points: baseline (4 weeks of age), 6 and 8 weeks of age after 2 and 4 weeks of treatment, respectively. Albumin and creatinine levels were assessed in urine samples of 8 animals per treatment group by ELISA.

[0981] At the end of the study, animals were euthanized by intraperitoneal injection of pentobarbital, and terminal blood was collected in EDTA coated tubes by cardiac puncture. Blood plasma was collected by centrifugation (3000 × g, 10 minutes at room temperature) and 50 μL blood plasma aliquots were transferred to 1.5 mL test tubes, frozen on dry ice and stored at -80°C.

[0982] deal with

[0983] Forty homozygous Col4a3 ko / ko mice were used in this study, divided into 4 groups with n=10 animals in each group. Starting from 4 weeks of age, animals were treated with vehicle or compound by oral gavage every day for 4 weeks. The reference compound ramipril was administered via drinking water, which was prepared once a week but replaced after 4 days at the latest. In addition, a wild-type control group without any treatment was included in the study, with n=6 animals. The treatment groups are summarized in the table below:

[0984]

[0985] Urine sampling

[0986] Urine samples were collected from all animals in groups A to D by direct pipetting of produced urine at baseline before treatment and at 6 and 8 weeks of age, respectively. If no urine was produced during fixation, the abdomen was massaged. Urine was collected in Eppendorf tubes, spun at 800 × g for 10 minutes at room temperature and the supernatant was transferred to a new tube and frozen at -20°C until use.

[0987] Biochemistry

[0988] Creatinine and albumin levels were analyzed in urine supernatants collected from 8 animals per group (n=96) from Groups A to D at 3 time points at baseline, 6 and 8 weeks of age.

[0989] Creatinine level measurement

[0990] Urine samples from all animals (n=8 per group, 4 groups, 3 time points, total n=96) were analyzed for creatinine levels. Enzyme assay of (DZ072B). The assay was performed according to the manufacturer's protocol with minor modifications for use in 96-well plates and reading in a standard plate luminometer (Cytation 5, Biotek).

[0991] Albumin level measurement

[0992] Albumin levels in urine supernatants collected from each animal in each group at 3 time points (total n=96) were analyzed using an Albumin Mouse ELISA Kit (ab108792; Abeam) according to the manufacturer's protocol.

[0993] Briefly, urine samples were centrifuged at 800×g for 10 minutes and diluted into diluent N. 50 μL of albumin standard or sample was added to each 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. The microplate was washed and then 50 μL of streptavidin-peroxidase conjugate was added to each well and incubated for 30 minutes. Thereafter, the microplate was washed again and incubated with 50 μL of chromogen substrate per well for 15 minutes. The reaction was stopped by adding 50 μL of stop solution per well. Albumin levels were determined by reading the absorbance at 450 nm immediately after adding the stop solution.

[0994] Plasma sampling

[0995] After confirming deep anesthesia, the chest cavity was opened and blood was collected by cardiac puncture using a 23-gauge needle. The needle was removed and the blood was transferred to a sample tube ( K2EDTA (potassium ethylenediaminetetraacetate). The tube must be inverted thoroughly to promote uniform distribution of EDTA and prevent clotting. Blood samples were centrifuged at 3000×g for 10 minutes at room temperature (22° C.). Plasma was transferred to pre-labeled 1.5 ml LoBind Eppendorf tubes (50 μl aliquot + rest), frozen on dry ice and stored at -80° C.

[0996] Blood urea nitrogen (BUN) colorimetric assay

[0997] All animals were analyzed for BUN plasma levels at the end of the study. TM The analysis was performed according to the manufacturer's protocol.

[0998] Quantitative Detection of Mouse Cystatin C

[0999] All animals were analyzed for cystatin C plasma levels at the end of the study. ELISA kit (Catalog number: ab119590). The analysis was performed according to the manufacturer's protocol.

[1000] result

[1001] Albumin level

[1002] In the first and second experiments, evaluation of albumin levels in the urine of homozygous Col4a3 ko / ko mice showed that albumin levels increased over time, and the results can be seen in Figure 1 and 6 In. At 4 weeks of age (baseline), similar albumin values ​​were observed in all groups. Although the stanazoxib treatment (B group) at 6 weeks of age showed that the albumin level increased more than the vehicle-treated group animals, the urine albumin content of ramipril (C group) in the first experiment was slightly reduced, and the reduction degree of albumin level in urine was greater in the second experiment. Interestingly, in two experiments, the albumin level of the combination of ramipril and stanazoxib (D group) was reduced than the vehicle-treated group mice. At 8 weeks of age, after processing homozygous Col4a3 ko / ko mice with ramipril and stanazoxib (D group), the albumin level was significantly reduced than the control mice (A group), and the average albumin level was reduced by stanazoxib treatment alone.

[1003] Creatinine level

[1004] Analysis of creatinine levels in urine showed no significant differences between the groups at all time points tested in both the first and second experiments. The results can be seen in Figure 2 and 7 middle.

[1005] Albumin / creatinine ratio

[1006] In the first and second experiments, the calculation of the albumin to creatinine ratio in the urine of 6-week-old Col4a3 ko / ko mice (Group B) after treatment with setanercept showed an increasing trend compared to vehicle-treated animals (Group A), as shown in Figure 2. Figure 3 and 8Detailed display in. On the contrary, Ramipril treatment (C group) reduces the ratio of albumin to creatinine, but does not reach significance in the first experiment (in the second experiment, the decline does reach significance). Combination treatment (Ramipril+Setacil) further reduces the ratio, wherein the first experiment reaches significance after using unpaired t test for statistical analysis. At 8 weeks of age, compared with vehicle treated animals, the ratio of albumin to creatinine in the Col4a3 ko / ko mice treated with Ramipril alone (C group) or with Setacil (D group) is significantly reduced, and Setacil also shows an average reduction (B group) when treated alone.

[1007] BUN and cystatin C levels in plasma samples

[1008] The results of the first experiment on blood urea nitrogen (BUN) and cystatin C in plasma samples were Figure 4 and 5 The results of the second experiment on blood urea nitrogen (BUN) in plasma samples were shown in Fig. 9 Shown in the middle.

[1009] In the first experiment, treatment with setanerxib alone, ramipril alone, and the combination of both showed significant reductions in BUN and cystatin C plasma levels compared to vehicle alone. The reductions were similar in all treatment groups. In the second experiment, the combination of ramipril and setanerxib showed a significant reduction in BUN.

Claims

1. A NOX inhibitor or a pharmaceutically acceptable salt thereof for use in treating Alport syndrome.

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

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

5. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is a NOX inhibitor according to formula (I): in: G 1 Selected from: H； Optionally substituted alkyl, such as aminocarbonylalkyl (eg, phenylacetamide); Optionally substituted C3-C8-cycloalkylalkyl; optionally substituted heterocycloalkylalkyl; Arylalkyl, for example phenylalkyl, for example phenylmethyl or 3-methylphenylmethyl; substituted arylalkyl, for example substituted phenylalkyl, for example substituted phenylmethyl (eg 4-fluorobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 4-bromobenzyl); heteroarylalkyl; and substituted heteroarylalkyl, for example substituted pyridinylalkyl, for example pyridin-2-ylmethyl; G 2 Selected from: H； optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl, for example phenyl (eg, 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, such as benzothiazolyl or pyridinyl; substituted heteroaryl, for example substituted benzothiazolyl (eg 1,3-benzothiazol-2-yl) or substituted pyridinyl (eg pyridin-2-yl); optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl; optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; Optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; Optionally substituted alkyl C3-C8-cycloalkyl; Optionally substituted C3-C8-cycloalkylalkyl; Optionally substituted alkylheterocycloalkyl; and optionally substituted heterocycloalkylalkyl; G 3 Selected from: H； optionally substituted alkyl, such as 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 C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; Optionally substituted alkyl C3-C8-cycloalkyl; Optionally substituted C3-C8-cycloalkylalkyl; Optionally substituted alkylheterocycloalkyl; and optionally substituted heterocycloalkylalkyl; G 4 Selected from: H； optionally substituted alkyl, such as optionally substituted pentyl (eg, isopentyl); optionally substituted heteroalkyl; Optionally substituted alkoxy, such as optionally substituted methoxy; (eg 2-methoxyethyl); optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkylaryl; Arylalkyl, such as benzyl or phenylethyl (eg 2-phenylethyl); substituted arylalkyl, for example substituted benzyl (eg benzoic acid methyl) or substituted phenylethyl (eg 4-methoxyphenylethyl); optionally substituted heteroaryl; optionally substituted alkylheteroaryl; optionally substituted heteroarylalkyl, for example optionally substituted thienylalkyl (for example optionally substituted thienylmethyl, for example thien-2-ylmethyl), optionally substituted imidazolylalkyl (for example optionally substituted imidazolylethyl, for example imidazo-4-ylethyl), optionally substituted indolylalkyl (for example optionally substituted indolylethyl, for example indol-3-ylethyl), optionally substituted furanylalkyl (for example optionally substituted furanylmethyl, for example furan-2-ylmethyl), optionally substituted benzodioxolylalkyl (for example optionally substituted benzodioxolylmethyl, for example 1,3-benzodioxol-5-ylmethyl), or optionally substituted pyridinylmethyl (for example pyridin-3-ylmethyl or pyridin-2-ylmethyl); optionally substituted alkenylaryl; optionally substituted arylalkenyl; optionally substituted alkenylheteroaryl; optionally substituted heteroarylalkenyl; Optionally substituted C3-C8-cycloalkyl; heterocycloalkyl, such as morpholinyl (e.g., 5-morpholin-4-yl), piperazinyl (e.g., 4-methylpiperazinyl), or piperidinyl (e.g., 4-methylbenzyl)piperidin-4-yl); substituted heterocycloalkyl, such as substituted morpholinyl (e.g. 5-morpholin-4-yl), substituted piperazinyl (e.g. 4-methylpiperazinyl) or substituted piperidinyl (e.g. 4-methylbenzyl)piperidin-4-yl); Optionally substituted alkyl C3-C8-cycloalkyl; Optionally substituted C3-C8-cycloalkylalkyl; optionally substituted alkylheterocycloalkyl; heterocycloalkylalkyl, for example morpholinylalkyl (for example morpholinylethyl or morpholinylpropyl, in particular 2-morpholin-4-yl-ethyl or 3-(morpholin-4-yl)propyl), piperazinylalkyl (for example piperazinylethyl, for example 2-(4-acetylpiperazin-1-yl)ethyl or 2-(4-hexanoylpiperazin-1-yl)ethyl), or pyrrolidinylalkyl (for example pyrrolidinylpropyl, for example 3-(2-oxopyrrolidin-1-yl)propyl), or tetrahydrofuranylalkyl (for example tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl); and substituted heterocycloalkylalkyl, for example 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, for example substituted 2-(4-acetylpiperazin-1-yl)ethyl or substituted 2-(4-hexanoylpiperazin-1-yl)ethyl), or substituted pyrrolidinylalkyl (e.g. substituted pyrrolidinylpropyl, for example substituted 3-(2-oxopyrrolidin-1-yl)propyl), or substituted tetrahydrofuranylalkyl (e.g. substituted tetrahydrofuranylmethyl, for example substituted tetrahydrofuran-2-ylmethyl); G 5 Selected from: 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 C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; Optionally substituted alkyl C3-C8-cycloalkyl; Optionally substituted C3-C8-cycloalkylalkyl; Optionally substituted alkylheterocycloalkyl; and optionally substituted heterocycloalkylalkyl; and pharmaceutically acceptable salts thereof.

6. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is a NOX inhibitor of formula (II): in: Ar 1 Selected from: Phenyl; Phenyl substituted with halogen such as chlorine (for example, wherein Ar 1 is 2-chlorophenyl); and Phenyl substituted with an alkoxy group such as methoxy G 1 and G 5 is H; G 3 Selected from: Optionally substituted C1-C6 alkyl, for example optionally substituted methyl; Phenyl; phenyl substituted by halogen, amino, alkylamino or alkoxy, for example, wherein the phenyl is 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 3-dimethylaminophenyl, 2-tri-methylaminophenyl, 3-methylaminophenyl, 3-aminophenyl or 4-methoxyphenyl; G 4 Selected from: H； C1-C6 alkyl, such as methyl, Substituted C1-C6 alkyl, such as substituted methyl, optionally wherein the C1-C6 alkyl is substituted with alkoxy, for example wherein the substituted C1-C6 alkyl is methoxyethyl, such as 2-methoxyethyl; heteroaryl C1-C6alkyl, for example pyridyl C1-C6alkyl (for example pyridylmethyl, in particular pyridyl-2-ylmethyl, pyridyl-3-ylmethyl, 6-methoxypyridin-3-ylmethyl, 2-methoxypyridin-4-ylmethyl) or pyrazinyl C1-C6alkyl, for example pyrazin-2-ylmethyl; substituted heteroaryl C1-C6 alkyl, for example substituted pyridyl C1-C6 alkyl (for example substituted pyridylmethyl, in particular substituted pyridyl-2-ylmethyl, substituted pyridyl-3-ylmethyl, substituted 6-methoxypyridin-3-ylmethyl, substituted 2-methoxypyridin-4-ylmethyl) or substituted pyrazinyl C1-C6 alkyl, for example substituted pyrazin-2-ylmethyl; Alkoxy C1-C6 alkyl, such as methoxyethyl (eg 2-methoxyethyl); and Substituted C1-C6 alkyl, such as substituted methoxyethyl (such as substituted 2-methoxyethyl) or G 3 and G 4 together form an optionally substituted 7-membered heterocycloalkyl ring containing two nitrogen atoms, and wherein the two nitrogens are linked via an optionally substituted C1-C3 alkyl moiety, and tautomers, geometric isomers, optically active forms and pharmaceutically acceptable salts thereof.

7. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is a NOX inhibitor according to formula (III): in: Ar 1 , G 1 and G 5 As defined in claim 5 or claim 6; G 6 Selected from: C1-C6 alkyl; Substituted C1-C6 alkyl; Aryl C1-C6 alkyl, for example benzyl; Substituted aryl C1-C6 alkyl, for example substituted phenyl C1-C6 alkyl, for example 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl; heteroaryl C1-C6 alkyl, for example pyridyl C1-C6 alkyl, for example pyridylmethyl (for example pyridyl-2-ylmethyl or pyridyl-3-ylmethyl) or furanyl C1-C6 alkyl, for example furanylmethyl (for example furan-3-ylmethyl); Substituted heteroaryl C1-C6 alkyl, for example substituted pyridyl C1-C6 alkyl, for example substituted pyridylmethyl (for example substituted pyridyl-2-ylmethyl or substituted pyridyl-3-ylmethyl) or substituted furanyl C1-C6 alkyl, for example substituted furanylmethyl (for example substituted furan-3-ylmethyl); and tautomers, geometric isomers, optically active forms and pharmaceutically acceptable salts thereof.

8. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is a NOX inhibitor according to formula (IV): in: A 1 , A 2 and A 3 Independently selected from: hydrogen; halogen; CN; CF3; CHF2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; Optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted alkoxy; an optionally substituted amino group; optionally substituted carboxyl; and optionally substituted alkoxycarbonyl; and R i Selected from: hydrogen; halogen; CN; CF3; CHF2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; Optionally substituted heteroalkyl; Optionally substituted heterocycloalkyl; and optionally substituted carboxyl; R ii Selected from: hydrogen; Optionally substituted C1-C6 alkyl; C3-C8 cycloalkyl; Optionally substituted haloC1-C6 alkyl; Optionally substituted haloC3-C8 cycloalkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; substituted heterocycloalkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted hydroxy C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted alkoxycarbonyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; optionally substituted alkoxy C3-C8 cycloalkyl; optionally substituted amino C3-C8 cycloalkyl; and optionally substituted halo C3-C8 cycloalkyl; Ar 3 Selected from: R 1 and R 4 Independently selected from: hydrogen; halogen; CN; CF3; CHF2; NH2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; Alkoxy; Amino; optionally substituted heterocycloalkyl; carboxyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; and Optionally substituted aminocarbonyl C1-C6 alkyl; R 2 Selected from: hydrogen; halogen; CF3; CHF2; NH2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted alkoxy; Amino; optionally substituted heterocycloalkyl; carboxyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted C3-C8 carboxycycloalkyl; and Optionally substituted aminocarbonyl C1-C6 alkyl; R 3 Selected from: hydrogen; halogen; CF3; CHF2; NH2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted alkoxy; Amino; optionally substituted heterocycloalkyl; carboxyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted C3-C8 carboxycycloalkyl; and Optionally substituted aminocarbonyl C1-C6 alkyl; R 5 Selected from: hydrogen; halogen; CF3; CHF2; NH2; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted alkoxy; Amino; optionally substituted heterocycloalkyl; carboxyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted aminoheterocycloalkyl C1-C6 alkyl; Optionally substituted C3-C8 carboxycycloalkyl; and optionally substituted aminocarbonyl C1-C6 alkyl, When R 1 , R 2 , R 3 and R 4 When one of the groups is not H, the other of the group is H, or R 1 , R 2 , R 3 , R 4 and R 5 Any of can be linked together to form an optionally substituted bicyclic heteroaryl; Ar 3 Also selected from optionally substituted bicyclic heteroaryl groups, in particular selected from the following: Where R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from: hydrogen; halogen; Hydroxyl; CN; CF3; CHF2; NH2; Alkoxy; Amino; carboxyl; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C3-C8 cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; acylamino; Urea group; Sulfonyl; as well as Sulfonylamino; R 14 Selected from: hydrogen; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; Optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl, carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C3-C8 cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl, and optionally substituted aminocarbonyl C3-C8 cycloalkyl; Ar 2 Selected from the following groups: Where R 15 , R 16 and R 19 are independently selected from: hydrogen; halogen; Hydroxyl; CN; CF3; CHF2; NH2; Alkoxy; Amino; carboxyl; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted alkenyl; Alkynyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; acylamino; Urea group; as well as sulfonyl; or Where R 15 , R 16 and R 19 Can be further selected from the following groups: wherein y, w, z and t are independently: an integer in the range of 1 to 3; Where h is: An integer in the range of 0 to 3; Where n is: An integer in the range of 0 to 4; Where G is selected from: N-R 23 ; O； S; and SO2; Where J is selected from: C(B)n; and NR 23 ; Wherein L is selected from: C-(B)n; N-R 23 ; O； S; and SO2; Where R 23 Selected from: hydrogen; aminocarbonyl; alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; C3-C8 cycloalkylC1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; and aminosulfonyl; Wherein B is selected from: hydrogen; halogen; Hydroxyl; CN; CF3; CHF2; NH2; Alkoxy; Amino; carboxyl; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C3-C8 cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; acylamino; Urea group; Sulfonyl; and Sulfonylamino; Where R 17 and R 18 Independently selected from: hydrogen; halogen; CN; CF3; CHF2; Alkoxy; Amino; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; Optionally substituted C3-C8 cycloalkyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted amino C3-C8 cycloalkyl; Acylamino; Urea group; Sulfonyl; aminosulfonyl; and Sulfonylamino; Where R 20 and R 22 Independently selected from: hydrogen; halogen; CN; CF3; CHF2; Alkoxy; Amino; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; Optionally substituted C3-C8 cycloalkylC1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; and optionally substituted aminoC3-C8cycloalkyl; Where R 21 Selected from: hydrogen; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; Heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkylC1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkylaryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; and Optionally substituted aminocarbonyl C3-C8 cycloalkyl; Where R 15 and R 16 can be linked together to form an optionally substituted bicyclic heteroaryl having the formula: Wherein X, Y and Z are each independently selected from: C(R 24 R 25 ); CH2C(R 24 R 25 ); C(=O); O； as well as N-R 26 ; Where R 24 and R 25 Each independently selected from: hydrogen; halogen; Hydroxyl; CN; CF3; CHF2; NH2; Alkoxy; Amino; carboxyl; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkylC1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; Acylamino; Urea group; Sulfonyl; as well as Sulfonylamino; Where R 24 and R 25 can be linked together to form an optionally substituted C 3- C8 cycloalkyl or optionally substituted heterocycloalkyl; Where R 26 Selected from: hydrogen; aminocarbonyl; Alkoxycarbonyl; Optionally substituted C1-C6 alkyl; Optionally substituted C3-C8 cycloalkyl; optionally substituted haloalkyl; optionally substituted heteroalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; Optionally substituted C3-C8 cycloalkylC1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl; Optionally substituted aryl C1-C6 alkyl; Optionally substituted heteroaryl C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; Amino C1-C6 alkyl; Optionally substituted carboxyl C1-C6 alkyl; Optionally substituted aminocarbonyl C1-C6 alkyl; Optionally substituted heterocycloalkyl C3-C8cycloalkyl; Optionally substituted aryl C3-C8 cycloalkyl; Optionally substituted heteroaryl C3-C8 cycloalkyl; Optionally substituted alkoxy C3-C8 cycloalkyl; Optionally substituted aminoC3-C8cycloalkyl; Optionally substituted carboxyl C3-C8 cycloalkyl; Optionally substituted aminocarbonyl C3-C8 cycloalkyl; and aminosulfonyl; Where R 15 and R 19 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 15 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 17 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein R 20 and R 21 can be joined together to form an optionally substituted bicyclic heteroaryl; and tautomers, geometric isomers, optically active forms and pharmaceutically acceptable salts thereof.

9. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is a NOX inhibitor represented by formula (V): in: X i Selected from CR 27 and N; Y i is selected from CH and N; A4 is selected from the following: -SIDE 31 -; -NR 30 -CHR 31 -; -CH2NR 30 -;as well as -CH2-O-; Where R 27 Select from the following: H； halogen; and optionally substituted C1-C6 alkyl; Where R 28 Select from the following: H； Halogens (e.g. chlorine, fluorine); optionally substituted alkoxy, for example 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 C1-C6 alkyl; Optionally substituted C1-C6 alkyl, for example optionally substituted methyl; Optionally substituted amino, for example optionally substituted C1-C6 alkylamino (for example 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 (eg methylpiperazin-1-yl); Optionally substituted C1-C6 alkylheterocycloalkyl, for example optionally substituted C1-C6 alkylpiperazine (eg methylpiperazin-1-yl); Optionally substituted amino C1-C6 alkyl; Optionally substituted alkoxy C1-C6 alkyl; -OR 34 ;as well as -NR 35 R 36 ; Where R 29 The formula is -(CHR 32 )n-A5; or R 29 With part of the CHR from A4 31 The optionally substituted aryl radicals form an optionally substituted ring selected from the group consisting of optionally substituted aryl radicals, such as optionally substituted phenyl radicals (e.g., phenyl radicals or phenyl radicals substituted with halogen radicals, such as fluoro radicals, phenyl radicals substituted with alkoxy radicals, such as methoxy radicals), and optionally substituted heteroaryl radicals, such as optionally substituted 1,3-dihydro-1H-indenyl radicals (e.g., 1-(dimethylamino)-2,3-dihydro-1H-inden-2-yl radicals, 2,3-dihydro-1H-inden-2-yl radicals, 2,3-dihydro-1H-inden-1-yl radicals), or optionally substituted 6,7-dihydro-5H-cyclopentapyridinyl radicals (e.g., 6,7-dihydro-5H-cyclopentapyridinyl radicals [b]pyridin-5-yl radicals, 2-methylpyridin- or optionally substituted 1,2,3,4-tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydronaphthyl) 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); or R 29 With some NR from A4 30 forming an optionally substituted ring selected from optionally substituted aryl and optionally substituted heteroaryl, such as optionally substituted isoindolyl (eg, isoindolin-2-yl, 1H-indol-1-yl); wherein n is an integer from 0 to 4 (e.g., 0, 1, 2, 3 or 4); Where R 30 is selected from H and optionally substituted alkyl, such as optionally substituted methyl; wherein A5 is an optionally substituted ring selected from 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. pyrimidinyl-2-yl); Where R 31 Select from the following: Η; Optionally substituted C1-C6 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-propanol, hydroxyisopropyl); Optionally substituted aminoC1-C6 alkyl, for example optionally substituted aminomethyl (eg dimethylaminomethyl, methylaminomethyl); Optionally substituted alkoxy C1-C6 alkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylmethyl, for example optionally substituted pyrrolidine C1-C6 alkyl (for example 3,3-difluoropyrrolidin-1-ylmethyl) or substituted piperazine C1-C6 alkyl (for example 4-methylpiperazin-1-ylmethyl) or heterocycloalkylethyl, for example optionally substituted morpholino C1-C6 alkyl (for example morpholinomethyl, morpholinoethyl) or optionally substituted pyrrolidine C1-C6 alkyl (for example pyrrolidinemethyl, pyrrolidineethyl); Optionally substituted aminocarbonyl (eg dimethylaminocarbonyl); Optionally substituted C2-C8 cycloalkyl, such as optionally substituted cyclopropyl; and Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (eg dimethylaminoethyl) or optionally substituted aminomethyl (eg dimethylaminomethyl); Where R 32 Select from the following: Η; Optionally substituted C1-C6 alkyl, for example optionally substituted methyl; an optionally substituted amino group; Optionally substituted C1-C6 alkylamino (eg, dimethylamino); and hydroxyl group; and For each repeating unit (CHR 32 ), R 32 The groups are independently selected; Where R 33 Select from the following: H； Halogens (such as fluorine); and Optionally substituted C1-C6 alkyl, for example methyl; Where R 34 Select from the following: H； Optionally substituted C1-C6 alkyl, for example optionally substituted methyl or optionally substituted ethyl (eg methoxyethyl, 2-(dimethylamino)ethyl, hydroxyethyl); Optionally substituted amino C1-C6 alkyl; optionally substituted heterocycloalkyl; Optionally substituted C2-C8 cycloalkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylmethyl, for example optionally substituted tetrahydropyranyl C1-C6 alkyl (for example tetrahydro-2H-pyran-4-yl) or optionally substituted piperidinylalkyl (for example 1-methylpiperidin-4-yl); Optionally substituted C2-C8 cycloalkylC1-C6 alkyl; optionally substituted alkoxy; Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (eg 2-(dimethylamino)ethyl); Optionally substituted aryl C1-C6 alkyl; and Optionally substituted heteroaryl C1-C6 alkyl; Where R 35 and R 36 Independently selected from: H； Optionally substituted C1-C6 alkyl, for example optionally substituted methyl (for example (1-methyl-1H-imidazol-4-yl)methyl) or optionally substituted ethyl (for example 2-methoxyethyl); Optionally substituted aminoC1-C6alkyl, for example optionally substituted aminoethyl (for example dimethylaminoethyl) or for example optionally substituted aminopropyl (for example dimethylamino)propyl); optionally substituted heterocycloalkyl, such as optionally substituted piperidine (eg 1-methylpiperidine); Optionally substituted C2-C8 cycloalkyl; Optionally substituted heterocycloalkyl C1-C6 alkyl, for example optionally substituted heterocycloalkylethyl, for example optionally substituted morpholino C1-C6 alkyl (for example 2-morpholinoethyl) or optionally substituted heterocycloalkylmethyl, for example optionally substituted tetrahydrofuran C1-C6 alkyl (for example tetrahydro-2H-pyran-4-ylmethyl) or piperidine C1-C6 alkyl (for example 1-methylpiperidin-4-yl)methyl or optionally substituted imidazolyl C1-C6 alkyl (for example (1-methyl-1H-imidazol-4-yl)methyl) optionally substituted C2-C8 cycloalkyl C1-C6 alkyl; optionally substituted alkoxy; Optionally substituted alkoxy C1-C6 alkyl, for example optionally substituted alkoxyethyl (eg 2-methoxyethyl); Optionally substituted aryl C1-C6 alkyl; and Optionally substituted heteroaryl C1-C6 alkyl, for example heteroaryl C1-C6 alkylmethyl, for example optionally substituted imidazolyl C1-C6 alkyl (for example 1-methyl-1H-imidazol-4-ylmethyl), optionally substituted amino C1-C6 alkyl, for example optionally substituted aminoethyl or optionally substituted aminopropyl (for example 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl)); and tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts and pharmaceutically active derivatives thereof.

10. The NOX inhibitor for use according to any one of claims 1 to 3, wherein the NOX inhibitor is selected from: 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-Benzyl-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 for use according to claim 8, wherein the NOX inhibitor is selected from: 5-(2-methoxypyridin-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-methoxypyridin-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-(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-cyclopropyloxypyridin-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-Bis(pyridin-4-yl)-1H-indole; 2-(Pyridin-3-yl)-5-(pyridin-4-yl)-1H-indole; 2,5-Bis(pyridin-3-yl)-1H-indole; 2-(1-methyl-1H-pyrazol-5-yl)-5-(pyridin-4-yl)-1H-indole; 5-(2-(4-methylpiperazin-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)-1-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)-1-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 for use according to any one of claims 1 to 3, wherein the NOx inhibitor is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.

13. A combination product comprising: (a) a NOX inhibitor or a pharmaceutically acceptable salt thereof, optionally wherein the NOX inhibitor is as defined in any one of claims 2 to 12; and (b) an ACE inhibitor or a pharmaceutically acceptable salt thereof, and / or an ARB or a pharmaceutically acceptable salt thereof, It is used to treat 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. A combination product for use according to claim 13 or claim 14, wherein the ACE inhibitor is selected from the group consisting of ramipril, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril and trandolapril.

16. A combination product for use according to any one of claims 13 to 15, wherein the combination product comprises: (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.

17. A combination product for use according to claim 13 or claim 14, wherein the ARB is selected from the group consisting of azilsartan, candesartan, eprosartan, sparsentan, irbesartan, losartan, Olmesartan, telmisartan and valsartan.

18. A combination product for use according to any one of claims 13 to 17, comprising a kit of parts comprising: (A) a pharmaceutical formulation comprising a NOX inhibitor or a pharmaceutically acceptable salt thereof, in admixture 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 (B) a pharmaceutical preparation comprising an ACE inhibitor or a pharmaceutically acceptable salt thereof, and / or an ARB or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, The components (A) and (B) are each provided in a form suitable for administration in combination with the other component.

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

20. A method of treating Alport syndrome, said method 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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