Nadph oxidase inhibitors, pharmaceutical compositions containing the same, and uses thereof

Abstract

Disclosed are compounds of Formula (I), or a geometric isomer, enantiomer, diastereomer, racemate, atropisomer, pharmaceutically acceptable salt, prodrug, or solvate thereof. The present invention further relates to compositions comprising compounds of Formula (I). The compounds and compositions described herein are useful for inhibiting the activity of NADPH oxidases.

Description

Background Technology

[0001] Reactive oxygen species (ROS) are various reactive molecules and free radicals derived from oxygen molecules, including superoxide ions (SOS). · O2 - ), peroxide ions ( · O2 -2 ), hydrogen peroxide (H2O2), hydroxyl group ( · OH) and hydroxyl ions (OH) - These molecules can be generated as byproducts during aerobic respiration or through oxidoreductases and metal-catalyzed oxidation reactions. Generally, ROS play important roles in immune and cellular signaling functions such as apoptosis, gene expression, and cell signaling pathways. However, excessive ROS production and / or insufficient ROS reduction can lead to ROS overload and oxidative stress.

[0002] When oxidative stress is generated, the systemic manifestation of ROS and the body's ability to eliminate reactive intermediates or repair damage after the reaction are out of balance. It has been proven that this imbalance will eventually lead to various acute and chronic diseases related to the cardiovascular system, inflammation, tumors and the nervous system.

[0003] Several enzymes involved in ROS generation exist both inside and outside the cell, such as nicotinamide adenine dinucleotide phosphate oxidase (NOX), xanthine oxidase, lipoxygenase, cyclooxgenase (COX), and substrate-coupled nitric oxide synthase. Among these enzymes, NOX can generate large amounts of ROS in non-cytophagocytes under both healthy and diseased conditions. This phenomenon warrants further investigation because inhibiting NOX activity could reduce oxidative stress without impairing the immune function of cytophagocytes. Summary of the Invention

[0004] This invention relates to a series of NADPH oxidase inhibitors, pharmaceutical compositions comprising said inhibitors, and methods for inhibiting NADPH oxidase (NOX).

[0005] In one embodiment, a compound having chemical formula (I) is provided, as well as a pharmaceutically acceptable salt, hydrate, or solvate of said compound.

[0006]

[0007] Where A represents selectivity and C1-C 20heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 ) replace; B is C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group, and B is selectively influenced by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, C1-C 20 Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22 SO2R 21 or SO2 (OR) 21 ) replace, wherein C1-C 10 Alkyl groups are selectively substituted with one or more halogens; R 11 R 12 R 21 R 22 Each is H, O, and Cl-C. 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens; It is a single or double bond; n is 0 or 1; X is N or C; Y is H, OH or NH2; Z is unsubstituted or C(O); R3 and R4 are each unsubstituted, H, C1-C 10 Alkyl or C6-C 20 Aryl group; and R5 is unsubstituted, H or C1-C. 10 alkyl.

[0008] In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises the compound having chemical formula (I) and at least one pharmaceutically acceptable excipient or carrier.

[0009] In yet another embodiment, a method for inhibiting NADPH oxidase (NOX) is provided. The method comprises administering to cells an effective amount of a compound having chemical formula (I), or an effective amount of a pharmaceutical composition comprising a compound as shown in formula (I) and at least one pharmaceutically acceptable excipient or carrier. Detailed Implementation

[0010] The foregoing and other aspects of this invention will be described in detail below in conjunction with other embodiments. It should be understood that this invention can be implemented in different ways and should not be construed as limited to the embodiments described herein. Rather, the embodiments listed herein provide a more thorough and complete description of the invention, and those skilled in the art will fully encompass the scope of the invention's technical solutions.

[0011] The terminology used herein is for describing specific embodiments of the invention only and is not intended to limit the scope of the invention. Unless otherwise stated, the singular terms such as “a” and “the” used herein and in the claims also refer to the plural.

[0012] As used herein, the words “comprising,” “including,” “having,” “characteristic,” or any other similar terms are intended to be non-limiting, and where otherwise limiting, the scope of such limitation shall prevail. For example, a composition, mixture, process, or method that includes a list of elements is not limited to those elements, but may include other elements not listed or inherent elements of the composition, mixture, process, or method.

[0013] The conjunction "composed of..." excludes any unstated elements, steps, or components. When this conjunction is used in a claim, it includes only the material itself, except for impurities that the material generally contains. When "composed of..." is located in a body clause of a claim, rather than immediately following the preamble, the scope is limited to the elements described in that clause, and other elements are not excluded from the overall scope of the claim.

[0014] In this invention, all carbon, hydrogen, oxygen, sulfur, halogen, or nitrogen contained in the functional groups and compounds may be selectively substituted by one or more corresponding isotopes, wherein the carbon isotopes include 12 C 13 C and 14 C; Hydrogen isotopes include hydrogen (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen); Oxygen isotopes include 16 O、 17 O、 18 O; sulfur isotopes include 32 S, 33 S, 34 S and 36S; nitrogen isotopes include 14 N and 15 N; Fluorine isotopes include 17 F and 19 F; Chlorine isotopes include 35 Cl and 37 Cl; Bromine isotopes include 79 Br and 81 Br.

[0015] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, octyl, and various branched alkyl isomers.

[0016] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having 1 to 3 carbon-carbon double bonds and containing 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. "Alkenyl" may also include polyenes, such as 1,2-propadienyl and 2,4-hexadienyl.

[0017] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having 1 to 3 carbon-carbon triple bonds and containing 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decanyne-4-yl, undecyn-3-yl, or dodecanyne-4-yl. "Alynyl" may also include groups containing multiple triple bonds, such as 2,5-hexadiynyl.

[0018] "Alkoxy" refers to -O-alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. This definition applies to all alkoxy groups described in this specification.

[0019] The term “halogen,” whether used succinctly or in compound terms (such as “halogenated alkyl”), or in descriptions such as “halogen-substituted alkyl,” includes fluorine, chlorine, bromine, or iodine. Furthermore, when the term “alkyl” is used in compound terms such as “halogenated alkyl”, or in descriptions such as “halogen-substituted alkyl,” the alkyl group may be partially or completely substituted with the same or different halogen atoms. Non-limiting examples of “halogenated alkyl” or “halogen-substituted alkyl” include F3C-, ClCH2-, CF3CH2-, and CF3CCl2-.

[0020] The S(O) and S(=O) structural formulas used in this paper represent sulfinyl groups. The SO2, S(O)2, and S(=O2) structural formulas used in this paper represent sulfonyl groups. The C(O) and C(=O) structural formulas used in this paper represent carbonyl groups. The CO2, C(O)O, and C(=O)O structural formulas used in this paper represent oxygen carbonyl groups. "CHO" stands for nail acyl group.

[0021] The term "aromatic" refers to a cyclic compound in which each atom lies in the same plane and has p-orbitals perpendicular to the plane of the ring. It also refers to a cyclic compound having (4n+2) π electrons forming the ring (where n is a positive integer), conforming to Hückel's rule. The term "aromatic ring or cyclic compound" refers to a carbocyclic or heterocyclic compound, or a ring or at least one ring of such a compound belonging to the aromatic family. The term "aromatic ring or cyclic compound" is also called "aromatic ring." An aromatic ring may contain a ring structure with 6 to 20 carbon atoms, including phenyl, benzyl, naphthyl, etc. An aromatic ring may also include substituted aryl groups, such as tolyl. The term "aromatic heterocyclic compound" refers to a heterocyclic compound in which the ring or at least one ring belongs to the aromatic family. The term "aromatic heterocyclic compound" is also called "aromatic heterocycle." An aromatic heterocycle may contain a ring structure with 1 to 20 carbon atoms and may further include at least one heteroatom selected from S, N, or O.

[0022] The term "carbocyclic group" refers to a saturated or unsaturated aromatic or non-aromatic ring, wherein the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 20-membered tricyclic ring. Carbocyclic groups may have bridged rings or spirocyclic rings. Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl. This definition applies to all carbocyclic groups described in this specification.

[0023] The term "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic cyclic compound, wherein the aromatic or non-aromatic cyclic compound may have a 1- to 8-membered monocyclic structure, a 4- to 12-membered bicyclic structure, or a 10- to 20-membered tricyclic structure, and includes at least one heteroatom selected from S, N, or O. The N or S atom selectively substituted on the heterocycle may be oxidized and enter various oxidation states. The carbocyclic ring may be linked by a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring.Non-limiting examples of heterocyclic groups include epoxyethyl, azacyclopropyl, oxzcyclobutyl, azacyclobutyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azacycloheptyl, pyridinyl, furyl, and thiophene. enyl, piperanyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, hexahydropyridinyl, morpholinyl, thiomorpholinyl, 1,3-dithia-, dihydrofuranyl l), dihydropyranyl, dithiacyclopentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridine The terms pyrrolopyridinyl, benzodihydrofuryl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, azatricyclo[5.3.1.1]dodecyl, azaadamantanyl, and oxaspiro[3.3]heptyl are used. This definition applies to all heterocyclic groups described in this specification.

[0024] As used herein, the term "selective" means that the event or situation described may but not necessarily occur, including the possibility that the event or situation may or may not occur. As used herein, the term "selectively substituted" describes an unsubstituted group, or a group containing at least one non-hydrogen substituent, wherein the non-hydrogen substituent does not impair the biological activity of the unsubstituted analog. Unless otherwise stated, the terms used herein shall be interpreted according to the following definitions. The term "selectively substituted" may be used interchangeably with "substituted or unsubstituted" and "(un)substituted". Unless otherwise stated, a selectively substituted group may have substituents at each substituted position, and each substitution reaction is independent of the others. For example, "a heterocycle selectively substituted with an alkyl group" means that the alkyl group may be present, but is not necessarily present, including the case where the heterocycle is substituted by or not substituted by the alkyl group.

[0025] As used herein, the term "pharmaceutically acceptable" (such as a carrier or excipient) means that the compound or composition is suitable for administration to a subject to achieve the therapeutic effects described herein, and that the subject will not experience harmful side effects at varying degrees of disease severity or treatment necessity. The term "carrier" refers to a material that does not cause significant irritation to an organism and does not impair the biological activity of a particular compound. The term "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of the compound. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycol, diluents, granules, lubricants, binders, and disintegrants.

[0026] As used herein, the term "effective dose" refers to the dose required to produce the desired effect (e.g., inhibition of NADPH oxidase) in a subject when each active ingredient is administered alone or in combination with one or more other active ingredients. Those skilled in the art will understand that the effective dose varies depending on the type and severity of the condition being treated, patient conditions (e.g., age, physical condition, body size, sex, and weight), duration of treatment, nature of concurrent therapy (if administered), specific route of administration, and other relevant factors familiar to healthcare professionals. These factors are common knowledge to those skilled in the art and can be addressed through routine experience. It is generally considered preferable to administer the maximum dose, i.e., the maximum safe dose under proper medical judgment, when administering individual ingredients or combinations of individual ingredients to a subject. However, those skilled in the art also understand that patients may insist on using lower or tolerable doses based on medical, psychological, or any other possible factors.

[0027] "Stereoisomers" refer to isomers with the same constituent molecules but different spatial arrangements, including cis-trans isomers, mirror-image isomers, and configurational isomers. The compounds of this invention can exist in one or more stereoisomer forms. Types of stereoisomers include mirror-image isomers, non-mirror-image isomers, racemic mixtures, blocked rotation isomers, and geometric isomers. Stereoisomers are isomers with the same constituent molecules but different atomic arrangements, including mirror-image isomers, non-mirror-image isomers, cis-trans isomers (also known as geometric isomers), and blocked rotation isomers. Blocked rotation isomers are formed when the free rotation of the single bonds of the isomers is restricted, resulting in a high rotational energy barrier, thus forming a group of isomers. Those skilled in the art will understand that stereoisomers, when enriched compared to other stereoisomers or isolated from other stereoisomers, can possess higher activity and / or bring positive benefits. Furthermore, those skilled in the art will understand how to separate, enrich, and / or selectively prepare the stereoisomers. The compounds of the present invention may exist as a mixture of stereoisomers, as individual stereoisomers, or as optically active structural forms.

[0028] The embodiments of the present invention described in the Summary of the Invention section also include the embodiments described below. In the following embodiments, unless further defined otherwise, the term "a compound of formula (I)" includes the substituents defined in detail in the Summary of the Invention section.

[0029] Example 1: A compound with chemical formula (I):

[0030]

[0031] Where A represents selectivity and C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 ) replace; B is C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group, and B is selectively influenced by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, C1-C 20Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22 SO2R 21 or SO2 (OR) 21 ) replace, wherein C1-C 10 Alkyl groups are selectively substituted with one or more halogens; R 11 R 12 R 21 R 22 Each is H, O, and Cl-C. 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens; It is a single or double bond; n is 0 or 1; X is N or C; Y is H, OH or NH2; Z is unsubstituted or C(O); R3 and R4 are each unsubstituted, H, C1-C 10 Alkyl or C6-C 20 Aryl group; and R5 is unsubstituted, H or C1-C. 10 alkyl.

[0032] Example 2: A compound having chemical formula (I), wherein A is selectively reacting with C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Mixed aromatic compounds.

[0033] Example 3: A compound with chemical formula (I), wherein A is selectively reactive with C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 )replace.

[0034] Example 4: A compound with chemical formula (I), wherein A is C6-C. 20 Aryl.

[0035] Example 5: A compound with chemical formula (I), wherein A is a C1-C... 20 heterocyclic fused C6-C 20 Aryl.

[0036] Example 6: A compound with chemical formula (I), wherein A is C1-C 20 Mixed aromatic compounds.

[0037] Example 7: A compound with chemical formula (I), wherein A is a C1-C... 20 C1-C heterocyclic fused 20 Mixed aromatic compounds.

[0038] Example 8: A compound having chemical formula (I), wherein A is a compound separated by one or more C1-C6 groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 ) Replaced C6-C 20 Aryl.

[0039] Example 9: A compound having chemical formula (I), wherein A is C1-C 20 heterocyclic fused C6-C 20 Aryl group, and further bound by one or more C1-C 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 )replace.

[0040] Example 10: A compound having chemical formula (I), wherein A is separated by one or more C1-C bonds. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 ) Replaced C1-C 20 Mixed aromatic compounds.

[0041] Example 11: A compound with chemical formula (I), wherein A is a C1-C... 20 C1-C heterocyclic fused 20 Heteroaryl groups, and further bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 )replace.

[0042] Example 12: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group.

[0043] Example 13: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl, C6-C 20 Aryl or C1-C 20 Mixed aromatic compounds.

[0044] Example 14: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group.

[0045] Example 15: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl, C6-C 20 Aryl or C1-C 20 Heterocyclic group.

[0046] Example 16: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl or C6-C 20 Aryl.

[0047] Example 17: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl or C1-C 20 Mixed aromatic compounds.

[0048] Example 18: A compound with chemical formula (I), wherein B is C1-C 10 Alkyl or C1-C 20 Heterocyclic group.

[0049] Example 19: A compound with chemical formula (I), wherein B is C6-C. 20 Aryl or C1-C 20 Mixed aromatic compounds.

[0050] Example 20: A compound with chemical formula (I), wherein B is C6-C. 20 Aryl or C1-C 20 Heterocyclic group.

[0051] Example 21: A compound with chemical formula (I), wherein B is C1-C 20 heteroaryl or C1-C 20 Heterocyclic group.

[0052] Example 22: A compound with chemical formula (I), wherein B is C1-C 10 alkyl.

[0053] Example 23: A compound with chemical formula (I), wherein B is C6-C. 20 Aryl.

[0054] Example 24: A compound with chemical formula (I), wherein B is C1-C 20 Mixed aromatic compounds.

[0055] Example 25: A compound with chemical formula (I), wherein B is C1-C 20 Heterocyclic group.

[0056] Example 26: A compound as described in any one of Examples 12-25, wherein B is reacted by one or more C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22 SO2R 21 or SO2 (OR) 21 )replace.

[0057] Example 27: A compound as in Example 26, wherein B is reacted by one or more C1-C 10 Alkyl substitution, and the C1-C 10 The alkyl group is replaced by one or more halogens.

[0058] Example 28: A compound as described in any one of Examples 8-11 and 26-27, wherein R 11 R 12 R 21 R22 Each is H, O, and Cl-C. 10 Alkyl or C6-C 20 Aryl.

[0059] Example 29: The compound as in Example 28, wherein R 11 R 12 R 21 R 22 Each is C1-C 10 Alkyl, and the C1-C 10 The alkyl group is replaced by one or more halogens.

[0060] Example 30: A compound with chemical formula (I), where n is 0.

[0061] Example 31: A compound with chemical formula (I), where n is 1.

[0062] Example 32: A compound with chemical formula (I), wherein X is N or C.

[0063] Example 33: A compound having chemical formula (I), wherein X is N and Y is H, OH or NH2.

[0064] Example 34: A compound with chemical formula (I), wherein X is N and Y is H.

[0065] Example 35: A compound having chemical formula (I), wherein X is C and Y is H, OH or NH2.

[0066] Example 36: A compound with chemical formula (I), wherein X is C and Y is H.

[0067] Example 37: A compound with chemical formula (I), wherein X is C and Y is OH.

[0068] Example 38: A compound with chemical formula (I), wherein X is C and Y is NH2.

[0069] Example 39: A compound having chemical formula (I), wherein Z is unsubstituent or C(O).

[0070] Example 40: A compound with chemical formula (I), wherein Z is unsubstituent.

[0071] Example 41: A compound with chemical formula (I), wherein Z is C(O).

[0072] Example 42: A compound having chemical formula (I), wherein R3 and R4 are each unsubstituented, H, C1-C 10 Alkyl or C6-C 20 Aryl.

[0073] Example 43: A compound having chemical formula (I), wherein R3 is unsubstituted and R4 is unsubstituted, H, C1-C 10 Alkyl or C6-C 20 Aryl.

[0074] Example 44: A compound having chemical formula (I), wherein R3 is unsubstituted and R4 is unsubstituted.

[0075] Example 45: A compound having chemical formula (I), wherein R3 is unsubstituent and R4 is H.

[0076] Example 46: A compound having chemical formula (I), wherein R3 is unsubstituent and R4 is C1-C. 10 alkyl.

[0077] Example 47: A compound having chemical formula (I), wherein R3 is unsubstituent and R4 is C6-C. 20 Aryl.

[0078] Example 48: A compound having chemical formula (I), wherein R3 is H and R4 is unsubstituent, H, C1-C 10 Alkyl or C6-C 20 Aryl.

[0079] Example 49: A compound having chemical formula (I), wherein R3 is H and R4 is unsubstituent.

[0080] Example 50: A compound having chemical formula (I), wherein R3 is H and R4 is H.

[0081] Example 51: A compound having chemical formula (I), wherein R3 is H and R4 is C1-C. 10 alkyl.

[0082] Example 52: A compound having chemical formula (I), wherein R3 is H and R4 is C6-C. 20 Aryl.

[0083] Example 53: A compound with chemical formula (I), wherein R3 is C1-C 10 Alkyl group and R4 is unsubstituted, H, C1-C 10 Alkyl or C6-C 20 Aryl.

[0084] Example 54: A compound with chemical formula (I), wherein R3 is C1-C 10 Alkyl group and R4 is unsubstituted.

[0085] Example 55: A compound with chemical formula (I), wherein R3 is C1-C 10Alkyl group and R4 is H.

[0086] Example 56: A compound with chemical formula (I), wherein R3 is C1-C 10 Alkyl and R4 is C1-C 10 alkyl.

[0087] Example 57: A compound with chemical formula (I), wherein R3 is C1-C 10 Alkyl and R4 is C6-C 20 Aryl.

[0088] Example 58: A compound with chemical formula (I), wherein R3 is C6-C 20 Aryl group with R4 being unsubstituent, H, C1-C 10 Alkyl or C6-C 20 Aryl.

[0089] Example 59: A compound with chemical formula (I), wherein R3 is C6-C 20 Aryl group and R4 is unsubstituent.

[0090] Example 60: A compound with chemical formula (I), wherein R3 is C6-C 20 Aryl group and R4 is H.

[0091] Example 61: A compound with chemical formula (I), wherein R3 is C6-C 20 Aryl and R4 is C1-C 10 alkyl.

[0092] Example 62: A compound with chemical formula (I), wherein R3 is C6-C 20 Aryl group and R4 is C6-C 20 Aryl.

[0093] Example 63: A compound having chemical formula (I), wherein R5 is unsubstituent, H or C1-C. 10 alkyl.

[0094] Example 64: A compound having chemical formula (I), wherein R5 is unsubstituent or H.

[0095] Example 65: A compound having chemical formula (I), wherein R5 is unsubstituted or C1-C. 10 alkyl.

[0096] Example 66: A compound having chemical formula (I), wherein R5 is H or C1-C. 10 alkyl.

[0097] Example 67: A compound with chemical formula (I), wherein R5 is unsubstituent.

[0098] Example 68: A compound with chemical formula (I), wherein R5 is H.

[0099] Example 69: A compound with chemical formula (I), wherein R5 is C1-C 10 alkyl.

[0100] The embodiments of the present invention (including Examples 1-69 above and any other embodiments described herein) can be combined in any way, and the variables described in the embodiments relate not only to compounds having chemical formula (I), but also to the starting compounds and intermediate compounds used to prepare compounds having chemical formula (I). Furthermore, the embodiments of the present invention (including Examples 1-69 above and any other embodiments described herein) and any combination of such embodiments relate to the compositions and methods of the present invention.

[0101] For combinations of Examples 1-69, please refer to the following examples:

[0102] Example A: A compound with chemical formula (I)

[0103]

[0104] Where A represents selectivity and C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 )replace;

[0105] B is C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group, and B is selectively influenced by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, C1-C 20 Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22SO2R 21 or SO2 (OR) 21 ) replace, wherein C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0106] R 11 R 12 R 21 R 22 Each is H, O, and Cl-C. 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0107] It can be a single bond or a double bond;

[0108] n is 0 or 1;

[0109] X is N or C;

[0110] Y is OH or NH2;

[0111] Z is unsubstituted or C(O);

[0112] R3 and R4 are both unsubstituted, H, C1-C. 10 Alkyl or C6-C 20 Aryl; and

[0113] R5 is unsubstituted, H or C1-C. 10 alkyl.

[0114] Example B: A compound as in Example A, and represented by chemical formula (II):

[0115]

[0116] Where A represents selectivity and C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR) 11 )replace;

[0117] B is C1-C10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group, and B is selectively influenced by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, C1-C 20 Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22 SO2R 21 or SO2 (OR) 21 ) replace, wherein C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0118] R 11 R 12 R 21 R 22 Each is H, O, and Cl-C. 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0119] Y is OH or NH2;

[0120] Z is unsubstituted or C(O); and

[0121] R5 is unsubstituted, H or C1-C. 10 alkyl.

[0122] Example C: A compound as in Example A, and represented by chemical formula (III):

[0123]

[0124] Where A represents selectivity and C1-C 20 heterocyclic fused C6-C 20 Aryl groups, or selectively related to C1-C 20 C1-C heterocyclic fused 20 Heteroaryl groups, and A is selectively bound by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, halogen, OR 11 C(O)R 11 C(O)OR 11 NR 11 R 12 SO2R 11 or SO2 (OR)11 )replace;

[0125] B is C1-C 10 Alkyl, C6-C 20 Aryl, C1-C 20 heteroaryl or C1-C 20 Heterocyclic group, and B is selectively influenced by one or more C1-C groups. 10 Alkyl, C6-C 20 Aryl, C1-C 20 Heterocyclic groups, halogens, OR 21 C(O)R 21 C(O)OR 21 NR 21 R 22 SO2R 21 or SO2 (OR) 21 ) replace, wherein C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0126] R 11 R 12 R 21 R 22 Each is H, O, and Cl-C. 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens;

[0127] Z is unsubstituted or C(O); and

[0128] R3 and R4 are both unsubstituted, H, C1-C. 10 Alkyl or C6-C 20 Aryl.

[0129] Example D: A compound as described in any of Examples A and C, wherein A is a substituted or unsubstituted C6-C. 20 Aryl, or with C1-C 20 heterocyclic fused C6-C 20 Aryl.

[0130] Example E: A compound as described in any of Examples A and D, wherein A is a compound labeled with one or more methoxy, (dimethylamine)phenyl, Br, OR 11 or C(O)R 11 Substituted phenyl, wherein R 11 H, O, Cl-C 10 Alkyl, C6-C 20 Aryl, wherein the C1-C 10 Alkyl groups are selectively substituted with one or more halogens.

[0131] Example F: A compound as described in any of Examples A and C, wherein A is a substituted or unsubstituted C1-C. 20 A heterocyclic group having at least one heteroatom selected from S, N or O.

[0132] Example G: A compound as in Example F, wherein A is pyrroline, furan, thiophene, pyridine, piperan, or thiopiperan.

[0133] Example H: A compound as described in any of Examples A and D, wherein A is a compound with C1-C2. 20 Heterocyclic fused substituted or unsubstituted C6-C 20 Aryl group having at least one heteroatom selected from S, N or O.

[0134] Example I: A compound as in Example H, wherein A is 1,3-benzodioxole, indoline, indole, indazole, benzofuran, benzo[c]thiophene, benzo[b]thiophene, 1,2-benzisoxazole, 1,2-benzisothiazole, 2,1-benzisothiazole, benzoxazole, or benzthiazole.

[0135] Example J: A compound as described in any of Examples A and B, wherein B is a substituted or unsubstituted C1-C. 10 alkyl.

[0136] Example K: A compound as in Example J, wherein B is methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

[0137] Example L: A compound as described in any of Examples A and B, wherein B is a substituted or unsubstituted C6-C. 20 Aryl.

[0138] Example M: ​​A compound as in Example L, wherein B is a compound surrounded by one or more methyl groups, CF3, halogen, pyrrolidine, or OR. 21 C(O)R 21 NR 21 R 22 or SO2R 21 Substituted phenyl groups.

[0139] Example N: A compound as in Example M, wherein R21 It is H, O, methyl, ethyl, n-propyl, or CF3; and R 22 It can be H or O.

[0140] Example O: A compound as described in any of Examples A and B, wherein B is a substituted or unsubstituted C1-C. 20 Heterocyclic group.

[0141] Example P: A compound as in Example O, wherein B is pyrroline, furan, thiophene, pyridine, piperan, or thiopiperan.

[0142] Example Q: A compound as described in any of Examples AP, where n is 0.

[0143] Example R: A compound as described in any of Examples A and Q, wherein X is C.

[0144] Example S: A compound as described in any of Examples A and B, wherein Y is H, OH or NH2.

[0145] Example T: A compound as described in any of Examples A and Q, wherein X is N.

[0146] Example U: A compound as in Example T, wherein Y is H or NH2.

[0147] Example V: A compound as described in any of Examples A, wherein Z is unsubstituted or C(O).

[0148] Example W: A compound as described in any of Examples AP, where n is 1.

[0149] Example X: A compound as in Example W, wherein R3 and R4 are each unsubstituted, H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl, benzyl, or naphthyl.

[0150] Example Y: A compound as in Example A, wherein R5 is unsubstituted, H, methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

[0151] Specific embodiments include compounds having chemical formula (I) selected from a group comprising:

[0152]

[0153]

[0154] Other important embodiments of the present invention are compositions comprising compounds formed from any of the foregoing embodiments, any other embodiments described herein, or any combination of the foregoing embodiments. The compositions can be formulated into oral pharmaceutical products using any safe, effective, and convenient dosage form. Preferably, the pharmaceutical composition may further comprise a pharmaceutically acceptable ingredient as defined in the preceding paragraphs. Numerous prior documents (such as the Handbook of Pharmaceuticals Excipients edited by Raymond C. Rowe, Paul J. Sheskey, and Marian E. Quinn) have disclosed oral and pharmaceutically acceptable salts, carriers, or excipients. In non-limiting embodiments, the pharmaceutically acceptable carrier or excipient may be selected from the group consisting of inert diluents, dispersants and / or granules, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and oils. The composition may optionally further comprise at least one other biologically active compound or formulation.

[0155] In one specific embodiment, the composition may be a pharmaceutical composition. The pharmaceutical composition may include, but is not limited to, a unit dose of an active ingredient (such as the compound of the present invention). For therapeutic purposes, the dosage unit may be a complete, independent pharmaceutical product, including but not limited to tablets or capsules, or a measurable volume of a solution, suspension, or other similar liquid containing a unit dose of the active ingredient. As used herein, the term "unit dose" refers to a dose of the active formulation administered to a subject in a single, but not limited to, oral, intravenous, intramuscular, intradermal, subcutaneous, intraspinal, transdermal, transplanted, sublingual, oral, rectal, vaginal, ocular, ear, nasal, inhalation, or nebulizer administration to inhibit NADPH oxidase (NOX) activity. Inhibition of NADPH oxidase (NOX) activity may require regular administration of a unit dose of the compound of the present invention to the subject, such as two or more unit doses per day, one unit dose with each meal, one unit dose every four hours or other time intervals, or only one unit dose per day.

[0156] Other important embodiments of the present invention are compositions for inhibiting NADPH oxidase (NOX) activity, comprising a compound formed from any of the above embodiments, any other embodiments described herein, or any combination of the foregoing embodiments, and at least one pharmaceutically acceptable excipient or carrier selected from the group consisting of inert diluents, dispersants and / or granules, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. The composition may optionally further comprise at least another biologically active compound or formulation. Embodiments of the present invention further include a method for inhibiting intracellular NADPH oxidase (NOX) activity, comprising administering to cells an effective amount of a compound or pharmaceutical composition of any of the above embodiments (as described herein).

[0157] Example

[0158] As described in schemes I to XII, one or more of the following methods and variations can be used to prepare compounds having chemical formula (I). Unless otherwise stated, the definitions of the components within the compounds are the same as those foregoing. The meanings of the abbreviations are listed below: DCM refers to dichloromethane, DMF refers to N,N-dimethylformamide, DMSO refers to dimethyl sulfoxide, EA refers to ethyl acetate, MeOH refers to methanol, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran. (NMR hydrogen spectrum) 1 H NMR) determination uses tetramethylsilane as a reference and reports the ppm value in the low field region; s refers to singlet, d refers to doublet, t refers to triplet, q refers to quartet, m refers to multiplet, dd refers to doublet, dt refers to doublet, and br s refers to broadened singlet.

[0159] A. Compound Synthesis

[0160] Various variations of the general synthesis methods described below will be apparent to those skilled in the art, and are all considered to be included within the scope of the claims of this invention.

[0161] A-1. Synthesis of compounds 2-20 and 24-27

[0162] Compounds 2-20 and 24-27 were synthesized using Scheme I shown in the figure below, details of which are described later.

[0163]

[0164] Option I

[0165] Step 1: Preparation of 2-(4-methoxyphenyl)-2-oxoethyl 2-amino-4,5-dimethoxybenzoate

[0166]

[0167] 2-Amino-4,5-dimethoxybenzoic acid (1.97 g, 10 mmol) was dissolved in DMF (20 mL), and potassium carbonate (1.38 g, 10 mmol) was added to the solution. The reaction mixture was heated to 90 °C and stirred for 1 hour, then cooled to 20 °C, and p-methoxy-2-bromoacetophenone (2.4 g, 10.5 mmol) was added, resulting in a slightly exothermic reaction that raised the temperature to 25-32 °C within 5 minutes. The reaction mixture was stirred for 30 minutes and heated to 50 °C, which was maintained for 30 minutes. The contents of the flask were then poured into a 100 g water-ice mixture. The precipitated solid was retained by filtration, rinsed with water, and dried. Ethanol was added to allow the dried solid to recrystallize further, forming compound 1, namely 2-(4-methoxyphenyl)-2-oxoethyl-2-amino-4,5-dimethoxybenzoate, with a yield of 3.3 g (95%).

[0168] Step 2: Preparation of 3-hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4(1H)-one 2,2,2-trifluoroacetate

[0169]

[0170] Compound 1 (0.6 g, 1.74 mmol) was dissolved in TFA, and the solution was heated and refluxed overnight until the reaction was complete. The reaction mixture was then cooled to room temperature, and the TFA was removed under vacuum. A water-ice mixture was added to the raffinate and stirred for 30 minutes. The solid was retained and washed with water and methanol to obtain 0.5 g (87%) of compound 2, namely 3-hydroxy-6,7-dimethyl-2-(4-dimethoxyphenyl)quinoline-4(1H)-one 2,2,2-trifluoroacetate.

[0171] Step 3: Preparation of 3,6,7-trihydroxy-2-(4-hydroxyphenyl)quinolin-4(1H)-one hydrobromide

[0172]

[0173] Compound 2 (0.2 g, 0.6 mmol) was added to 20 mL of hydrobromic acid (47%) to form a suspension, and heated to 100 °C in dry nitrogen for 23 hours. The solvent was then allowed to evaporate under reduced external pressure, and the product precipitated by crystallization (MeOH / EA = 1:3 was added during crystallization), finally yielding compound 3, namely 3,6,7-trihydroxy-2-(4-hydroxyphenyl)quinoline-4(1H)-one hydrobromide, in 25% yield.

[0174] Similarly, by replacing the p-methoxy-2-bromoacetophenone in step 1 with the desired material, compounds 4-20 and 24-27 can be generated through the above steps.

[0175] A-2. Synthesis of compounds 21 and 22

[0176] Step 1A: Preparation of 2-bromo-1-(2-ethoxyphenyl)ethan-1-one

[0177]

[0178] Option II

[0179] 5 mL of bromoethane (67 mmol) was added to suspensions of 1-(2-hydroxyphenyl)ethyl ketone (2.0 g, 14.69 mmol) and anhydrous potassium carbonate (2.6 g, 18.8 mmol), and DMF (80 mL). The mixture was heated to 50 °C until the initial ethyl ketone had completely reacted. The mixture was cooled to room temperature and filtered, and the solvent was removed using a rotary evaporator. The residue was purified by rapid column chromatography to obtain a colorless, oily 1-(2-ethoxyphenyl)ethyl ketone, using n-hexane / EA (9:1) as the eluent. The product yield was 95%.

[0180] In addition, 1-(2-ethoxyphenyl)ethyl ketone (2.55 g, 15.53 mmol) was dissolved in diethyl ether (40 mL), and the mixture was stirred at room temperature in the dark while bromine (0.7 mL, 14 mmol) was added dropwise. The reaction mixture was washed with saturated sodium carbonate aqueous solution. The product was dried over magnesium sulfate and then filtered. The filtrate was retained and volatiles were removed under low pressure to yield 2-bromo-1-(2-ethoxyphenyl)ethyl ketone. This compound was purified by rapid column chromatography (n-hexane / EA = 9:1), with a yield of 1.8 g (48%).

[0181] The obtained compounds were used in steps 1-3 of A-1 to replace p-methoxy-2-bromoacetophenone to prepare compounds 21 and 22.

[0182] A-3. Synthesis of Compound 23

[0183] Step 1A: Preparation of 2-bromo-1-(2-methylsulfonyl)phenyl)ethan-1-one

[0184]

[0185] Option III

[0186] A mixture of 1-(2-iodophenyl)ethan-1-one (1.06 g, 4.06 mmol), sodium methanesulfonate (0.83 g, 8.12 mmol), and copper iodide (77 mg, 0.4 mmol) in 10 mL of DMSO was heated to 100 °C in argon. The mixture was cooled using EA and water to separate the layers. The organic layer was separated first, and the aqueous layer was extracted twice using EA. The combined organic layers were washed with brine, dried over magnesium sulfate, and finally concentrated under vacuum to yield 1-(2-methylsulfonyl)phenyl)ethan-1-one, a yellow solid, in a yield of 0.77 g (95%).

[0187] At room temperature, 0.1 g (0.5 mmol) of 1-(2-methylsulfonyl)phenyl)ethyl ketone dissolved in EA (10 mL) was added dropwise to a mixture of EA (6 mL) and stirred with copper(II) bromide (0.22 g, 0.98 mmol). After the addition was complete, the mixture was heated at 80 °C for 18 hours. The mixture was then cooled to room temperature, filtered, and the precipitate was washed with EA (10 mL). The EA solution was treated with water to separate the organic layer, which was then dried with sodium sulfate and concentrated under vacuum to obtain the crude product 2-bromo-1-(2-methylsulfonyl)phenyl)ethyl ketone. This compound was purified by column chromatography (DCM / n-hexane = 2 / 1) to obtain a purified product of 0.115 g (82%).

[0188] The obtained compound was used in steps 1-3 of A-1 to replace p-methoxy-2-bromoacetophenone to prepare compound 23.

[0189] A-4. Synthesis of compounds 29 and 30

[0190]

[0191] Option IV

[0192] Preparation of 2-(2-aminophenyl)-3-hydroxy-6,7-dimethoxyquinolin-4(1H)-one

[0193]

[0194] Following the procedure in Scheme I, compound 29, 3-hydroxy-6,7-dimethoxy-2-(2-nitrophenyl)quinolin-4(1H)-one 2,2,2-trifluoroacetate, was obtained. Hydrazine hydrate (50%) (0.4 mL, 6.6 mmol) was added to an ethanol solution (12 mL) containing compound 29 (0.3 g, 0.66 mmol), and excess Raney nickel slurry was slowly added to water (1 mmol). The reaction mixture was stirred at 70 °C for 1 hour until no more bubbles were generated. The mixture was then cooled to room temperature and filtered through Celite diatomaceous earth. The filtrate was concentrated under low pressure and the residue was washed with water / MeOH to produce product 30, namely 2-(2-aminophenyl)-3-hydroxy-6,7-dimethoxyquinoline-4(1H)-one (0.19 g, 93%).

[0195] A-5. Synthesis of compounds 32 and 33

[0196]

[0197] Option V

[0198] Step 1: Preparation of bis(2-(4-methoxyphenyl)-2-oxoethyl)2-aminoterephthalate

[0199]

[0200] Potassium carbonate (1.38 g, 10 mmol) and p-methoxy-2-bromoacetophenone (2.4 g, 10.5 mmol) were added to a DMF (20 mL) solution of 2-aminoterephthalic acid (0.91 g, 5 mmol). The reaction mixture was heated at 50 °C and stirred for 18 hours. The contents of the flask were then poured into a 100 g water-ice mixture. The precipitated solid was retained by filtration and washed with water and methanol to yield compound 31, bis(2-(4-methoxyphenyl)-2-oxoethyl)-2-aminoterephthalate, in a yield of 1.9 g (80%).

[0201] Step 2: Preparation of 2-(4-methoxyphenyl)-2-oxoethyl 3-hydroxy-2-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-7-carboxylate 2,2,2-trifluoroacetate

[0202] Compound 31 (0.5 g, 1.1 mmol) was dissolved in TFA (12 mL), and the solution was heated and refluxed overnight until the reaction was complete. The reaction mixture was then cooled to room temperature, and the TFA was removed under vacuum. A water-ice mixture was added to the raffinate and stirred for 30 minutes. The solid was retained and washed with water and methanol to obtain 0.5 g (79%) of compound 32, namely 2-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-2-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-7-carboxylate 2,2,2-trifluoroacetate.

[0203] Step 3: Preparation of 3-hydroxy-2-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-7-carboxylic acid

[0204]

[0205] Add 5 mL of 1N lithium hydroxide aqueous solution (LiOH) (aq) The compound 32 (0.1 g, 0.17 mmol) was added to a 5 mL THF solution, stirred at room temperature, and allowed to stand overnight until the reaction was complete. The reaction mixture was then cooled to 0 °C, and 2 N HCl was slowly added until the pH reached 1-2. The solid was retained and washed with water and methanol to obtain a yield of 23 mg of compound 33, namely 3-hydroxy-2-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-7-carboxylic acid.

[0206] A-6. Synthesis of Compound 34

[0207]

[0208] Solution VI

[0209] A sodium ethoxide solution (2 mmol Na dissolved in 5 mL anhydrous ethanol) was added to a suspension of 2,3-dihydro-2,3-dioxo-1H-indole (0.17 g, 1.0 mmol) and 2-bromo-2-methoxyacetophenone (0.23 g, 1.0 mmol) in 5 mL anhydrous ethanol. The mixture was maintained at 0–5 °C for 2 hours. The reaction mixture was then heated to room temperature and stirred for 18 hours, followed by the addition of 2N HCl. (aq) The mixture was acidified and extracted with EA. The organic layer was dried with magnesium sulfate and concentrated under low pressure to obtain a crude product. The crude product was purified by column chromatography (EA / n-hexane = 1 / 2) to yield 0.1 g (30%) of compound 34, namely 3-hydroxy-6-methoxy-2-(2-methoxybenzoyl)quinolin-4(1H)-one.

[0210] A-7. Synthesis of compounds 35-38

[0211] Step 1: Preparation of 2-amino-1-(2-chlorophenyl)ethan-1-one hydrochloride

[0212]

[0213] Option VII

[0214] Sodium azide (1.2 g) was added to a DMSO solution in which 3.0 g (12.85 mmol) of 2-bromo-1-(2-chlorophenyl)ethan-1-one was completely dissolved. The mixture was stirred at room temperature for 15 hours and then diluted with water. EA was added to separate the layers, and each layer was extracted. The combined organic layers were dried over magnesium sulfate, filtered through a rotary evaporator, and concentrated to yield 2.3 g (11.8 mmol) of the compound 2-azido-1-(2-chlorophenyl)ethan-1-one.

[0215] Concentrated HCl (2 mL) was added to 100 mL of a MeOH solution containing 2.3 g (11.8 mmol) of 2-azido-1-(2-chlorophenyl)ethyl ketone and 0.5 g of 5% Pd / C, and stirred for 6 hours at room temperature and 1 atm of hydrogen. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated. The residue was not purified to obtain a yield of 2.2 g (10.73 mmol) of the product, namely 2-amino-1-(2-chlorophenyl)ethyl ketone hydrochloride.

[0216] Step 2: Preparation of 2-(2-chlorophenyl)-7,8-dimethoxy-3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one and 3-amino-2-(2-chlorophenyl)-6,7-dimethoxyquinolin-4(1H)-one

[0217]

[0218] Scheme VIII

[0219] A solution of 2-amino-1-(2-chlorophenyl)ethyl ketone hydrochloride (1.0 g, 4.9 mmol), indomethacin (0.9 g, 4.45 mmol), and sodium carbonate (0.6 g, 5.34 mmol) in water (20 mL) was stirred at 80 °C for 4 hours. After the solution cooled to room temperature, the precipitate was retained by filtration and washed with water and ether to produce compound 35, namely 2-(2-chlorophenyl)-7,8-dimethoxy-3,4-dihydro-5H-benzo[e][1,4]diazapine-5-one, in a yield of 870.0 mg (2.64 mmol).

[0220] A mixture of compound 35 (2-(2-chlorophenyl)-7,8-dimethoxy-3,4-dihydro-5H-benzo[e][1,4]diazapine-5-one) (100.0 mg, 0.30 mmol) and PPA (5 mL) was stirred at 150 °C for 2 hours. After the mixture cooled to 0 °C, it was poured into an aqueous sodium carbonate solution, and water was added after the foaming stopped. After stirring for 30 minutes, a solid product was filtered off. The product was washed with water and methanol to obtain compound 36, namely 3-amino-2-(2-chlorophenyl)-6,7-dimethoxyquinoline-4(1H)-one, in a yield of 10.0 mg (0.03 mmol).

[0221] Similarly, compounds 37-38 can be synthesized according to the methods described in schemes VII and VIII.

[0222] Synthesis of Compound 39 (A-8)

[0223]

[0224] Solution IX

[0225] Compound 39 was synthesized using scheme IX, which is similar to scheme I.

[0226] A-9. Synthesis of Compound 40

[0227]

[0228] Option X

[0229] Compound 25 (0.3 g, 1.3 mmol) and 3-(N,N-dimethylamino)phenylboronic acid (0.258 g, 1.56 mmol) were added to 3 mL of ethanol, followed by sodium carbonate (1.1 g, 10.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol). The reaction mixture was heated and refluxed overnight, and after cooling to room temperature, the raffinate was filtered off. The filtrate was extracted with EA and dried under vacuum. The dried raffinate was then treated with column chromatography (eluent: EA: n-hexane, 1:1) to obtain 0.42 g (80%) of compound 40.

[0230] A-10. Synthesis of compounds 41-44

[0231] Step 1: Preparation of 3-hydroxy-6,7-dimethoxy-2-(2-trifluoromethyl)phenyl)quinolin-4(1H)-one

[0232]

[0233] Option XI

[0234] 1N NaOH (0.1 mL) was added to an aqueous solution in which compound 17 (30.0 mg, 0.06 mmol) was completely dissolved, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the precipitate was retained and then washed with water to produce 13.0 mg (0.04 mmol) of free base compound 41, namely 3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one.

[0235] Step 2A: Preparation of 3-hydroxy-6,7-dimethoxy-2-(2-trifluoromethyl)phenyl)quinolin-4(1H)-onehydrocholoride

[0236]

[0237] Solution XII

[0238] To a MeOH / DCM (MeOH:DCM = 2:1) cosolvent solution in which compound 41 (0.29 g, 0.79 mmol) was completely dissolved, 2N HCl dissolved in diethyl ether was added, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the precipitate was retained and washed with diethyl ether to produce 0.17 g (0.42 mmol) of compound 42, namely 3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one hydrochloride.

[0239] Step 2B: Preparation of 3-hydroxy-6,7-dimethoxy-2-(2-trifluoromethyl)phenyl)quinolin-4(1H)-oneacetate

[0240]

[0241] Acetic acid (0.01 mL) was added to a MeOH / DCM (MeOH:DCM = 2:1) cosolvent solution in which compound 41 (3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one (28.0 mg, 0.08 mmol) was completely dissolved, and the mixture was stirred at 100 °C for 15 hours. The mixture was filtered, and the precipitate was retained and washed with diethyl ether to produce compound 43, namely 3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one acetate, in a yield of 6.0 mg (0.014 mmol).

[0242] Step 2C: Preparation of 3-hydroxy-6,7-dimethoxy-2-(2-trifluoromethyl)phenyl)quinolin-4(1H)-onemethanesulfonate

[0243]

[0244] Methylsulfonic acid (16.3 μL) was added to a MeOH / DCM (MeOH:DCM = 2:1) cosolvent solution in which compound 41 (3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one (75.0 mg, 0.21 mmol) was completely dissolved, and the mixture was stirred at room temperature for 15 hours. The mixture was filtered, and the precipitate was retained and washed with diethyl ether to produce compound 44, namely 3-hydroxy-6,7-dimethyl-2-(2-trifluoromethyl)phenyl)quinoline-4(1H)-one methanesulfonate, in a yield of 21.0 mg (0.046 mmol).

[0245] Synthesis of Compounds A-11, 45-50

[0246] Compounds 45-50 were synthesized according to the method described in scheme XI.

[0247] A-12. Synthesis of compounds 51-52

[0248] Compounds 51-52 were synthesized according to the method described in scheme XII.

[0249] B. Pharmaceutically acceptable salts

[0250] As used herein, the term "active formulation" includes pharmaceutically acceptable salts of the compounds described herein. A pharmaceutically acceptable salt is a salt that retains the intended biological activity of the parent compound without causing unintended toxicity. Examples of such salts include (a) acid addition salts composed of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and salts composed of organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.; and (b) salts composed of elemental ions, such as chloride, bromine, and iodide ions. In other specific embodiments, the pharmaceutically acceptable salt is composed of malic acid. In a specific embodiment, the pharmaceutically acceptable salt is composed of hydrochloric acid. The active formulation used to prepare the compositions of the present invention may also have a pharmaceutically acceptable free base form. The free base form of the compound is less soluble than its salts, thus the free base composition has the use of stabilizing the concentration of the active formulation in the target region. Undissolved active formulation near the target region cannot trigger a physiological response, but can store a gradually dissolving, bioavailable drug.

[0251] Compound Index

[0252] *Chemical Formula

[0253] *Exact Mass: Precise molecular weight

[0254] *Molecular Weight: Molecular Weight

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] Biological Examples of the Invention

[0272] Another aspect of the present invention relates to a method for inhibiting intracellular NADPH oxidase (NOX), comprising administering to the cells an effective amount of a compound or pharmaceutical composition as described in the embodiments of this invention.

[0273] As described in this case, NOX-active samples include enzymes; tissue or cell cultures; biological samples, such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; and biological samples, such as cell extracts, especially recombinant cells expressing NOX. Samples may be contained in any medium including water and organic solvent / water mixtures.

[0274] To determine the effect of the compound or composition of the present invention on inhibiting NOx activity after using it, any method including direct or indirect measurement of NOx activity can be used. Quantitative, qualitative, and semi-quantitative methods for determining NOx activity are all methods envisioned in this invention. Commonly used methods are one of the methods described below, but any other method, such as measuring in vivo physiological characteristics, may also be used.

[0275] The effectiveness of the compounds or compositions of the present invention in inhibiting NOx activity can be determined using conventional standard screening procedures. For example, the following general procedure can be used to determine the effectiveness of the compounds or compositions in inhibiting NOx activity.

[0276] Experiments using HT29 cells expressing NOX1 as subjects:

[0277] HT29 cells were cultured in T75 flasks (Corning). When cell coverage reached 70-80%, the cells were digested into small fragments using trypsin, collected with Hank's balanced salt solution (HBSS), and counted. A final volume of 70 μL of 1-2 x 10⁻⁶ cells was then added. 5 Cells were placed into each well of a 96-well white culture dish (Corning). 10 μL of GKT137831, DMSO, and the test compound were added to each well in the different cell culture dishes at 37°C, and the reaction was allowed to proceed for 30-60 minutes. The final concentration of the mixture was equivalent to 100 nM or 1000 nM of GKT137831 or the test compound, and 0.1% DMSO. Then, 20 μL of a mixture containing 100 μM luminol and 0.4 units (final concentration) of HRP was added. The luminescence values ​​were measured using a SpectraMax i3 multifunction reader (Molecular Devices, Sunnyvale, CA, USA). According to the experimental design, when the compound inhibits NOX1 activity, it reduces the amount of ROS generated in the cells, making the probe less likely to react with ROS, thus reducing the luminescence of the culture dish wells. Each compound was tested twice at concentrations of 100 nM and 1000 nM. The DMSO and GKT137831 wells were set as the negative control group and the positive control group, respectively, and the measured activities were set to 0% and 100%, respectively.

[0278] Experiments using HL60 cells expressing NOX2:

[0279] HL-60 cells with high NOX2 expression were stimulated with phorbol myristate acetate (PMA) to induce an oxidative burst assay. First, a specific O2-detecting assay was performed. 2-The chemical fluorescent probe L012 was used to measure the ROS generated in the experiment. DMSO was used to separate the HL-60 cell suspension into layers, and then L012 was added to achieve a final concentration of 100 μM. Next, 80 μL of the cell suspension was aliquoted into equal portions (each portion 2.5 x 10⁻⁶). 5 Cells were transferred into each well of a 96-well plate. A specific concentration of the test compound was added directly to each well, and the mixture was incubated in the dark at 37°C for 30–60 minutes. After incubation, 10 ng / mL PMA was added to induce cellular oxidative burst, and the chemiluminescence signal was recorded every 5 minutes using a SpectraMax i3 multifunction reader (Molecular Devices, Sunnyvale, CA, USA) for a total observation time of 60 minutes.

[0280] Experiments using HEK293 cells that overexpress NOX4:

[0281] Using Amplex TM Red Hydrogen Peroxide / Peroxidase Test Kit (Amplex) TM The Red Hydrogen Peroxide / Peroxidase Assay Kit (model A22188; Invitrogen, Carlsbad, CA, USA) was used to determine the concentration of extracellular H2O2 released from HEK293 cells stably overexpressing NOX4. NOX4-selected cells in the exponential growth phase were cut into small fragments using trypsin, followed by washing and uniform dispersion. After cell fragmentation, cells (3 x 10⁻⁶ cells) were... 4 Cells were resuspended in 100 μL of 1x Krebs-Ringer glucose phosphate (KRPG) buffer containing different concentrations of GKT137831 or the test compound, and then incubated at 37°C for 30 min. Cells were then mixed with 100 μL of Amplex Red formulation solution (KRPG buffer containing 50 μM Amplex Red and 0.1 units / mL HRP), and each experimental condition was measured twice. Samples were incubated in the dark at 37°C for 90 min and centrifuged at 2,500 g for 5 min. The supernatant was placed in a 96-well plate and measured using a SpectraMax i3 multifunction reader (Molecular Devices, Sunnyvale, CA, USA) at emission wavelengths of 530 nm and 590 nm, respectively. DMSO and GKT137831 wells were set as negative and positive control groups, respectively, and the measured activity was set as 0% and 100%, respectively.

[0282] Representative examples of compounds with chemical formula (I) that can inhibit NOx activity are shown in the table below. Wherein, A represents a NOx inhibition percentage greater than or equal to 80% by the compound; B represents a NOx inhibition percentage between 50% and 79% by the compound; C represents a NOx inhibition percentage between 20% and 49% by the compound; and D represents a NOx inhibition percentage less than or equal to 19% by the compound.

[0283] Percentage of NOx inhibited by the compound

[0284]

[0285]

[0286]

[0287] Those skilled in the art will understand that various modifications and variations can be made to the embodiments disclosed in this invention. For the purposes of this specification, the description and examples should be considered merely exemplary, and the actual scope of the invention is defined by the claims and their equivalents.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the group consisting of the following compounds: 。 2. A pharmaceutical composition, characterized in that, It comprises the compound as described in claim 1, and at least one pharmaceutically acceptable excipient or carrier.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the group consisting of the following compounds: 。

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