Substituted naphthyl p38 alpha map kinase inhibitors

Abstract

Disclosed are substituted naphthyl p38a mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and use of the substituted naphthyl p38a mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for the treatment of disease.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 164,664, filed March 23, 2021, pursuant to 35 USC § 119(e), which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates to substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for the treatment of diseases.

[0003] sequence list

[0004] This application contains a sequence list that has been electronically submitted in ASCII format, and is incorporated herein by reference in its entirety. The ASCII copy, created on March 21, 2022, is named 67LZ-000610PC-349166_SL.txt and is 755 bytes in size.

[0005] background

[0006] Mitogen-activated protein kinases (MAPKs) are serine / threonine protein kinases that process and regulate cellular properties that respond to a wide range of extracellular stimuli. These enzymes phosphorylate the OH groups of serine or threonine residues in proteins and play important roles in the regulation of cell proliferation, differentiation, survival, and apoptosis. Several different MAPKs have been identified in mammalian cells, including p38 MAPK.

[0007] p38 MAPKs are a class of MAPKs that respond to stress stimuli such as inflammatory cytokines and reactive oxygen species (ROS), and are involved in a wide range of signal transduction pathways that stimulate different biological functions. For example, p38 MAPKs have been found to play important roles in the regulation of pro-inflammatory signaling networks and the biosynthesis of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in immune cells.

[0008] Studies have shown that p38 MAPK contributes to the pathogenesis of chronic inflammation, leading to preclinical or clinical trials of p38 MAPK inhibitors for use in inflammatory diseases such as rheumatoid arthritis and asthma.

[0009] p38 MAPK comprises four isoforms (α, β, γ, and δ). p38α MAPK was the first p38 MAPK isoform identified and was initially thought to be a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. Inhibition of p38 MAPK has been shown to effectively alleviate symptoms of inflammatory diseases such as rheumatoid arthritis, cardiovascular disease, and inflammatory pain.

[0010] Many p38 MAPK catalytic inhibitors are ineffective and toxic, likely due to the loss of activity against non-inflammatory p38 and p38α-dependent counterregulatory responses. There is a growing expectation for p38α MAPK inhibitors that can selectively block certain p38α MAPK functions while preserving key counterregulatory and homeostatic functions for the treatment of inflammatory and neoplastic diseases. Summary of the Invention

[0011] According to the present invention, the compound has the structure of formula (6):

[0012] (6)

[0013] Or its pharmaceutically acceptable salt, wherein,

[0014] R 1 Selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol;

[0015] R 2 To replace C 5-8 Heterocyclic alkyl groups;

[0016] R 3 Selected from –C(=O)– and –S(=O)2–; and

[0017] R 4 Selected from –N(R) 5 )2, where each R 5 Independently selected from hydrogen and C 1-4 alkyl.

[0018] According to the present invention, a pharmaceutical composition comprises a compound according to the present invention or a pharmaceutically acceptable salt thereof.

[0019] According to the present invention, a method of treating a patient’s disease comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound according to the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is treated by inhibiting the p38α MAPK receptor. Attached Figure Description

[0020] The accompanying drawings described herein are for illustrative purposes only. The drawings are not intended to limit the scope of this disclosure.

[0021] Figure 1 The cell viability (black) and IC50 of SARS-CoV-2 cell lines treated with compound (4) are shown. 50 (Red) curve.

[0022] Figure 2 The cell viability (black) and IC50 of SARS-CoV-2 cell lines treated with compound (1) are shown. 50 (Red) curve.

[0023] Figure 3 The cell viability (black) and IC50 of SARS-CoV-2 cell lines treated with compound (2) are shown. 50 (Red) curve. Detailed Implementation

[0024] There is no hyphen ("-") between two letters or symbols used to indicate the attachment point of a part or substituent. For example, –CONH2 is attached via a carbon atom.

[0025] "Alkyl" refers to a saturated, branched, or straight-chain monovalent hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of alkyl groups include methyl; ethyl, such as ethane, vinyl, ethynyl; propyl, such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyl, such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and so on. The term "alkyl" includes groups having any degree or level of saturation. Right now A group having only a carbon-carbon single bond, a group having one or more carbon-carbon double bonds, a group having one or more carbon-carbon triple bonds, and a combination of carbon-carbon single, double, and triple bonds. The terms alkyl, alkenyl, and ynyl are used when referring to a specific level of saturation. An alkyl group can be C10-300. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, ethyl, or methyl.

[0026] "Alkoxy" refers to a free radical. OR, where R is an alkyl group as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be C10, C2 ... 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkyl, ethoxy, or methoxy.

[0027] "Aryl" itself, or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups encompass: 5- and 6-membered carbocyclic aromatic rings, such as benzene; bicyclic systems in which at least one ring is a carbocyclic ring and is aromatic, such as naphthalene, indane, and tetralin; and tricyclic systems in which at least one ring is a carbocyclic ring and is aromatic, such as fluorene. Aryl groups also encompass polycyclic systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocyclic alkyl ring. For example, aryl groups include benzene rings fused to 5- to 7-membered heterocyclic alkyl rings containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic systems in which only one ring is a carbocyclic aromatic ring, the radical carbon atom can be on either the carbocyclic aromatic ring or the heterocyclic alkyl ring. Examples of aryl groups include, but are not limited to, those derived from the following groups: acephenanthrylene, acenaphthene, phenanthrylene, anthracene, chamomile ring, benzene, chrysopraseene, fluorene, hexane, hexane, hexalene, as-indacene, s-indacene, indene, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, cyclopentadiene, pentanene, perylene, phenalene, phenalene, phenanthracene, pleiadene, pyrene, anthracene, rubiginene, benzophenanthrene, trinaphthalene, etc. The aryl group can be C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or phenyl. However, aryl does not in any way include or overlap with heteroaryl as defined separately herein.

[0028] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethenyl, 2-phenylvinyl, naphthylmethyl, 2-naphthylethenyl, 2-naphthylvinyl, naphthylbenzyl, 2-naphthylphenylethenyl, etc. When referring to a specific alkyl moiety, the nomenclature arylalkyl, arylalenyl, or arylynyl is used. Arylalkyl groups can be C16-3 ...7-16 Araneyl groups, For example The alkyl, alkenyl, or ynyl moiety of an aralkyl group is C 1-6 And the aryl moiety is C 6-10。 Aryl groups can be C 7-16 Aryl groups, For example The alkyl, alkenyl, or ynyl moiety of an aralkyl group is C 1-6 And the aryl moiety is C 6-10 Arylalkyl groups can be C 7-9 arylalkyl, wherein the alkyl moiety may be C 1-3 The alkyl group and the aryl group can be phenyl. The aryl alkyl group can be C10. 7-16 Arylalkyl, C 7-14 Arylalkyl, C 7-12 Arylalkyl, C 7-10 Arylalkyl, C 7-8 Arylalkyl or benzyl.

[0029] Bioavailability refers to the rate and amount of a drug that reaches the patient's systemic circulation after administration of the drug or its prodrug, and can be determined by evaluating, for example, a curve of plasma or blood concentration versus time. Parameters used to characterize a curve of plasma or blood concentration versus time include the area under the curve (AUC) and the time to maximum concentration (T). max ) and maximum drug concentration (C max ), where C max The maximum concentration of a drug in a patient's plasma or blood after administration of a given dose or form of drug, and T max To achieve the maximum concentration (C0) of a drug in a patient's plasma or blood after administration of a given dose or form of drug. max (Time)

[0030] "Oral bioavailability" (F%) refers to the fraction of an orally administered drug that reaches the systemic circulation. Oral bioavailability is the product of the absorption fraction, the fraction eliminated through the intestinal wall, and the fraction eliminated through the liver; and factors affecting bioavailability can be divided into physiological factors, physicochemical factors, and biopharmaceutical factors.

[0031] The term "compound" disclosed herein includes, in part, any specific compound within the disclosed formula. Compounds can be identified by their chemical structure and / or by their chemical name. Compounds are named using the ChemBioDraw Professional 17.1.0.105 (9) (CambridgeSoft, Cambridge, MA) naming program. In the event of a conflict between chemical structure and chemical name, the chemical structure determines the identity of the compound. Compounds described herein may contain one or more stereocenters and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (…). Right now Geometric isomers, enantiomers, diastereomers, or transisomers. Therefore, any chemical structure having a relative configuration described in whole or in part within the scope of this specification covers all possible enantiomers and stereoisomers of the compound shown, including the stereoisomeric pure form ( For example (Geometrically pure, enantiomerically pure, or diastereomeric pure) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be separated into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0032] The compounds and portions disclosed herein include optical isomers of the compounds and portions, their racemates, and other mixtures thereof. In such embodiments, a single enantiomer or diastereomer may be obtained by asymmetric synthesis or by resolution of a racemate. Resolution of a racemate may be accomplished, for example, by conventional methods, such as crystallization in the presence of a resolving agent or by chromatography, for example, using a chiral high-performance liquid chromatography (HPLC) column with a chiral stationary phase. Furthermore, the compounds include compounds having double bonds as single geometric isomers or mixtures thereof. Z )-and( E (or cis and trans forms).

[0033] Compounds and portions may also exist in several tautomer forms, including enols, ketones, and mixtures thereof. Therefore, the chemical structures described herein encompass all possible tautomer forms of the compounds presented. Compounds may exist in both unsolvated and solvated forms (including hydrated forms). Some compounds may exist in multiple crystalline, cocrystalline, or amorphous forms. Compounds include their pharmaceutically acceptable salts, or pharmaceutically acceptable solvates of any of the aforementioned free acid forms, and any of the aforementioned crystalline forms.

[0034] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl radical. Cycloalkyl groups can be C10, C20, C30, C40, C50, C60, C60, C70, C6 ... 3-8 cycloalkyl, C 3-5 cycloalkyl, C 5-6 Cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. The cycloalkyl group may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0035] "Cycloalkylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by a cycloalkyl group as defined herein. When referring to a specific alkyl moiety, the nomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylynyl is used. A cycloalkylalkyl group can be C10-3 ... 4-30 cycloalkyl alkyl For example The alkyl, alkenyl, or ynyl moiety of a cycloalkyl group is C 1-10And the cycloalkyl group of the cycloalkyl group is C 3-20 . Cycloalkyl alkyl can be C 4-20 cycloalkyl alkyl For example The alkyl, alkenyl, or ynyl moiety of a cycloalkyl group is C 1-8 Furthermore, the cycloalkyl moiety of the cycloalkyl group is C. 3-12 . Cycloalkyl alkyl can be C 4-9 Cycloalkylalkyl, wherein the alkyl moiety of the cycloalkylalkyl group is C10. 1-3 Alkyl, and the cycloalkyl moiety of the cycloalkyl group is C 3-6 Cycloalkyl. Cycloalkyl groups can be C16-264-3 ... 4-12 cycloalkylalkyl, C 4-10 cycloalkylalkyl, C 4-8 cycloalkyl alkyl and C 4-6 Cycloalkyl alkyl groups. Cycloalkyl alkyl groups can be cyclopropylmethyl (–CH2–cyclo-C3H5), cyclopentylmethyl (–CH2–cyclo-C5H9), or cyclohexylmethyl (–CH2–cyclo-C6H5). 11 The cycloalkyl group can be cyclopropylvinyl (–CH=CH–cyclo-C3H5), cyclopentylethynyl (–C≡C–cyclo-C5H9), etc.

[0036] "Cycloalkylheteroalkyl" itself, or as part of another substituent, refers to a heteroalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the alkyl group are independently replaced by one or more heteroatom groups of the same or different nature, and in which one of the hydrogen atoms bonded to the carbon atom is replaced by the cycloalkyl group. When referring to a specific alkyl moiety, the nomenclature cycloalkylheteroalkyl, cycloalkylheterenoyl, and cycloalkylheterynyl is used. In cycloalkylheteroalkyl groups, the heteroatom groups may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatom groups may be selected from –O– and –NH–, or the heteroatom groups may be –O– or –NH–.

[0037] "Cycloalkoxy" refers to a free radical. OR, where R is a cycloalkyl group as defined herein. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. A cycloalkoxy group can be C10-2000. 3-6 Cycloalkoxy, C 3-5 Cycloalkoxy, C 5-6 Cycloalkoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy.

[0038] "Disease" refers to any of the aforementioned diseases, conditions, illnesses, or symptoms.

[0039] As defined under 21 USC § 321(g)(1), “drug” means “(A) any article recognized in the Official Pharmacopeia of the United States, the Official Homeopathic Pharmacopeia of the United States, or the Official National Formulary or any supplement to any of them; and (B) an article intended for the diagnosis, cure, relief, treatment or prevention of disease in humans or other animals; and (C) an article intended to affect the structure or any function of the body of humans or other animals (other than food)... . . ."

[0040] "Halogen" refers to fluorine, chlorine, bromine, or iodine groups.

[0041] "Heteroalkoxy" refers to an alkoxy group in which one or more carbon atoms are replaced by heteroatoms. 1-6 Zykaloxy, C 1-5 Zykaloxy, C 1-4 Hexaalkoxy or C 1-3 Heteroalkoxy groups. In heteroalkoxy groups, the heteroatom group can be selected from –O–, –S–, –NH–, –NR– (where R is C). 1-6 Alkyl groups, –SO–, –SO2–, –Si–, and –B–, or heteroatomic groups may be selected from –O– and –NH–, or heteroatomic groups may be –O– and –NH–. 1-6 Zykaloxy, C 1-5 Zykaloxy, C 1-4 Hexaalkoxy or C 1-3 Heteroalkoxy.

[0042] "Heteroalkyl" itself, or as part of another substituent, refers to an alkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced by one or more heteroatom groups, either the same or different. Examples of heteroatom groups include –O–, –S–, –Si–, –B–, –NH–, –NR–, –O–O–, –S–S–, =N–N=, –N=N–, –N=N–NR–, –PR–, –P(O)OR–, –P(O)R–, –POR–, –SO–, –SO2–, and –Sn(R)2–, where each R is independently selected from hydrogen, C… 1-6 Alkyl, substituted C 1-6 Alkyl, C 6-12 Aryl, substituted C 6-12 Aryl, C 7-18 Arylalkyl 、 Replacement C 7-18 Arylalkyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl 、 C 3-7 Heterocyclic alkyl, substituted C 3-7 Heterocyclic alkyl, C 1-6Heteroalkyl, substituted C 1-6 Heteroalkyl, C 6-12 heteroaryl, substituted C 6-12 heteroaryl, C 7-18 Heteroarylalkyl and substituted C 7-18 Heteroarylalkyl. Each R can be independently selected from hydrogen and C. 1-3 Alkyl group. For example, referring to C 1-6 Heteroalkyl means a C-aryl group in which at least one carbon atom (and some associated hydrogen atoms) is replaced by a heteroatom. 1-6 Alkyl group. For example, C 1-6 Heteroalkyl groups include groups having five carbon atoms and one heteroatom, and groups having four carbon atoms and two heteroatoms. In heteroalkyl groups, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, and –B–, or the heteroatom group can be selected from –O– and –NH–, or the heteroatom group can be –O– or –NH–. The heteroalkyl group can be C… 1-6 Heteroalkyl, C 1-5 Heteroalkyl, or C 1-4 Heteroalkyl, or C 1-3 Heteroalkyl groups.

[0043] "Heteroaryl" itself, or as part of another substituent, refers to a monovalent heteroaryl radical derived by removing a hydrogen atom from a single atom of a parent heteroaryl ring system. Heteroaryl encompasses polycyclic systems having at least one heteroaryl ring fused to at least one other ring, which can be aromatic or non-aromatic. For example, heteroaryl encompasses bicyclic rings, where one ring is a heteroaryl ring and the second ring is a heterocyclic alkyl ring. In such fused bicyclic heteroaryl ring systems where only one ring contains one or more heteroatoms, the radical carbon can be located on an aromatic ring or a heterocyclic alkyl ring. When the total number of N, S, and O atoms in a heteroaryl exceeds one, the heteroatoms can be adjacent to each other or not. The total number of heteroatoms in a heteroaryl does not exceed two. In the heteroaryl group, the heteroatomic group can be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, and –B–, or the heteroatomic group can be selected from –O– and –NH–, or the heteroatomic group can be –O– or –NH–. The heteroaryl group can be selected from, for example, C. 5-10 heteroaryl, C 5-9 heteroaryl, C 5-8 heteroaryl, C 5-7 heteroaryl, C 5-6 Heteroaryl, C5 heteroaryl or C6 heteroaryl.

[0044] Examples of heteroaryl groups include those derived from the following groups: acridine, arsine, carbazole, α-carboline, chromane, chromene, cycloline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, naphthyl-2-diazine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrrolidinium, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthan, thiazolidinedione, and oxazolidine. Heteroaryl groups can be derived from, for example, thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, a heteroaryl group can be a C5 heteroaryl group and can be selected from furanyl, thiophene, pyrrole, imidazole, pyrazolyl, isothiazolyl, or isoxazolyl. A heteroaryl group can also be a C6 heteroaryl group and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0045] "Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and some associated hydrogen atoms) is replaced by a heteroatom. Heteroarylalkyl groups can be C16-3 ... 6-16 Heteroarylalkyl, C 6-14 Heteroarylalkyl, C 6-12 Heteroarylalkyl, C 6-10 Heteroarylalkyl, C 6-8 Heteroarylalkyl, or C7 heteroarylalkyl, or C6 heteroarylalkyl. In heteroarylalkyl, the heteroatomic group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si– and –B–, or the heteroatomic group may be selected from –O– and –NH–, or the heteroatomic group may be –O– or –NH–.

[0046] "Heterocyclic alkyl" refers to a moiety having two heterocyclic alkyl groups. Heterocyclic alkyl groups can be fused rings or spirocyclic compounds.

[0047] "Heterocyclic alkyl" itself, or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or different heteroatoms; or it refers to a parent aromatic ring system in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or different heteroatoms, such that the ring system violates Hückel's rule. Examples of heteroatoms that replace carbon atoms include N, P, O, S, B, and Si. Examples of heterocyclic alkyl groups include groups derived from epoxides, acridine, thiapropylcyclohexane, imidazoline, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, and quinine rings. Heterocyclic alkyl groups can be C5 heterocyclic alkyl groups and are selected from pyrrolidine, tetrahydrofuranyl, tetrahydrothiophenyl, imidazoalkyl, oxazolidine, thiazoalkyl, doxolanyl, and dithiohexylcyclopentyl. The heterocyclic alkyl group can be a C6 heterocyclic alkyl group and can be selected from piperidinyl, tetrahydropyranyl, piperazinyl, oxazinyl, dithiaalkyl, and dioxane. 3-8 Heterocyclic alkyl, C 3-8 Heterocyclic alkyl, C 3-5 Heterocyclic alkyl, C 5-6 Heterocyclic alkyl, C5 heterocyclic alkyl, or C6 heterocyclic alkyl. In heterocyclic alkyl, the heteroatom group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatom group may be selected from –O– and –NH–, or the heteroatom group may be –O– or –NH–.

[0048] "Heterocyclic alkyl alkyl" refers to a cycloalkyl alkyl group in which one or more carbon atoms (and some associated hydrogen atoms) of the cycloalkyl ring are independently replaced by the same or different heteroatoms. Heterocyclic alkyl alkyl can be C 4-12 Heterocyclic alkyl alkyl, C 4-10 Heterocyclic alkyl alkyl, C 4-8 Heterocyclic alkyl alkyl, C 4-6 Heterocyclic alkyl alkyl, C 6-7 Heterocyclic alkyl alkyl, or C6 heterocyclic alkyl alkyl, or C7 heterocyclic alkyl alkyl. In heterocyclic alkyl alkyl, the heteroatomic group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatomic group may be selected from –O– and –NH–, or the heteroatomic group may be –O– or –NH–.

[0049] "Parent aromatic ring system" refers to a ring-shaped conjugated system with 4n+2 electrons. (pi) Unsaturated cyclic or polycyclic ring systems (Hückel's rule) of electronic systems. The definition of "parent aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indene, indene, benzo[a]naphthalene, etc. Examples of parent aromatic ring systems include acephenanthrylene, acenaphthene, acephenanthrylene, anthracene, chamomile ring, benzene, acephenene, fluorene, hexane, hexane, hexalene, asymmetric-indane, symmetric-indane, indene, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, cyclopentadiene, pentaphenene, perylene, benzo[a]naphthalene, phenanthrene, benzo[a]naphthalene, pleiadene, pyrene, pyrane, rubidium, benzo[a]phenanthrene, trinaphthalene, etc.

[0050] "Hydrate" refers to the incorporation of water in stoichiometric proportions into the crystal lattice of the compounds described herein, resulting in the formation of an adduct. Methods for preparing hydrates include, but are not limited to, storage in an atmosphere containing water vapor, water-based dosage forms, or conventional pharmaceutical processing steps, such as crystallization. Right now Hydrates can be formed from water or a mixture of aqueous solvents, via freeze-drying, wet granulation, aqueous film coating, or spray drying. In some cases, hydrates can also form from crystalline solvates when exposed to water vapor or when anhydrous materials are suspended in water. Hydrates can also crystallize in more than one form, resulting in polymorphism.

[0051] "Parent aromatic ring system" refers to a system with conjugation Unsaturated cyclic or polycyclic ring systems of electronic systems. Specifically, the definition of "parent aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indene, indene, and benzo[a]naphthalene. wait Examples of parent aromatic ring systems include anthracene, acenaphthene, phenanthrene, anthracene, chamomile ring, benzene, cyclohexene, fluorene, hexaphenylene, phenanthrene, and hexalene. asymmetry -Yinda Province, symmetry -Index, Index, Naphthalene, Octaphene, Octaphene, Oleophane, Pentyl-2,4-diene, Pentylene, Cyclopentadiene, Pentylene, Dinaphthalene, Benzo[a]naphthalene, Phenylenol, Dinaphthalene, Heptoxyne, Pyrene, Pyrthane, Rubin, Benzo[a]phenanthrene and Trinaphthalene.

[0052] A "parent heteroaromatic ring system" refers to a system in which one or more carbon atoms (and any associated hydrogen atoms) are independently surrounded by the same or different heteroatoms to maintain the continuity of the aromatic system. - Characteristics of electronic systems and their correspondence to Hückel's rule (4n+2) - Aromatic ring systems where the number of electrons is replaced. Examples of heteroatoms replacing carbon atoms include N, P, O, S, Si, and B. 。 The definition of "parent heteroaromatic ring system" specifically includes fused ring systems, in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as arsene, benzodioxane, benzofuran, chromane, chromene, indole, dihydroindole, xanthene, etc. Examples of parent heteroaromatic ring systems include arsene, carbazole, etc. -Carboline, chromene, cinnamoline, furan, imidazole, indazole, indole, indoleline, indoleazine, isobenzofuran, isochromene, isoindole, isoindoleline, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, naphthalene-intercalated diazoxide, phenanthridine, phenanthroxoryl, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolizine, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthanil and thiazolidinedione, oxazolidine.

[0053] "Patient" refers to a mammal, such as a human.

[0054] "Pharmaceutical acceptable" means that a substance is approved by or may be approved by a regulatory agency of the federal or state government or is listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals and more specifically for use in humans.

[0055] "Pharmaceutically acceptable salts" are salts of compounds that possess the desired pharmacological activity of their parent compounds. These salts include acid addition salts, which are formed from an inorganic acid and one or more protonable functional groups within the parent compound, such as primary, secondary, or tertiary amines. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts can be formed from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc. One or more acidic protons present in the parent compound are replaced by metal ions. For example Alkali metal ions, alkaline earth metal ions, or aluminum ions, or combinations thereof, may be substituted; or replaced with organic bases such as ethanolamine, diethanolamine, triethanolamine, etc. NWhen coordinated with methylglucosamine, salts can be formed. Pharmaceutically acceptable salts can be hydrochloride salts. Pharmaceutically acceptable salts can be sodium salts. In compounds having two or more ionizable groups, pharmaceutically acceptable salts can contain one or more counterions, such as disalts, for example, dihydrochloride salts.

[0056] The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or amorphous form. Where a specific pharmaceutically acceptable salt is disclosed, it should be understood that that specific salt ( For example Examples of salts include salts containing hydrochloride, and other salts can be formed using techniques known to those skilled in the art. Furthermore, those skilled in the art will be able to convert pharmaceutically acceptable salts into corresponding compounds, free bases, and / or free acids using techniques generally known in the art.

[0057] "Pharmaceutical acceptable mediator" means a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or any combination thereof, which can be administered to a patient together with the compounds provided in this disclosure and does not destroy the pharmacological activity of the compound when administered in a dose sufficient to provide a therapeutically effective amount and is non-toxic.

[0058] "Pharmaceutical composition" refers to a compound provided in this disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable mediator, used to administer the compound provided in this disclosure or a pharmaceutically acceptable salt thereof to a patient. Pharmaceutically acceptable mediators are known in the art.

[0059] "Prevention" refers to reducing the risk of developing a disease or condition. Right now This means that the clinical symptoms of at least one disease will not develop in patients who may be exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease. In some embodiments, "prevention" means alleviating the symptoms of a disease by administering the compounds provided in this disclosure in a preventive manner. The application of therapeutic agents to prevent the onset of a disease is called "prevention." The compounds provided in this disclosure provide excellent prevention due to their low long-term side effects over long periods of time.

[0060] A "solvent" is a molecular complex of a compound with one or more solvent molecules in stoichiometric or non-stoichiometric amounts. These solvent molecules are commonly used in the pharmaceutical industry and are known to be harmless to patients, such as water or ethanol. The compound or a portion of its molecular complex with a solvent can be stabilized by non-covalent molecular forces such as electrostatic forces, van der Waals forces, or hydrogen bonds. The term "hydrate" refers to a solvate in which one or more solvent molecules are water.

[0061] "Solvate" refers to a solvent incorporated into the crystal lattice of a compound described herein in a stoichiometric proportion, resulting in the formation of an adduct. Methods for preparing solvates include, for example, storage in a solvent-containing atmosphere, a dosage form including the solvent, or conventional pharmaceutical processing steps, such as, for example, crystallization. Right now (from solvent or mixed solvent), vapor diffusion 。 In some cases, solvates can also form from other crystalline solvates or hydrates when exposed to solvents or when the material is suspended in a solvent. Solvates can crystallize in more than one form, resulting in solvate polymorphism.

[0062] "The compounds provided in this disclosure" refers to the compounds covered by formula (6) and their pharmaceutically acceptable salts. In some embodiments, the compounds provided in this disclosure may further include the compounds covered by formula (6), pharmaceutical salts of any of the above compounds, solvates, hydrates and / or prodrugs.

[0063] The compounds provided in this disclosure also include crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof. The terms "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0064] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Each substituent can be independently selected from deuterated, halogenated, –OH, –CN, –CF3, –OCF3, =O, –NO2, C 1-6 Alkoxy, C 1-6 Alkyl, –COOR, –NR2, and –CONR2; wherein each R is independently selected from hydrogen and C. 1-6 Alkyl group. Each substituent may be independently selected from deuterated, halogenated, –NH2, –OH, C 1-3 Alkoxy groups and C 1-3 Alkyl, trifluoromethoxy, and trifluoromethyl. Each substituent may be independently selected from deuterated, –OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Each substituent may be independently selected from deuterated, C 1-3 Alkyl, =O, C 1-3 Alkyl, C 1-3 Alkoxy and phenyl. Each substituent can be independently selected from deuterated, –OH, –NH2, C 1-3 Alkyl and C1-3 Alkyl group.

[0065] "Sustained release" refers to the release of a compound from a dosage form of a pharmaceutical composition at a rate that effectively achieves therapeutic or preventative concentrations of the compound or its active metabolites over a prolonged period of time, relative to the effect achieved by an immediately released formulation of the same compound administered via the same route of administration. In some embodiments, the release of the compound occurs over a period of at least about 4 hours, such as at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours, and in some embodiments, at least about 24 hours.

[0066] "Treatment" or "management" of a disease means preventing or improving the disease or at least one clinical symptom of the disease or condition, reducing the risk of developing the disease or at least one clinical symptom of the disease, reducing the development of the disease or at least one clinical symptom of the disease, or reducing the risk of developing the disease or at least one clinical symptom of the disease. "Treatment" or "management" also refers to physical ( For example Stabilization of observable symptoms), physiologically ( For example "Treatment" or "treatment" also refers to the suppression of disease in patients who may be exposed to or susceptible to the disease or condition, or the delay of the onset of the disease or the delay of the onset of at least one or more symptoms of the disease, even if the patient has not yet experienced or exhibited symptoms of the disease.

[0067] "Therapeutic effective amount" means the amount of a compound that, when administered to a patient for the treatment of a disease or at least one clinical symptom of a disease, is sufficient to affect the disease or its symptoms. "Therapeutic effective amount" can vary, for example, depending on the compound, the disease and / or the symptoms of the disease, the severity of the disease and / or the symptoms of the disease or condition, the age, weight, and / or health status of the patient to be treated, and the judgment of the prescribing physician. The appropriate amount in any given situation can be determined by a person skilled in the art or can be determined through routine experiments.

[0068] "Therapeutic effective dose" refers to a dose that provides effective treatment for a patient's disease or condition. Therapeutic effective doses can vary from compound to compound and from patient to patient, and can depend on a variety of factors, such as the patient's condition and route of delivery. Therapeutic effective doses can be determined according to standard pharmacological procedures known to those skilled in the art.

[0069] "Mediator" refers to a diluent, excipient, or carrier that is administered to a patient along with a compound. A mediator can be a pharmaceutically acceptable mediator. Pharmaceutically acceptable mediators are those known in the art.

[0070] Binding affinity refers to the strength of the binding interaction between a single biomolecule and its ligand / binding partner. Binding affinity is expressed as IC50. 50 The binding affinity can be determined by phage ELISA competitive assay.

[0071] "Modulate" refers to changes in the biological activity of biomolecules such as proteins, genes, peptides, or antibodies, where such changes may involve an increase in the biological activity of the biomolecule (such as increased activity, activating, activating, expressing, upregulating, and / or increasing expression) or a decrease in the biological activity of the biomolecule (such as decreased activity, antagonizing, inhibiting, inactivating, downregulating, and / or decreasing expression).

[0072] For example, the compounds described herein can modulate, for example, the inhibition of p38α MAPK protein. Compared to other MAPK or p38MAPK proteins, the compounds provided in this disclosure can selectively modulate, for example, the inhibition of p38α MAPK protein. Compared to other MAPK or p38 MAPK proteins, the compounds provided in this disclosure can selectively modulate, for example, the inhibition of p38α MAPK protein.

[0073] A "part" refers to a specific segment or functional group of a molecule. A chemical part is usually a recognized chemical entity that is embedded in or attached to a molecule.

[0074] Reference is now made in detail to certain compounds, compositions, and methods. The disclosed compounds, compositions, and methods are not intended to limit the claims. Rather, the claims are intended to cover all substitutions, modifications, and equivalents.

[0075] The compounds disclosed herein are selective inhibitors of the p38α MAPK protein. The pharmaceutical compositions disclosed herein include the compounds disclosed herein. The compounds and pharmaceutical compositions disclosed herein can be used to treat diseases, wherein the disease is treated by inhibiting the p38α MAPK protein.

[0076] Catalytic inhibitors of p38α MAPK can block the expression of pro-inflammatory cytokines and block other p38α MAPK signaling pathways that are important for establishing and maintaining homeostasis.

[0077] As an alternative to catalytic inhibitors, the compounds disclosed herein target the substrate-binding groove of p38α MAPK, which extends between two acidic plaques (referred to as CD and ED domains) of the MAPK receptor and is distinct from the DEF substrate-binding pocket. Downstream substrates, upstream activated kinases, and potentially scaffold molecules interact with p38 MAPK through these sites. The compounds disclosed herein can selectively bind to p38α MAPK instead of p38β, stabilizing endothelial barrier function in human pulmonary microvascular endothelial cells (HMVECL) and / or inhibiting lipopolysaccharide (LPS)-induced pro-inflammatory gene expression in THP-1 cells.

[0078] The compounds provided in this disclosure include R. 2 Compounds of formula (6) containing substituted fused rings and wherein R 2 Compounds comprising a substituted monocyclic ring of formula (6). Compounds provided by this disclosure may comprise a structure having formula (6):

[0079] (6)

[0080] Or its pharmaceutically acceptable salt, wherein,

[0081] R 1 Can be selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol;

[0082] R 2 It can be a substitute for C 5-12 Heterocyclic alkyl groups;

[0083] R 3 It can be selected from –C=O and –S(=O)2; and

[0084] R 4 Can be selected from –N(R) 5 )2, where each R 5 It can be independently selected from hydrogen and C. 1-4 alkyl.

[0085] In the compound of formula (6), each of one or more substituents may be independently selected from, for example, –OH, =O, –NH2, –NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Zykaloxy, C 1-6 Heterocyclic alkyl, C 5-6heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Alkoxy, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, C 1-6 Substituted alkoxy groups, substituted C groups 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatic compounds.

[0086] In the compound of formula (6), each of one or more substituents may be independently selected from –OH, =O, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Heteroalkyl, C 1-3 Heteroalkoxy, substituted C 1-3 Alkyl, substituted C 1-3 Alkoxy, substituted C 1-3 Heteroalkyl and substituted C 1-3 Heteroalkoxy.

[0087] In the compound of formula (6), each of one or more substituents may be independently selected, for example, –OH, =O, C. 1-3 Alkyl and C 1-3 Alkyl group.

[0088] In the compound of formula (6), each of one or more substituents can be =O.

[0089] In the compound of formula (6), each of one or more heteroatoms may be independently selected from N and O.

[0090] In the compound of formula (6), R 1 It can be C 1-4 Alkyl.

[0091] In the compound of formula (6), R 1 It can be ethanediyl.

[0092] In the compound of formula (6), R 1 It can be methanediol.

[0093] In the compound of formula (6), R 2 It can be a substituted C6 heterocyclic alkyl group.

[0094] In the compound of formula (6), each of one or more heteroatoms may be selected from O and N.

[0095] In the compound of formula (6), R 2 It can be 4-morpholino.

[0096] In the compound of formula (6), R 2 It can be a substituted 4-morpholino group.

[0097] In the compound of formula (6), R 2 It can be a 3-substituted 4-morpholino.

[0098] In the compound of formula (6), R 2 It can be a C5 heterocyclic alkyl, C6 heterocyclic alkyl, C7 heterocyclic alkyl, C8 heterocyclic alkyl, or C9 heterocyclic alkyl.

[0099] In the compound of formula (6), R 2 C 5-12 The nitrogen-heteroatom of the heterocyclic alkyl moiety is bonded to R 1 .

[0100] In the compound of formula (6), R 2 It can be a single-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 .

[0101] In the compound of formula (6), R 2 It can be a single-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 It also has at least one epoxy heteroatom.

[0102] In the compound of formula (6), R 2 It can be a single-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 It also has at least one epoxy heteroatom and at least one oxo (=O) substituent.

[0103] In the compound of formula (6), R 2 It can be a double-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 .

[0104] In the compound of formula (6), R 2 It can be a double-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 It also has at least one epoxy heteroatom.

[0105] In the compound of formula (6), R 2 It can be a double-ring C 5-12 Heteroalkyl rings, wherein the cyclic nitrogen heteroatom is bonded to R 1 It also has at least one epoxy heteroatom and at least one oxo (=O) substituent.

[0106] In the compound of formula (6), R 2 It can be selected from 4λ 2 -morpholino-3-one, 4λ 2 -morpholino-2-one, 1,3λ 2 -Oxazinidine-4-one, 1,3λ 2 -Oxazinidine-5-one, 1,3λ 2 -Oxazinyl-6-one, 3λ 2 -Oxazolidin-2-one, 3λ 2 -Oxazolidin-4-one and 3λ 2 -Oxazolidin-5-one.

[0107] In the compound of formula (6), each of the one or more substituents may be selected from –OH, =O and –N(R). 5 )2, where each R 5 It can be independently selected from hydrogen and C. 1-3 alkyl.

[0108] In the compound of formula (6), each of one or more substituents may be –OH.

[0109] In the compound of formula (6), each of one or more substituents can be =O.

[0110] In the compound of formula (6), each of one or more substituents may be –N(R 5 )2, where each R 5 It can be independently selected from hydrogen and C. 1-3 alkyl.

[0111] In the compound of formula (6), R 3 It can be selected from C(=O) and S(O)2.

[0112] In the compound of formula (6), R 3 It can be C (=O).

[0113] In the compound of formula (6), R 3 It could be S(O)2.

[0114] In the compound of formula (6), R 4 It can be bonded to the 3-, 4-, 5-, 6-, or 7-position of the naphthyl group.

[0115] In the compound of formula (6), R 4 It can be bonded to the 5-position of the naphthyl group.

[0116] In the compound of formula (6),

[0117] R 1 It can be C1-3 Alkyl;

[0118] R 2 It can be a substituted 4-morpholino group;

[0119] R 3 It can be selected from C(=O) and S(=O)2; and

[0120] R 4 Can be selected from –N(R) 5 )2, where each R 5 It can be independently selected from hydrogen and C. 1-3 alkyl.

[0121] In the compound of formula (6),

[0122] R 1 It can be methane dimethyl;

[0123] R 2 It can be a substituted 4-morpholino group;

[0124] R 3 It can be S(O)2; and

[0125] R 4 It can be –N(R) 5 )2, where each R 5 It can be independently selected from hydrogen and methyl.

[0126] In the compound of formula (6),

[0127] R 1 It can be methane dimethyl;

[0128] R 2 It can be a substituted 4-morpholino group;

[0129] R 3 It can be C (=O); and

[0130] R 4 It can be –N(R) 5 )2, where each R 5 It can be independently selected from hydrogen and methyl.

[0131] In the compound of formula (6), R 2 It can be a 3-substituted 4-morpholino.

[0132] In the compound of formula (6), in R 2 In the part, the substituent can be =O.

[0133] In the compound of formula (6), R 4It can be selected from –NH(–CH3) and –N(–CH3)2.

[0134] In the compound of formula (6), R 4 It can be –NH (–CH3).

[0135] In the compound of formula (6), R 4 It can be –N(–CH3)2.

[0136] The compounds in formula (6) can be selected from:

[0137] 4-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0138] 4-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0139] 4-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0140] 5-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0141] 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0142] 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0143] 6-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0144] 6-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; and

[0145] 6-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0146] Or a pharmaceutically acceptable salt of any of the above.

[0147] The compound of formula (6) can be 5-amino- N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (compound 5) or a pharmaceutically acceptable salt thereof:

[0148] (5).

[0149] The compound of formula (6) can be 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2) or a pharmaceutically acceptable salt thereof:

[0150] (2).

[0151] The compound of formula (6) can be 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3) or a pharmaceutically acceptable salt thereof:

[0152] (3).

[0153] The compound of formula (6) can be a solvate, a pharmaceutically acceptable salt, or a combination thereof.

[0154] In the compounds of formula (6), the pharmaceutically acceptable salt can be a hydrochloride salt.

[0155] The compound of formula (6) can be a pharmaceutically acceptable salt of the compound of formula (6), its hydrate, or a solvation of any of the above.

[0156] In some embodiments, the compounds provided in this disclosure are not compounds of formula (1) (5-(methylamino)- N -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide):

[0157] (1).

[0158] The compounds provided in this disclosure may be p38 MAPK inhibitors, such as selective p38 MAPK inhibitors and / or p38α MAPK protein activity modulators.

[0159] The compounds disclosed herein can be selective inhibitors of p38α MAPK. Compared to the catalytic binding sites of p38α MAPK, the selective p38α MAPK inhibitors disclosed herein have a higher binding affinity (lower IC50) to the p38α MAPK target pocket. 50The compounds provided by this invention can selectively inhibit p38α MAPK. The p38α MAPK inhibitor can bind to p38α MAPK near its substrate-binding groove, which extends between two acidic plaques (referred to as CD and ED domains). The binding pocket can be defined at least by residues R49, H107, L108, and K165 of p38α MAPK. The binding pocket and methods for determining selective binding to the selective binding pocket are described, for example, in U.S. Application No. 2020 / 0331874 A1 and U.S. Application No. 2019 / 0151324 A1.

[0160] Complementary techniques can be used to confirm the selective binding of the compounds provided in this disclosure to p38α MAPK. For example, selective p38α MAPK inhibitors can show a concentration-dependent increase in the melting temperature of p38α rather than p38P, as determined by differential scanning fluorometry (DSF) to detect ligand-induced protein stability. pass STD-NMR, which measures low-affinity protein / ligand binding by nonscalar magnetization transfer from protein to ligand protons, can be used to confirm the specific binding of compounds to p38α and localize the interaction to the aromatic ring at the binding site. p38α MAPK inhibitors induce a concentration-dependent increase in the p38α MAPK melting temperature. The melting temperature T can be measured at p38α MAPK inhibitor concentrations (such as 100 µM) between 1 nM and 1,000 μM. m The difference can be significant. For example, the difference in melting temperature can be from 0.1°C to approximately 2°C.

[0161] The compounds disclosed herein can interact with pockets near the ED substrate docking sites of p38 MAPK.

[0162] The compounds provided in this disclosure can bind to p38α MAPK near the substrate-binding groove of p38α MAPK, which extends between the CD and ED domains.

[0163] The compounds disclosed herein can inhibit MK2 phosphorylation through interaction with p38α MAPK.

[0164] The compounds disclosed herein can react with 4-chloro- N -(4-((1,1-thiomorpholino)methyl)phenyl)benzamide competitively binds to p38α MAPK.

[0165] The compounds disclosed herein have a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0166] The p38α MAPK inhibitors provided in this disclosure may have logP values ​​of, for example, -5 to 10, -3 to 8, 0 to 5, 0.1 to 3, 0.1 to 1, 0.5 to 1.5, 0.75 to 2, 1 to 2.5, or 1.75 to 3. LogP is a measure of drug solubility and is defined as the logarithm of the octanol / water partition coefficient of the drug.

[0167] Phosphorylation of MK2 may be involved in binding to the ED site adjacent to the target pocket in the p38α MAPK. The target pocket can be defined by amino acids R49, H107, L108, and K165 in the p38α MAPK. (This last part is a repetition of the previous sentence and can be omitted.)

[0168] The p38α MAPK inhibitors provided in this disclosure can at least partially inhibit MK2 phosphorylation. For example, Western blotting can be used to measure the inhibition of MK2 phosphorylation by the compounds provided in this disclosure in anisin-stimulated HeLa cells.

[0169] The p38α MAPK inhibitors provided in this disclosure can stabilize endothelial or epithelial barrier function. Endothelial barrier permeability can be measured by exposure to TNFα alone or in combination with high heat, followed by measurement of permeability to 10 kDa dextran. For example, endothelial barrier stability can be assessed by pretreatment with the compounds provided in this disclosure before and after permeability measurement, wherein stabilization can be expressed as a percentage reduction in the increase in permeability before and after pretreatment. The increase in permeability caused by 10 kDa dextran can be reduced from 5% to more than 100%, such as, for example, greater than 5%, greater than 10%, greater than 20%, greater than 40%, greater than 60%, greater than 80%, or greater than 100%.

[0170] The p38α MAPK inhibitors provided in this disclosure can modulate TNFα-induced gene expression in human lung microvascular endothelial cells (HMVECLs), as determined using, for example, RNASeq. For example, HMVECLs can be pretreated with an appropriate concentration of the p38α MAPK inhibitor for a period of time, followed by stimulation with TNFα for a period of time. The p38α MAPK inhibitors provided in this disclosure can inhibit genes such as PRRG4, TSLP, CCLI7, EXOC3L4, MMP9, IDOI, CXCL10, CD200, SLCI5A3, VDR, ILIB, GPR88, CD207, TCHH, HAS3, GBPIPI, MUC4, ELOVL7, CXCL11, GBP4, PLAIA, and / or CXCL5.

[0171] The effect of p38α MAPK inhibitors on the expression of inflammatory cytokines can be determined by pretreating PMA-differentiated THPI cells with p38α MAPK inhibitors, followed by LPS stimulation, and collecting RNA after a period of time for analysis using a PCR-based cytokine array. p38α MAPK inhibitors can suppress the expression of multiple genes, such as IL-1A, IL-8, TNFSF8, CXCL5, CCL7, CCLI7, TNFSF9, IL-1B, CXCL1, TNFSF5, CCL5, CCL4, CCL20, CXCL2, TNF, or BMP6. p38α MAPK inhibitors can also suppress Smad3 expression, which drives Foxp3 T cell differentiation and inhibits interferon-γ. The reduction in inflammation can be measured by comparing the fold change in mRNA levels at different concentrations of p38α MAPK inhibitors with unstimulated PMA-differentiated THPI cells.

[0172] Some compounds of formula (6) may be corresponding compounds having an amine substituent on the naphthyl moiety. N Metabolites of -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide. For example, compounds of formula (2) (5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; compound 2) and compounds of formula (3) (5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; compound 3) can be compound (4) (5-(dimethylamino)- N -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide; metabolites of compound (4):

[0173] (2)

[0174] (3)

[0175] (4).

[0176] After compound (4) is administered to the subject, compound (4) can... in vivo Metabolism provides compounds of formula (3), formula (2), and formula (1) (5-(methylamino)- N -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (compound 1)):

[0177] (1).

[0178] The compounds of formula (6) can be synthesized using methods known in the art.

[0179] For example, (4-aminophenyl)methanol (A) can react with Boc2O in CH2Cl2 to provide the Boc-protected compound (4-(hydroxymethyl)phenyl)carbamic acid. Uncle Butyl ester (B). The Boc-protected intermediate (B) can react with PDC in CH2Cl2 to provide (4-acetylphenyl)carbamic acid. Uncle Butyl ester (C). Intermediate (C) can be reacted with a suitable substituted morpholine in the presence of NaBH(OAc)2 in an organic solvent such as 1,2-dichloroethane (DCE) to provide the corresponding substituted (4-(morpholinomethyl)phenyl)carbamic acid. Uncle Butyl ester (D). Intermediate (D) can be deprotected in the presence of 4M HCl in methanol solution to provide the corresponding substituted 4-(morpholinomethyl)aniline dihydrochloride (E). Salt (E) can be reacted with suitable substituted... S -(naphthyl-1-yl)thiochlorate (F) N,N - The reaction in dimethylformamide (DMF) in the presence of diisopropylethylamine (DIPEA) provides the corresponding compound of formula (6).

[0180] The compounds provided in this disclosure can be incorporated into pharmaceutical compositions for administration to patients via any suitable route of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or local administration. The pharmaceutical compositions provided in this disclosure can be injectable formulations. The pharmaceutical compositions provided in this disclosure can be injectable intravenous formulations. The pharmaceutical compositions provided in this disclosure can be oral formulations. Oral formulations can be oral dosage forms. The pharmaceutical compositions can be formulated for intravenous or subcutaneous administration.

[0181] The pharmaceutical compositions provided in this disclosure may comprise a therapeutically effective amount of a compound of formula (6) and a suitable amount of one or more pharmaceutically acceptable mediators to provide a composition for appropriate administration to a patient. Suitable pharmaceutical mediators and methods for preparing pharmaceutical compositions are described in the art.

[0182] Assessing individual patient responses to therapy and qualifying patients for optimal treatment is one of the greatest challenges facing modern healthcare and drives the trend toward personalized medicine. Compounds of formula (6) can exhibit targeting selectivity, for example, targeting selectivity for certain cancers and immune cells. Radiolabeling compounds of formula (6) for use in positron emission tomography (PET) or single-photon emission computed tomography (SPECT) can be used to predict treatment targeting based on single-study, case-patient analysis, thereby excluding patients not expected to benefit from treatment. PET / SPECT scans using compounds of formula (6), once correlated with concentration, can provide a three-dimensional distribution map, which can then be used for macroscopic dose calculations.

[0183] The compounds of formula (6) and / or their pharmaceutical compositions are generally effective in achieving the intended purpose when used. For the treatment of diseases such as cancer, autoimmune diseases, or inflammatory diseases, the compounds of formula (6) and / or their pharmaceutical compositions are administered or applied in therapeutically effective amounts.

[0184] The amount of the compound of formula (6) and / or any of the above-mentioned pharmaceutical compositions that effectively treat a specific condition or disease will depend in part on the nature of the condition or disease and can be determined by standard clinical techniques known in the art. Furthermore, alternatively, [the following methods may be used]. in vitro or in vivo Measurements are used to help determine the optimal dosage range. Among other factors, the amount of the compound of formula (6) and / or any of the above-mentioned pharmaceutical compositions will depend on the patient being treated, the patient's weight, the severity of the ailment, the method of administration, and the prescribing physician's judgment.

[0185] Before being used on humans, it was possible in vitro and in vivo The desired therapeutic activity of the compound of formula (6) is determined. For example, in vitro Assays can be used to determine whether the administration of a specific compound or combination of compounds is preferred. Animal model systems can also be used to demonstrate the efficacy and safety of the compound.

[0186] In some embodiments, a therapeutically effective dose of a compound of formula (6) and / or any of the above-described pharmaceutical compositions will provide therapeutic benefit without causing significant toxicity. The toxicity of a compound of formula (6) and / or any of the above-described pharmaceutical compositions can be determined using standard pharmaceutical procedures and can be readily determined by a person skilled in the art. The dose ratio between toxicity and therapeutic effect is the therapeutic index. Compounds of formula (6) and / or any of the above-described pharmaceutical compositions exhibit a particularly high therapeutic index in treating diseases and conditions. The dosage of compounds of formula (6) and / or any of the above-described pharmaceutical compositions can be within a cyclic concentration range that includes the effective dose with minimal toxicity.

[0187] The compounds and pharmaceutical compositions provided in this disclosure may be included in a kit for administering the compound to a patient for therapeutic purposes. The kit may include a pharmaceutical composition comprising a compound provided in this disclosure for administration to a patient, and instructions for administering the pharmaceutical composition to the patient. The kit may be suitable for treating cancer, treating autoimmune diseases, or treating inflammatory diseases. A kit for treating cancer, for treating autoimmune diseases, or for treating inflammatory diseases may include the compounds or pharmaceutical compositions provided in this disclosure, and instructions for administering the compound to a patient.

[0188] The compounds and pharmaceutical compositions provided in this disclosure may be included in containers, packages or dispensers together with instructions for use.

[0189] The instructions provided with the kit may be printed and / or supplied as, for example, electronically readable media, videotapes, audiotapes, flash memory devices, or may be published on an Internet address or distributed as electronic information to patients and / or healthcare providers.

[0190] The compounds and pharmaceutical compositions disclosed herein can be used to treat patients’ diseases.

[0191] The compounds and pharmaceutical compositions provided in this disclosure can be used to treat diseases in which the etiology is associated with the upregulation and / or downregulation of the p38α MAPK protein.

[0192] The methods provided in this disclosure include treating a patient’s disease, the method comprising administering a therapeutically effective amount of the compound or composition provided in this disclosure to a patient in need of such treatment, wherein the disease is treated by inhibiting the p38α MAPK protein.

[0193] The p38 mitogen-activated protein kinase (MAPK) family of stress- and cytokine-activated kinases is involved in the pathogenesis of many human diseases, including cancer, rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI). Among the many important biological processes regulated by p38MAPK, the regulation of endothelial and epithelial barrier function, leukocyte transport, and cytokine expression are central to the pathogenesis of acute and chronic inflammatory diseases.

[0194] The compounds and pharmaceutical compositions disclosed herein can be used to treat cancer in patients. Cancer can be, for example, a solid tumor or a metastatic tumor.

[0195] The methods provided in this disclosure include methods for treating cancer in patients, the methods comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions provided in this disclosure to a patient in need of such treatment.

[0196] Suitable examples of cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, and papillary... Cancer, pineal gland tumor, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovial sarcoma, testicular cancer, small cell lung cancer, laryngeal cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, and Hodgkin's disease.

[0197] Examples of suitable cancers include pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, Wilms' tumor, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, stomach cancer, colon cancer, prostate cancer, genitourinary cancer, thyroid cancer, esophageal cancer, myeloma, multiple myeloma, adrenal cancer, renal cell carcinoma, endometrial cancer, and adrenal gland cancer. Cortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, or retinoblastoma. Cancer can be acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, prostate cancer, rhabdomyosarcoma, and so on. Colorectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovial sarcoma, testicular cancer, small cell lung cancer, laryngeal cancer, uterine cancer, Wilms' tumor, leukemia, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

[0198] The compounds and pharmaceutical compositions disclosed herein may be used to treat one or more of the following cancers: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumors, basal cell carcinoma (non-melanoma), B-cell lymphoma, bladder cancer, bone cancer, brain and spinal cord tumors, brainstem cancer, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, head and neck cancer, embryonal tumors of the central nervous system, cerebellar astrocytoma, astrocytoma / malignant glioma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, and desmoplastic small round cell tumor. Ductal carcinoma, dysplastic carcinoma, endocrine pancreatic tumors (islet cell tumors), endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing family tumors, extracranial germ cell tumors, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic tumors, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, lymphoblastic hematopoietic tumors, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway gliomas, ID-related lymphoma, intraocular melanoma, islet cell tumors, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, male breast cancer, malignant fibrous histiocytoma, malignant germ cell tumor, malignant mesothelioma Medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, spinal dysplasia, myeloproliferative neoplasms, nasal and paranasal sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal carcinoma, osteosarcoma, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumor, low-malignancy ovarian tumor, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papilloma, paraganglioma, paranasal sinus and nasal cavity carcinoma, parathyroid carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasmacytoma / multiple myeloma Tumors, pleural pulmonary blastoma, breast cancer during pregnancy, primary central nervous system lymphoma, primary liver cancer, occult primary metastatic squamous neck cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, respiratory tract cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Cezari syndrome, skin cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma (non-melanoma), gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma, urethral cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, and any of the above systemic and central metastases.

[0199] The methods disclosed herein include methods for treating cancer, wherein the cancer is selected from breast cancer and melanoma.

[0200] The methods provided in this disclosure include methods for treating inflammatory diseases in patients, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need of such treatment.

[0201] Examples of inflammatory diseases include allergies, Alzheimer's disease, anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma, autism, carpal tunnel syndrome, celiac disease, colitis, Crohn's disease, congestive heart failure, dermatitis, diabetes, diverticulitis, eczema, fibromyalgia, fibrosis, gallbladder disease, gastroesophageal reflux disease, Hashimoto's thyroiditis, heart attack, hepatitis, irritable bowel syndrome, kidney failure, lupus, multiple sclerosis, nephritis, neuropathy, pancreatitis, Parkinson's disease, psoriasis, polymyalgia rheumatica, rheumatoid arthritis, scleroderma, stroke, surgical complications, and ulcerative colitis.

[0202] The methods provided in this disclosure include methods for treating inflammatory diseases in patients, wherein the inflammatory diseases are selected from, for example, acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation of hypercholesterolemia, pain, diabetes (including type 1 and type 2 diabetes) and rheumatoid arthritis.

[0203] The methods provided in this disclosure include methods for treating autoimmune diseases in patients, the methods comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions provided in this disclosure to a patient in need of such treatment.

[0204] The compounds or pharmaceutical compositions disclosed herein can be used to treat autoimmune diseases. Autoimmune diseases can be defined as human diseases in which the immune system attacks its own proteins, cells, and / or tissues. For example... The Autoimmune Diseases A comprehensive list and review of autoimmune diseases can be found in Rose and Mackay, 2014, Academic Press.

[0205] Examples of autoimmune diseases include Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBN nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic disorders, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear diseases, autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Balo's disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Chagas disease, cicatricial pemphigoid, and Co. Gan syndrome, cold agglutinin disease, congenital heart disease, Coxsackie myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Devic disease, discoid lupus, Derester syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpest syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schoenlein purpura, herpes gestationis or pemphigoid of pregnancy, hypogammaglobulinemia, IgA nephropathy, IgG4 Related diseases include: sclerosis, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, sclerosing lichen, woody conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Moren's keratitis, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigus, optic neuritis, relapsing rheumatism, PANDAS, paraneoplastic cerebellar degeneration, and paroxysmal nocturnal hemoglobinuria. Urine, Paro syndrome, ciliary body plaque inflammation, Parsenaeus-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, nausea anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrene, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity,Stiff-person syndrome, subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, aortitis, temporal arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0206] The compounds or pharmaceutical compositions provided in this disclosure may be used to treat autoimmune diseases such as, for example, lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous abortion, atopic diseases, and inflammatory bowel disease.

[0207] The compounds or pharmaceutical compositions provided in this disclosure may be administered in combination with one or more other therapeutic agents for the treatment of autoimmune diseases. The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with one or more immunosuppressants, including, for example, corticosteroids such as prednisone, budesonide, and prednisolone; Janus kinase inhibitors such as tofacitinib; calcineurin inhibitors such as cyclosporine and tacrolimus; mTOR inhibitors such as sirolimus and everolimus; IMDH inhibitors such as azathioprine, leflunomide, and mycophenolate mofetil; biologics such as abatacept, adalimumab, anaprolein, cetrus, etanercept, golimumab, infliximab, icorizumab, natezil, rituximab, secukinumab, tocilizumab, utekumab, and vedolizumab; and monoclonal antibodies such as baliximab and daliximab.

[0208] The methods provided in this disclosure include methods for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure, wherein the disease is selected from acute coronary syndrome, acute lung injury, acute respiratory distress syndrome (ARDS), Alzheimer’s disease, asthma, cardiovascular disease, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, major depressive disorder, multiple sclerosis, neuropathic pain, and rheumatoid arthritis.

[0209] The compounds or pharmaceutical compositions provided in this disclosure may be administered together with one or more other therapeutic agents for treating age-related diseases such as hearing loss, muscle regeneration, and Werner syndrome.

[0210] The methods provided in this disclosure include methods for treating a patient’s disease, which include administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need, wherein the disease is an age-related disease, such as, for example, hearing loss, muscle degeneration, Werner syndrome, cellular aging, or Alzheimer’s disease.

[0211] The methods provided in this disclosure include methods for treating a patient’s disease, the method comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need, wherein the disease is selected from sudden idiopathic hearing loss, drug-induced hearing loss, age-related hearing loss, and Duchenne muscular dystrophy.

[0212] The methods provided in this disclosure include methods for treating viral diseases in patients, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need. Viral diseases may be SARS-CoV-19 and SARS-CoV-2.

[0213] The amount of the compound of formula (6) or its pharmaceutical composition provided in this disclosure that is effective in treating diseases can depend at least in part on the nature of the disease and can be determined by standard clinical techniques known in the art. Furthermore, it can be employed... in vitro or in vivo Measurements are used to help determine the optimal dosage range. The dosing regimen and dosing interval can also be determined by methods known to those skilled in the art. Among other factors, the amount of the compound of formula (6) provided in this disclosure administered may depend on the patient being treated, the patient's weight, the severity of the disease, the route of administration, and the judgment of the prescribing physician.

[0214] For systemic administration, the effective therapeutic dose can initially be from... in vitro Estimate during measurement. It can also be obtained using techniques known in the art from... in vivo data For example Animal models estimate the initial dose. This information can be used to more accurately determine the effective dose for humans. Those skilled in the art can optimize human administration based on animal data.

[0215] The dosage and appropriate dosing interval of the compound of formula (6) provided in this disclosure can be selected to maintain a sustained therapeutically effective concentration of the compound of formula (6) provided in this disclosure in the patient's blood, and in some embodiments, not exceed the minimum adverse concentration.

[0216] Pharmaceutical compositions comprising compounds of formula (6) provided in this disclosure may be administered, for example, once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. Administration may be provided alone or in combination with other drugs and may continue for the time necessary to effectively treat the disease. Administration may also be performed using continuous or semi-continuous administration over a period of time. Administration includes administering the pharmaceutical composition to mammals, such as humans, in a fed or fasted state.

[0217] The pharmaceutical composition may be administered as a single or multiple dosage form or as a continuous or cumulative dose over a period of time. When multiple dosage forms are used, the amount of the compound of formula (6) provided in this disclosure contained in each of the multiple dosage forms may be the same or different.

[0218] A suitable daily dosage range could be, for example, about 2 μg to about 200 mg per kilogram of body weight of the compound of formula (6) provided in this disclosure.

[0219] A suitable daily dosage range could be, for example, per square meter (m²). 2 The compound of formula (6) provided in this disclosure is available in amounts of about 1 μg to about 50 mg on the body surface.

[0220] The compound of formula (6) provided in this disclosure may be administered, for example, at a dose of 0.001 mg / day to 100 mg / day or at any other suitable daily dose, to treat a patient’s cancer. The dose may be, for example, 0.01 μg / kg body weight / week to 100 μg / kg body weight / week or any other suitable dose.

[0221] A pharmaceutical composition comprising a compound of formula (6) provided in this disclosure can be administered to treat a patient’s cancer so as to provide a therapeutically effective concentration of the compound of formula (6) provided in this disclosure in the patient’s blood or plasma. The therapeutically effective concentration of the compound of formula (6) provided in this disclosure in the patient’s blood can be, for example, from 0.01 μg / L to 1,000 μg / L, from 0.1 μg / L to 500 μg / L, from 1 μg / L to 250 μg / L, or from about 10 μg / L to about 100 μg / L. The therapeutically effective concentration of the compound of formula (6) provided in this disclosure in the patient’s blood can be, for example, at least 0.01 μg / L, at least 0.1 μg / L, at least 1 μg / L, at least about 10 μg / L, or at least 100 μg / L. The therapeutically effective concentration of the compound of formula (6) in the patient’s blood can be, for example, less than an amount that would cause unacceptable adverse reactions (including adverse reactions to homeostasis). The therapeutically effective concentration of the compound of formula (6) in the patient’s blood can be an amount sufficient to restore and / or maintain the patient’s homeostasis.

[0222] The pharmaceutical composition provided in this disclosure can be applied to treat a patient’s disease so as to provide a therapeutically effective concentration of the compound of formula (6) in the patient’s blood for a period of time, such as, for example, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day or 2 days.

[0223] The dosage of the compound in formula (6) can be varied during the treatment regimen.

[0224] In addition to the compounds of formula (6), the pharmaceutical compositions provided in this disclosure may further include one or more pharmaceutically active compounds. Such compounds may be provided, for example, to treat cancer treated with compounds of formula (6) or to treat diseases, conditions or illnesses other than cancer being treated with compounds of formula (6), to treat side effects caused by administration of compounds of formula (6), to enhance the efficacy of compounds of formula (6), and / or to modulate the activity of compounds of formula (6).

[0225] The compound of formula (6) provided in this disclosure can be used in combination with at least one other therapeutic agent. The compound of formula (6) can be administered to a patient together with another compound to treat the patient's cancer. The at least one other therapeutic agent can be a different compound of a second formula (6). The compound of formula (6) and at least one other therapeutic agent can act additively or synergistically with another compound of formula (6) in some embodiments. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or mediator comprising the compound of formula (6), or can be in a separate pharmaceutical composition or mediator. Therefore, the method provided in this disclosure further includes, in addition to administering the compound of formula (6), administering one or more therapeutic agents for the effective treatment of cancer or diseases, conditions or illnesses other than cancer. The method provided in this disclosure includes administering the compound of formula (6) and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic efficacy of the compound of formula (6) and / or does not produce an adverse combination effect.

[0226] The administration of a pharmaceutical composition comprising a compound of formula (6) may be performed concurrently with the administration of another therapeutic agent, which may be a portion of the same pharmaceutical composition comprising the compound of formula (6), or in a pharmaceutical composition different from the pharmaceutical composition comprising the compound. The compound of formula (6) may be administered before or after the administration of the other therapeutic agent. In some combination therapies, the combination therapy may include alternating administration of the compound of formula (6) and a composition comprising the other therapeutic agent. For example To minimize adverse drug effects associated with a particular drug. When a compound of formula (6) is administered concurrently with another therapeutic agent that may potentially produce adverse drug effects (including, for example, toxicity), the other therapeutic agent may be administered at a dose that falls below the threshold for triggering an adverse drug reaction.

[0227] Pharmaceutical compositions comprising compounds of formula (6) provided herein may be administered together with one or more substances, for example, to enhance, modulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of compounds of formula (6). For example, pharmaceutical compositions comprising compounds of formula (6) may be co-administered with an active agent having a pharmacological effect that enhances the therapeutic efficacy of compounds of formula (6).

[0228] The compound of formula (6) or a pharmaceutical composition thereof may be administered in combination with an agent known or believed to be effective in treating a patient’s disease, such as cancer, an autoimmune disease or an inflammatory disease, such as the same disease being treated with the compound of formula (6).

[0229] The compound of formula (6) or its pharmaceutical composition may be administered in combination with a drug known or believed to interfere with cell proliferation.

[0230] The compound of formula (6) or its pharmaceutical composition may be used in combination with agents known or believed to interfere with cellular metabolism, act as an antimetabolite, interfere with RNA transcription, interfere with RNA translation, interfere with cellular protein synthesis, interfere with DNA synthesis and the synthesis of precursors for replication, interfere with purine synthesis, interfere with nucleoside synthesis, interact with mTOR, act as an mTOR inhibitor, or interfere with cell cycle checkpoints.

[0231] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with checkpoint inhibitors, including CTLA-4 inhibitors such as ipilimumab; PD-1 inhibitors such as pembrolizumab and nivolumab; and / or PD-1 inhibitors such as atezolizumab, avelumab, and durvalumab. The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with immunomodulators such as CD137 / 4-1BB, CD27, GIYR, and / or OC40.

[0232] The compounds of formula (6) or their pharmaceutical compositions may be administered in combination with agents known or believed to be cytotoxic to cause DNA damage, cell cycle arrest, or mitotic catastrophe.

[0233] The compound of formula (6) or its pharmaceutical composition may be used in combination with an agent known or believed to regulate glutathione concentration, regulate intracellular glutathione concentration, reduce intracellular glutathione concentration, reduce intracellular glutathione uptake, reduce glutathione synthesis or reduce intracellular glutathione synthesis.

[0234] The compound of formula (6) or its pharmaceutical composition may be used in combination with an agent known or believed to interfere with, reduce or promote angiogenesis.

[0235] The compounds of formula (6) or their pharmaceutical compositions may be used in combination with agents known or believed to interfere with hormone homeostasis, hormone synthesis, hormone receptor binding or hormone signal transduction.

[0236] The compound of formula (6) or its pharmaceutical composition may be used in combination with agents known or believed to interfere with growth factor homeostasis, interfere with growth factor receptor expression, interfere with growth factor binding to growth factor receptor, interfere with growth factor receptor signal transduction, interfere with Hedgehog (Hh) signal transduction, inhibit Hedgehog pathway signal transduction, inhibit ALK (anaplastic lymphoma kinase) pathway signal transduction, or inhibit non-homologous end junction (NHEJ) pathway.

[0237] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with one or more agents known or believed to be: VEGFR (vascular endothelial growth factor receptor) inhibitors, RTK (receptor tyrosine kinase) inhibitors, sodium channel current blockers, aFAK (focal adhesion kinase) inhibitors, GLI (glioma-associated oncogene) inhibitors, GLI1 inhibitors, GLI2 inhibitors, GLI3 inhibitors, MAPK (mitogen-activated protein kinase) inhibitors, MAPK / ERK pathway (also known as Ras-Raf-MEK-ERK pathway) inhibitors, MEK1 inhibitors, MEK2 inhibitors, MEK5 inhibitors, MEK5 / ERK5 inhibitors, aRTA (renal tubular acidosis) inhibitors, ALK (anaplastic lymphoma kinase) inhibitors, Aa LK kinase inhibitors, nuclear translocation inhibitors, PORCN (porcupine) inhibitors, 5-ARI (5α-reductase inhibitors), topoisomerase inhibitors, Ras (rat sarcoma) inhibitors, K-ras inhibitors, CERK (ceramide kinase) inhibitors, PKB (protein kinase B, also known as AKT) inhibitors, AKT1 inhibitors, EZH2 (zeste gene enhancer homolog 2) inhibitors, BET (bromodomain and superterminal domain motif) inhibitors, SYK (spleen tyrosine kinase) inhibitors, JAK (janus kinase) inhibitors, SYK / JAK inhibitors, IDO (indoleamine-pyrrole-2,3-dioxygenase) inhibitors, IDO1 inhibitors, RXR (retinoic acid X receptor) activators, selective RXR activators, p-glycoprotein inhibitors, ERK inhibitors, PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors, BRD (bromine-containing domain protein) inhibitors, BRD2 inhibitors, BRD3 inhibitors, BRD4 inhibitors, BRDT (bromine-containing domain testis-specific protein), reverse transcriptase inhibitors, NRT (nucleoside analog reverse transcriptase) inhibitors, PIM (Moroni virus proviral integration) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, photosensitizers, radiosensitizers, ROS (proto-oncogene, receptor tyrosine kinase) inhibitors, ROS1 (proto-oncogene 1) inhibitors, CK (casein kinase) inhibitors, CK2 inhibitors, Bcr-Abl (breakpoint cluster region-Abelson proto-oncogene) tyrosine kinase inhibitors such as dasatinib, microtubule stabilizers, microtubule depolymerization / decomposition inhibitors, DNA intercalation agents, androgen receptor antagonists, chemopreservatives, HDAC (histone deacetylase) inhibitors, D PP (dipeptidyl dipeptidyl peptidase) inhibitors, DPP-4 inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, kinase inhibitors such as imatinib, tyrosine kinase inhibitors such as nilotinib, ARP (poly(ADP-ribose) polymerase) inhibitors, CDK (cyclin-dependent kinase) inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, HIF1α (hypoxia-inducible factor 1-α) inhibitors, DNA ligase inhibitors, DNA ligase IV inhibitors, NHEJ (non-homologous end joining) inhibitors, DNA ligase IV, NHEJ inhibitors and RAF inhibitors, TKIs and RAF inhibitors, TKIs and RAF inhibitors such as sorafenib, PDT (photodynamic therapy) sensitizers, ATR (ataxia-telangiectasia and Rad3-related protein kinase) inhibitors, or combinations thereof.

[0238] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with one or more chemotherapeutic agents, such as, for example, VEGFR inhibitors, such as fruquintinib, motracene / AMG-706, vastarani; RTK inhibitors, such as panatinib; sodium channel blockers, such as GS967; FAK inhibitors, such as TAE226; GLI1 and GLI2 inhibitors, such as GANT61; MEK inhibitors, such as bismitinib; RTA inhibitors, such as linivani; ALK inhibitors, such as brigatinib; bromopyruvate; DNA alkylating agents, such as thiotepa; nuclear transfer factors, such as JSH-23; PORCn inhibitors, such as Wnt-C59; 5α - Reductase inhibitors, such as dutasteride; topoisomerase inhibitors, such as carrubicin; RAS inhibitors, such as Kobe0065; CerK inhibitors, such as NVP-231; AKT inhibitors, such as Uprosite; EZH2 inhibitors, such as GSK-503; BET bromodomain inhibitors, such as OTX015; MEK5 / ERK5 inhibitors, such as BIX02189; Syl / JAK inhibitors, such as cedutinib; IDO1 inhibitors, such as NLG919; retinaldehyde X receptor activators, such as bexarotin; PGP inhibitors, such as atenimidamine hydrochloride or acotilimab hydrochloride; Erk inhibitors, such as SCH7 72984; PI3K inhibitors, such as gedatolisib; JAK inhibitors, such as ruxolitinib; AKT inhibitors, such as afuresertib or afuresertib hydrochloride; ALK1 inhibitors, such as ceritinib; HDAC inhibitors, such as ibexitol; DPP inhibitors, such as ozogliptin; EGFR inhibitors, such as gefitinib; EZH2 inhibitors, such as GSK126; BTK inhibitors, such as ibrutinib; kinase inhibitors, such as imatinib hydrochloride; IDO inhibitors, such as INCB024360; DNA cross-linking agents, such as mitomycin C; tyrosine kinase inhibitors, such as nifedipine. Rotinib; PARP inhibitors, such as olaparib; tubulin stabilizing agents, such as paclitaxel; CDK4 / 6 inhibitors, such as palbociclib; RTK inhibitors, such as sunitinib; PDT sensitizers, such as tarapofen; p-glycoprotein inhibitors, such as tariquidar; ATR inhibitors, such as VE-822; HDAC inhibitors, such as PCI-24781; DPP inhibitors, such as ozogliptin; EGFR inhibitors, such as gefinib; EZH2 inhibitors, such as GSK126; BTK inhibitors, such as ibrutinib; IDO inhibitors, such as INCB024360; or combinations of any of the above.

[0239] The compound of formula (6) or its pharmaceutical composition may be administered in combination with another chemotherapeutic agent, such as, for example N- Acetylcysteine ​​(NAC), Doxorubicin, Alemumab, Amifostine, Arsenic Trioxide, Ascorbic Acid, Bendamustine, Bevacizumab, Bortezomib, Busulfan, Butylthionine-sulfonamide, Carfilzomib, Carmustine, Clofarabine, Cyclophosphamide, Cyclosporine, Cytarabine, Dasatinib, Actinomycin, Defibrinolytic acid, Dexamethasone, Docetaxel, Doxorubicin, Etoposide, Filgranate, Fluorouracil, Fludarabine, Gemmaconazole Sitabine, interferon-alpha, iprimma, lenalidomide, leucovorin, melphalan, mycophenolate mofetil, paclitaxel, parivmin, parbistat, pefigextin, prednisolone, prednisone, lenalidomide, rituximab, sirolimus, sodium 2-mercaptoethanesulfonate (MESNA), sodium thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, or a combination of any of the above.

[0240] The compounds of formula (6) or pharmaceutical compositions thereof may be used in combination therapy with other chemotherapeutic agents, which include one or more antimetabolites, such as folic acid analogs; pyrimidine analogs, such as fluorouracil, fluorouridine, and cytosine; purine analogs, such as mercaptopurine, thioguanine, and pentostatin; and natural products, such as vincristine, vinblastine, etoposide, tertiposide, actinomycin D, doxorubicin, doxorubicin, bleomycin, mitomycin C, L - Asparaginase and interferon α; platinum coordination complexes, such as cisplatin and carboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists, such as prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, flumethasone, flutamide, and leuprolide; anti-angiogenic agents or inhibitors, such as angiostatin, retinoic acid, paclitaxel, estradiol derivatives, and thiazopyrimidine derivatives; apoptosis preventives; tripterygium wilfordii; colchicine; ruliconazole; and radiotherapy.

[0241] The compounds of formula (6) or their pharmaceutical compositions may be co-administered with compounds that inhibit DNA repair, such as, for example, O6-benzylguanine (O6-BG).

[0242] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with one or more chemotherapeutic agents, such as, for example, abamoricin, abiraterone, abiraterone acetate, acetylcysteine, ararubicin hydrochloride, doxorubicin, adenine, afatinib, afatinib maleate, alenzabumab, alendronate sodium, retinoic acid, allopurinol sodium, hexamethylmelamine, amifostine, aminoglutethimide, aminolevulinic acid, alanine, anastrozole, angiostatin, aprepitant, arsenic trioxide, ascorbic acid, L-asparaginase, azacitidine, azathioprine sodium, badoxifene (serm), belistat, bendamustine hydrochloride, O6-benzylguanine, bevacizumab, bexarotin, bicalutamide, pyricol, bleomycin sulfate, Bortezomib, Bosutinib, Bivudine, Busereline, Busulfan, Butyrine-sulfonamide, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carpoquinone, Carfilzomib, Carmoflu, Carmustine, Ceritinib, Chlorbutamol, Cisplatin, Cladribine, Clodronate Disodium, Clofarabine, Crizotinib, Cyclophosphamide, Cyclosporine, Cytarabine, Cytosine Benzoside, Darafenib, Dacarbazine, Actinomycin D, Dasatinib, Actinomycin D, Donomycin, Decitabine, Desciglioside, Degarelix acetate, Dexamethasone, Dextromethorphan hydrochloride, Diazinon, Diethylstilbestrol, Docetaxel, Deoxyfluorouridine, Doxorubicin hydrochloride, Doxorubicin free base, Drotahistamine propionate, Dutasteride, Eltrombopag, Enzalutamide, Hydrochloride Epirubicin, Eribulin Mesylate, Erlotinib Hydrochloride, Estrostine Sodium Phosphate, Ethinylestradiol, Etoposide Phosphate, Etoposide, Iverolimus, Exemestane, Fentanyl, Filgrastim, Fingolimod, Fluorouracil, Fludarabine Phosphate, Fluorouracil, Flumethasone, Flutamide, Formexane, Mefenamic Acid, Fosapiram, Formosine, Fulvestrant, Gefitinib, Gemcitabine Hydrochloride, Gemcitabine Free Base, Glutathione, Phosphoramide Mustard, Glycophosphoryl Mustard, Goserelin Acetate, Granisetron Hydrochloride, Heptaplatin, Hexyl 5-Aminolevulinate, Histamine Relin Acetate, Hydroxyprogesterone Hexanoate, Hydroxyurea, Ibandronate Sodium, Ibrutinib, Icotinib, Idarubicin Hydrochloride, Adelaide, Iodidine, Ifosfamide, Interferon Alpha, Imaryl Mesylate Tinidone, Imiquimod, phorbol methylbutyrate, Iprimumab, Irinotecan hydrochloride, Ixaspiron, Lanreitide acetate, Lapatinib free base, Lapatinib xylenesulfonate, Lasoxifen, Lenalidomide, Letrozole, Calcium leucovorin, Leuprorelin acetate, Levamisole hydrochloride, Levofolinic acid calcium, Iodobenzylguanidine, Lobaplatin, Lomustine, Maropitane, Masoronol, Nitrogen mustard hydrochloride, Medroxyprogesterone acetate, Medroxyprogesterone acetate, Melphalan hydrochloride, Mercaptopurine, Sodium mercaptoethanesulfonate, Methotrexate, Methoxarin, Methylaminolevulinate, Methylene blue, Isomethylindole, Mivaminide, Mitefocin, Miplatin, Photomycin, Dibromomannitol, Mitomycin C, Mitotane, Mitoxantrone hydrochloride, Mycophenolate mofetil, Nabiximols, Nafarelin, NandroloneNedaplatin, Neraphe, Netupira, Nilotinib, Nilumet, Nimustine, Nintedanib, Nocodaazole, Octreotide, Olaparib, Homoharringtonine, Ondansetron Hydrochloride, Oxaliplatin, Paclitaxel, Palbociclib, Palivmin, Palonosetron Hydrochloride, Pamidronate Disodium, Pabistat, Parretoxin, Pazopanib Hydrochloride, PEGylated Filgrastim, Pemetrexed Disodium, Pentostatin Pepromycin, Piperobromide, Pirarubicin, Presalifos, Pcacardine, Pomalidomide, Panatinib, Porphyrom sodium, Pofibromycin, Pralatrexate, Prenimustine, Prednisolone, Prednisone, Procarbazine Hydrochloride, Quinolotine Hydrochloride, Raloxifene, Raltitrexed, Ladotinib, Ramustine, Retinoic Acid, Lenalidomide, Rituximab, Romidixin, Ruxoritinib, Ruxoritinib Phosphate Sorafenib, sirolimus, sodium thiosulfate, sorafenib free base, sorafenib tosylate, streptozotocin, sufentanil, sunitinib, tacrolimus, tarapofen sodium, tamibarbitine, tamoxifen citrate, tapentadone, temopofen, temozolomide, tesimolimus, teniposide, teriflunomide, teniposide, testosterone lactone, testosterone propionate, thalidomide, thioguanine, thiamethoxam The following are listed: Thymosin, Tocinib Phosphate, Topotecan Hydrochloride, Toremifene Citrate, Trabectin, Trametinib, Retinoic Acid, Tralostane, Triptorelin, Tropanetron, Uramustine, Pentorubicin, Vandetanib, Vidocin, Vermuprin, Vertepofen, Vincristine, Vincristine Sulfate, Vincristine Free Base, Vincristine, Vinorelbine Tartrate, Vorinostat, and Zoledronic Acid.

[0243] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in combination with one or more chemotherapeutic agents, such as, for example, pomazenil, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, acalabutinib, AC-T, ADE, trastuzumab-metazine conjugate, afatinib maleate, interleukin, alectinib, alenzab, alpelisib, amifostine, aminolevulinate, anastrozole, apalutamide, aprepitant, arsenic trioxide, Erwinia soft rot asparaginase, atezolizumab, avelumab, and axicabtagenes. ciloleucel), axitinib, azacitidine, BEACOPP, belistat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bismitinib, bleomycin sulfate, bonatetumab, bortezomib, bosutinib, bentuximab, brigatinib, BuMel, busulfan, cabazitaxel, cabozantinib malate, CAF, long-acting pegylated asparaginase (calaspargase)pegol-mknl), capecitabine, caplacizumab-yhdp, CAPOX, carboplatin, carboplatin-paclitaxel, carfilzomib, carmustine, carmustine implant, CEM, cemiplimab-rwlc, ceritinib, cetuximab, CEV, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, cladribine, clofarapine, CMF, cobitinib, curpannice hydrochloride, COPDAC, COPP, COPP-ABV, crizotinib CVP, Cyclophosphamide, Cytarabine, Cytarabine Liposome, Darafenib Mesylate, Dacarbazine, Dacomitinib, Actinomycin D, Daramumumab, Alfadabepoline, Dasatinib, Dornoxomil Hydrochloride, Dornoxomil Hydrochloride and Cytarabine Liposome, Decitabine, Desmodium, Degarelix, Deniproleukin, Denoxin, Dexamethasone, Dexrazoxen Hydrochloride, Denutoxici, Docetaxel, Doxorubicin Hydrochloride, Doxorubicin Liposome, Dvorumab, Duveritase, Elotuzumab, Eltrombopag Ethanolamine, Elapavumab (emapalum) ab)-lzsg, Enxidipine, Cannefenib, Enzalutamide, Epirubicin Hydrochloride, EPOCH, Ibertin Afa, Erdatinib, Eribulin Mesylate, Erlotinib Hydrochloride, Etoposide, Etoposide Phosphate, Iverolimus, Exemestane, FEC, Filgrastim, Fludarabine Phosphate, Fluorouracil Injection, Topical Fluorouracil, Flutamide, Folfiri, Folfiri-Bevacizumab, Folfiri-, Folfirinox, Folfox, Fotatinib Disodium, FU-LV, Fulvestrant, Gefitinib, Gemcitabine Hydrochloride Gemcitabine, Gemcitabine-Cisplatin, Gemcitabine-Oxaliplatin, Gemtuzumab, Gitertinib Fumarate, Graziba Maleate, Glucapeptide, Goserelin Acetate, Granisetron, Bivalent HPV Vaccine, Bivalent HPV Vaccine, Recombinant HPV 9-valent Vaccine, Recombinant HPV 4-valent Vaccine, Recombinant HPV 4-valent Vaccine, Hydroxyurea, Hyper-CVAD, Tiimomab, Ibrutinib, ICE, Idarubicin Hydrochloride, Adelaide, Ifosfamide, Imatinib Mesylate, Imiquimod, Oxytocillin, Recombinant Interferon Alpha-2b, Iodine Benzylguanidine 131I. Iprimumab, Irinotecan Hydrochloride, Irinotecan Liposome Hydrochloride, Ivoximab, Ixaspirone, Ixazomir Citrate, JEB, Lanreotide Acetate, Lapatinib Benzoate, Larotrectinib Sulfate, Lenalidomide, Lenvatinib Mesylate, Letrozole, Calcium Leucovorin, Leuprorelin Acetate, Lomustine, Lorlatinib, Lutetrazolium-177 Injection, Nitrogen Mustard Hydrochloride, Medroxyprogesterone Acetate, Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Methotrexate, Methylnaltrexone Bromide, Midotoxaline, Mitomycin C, Mitoxantrone Hydrochloride, Mogomezumab, Moxetumomabpasudotox-tdfk, MVAC, Nexituzumab, Nerabin, Lenatinib Maleate, Netupitant, Palonosetron Hydrochloride, Nile Niramimet, Niraparib Tosylate Monohydrate, Nivolumab, Omega-1, OEPA, Ofamumab, OFF, Olaparib, Olaparib, Homoharringtonine, Ondansetron Hydrochloride, OPPA, Osimertinib Mesylate, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-Stabilized Nanoparticles, PAD, Palbociclib, Palivmin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Pabistat, Pazopanib Hydrochloride, PCV, PEB, Pegaspargase, Pegylated Filgrastim, Pegylated Interferon Alpha-2b, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Presalifovir, Palostatumab Vitol (polatuzumab) vedotin-piiq, pomalidomide, panatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, propranolol hydrochloride, radium-223 dichloride, raloxifene hydrochloride, ramucirumab, raburizine, eculizumab, R-CHOP, R-CVP, recombinant bivalent HPV vaccine, recombinant nine-valent HPV vaccine, recombinant quadrivalent HPV vaccine, recombinant interferon alpha-2b, regorafenib, R-EPOCH, ribociclib, R-ICE, rituximab, rituximab and human hyaluronidase, lorapidan hydrochloride, romidesin, romistachytin, ricatapab camphor sulfonate, ruxolitinib phosphate, sutuximab, sipuleucel-t, sorafenib tosylate, STANFORDV, sunitinib malate, TAC, tagraxofusp-erzs, taprazole tosylate, talc, latamogin, tamoxifen citrate, temozolomide, tesimolimus, thalidomide, thioguanine, thiotepa, tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, TPF, trabectedin, trametinib, trastuzumab, trastuzumab and hyaluronidase-oysk, trifluorouridine and tebipyrimidine hydrochloride, uridine triacetate, VAC, pentorubicin, VAMP, vandetanib, VeIP, vemurafenib, vinorelbine sulfate, vincristine sulfate liposome, vinorelbine tartrate, VIP, vemodega, vorinostat, XELIRI, XELOX, aflibercept, zoledronic acid, and combinations thereof.

[0244] The compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered to a patient in combination with another compound known for treating inflammatory diseases, autoimmune diseases, or age-related diseases that are being treated with the compounds provided in this disclosure.

[0245] The efficacy of the compound of formula (6) or its pharmaceutical composition in treating cancer, inflammatory diseases or autoimmune diseases can be obtained through the use of... in vitro And animal studies and evaluation in clinical trials.

[0246] The method for inhibiting p38α MAPK provided in this disclosure includes contacting p38α MAPK with a compound provided in this disclosure to reach a pocket near the ED substrate docking site of p38α MAPK.

[0247] The method for inhibiting p38α MAPK disclosed herein does not result in the loss of the p38α-dependent counterregulatory response. The p38α-dependent counterregulatory response is associated with mitogens and activated protein kinases-1 (MSK1) or MSK2. When targeting the p38α ED substrate docking site, the inhibitors disclosed herein avoid interference with CD-specific substrates (including MSK1 / 2), thereby limiting inflammation through the expression of IL-10 and DUSP2.

[0248] Aspects of the present invention

[0249] Aspect 1. A compound having the structure of formula (6):

[0250] (6)

[0251] Or its pharmaceutically acceptable salt, wherein,

[0252] R 1 Selected from C1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol;

[0253] R 2 To replace C 5-12 Heterocyclic alkyl groups;

[0254] R 3 Selected from –C(=O)– and –S(=O)2–; and

[0255] R 4 Selected from –N(R) 5 )2, where each R 5 Independently selected from hydrogen and C 1-4 alkyl.

[0256] Aspect 2. The compound according to Aspect 1, wherein each of one or more substituents is independently selected from –OH, =O, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl and C 5-6 Mixed aromatic compounds.

[0257] Aspect 3. The compound according to aspect 1, wherein each of one or more substituents is independently selected from –OH, =O, –NH2, –NO2, C 1-3 Alkyl and C 1-3 Heteroalkyl groups.

[0258] Aspect 4. The compound according to aspect 1, wherein each of one or more substituents is independently selected from –OH, =O, and C. 1-3 alkyl.

[0259] Aspect 5. The compound according to aspect 1, wherein each of one or more substituents is =O.

[0260] Aspect 6. The compound according to any one of Aspects 1 to 5, wherein R 1 C 1-4 Alkyl.

[0261] Aspect 7. The compound according to any one of Aspects 1 to 5, wherein R 1 It is ethanediyl.

[0262] Aspect 8. The compound according to any one of Aspects 1 to 5, wherein R 1 It is a dimethylmethane.

[0263] Aspect 9. The compound according to any one of Aspects 1 to 5, wherein R 2 It is a substituted C6 heterocyclic alkyl group.

[0264] Aspect 10. The compound according to aspect 9, wherein each of one or more heteroatoms is independently selected from O and N.

[0265] Aspect 11. The compound according to any one of Aspects 1 to 10, wherein R 2 It is morpholino-4-yl.

[0266] Aspect 12. The compound according to any one of Aspects 1 to 10, wherein R 2 It is a monosubstituted morpholino-4-yl group.

[0267] Aspect 13. The compound according to any one of Aspects 1 to 10, wherein R 2 It is a 3-substituted morpholino-4-yl group.

[0268] Aspect 14. The compound according to any one of Aspects 12 to 13, wherein each of one or more substituents is independently selected from –OH, =O, –N(R) 5 )2, where each R 5 Independently selected from hydrogen and C 1-3 alkyl.

[0269] Aspect 15. The compound according to any one of Aspects 12 to 13, wherein each of the one or more substituents is –OH.

[0270] Aspect 16. The compound according to any one of aspects 12 to 13, wherein each of the one or more substituents is =O.

[0271] Aspect 17. The compound according to any one of aspects 12 to 13, wherein each of one or more substituents is –N(R 5 )2, where each R 5 Independently selected from hydrogen and C 1-3 alkyl.

[0272] Aspect 18. The compound according to any one of Aspects 1 to 17, wherein R 3 Selected from –C(=O)– and –S(O)2–.

[0273] Aspect 19. The compound according to any one of Aspects 1 to 17, wherein R 3 For –C(=O)–.

[0274] Aspect 20. The compound according to any one of Aspects 1 to 17, wherein R 3It is –S(O)2–.

[0275] Aspect 21. The compound according to any one of Aspects 1 to 20, wherein R 4 It is bonded to the 3-, 4-, 5-, 6-, or 7-position of the naphthyl moiety.

[0276] Aspect 22. The compound according to any one of Aspects 1 to 20, wherein R 4 It is bonded to the 5-position of the naphthyl moiety.

[0277] Aspect 23. The compound according to aspect 1, wherein,

[0278] R 1 C 1-3 Alkyl;

[0279] R 2 The substituted 4-morpholino group;

[0280] R 3 Selected from –C(=O)– and –S(O)2–; and

[0281] R 4 Selected from –N(R) 5 )2, where each R 5 Independently selected from hydrogen and C 1-3 alkyl.

[0282] Aspect 24. The compound according to aspect 1, wherein,

[0283] R 1 It is a dimethylmethane;

[0284] R 2 The substituted 4-morpholino group;

[0285] R 3 It is –S(O)2–; and

[0286] R 4 For –N(R) 5 )2, where each R 5 It is independently selected from hydrogen and methyl.

[0287] Aspect 25. The compound according to any one of Aspects 23 to 24, wherein R 2 It is a 3-substituted 4-morpholino group.

[0288] Aspect 26. The compound according to any one of Aspects 23 to 25, wherein in R 2 In the part, the substituent is =O.

[0289] Aspect 27. The compound according to any one of Aspects 23 to 26, wherein R 4 Selected from –NH(–CH3) and –N(–CH3)2.

[0290] Aspect 28. The compound according to aspect 1, wherein the compound is selected from:

[0291] 4-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0292] 4-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0293] 4-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0294] 5-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0295] 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0296] 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0297] 6-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0298] 6-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; and

[0299] 6-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

[0300] Or a pharmaceutically acceptable salt of any of the above.

[0301] Aspect 29. The compound according to aspect 1, wherein the compound is 5-amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (compound 5) or a pharmaceutically acceptable salt thereof:

[0302] .

[0303] Aspect 30. The compound according to aspect 1, wherein the compound is 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2) or a pharmaceutically acceptable salt thereof:

[0304] .

[0305] Aspect 31. The compound according to aspect 1, wherein the compound is 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3) or a pharmaceutically acceptable salt thereof:

[0306] .

[0307] Aspect 32. The compound according to any one of aspects 1 to 31, wherein the compound inhibits the p38α MAPK receptor.

[0308] Aspect 33. The compound according to any one of aspects 1 to 32, wherein the compound selectively inhibits the p38α MAPK receptor.

[0309] Aspect 34. The compound according to any one of Aspects 1 to 33, wherein the compound has a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0310] Aspect 35. The compound according to any one of Aspects 1 to 34, wherein the compound binds to a selective binding site of p38α MAPK, wherein the binding bag is defined by at least residues R49, Hl07, Ll08 and Kl65 of p38α MAPK.

[0311] Aspect 36. The compound according to aspect 35, wherein the compound is reacted with 4-chloro- N -(4-((1,1-thiomorpholino)methyl)phenyl)benzamide competitively binds to this selective binding site.

[0312] Aspect 37. The compound according to any one of Aspects 1 to 36, wherein the compound inhibits the production of 4-chloro- by anisin-stimulated HeLa cells. N -(4-((1,1-thiomorpholino)methyl)phenyl)benzamide-induced phosphorylation of MK2.

[0313] Aspect 38. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 37 or a pharmaceutically acceptable salt thereof.

[0314] Aspect 39. The pharmaceutical composition according to aspect 38, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 37 for treating a patient’s disease.

[0315] Aspect 40. The pharmaceutical composition according to aspect 39, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0316] Aspect 41. The pharmaceutical composition according to aspect 39, wherein the disease is cancer.

[0317] Aspect 42. The pharmaceutical composition according to aspect 39, wherein the disease is an inflammatory disease.

[0318] Aspect 43. The pharmaceutical composition according to aspect 39, wherein the disease is an autoimmune disease.

[0319] Aspect 44. The pharmaceutical composition according to aspect 39, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0320] Aspect 45. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 37, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0321] Aspect 46. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of any one of aspects 1 to 37 of the compound or a pharmaceutically acceptable salt thereof, wherein the disease is cancer.

[0322] Aspect 47. The method according to aspect 46, wherein the cancer is selected from breast cancer and melanoma.

[0323] Aspect 48. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of any one of aspects 1 to 37 of the compound or a pharmaceutically acceptable salt thereof, wherein the disease is an inflammatory disease.

[0324] Aspect 49. The method according to aspect 48, wherein the inflammatory disease is selected from acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation of hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

[0325] Aspect 50. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of any one of aspects 1 to 37 of the compound or a pharmaceutically acceptable salt thereof, wherein the disease is an autoimmune disease.

[0326] Aspect 51. The method according to aspect 50, wherein the autoimmune disease is selected from lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous abortion, atopic diseases, and inflammatory bowel disease.

[0327] Aspect 52. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of any one of aspects 1 to 37 of the compound or a pharmaceutically acceptable salt thereof, wherein the disease is an age-related disease.

[0328] Aspect 53. The method according to aspect 52, wherein the age-related disease is selected from hearing loss, muscle degeneration, Werner syndrome, cellular aging, and Alzheimer's disease.

[0329] Aspect 54. A method of treating a patient’s disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 37, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0330] Aspect 55. A method for inhibiting p38α MAPK receptor, comprising contacting the p38α MAPK receptor with a compound according to any one of aspects 1 to 37 or a pharmaceutically acceptable salt thereof.

[0331] Aspect 56. A method of inhibiting p38α MAPK receptors in a patient, comprising administering to the patient a pharmacologically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 37.

[0332] Aspect 57. The method according to aspect 56, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

[0333] Aspect 58. The method according to aspect 57, wherein inhibition of the p38α MAPK receptor does not result in the loss of p38α-dependent counterregulatory response.

[0334] Aspect 59. The method according to aspect 58, wherein the p38α-dependent counterregulatory response involves mitogens and activated protein kinase-1 (MSK1) or MSK2.

[0335] Aspect 60. The method according to any one of Aspects 57 to 59, wherein the p38α MAPK receptor is selectively inhibited to stabilize endothelial or epithelial barrier function.

[0336] Aspect 61. The method according to any one of Aspects 57 to 60, wherein selective inhibition of the p38α MAPK receptor reduces inflammation.

[0337] Aspect 62. The method according to any one of Aspects 57 to 61, wherein selective inhibition of the p38α MAPK receptor alleviates KPS-induced lung injury.

[0338] Aspect 63. The method according to any one of aspects 57 to 62, wherein the p38α MAPK receptor is selectively inhibited to regulate leukocyte transport.

[0339] Aspect 64. The method according to any one of Aspects 57 to 63, wherein the p38α MAPK receptor is selectively inhibited to regulate cytokine expression.

[0340] Example

[0341] The following examples describe in detail the synthesis of compounds of formula (6), the characterization of compounds of formula (6), and the uses of compounds of formula (6). It will be apparent to those skilled in the art that many modifications can be made to the materials and methods without departing from the scope of this disclosure.

[0342] Example 1

[0343] 5-(methylamino)- N Synthesis of 1-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1)

[0344]

[0345]

[0346] Step 1: 5-(((benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b).

[0347]

[0348] Add 2M NaOH to a solution of 5-aminonaphthalene-1-sulfonic acid (1a) (50.2 g, 0.2249 mol) in 0.1M NaHCO3 (40 mL) until the pH is adjusted to 10. Add benzyl chloroformate (57.54 g, 0.3373 mol) at 0 °C. (mol) was added to the stirred solution. The temperature was raised to 25°C and stirring was continued for 3 hours. LCMS showed the target molecule as the main peak. The reaction mixture was adjusted to pH 2 with 4M HCl, concentrated under reduced pressure, and purified by Biotage® Isolera One chromatography (C18 column, eluted with 10% to 95% MeCN / H2O containing 0.1% HCOOH) to give 5-(((benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b) (30.5 g) as a purple solid. LCMS: m / z 355.9 [M+H] - .

[0349] Step 2: 5-(((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1c).

[0350]

[0351] Sodium hydride (60%, in mineral oil, 4.5 g, 0.1109 mol) was added to a solution of 5-(((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1b) (30.5 g, 0.08534 mol) in anhydrous DMF (300 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 min and iodomethane (15.7 g, 0.1109 mol) was added dropwise. After the addition was complete, the resulting solution was stirred at 23 °C for 2 h and then quenched with water. LCMS showed the main peak as the desired target molecule. The mixture was purified by Biotage® Isolera One chromatography (C18 column, eluted with 10% to 95% MeCN / H2O containing 0.1% HCOOH) to give 5-(((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1c) (12 g) as an oil. LCMS: m / z369.9 [M+H] - .

[0352] Step 3: (5-(chlorosulfonyl)naphth-1-yl)(methyl)carbamate (1d).

[0353]

[0354] A stirred mixture of 5-(((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1c) (12 g, 0.03231 mol) and PCl5 (6.73 g, 0.03231 mol) in toluene (100 mL) was heated at 120 °C for 3 hours. TLC indicated the formation of new spots. The reaction mixture was cooled to 23 °C and concentrated under vacuum, and the resulting crude (5-(chlorosulfonyl)naphthalene-1-yl)(methyl)carbamate (1d) (16.17 g, TLC purity approximately 80%) was used in the next step without further purification. LCMS: m / z 427.1 [M+H] + .

[0355] Step 4: (5-( N -(4-(morpholinomethyl)phenyl)aminosulfonyl)naphth-1-yl)carbamate (1e).

[0356]

[0357] Triethylamine (7.00 g, 0.06926 mol) was added to a stirred solution of 4-(morpholinomethyl)aniline (3.66 g, 0.01731 mol) in dichloromethane (60 mL) at 0 °C. After stirring at the same temperature for 30 min, (5-(chlorosulfonyl)naphth-1-yl)(methyl)carbamate (1d) (6.75 g, 0.01731 mol) was added. The resulting solution was stirred overnight at 45 °C, cooled to room temperature, and quenched with water. LCMS showed the desired target molecule as the main peak. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give methyl(5-( N 4-(4-(morpholinomethyl)phenyl)aminosulfonyl)naphth-1-yl)-carbamate (1e) (4.6 g), as a yellow solid. LCMS: m / z 546.1 [M+H] + .

[0358] Step 5: 5-(methylamino)- N -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1).

[0359]

[0360] Add 5% Pd / C (8 g) to a stirred solution of 8 (4.6 g, 0.00843 mol) in ethyl acetate (50 mL). Stir the reaction mixture at 23 °C for 24 hours under a H2 atmosphere (balloon). LCMS showed depletion of the starting material. Pass the reaction mixture through a Celite filter. ® The mixture was filtered through a plug filter and the resulting filtrate was concentrated under vacuum. The resulting crude residue was then subjected to reverse-phase Biotage. ® Purification by column chromatography (40 g C18 column) using ACN / water (0.1% HCOOH) (0-100%) yielded the title compound 5-(methylamino)- N -(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1) (1.12 g), as a greenish-yellow solid. LCMS Rt = 1.25 min; for [M+H]+, the calculated m / z is 412.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.57 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.26 – 8.16 (m, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.59– 7.44 (m, 2H), 7.13 (s, 2H), 7.02 (s, 2H), 6.65 (d, J = 4.9 Hz, 1H), 6.59(d, J = 7.8 Hz, 1H), 3.57 (s, 4H), 2.88 (d, J = 4.6 Hz, 3H), 2.28 (s, 3H).

[0361] Example 2

[0362] 5-(methylamino)- N Synthesis of -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2)

[0363]

[0364]

[0365] Step 6: 4-(4-nitrobenzyl)morpholin-3-one (2a).

[0366]

[0367] A stirred mixture of morpholino-3-one (20 g, 0.1978 mol), 1-(bromomethyl)-4-nitrobenzene (38.89 g, 0.1800 mol), and Cs₂CO₃ (116.65 g, 0.3580 mol) in acetonitrile (300 mL) was heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a Celite® stopper, and the filtrate was concentrated under vacuum. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 4-(4-nitrobenzyl)morpholino-3-one (2a) (24.83 g) as a yellow solid. LCMS: m / z 237.1 [M+H] + .

[0368] Step 7: 4-(4-aminobenzyl)morpholin-3-one (2b).

[0369]

[0370] 10% Pd / C (6 g) was added to a stirred solution of 4-(4-nitrobenzyl)morpholin-3-one (2b) (24.8 g, 0.1050 mol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 1 hour under a H2 atmosphere (balloon). LCMS showed the target molecule as the main peak. The mixture was filtered through a Celite® bed filter, and the filtrate was concentrated under vacuum. Crude 4-(4-aminobenzyl)morpholin-3-one (2b) (18.4 g) was used in the next step without any further purification. LCMS: m / z 207.1 [M+H] + Step 8: (5-( N -(4-((3-oxomorpholino)methyl)phenyl)aminosulfonyl)naphthal-1-yl)benzyl carbamate (2c).

[0371]

[0372] Triethylamine TEA (8.89 g, 0.02416 mol) was added to a stirred solution of 4-(4-aminobenzyl)morpholin-3-one (2b) (4.53 g, 0.02196 mol) in dichloromethane (70 mL) at 0 °C, while maintaining the temperature at 0 °C throughout the addition. After the addition was complete, the reaction mixture was stirred at 0 °C for another 30 minutes. Benzyl (5-(chlorosulfonyl)naphth-1-yl)(methyl)carbamate (1d) (9.42 g, 0.02416 mol) was added over several minutes. The resulting solution was stirred overnight at 45 °C. The reaction mixture was cooled to room temperature and quenched with H₂O. LCMS showed the target molecule as the dominant peak. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl(5-( N -(4-((3-oxomorpholino)methyl)phenyl)aminosulfonyl)naphth-1-yl)-carbamate (2c) (5.3 g), as a yellow solid. LCMS: m / z 558.1 [M+H] - .

[0373] Step 9: 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2).

[0374]

[0375] To methyl (5-( N 10% Pd / C (10 g) was added to a stirred solution of 1-(4-((3-oxomorpholino)methyl)phenyl)-aminosulfonyl)-naphth-1-yl)carbamate (2c) (5.3 g, 9.47 mmol) in ethyl acetate (50 mL). The reaction mixture was then stirred at 23 °C for 24 h under a H2 atmosphere (balloon). LCMS showed SM depletion. The reactants were filtered through a diatomaceous earth stopper and the resulting filtrate was concentrated under vacuum. The resulting crude residue was purified by Biotage® reversed-phase column chromatography (40 g C18 column, acetonitrile / H2O (0.1% HCOOH) 0-100%) to give 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide (2) (1.02 g), as a greenish-yellow solid. LCMS (Shimadzu 2020): Rt = 1.81 min; for [M+H]+, the calculated m / z is 426.15. 1 H NMR (400 MHz, DMSO- d6) δ 10.53 (s,1H), 8.36 (d, J = 8.6 Hz, 1H), 8.13 (dd, J = 7.4, 1.1 Hz, 1H), 7.87 (d, J =8.6 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.98 – 6.92 (m,2H), 6.58 (d, J = 4.9 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 4.32 (s, 2H), 4.01(s, 2H), 3.71 (t, J = 5.9, 4.4 Hz, 2H), 3.09 (t, J = 5.9, 4.4 Hz, 2H), 2.81(d, J = 4.6 Hz, 3H)。

[0376] Example 3

[0377] 5-(dimethylamino)- N Synthesis of -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3)

[0378]

[0379]

[0380]

[0381] TEA (13.74 g, 0.1358 mol) was added to a stirred solution of 4-(4-aminobenzyl)morpholin-3-one (2b) (7 g, 0.03394 mol) in dichloromethane (70 mL) at 0 °C, and the reaction was maintained at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 min. 5-(dimethylamino)naphthalene-1-sulfonyl chloride (1d) (10.07 g, 0.03733 mol) was added over several minutes. The resulting solution was stirred overnight at 45 °C. The reaction mixture was then cooled to room temperature and quenched with water. LCMS showed the main peak as the desired target molecule. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and the resulting filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC (eluting with 30% to 100% H2O / MeCN containing 0.1% HCOOH acid) and neutralized with 2M NaOH aqueous solution to give 5-(dimethylamino)-N-(4-(((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide (3), a green solid. LCMS [M+H]+440.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.66 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 7.4, 1.2 Hz, 1H), 7.60 (ddd, J = 8.6,7.5, 2.4 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 7.00(d, J = 8.6 Hz, 2H), 4.36 (s, 2H), 4.04 (s, 2H), 3.73 (dd, J = 5.9, 4.4 Hz, 2H), 3.12 (t, J = 5.2 Hz, 2H), 2.80 (s, 6H).

[0382] Example 4

[0383] 5-(dimethylamino)- N Synthesis of 1-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (4)

[0384]

[0385] The synthesis of compound (4) is disclosed in Example 9 of U.S. Application Publication No. 2020 / 0331874 A1.

[0386] Example 5

[0387] Bioanalytical procedures for toxicological and clinical samples

[0388] The following methods were used for bioanalysis of samples from 2-week toxicology studies and clinical samples.

[0389] Bioanalyses were performed on the samples according to validated methods. Monkey plasma samples were extracted by protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada) and an ACE® Excel® 2 C18 column (50 × 3.0 mm, 2 µm particle size). Acquisition and peak integration were performed using Analyst® software 1.6.3 (AB Sciex). Peak areas of analytes and internal standards were imported into Watson LIMS® software version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) for standard curve regression analysis and analyte quantification in the samples. All analytical instruments and software were validated using appropriate procedures.

[0390] Example 6

[0391] Bioanalytical procedures for non-GLP pharmacokinetic studies

[0392] The following methods are used for bioanalysis of samples in non-GLP pharmacokinetic studies.

[0393] Bioanalyses were performed on samples according to validated methods. Plasma samples were extracted by protein precipitation and analyzed by UPLC-MSMS using a Shimadzu UPLC and API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada) and a WatersAcquity UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 µm particle size). Acquisition and peak integration were performed using Analyst® software 1.6.3 (AB Sciex). Peak areas of analytes and internal standards were imported into Watson LIMS® software version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) for standard curve regression analysis and analyte quantification in the samples. All analytical instruments and software were validated using appropriate procedures.

[0394] Example 7

[0395] p38 MAPK Substrate Phosphorylation Overview

[0396] The ability of the compounds provided in this disclosure to selectively inhibit phosphorylation consistent with their target was assessed. HeLa cells were pretreated for 30 min with 10 µM SB203580, 50 µM test compound, or 0.1% DMSO medium control, followed by treatment with p38 activator, anisomycin (25 µg / mL), and phosphorylated test compound, and Stat-I was analyzed by immunoblotting.

[0397] Example 8

[0398] Specifically binds to p38α MAPK

[0399] DSF was used to analyze the concentration-specific binding of compounds of formula (6) to p38α MAPK and p38β MAPK. To confirm the binding of the test compounds to the CADD target bag, DSF was used to compare the binding of the compounds with wild-type p38α MAPK and the binding of SB203580 to a mutant with four of the ten substituted target bag amino acids (R49K / HL107-8TF / KI65R). This mutant could exhibit the same SB203580 binding as wild-type p38α MAPK, but could not exhibit the binding of the test compounds.

[0400] Saturation transfer was used to confirm the selective binding of the test compound to the CADD targeting bag in p38α MAPK.

[0401] Example 9

[0402] Pharmacokinetics

[0403] The pharmacokinetics of compounds (1) through (4) were determined in mice, rats and monkeys.

[0404] Mouse studies.

[0405] Female CD1 mice (n=9) received a single intraperitoneal dose of compound (4) at a dose of 1 mg / mouse. Prior to administration, a dosing formulation was prepared in 4% DMSO and 96% PBS using compound (4) at a dose of 2 mg / mL. Blood samples were collected from mice at designated time points. After collection, the samples were centrifuged (at 4°C, 2500 rpm, 10 min), and the resulting plasma was recovered and frozen (-60°C).

[0406] Bioanalyses targeting compounds (1) through (4) were performed on plasma samples. Mouse plasma samples were extracted via protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada) and a Waters Acquity® UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 µm particle size). Acquisition and peak integration were performed using Analyst® 1.7 software. Standard curve regression and quantification of analytes in the samples were performed using Analyst® software.

[0407] Based on plasma concentration data of compound (4) and metabolites (1) to (3), pharmacokinetic parameters were calculated using a non-compartmental method with WinNonlin® software version 8.1 (Certara®, Inc.). The area under the concentration-time curve (AUC) of compounds (1) to (4) was calculated. inf ). Percentage AUC of each metabolite inf (%AUC inf ) Calculate the AUC for each corresponding metabolite inf Divided by the AUC of compound (4) inf The ratio.

[0408] Rat research.

[0409] Male Sprague-Dawley rats (n=3) received a single intravenous bolus dose of compound (4) at a concentration of 10 mg / kg. The dosing formulation was prepared prior to administration using 5 mg / mL of compound (4) in a 14% (w / v) solution of sulfobutyl ether-β-cyclodextrin (SBECD) in deionized water. Blood samples were collected from each rat at designated time points. After collection, the samples were centrifuged (at approximately 4°C, 2500 rpm, 10 min), and the resulting plasma was recovered and frozen (-60°C).

[0410] Bioanalyses targeting compounds (1) through (4) were performed on the samples. Rat plasma samples were extracted from mice via protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada) and a Waters Acquity® UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 µm particle size). Acquisition and peak integration were performed using Analyst® 1.7 software. Standard curve regression and quantification of analytes in the samples were performed using Analyst® software.

[0411] Pharmacokinetic parameters were calculated using a non-compartmental method from plasma concentration data of compound (4) and metabolites (1) through (3) using WinNonlin® software version 8.1 (Certara®, Inc.). The area under the concentration-time curve (AUC) of compounds (1) through (4) was calculated. inf ). Percentage of metabolites (AUC) inf Calculate the AUC for each corresponding metabolite. inf Divided by the AUC of compound (4) inf The ratio.

[0412] Monkey research:

[0413] Male cynomolgus monkeys (n=3) received a single intravenous infusion of 5 mg / kg compound (4) over 2 hours (2.5 mL / kg / hour). The dosing formulation was prepared prior to administration using 1 mg / mL of compound (4) in a 14% w / v solution of sulfobutyl ether-β-cyclodextrin (SBECD) in deionized water. Blood samples were collected from each monkey at designated time points. After collection, the samples were centrifuged (at 4°C, 2500 rpm, 10 min), and the resulting plasma was recovered and frozen (-60°C).

[0414] Bioanalyses targeting compounds (1) through (4) were performed on the samples. Monkey plasma samples were extracted from mice via protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada) and either an ACE® Excel® 2 C18 column (50 mm × 3.0 mm, 2 µm particle size) or a Waters Acquity® UPLC BEHC18 column (50 mm × 2.1 mm, 1.7 µm). Acquisition and peak integration were performed using Analyst® software version 1.6.3. Standard curve regression and quantification of the analytes in the samples were performed using Watson LIMS® software version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) or Analyst® software.

[0415] Pharmacokinetic parameters were calculated using a non-compartmental method from plasma concentration data of compound (4) and its metabolites using WinNonlin® software version 8.1 (Certara®, Inc.). The area under the concentration-time curve (AUC) of compounds (1) to (4) was calculated. inf ). Percentage AUC of each metabolite inf Calculate the AUC for each corresponding metabolite. inf Divided by the AUC of compound (4) inf The ratio.

[0416] After oral administration of compound (2) to mammals, metabolites having the structure of formula (1), (2) or (3) exhibited %AUC relative to compound (4) as shown in Table 1. inf (100×AUC) 代谢物 / AUC 化合物(4) ).

[0417] Table 1. Compound (4) in vivo %AUC of metabolites.

[0418]

[0419] Example 10

[0420] Antiviral effects in SARS-CoV-2 infected cell lines

[0421] A549-ACE2 cells (Institut Pasteur, Paris, France) were cultured in DMEM (Corning) supplemented with 10% FBS (peak serum) and maintained at 37°C and 5% CO2. HEK293T-ACE2 cells (ATCC, CRL-3216) were maintained in DMEM (Corning) supplemented with 10% FB (peak serum) and penicillin / streptomycin (Corning) at 37°C and 5% CO2. Ectopic hACE2 expression cells were generated via transduction using a lentiviral vector expressing human ACE2. Puromycin-resistant cells with hACE2 surface expression were sorted after staining with AlexaFluor 647-conjugated goat anti-hACE2 antibody. Cells were then cloned and screened for their ability to support SARS-CoV-2 replication. All cell lines used were periodically screened for mycoplasma contamination using a universal mycoplasma detection kit (ATCC, 30-1012K).

[0422] SARS-CoV-2 isolate BetaCoV / France / IDF0372 / 2020 was provided by the National Reference Center for Respiratory Viruses, hosted by the Pasteur Institute (Paris, France). This isolate was derived from a human sample. It was provided through the European Virus Archives Global Access (EVAg) platform. A viral stockpile was prepared by propagation in Vero E6 cells in DMEM supplemented with 2% FBS. Viral titers were determined by plaque assays in minimum essential medium (MEM) supplemented with 2% (v / v) FBS (Invitrogen) and 0.05% agarose.

[0423] All experiments involving live SARS-CoV-2 were conducted in accordance with the Paris Pasteur Institute-approved laboratory biosafety level 3 (BSL-3) control procedures.

[0424] Two hours prior to infection, the culture medium, including a DMSO control, was replaced with DMEM (2% FBS) containing the target compound at a concentration 50% higher than the indicated concentration. The plates were then transferred to a BSL-3 facility, and the same volume of SARS-CoV-2 was added to the DMEM (2% FBS) to achieve the desired final compound concentration. The plates were returned to the incubator and incubated at 37°C / 5% CO2 for 48 hours. All assays were performed biologically independent in triplicate.

[0425] Viral genome detection was performed directly from the inactivated supernatant using RT-qPCR. SARS-CoV-2 specific primers targeting the N gene region were used: 5′-TAATCAGACAAGGAACTGATTA-3′ (SEQ ID NO: 1) (forward) and 5′-CGAAGGTGTGACTTCCATG-3′ (SEQ ID NO: 2) (reverse) with Luna. ® The Universal One-Step RT-qPCR Kit (NEB) is available at Applied Biosystems QuantStudio. ® The system was used on a thermal cycler with the following cycling conditions: 55°C for 10 minutes, 95°C for 1 minute, and 95°C for 10 seconds for 40 cycles, followed by 60°C for 1 minute. The viral genome count was expressed as PFU equivalents / mL and calculated using a standard curve plotted with RNA derived from a viral stock at a known viral titer.

[0426] According to the manufacturer's instructions, use CellTiter ® The Glo luminescence cell viability assay (Promega) is used to measure cell viability in Tecan Infinite. ® Luminescence was measured in a 2000 plate reader. Cytotoxicity was performed using the same compound dilutions and simultaneously with virus replication assays in uninfected cells. Percentage of viability was calculated relative to untreated cells (100% viability) and cells lysed with 20% ethanol (0% viability).

[0427] The Hill function was fitted to each dose-response curve using the lsqcurvefit function in MATLAB (R2018a). The IC50 (virus) value was defined as the concentration at which a percentage measurement (viral or cell viability quantification) exceeded 50%. If the fitted curve did not start above 50% and cross below 50% throughout the dose-response process, the IC50 value was marked as greater than the maximum test concentration.

[0428] Cell viability (black) and IC50 (red) curves of SARS-CoV-2 cell lines treated with compounds (4), (1), or (2) are shown in the figures. Figure 1-3 middle.

[0429] Finally, it should be noted that alternative ways of implementing the embodiments disclosed herein exist. Therefore, these embodiments are to be considered illustrative rather than restrictive, and the claims are not limited to the details given herein, but may be modified within the scope of the claims and their equivalents.

Claims

1. Compounds having the structure of formula (6): (6) Or its pharmaceutically acceptable salt, wherein, R 1 C 1-4 Alkyl; R 2 It is a 3-substituted morpholino-4-yl; R 3 For –S(=O)2–; R 4 For –N(R) 5 )2, where each R 5 Independently selected from hydrogen and C 1-4 alkyl; R 4 Bonded to the 5-position of the naphthyl group; and The substituent is =O.

2. The compound according to claim 1, wherein, R 1 It is a dimethylmethane.

3. The compound according to claim 1, wherein the compound is selected from: 5-Amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; and 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; Or a pharmaceutically acceptable salt of any of the above.

4. The compound according to claim 1, wherein the compound is 5-amino- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (5) or a pharmaceutically acceptable salt thereof: 。 5. The compound according to claim 1, wherein the compound is 5-(methylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2) or a pharmaceutically acceptable salt thereof: 。 6. The compound according to claim 1, wherein the compound is 5-(dimethylamino)- N -(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3) or a pharmaceutically acceptable salt thereof: 。 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable mediator.

8. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating a patient with a viral disease, wherein the viral disease is SARS-CoV-2.

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