Substituted naphthyl P38 alpha mitogen-activated protein kinase inhibitors

Abstract

To provide substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating diseases.SOLUTION: A compound having the structure of formula (6), or a pharmaceutically acceptable salt thereof, is provided.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] The present disclosure relates to substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and uses of the substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating disease.

[0003] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on March 21, 2022, is named 67LZ-000610PC-349166_SL.txt, and is 755 bytes in size. [Background technology]

[0004] Mitogen-activated protein kinases (MAPKs) are serine / threonine protein kinases that process and regulate cellular properties in response to a wide range of extracellular stimuli. These enzymes phosphorylate serine or threonine OH groups in proteins and play important roles in regulating cell proliferation, differentiation, survival, and apoptosis. In mammalian cells, several different MAPKs have been identified, including p38 MAPK.

[0005] p38MAPK is a class of MAPK that responds to stress stimuli, such as inflammatory cytokines and reactive oxygen species (ROS), and is involved in a wide range of signaling pathways that stimulate different biological functions. For example, p38MAPK has been shown to play an essential role in regulating proinflammatory signaling networks and cytokine biosynthesis, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in immune cells.

[0006] Studies have shown that p38MAPK contributes to the development of chronic inflammation, leading to preclinical and clinical trials for the application of p38MAPK inhibitors in inflammatory diseases such as rheumatoid arthritis and asthma.

[0007] p38MAPK contains four isoforms (α, β, γ, and δ). p38α MAPK was the first isoform of p38MAPK to be identified and was first recognized as a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. Inhibition of p38MAPK has been shown to effectively alleviate the symptoms of inflammatory diseases such as rheumatoid arthritis, cardiovascular disease, and inflammatory pain.

[0008] Many p38 MAPK catalytic inhibitors are ineffective and cause toxicity, likely due to loss of activity against non-inflammatory p38 and p38α-dependent counterregulatory responses. p38α MAPK inhibitors that can selectively block specific p38α MAPK functions and preserve important counterregulatory and homeostatic functions are desirable for the treatment of inflammatory and oncological diseases. Summary of the Invention

[0009] According to the present invention, the compound has the structure of formula (6): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But C 1-4 Alkanediyl, C 1-4 Heteroalkanediyl, substituted C 1-4 Alkanediyl and substituted C 1-4 heteroalkanediyl; R 2 But substitution C 5-8 is heterocycloalkyl, R 3 is selected from -C(=O)- and -S(=O)-; R4 But -N(R 5 )2, and each R 5 are independently hydrogen and C 1-4 alkyl.

[0010] According to the present invention, the pharmaceutical composition comprises a compound according to the present invention or a pharmaceutically acceptable salt thereof.

[0011] According to the present invention, a method of treating a disease in a patient comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, wherein the disease is treated by inhibiting the p38α MAPK receptor. [Brief explanation of the drawings]

[0012] The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure.

[0013] [Figure 1] Figure 1 shows cell viability (black) and IC50 (red) curves for SARS-CoV-2 cell lines treated with compound (4). [Figure 2] Figure 1 shows cell viability (black) and IC50 (red) curves for SARS-CoV-2 cell lines treated with compound (1). [Figure 3] Figure 1 shows cell viability (black) and IC50 (red) curves for SARS-CoV-2 cell lines treated with compound (2). DETAILED DESCRIPTION OF THE INVENTION

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a moiety or substituent, for example, -CONH2 is attached through a carbon atom.

[0015] "Alkyl" refers to a saturated, branched, or straight-chain, monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of alkyl groups include methyl; ethyl, such as ethanyl, ethenyl, and ethynyl; propyl, such as propan-1-yl, propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl, and prop-2-yn-1-yl; butan-1-yl, butan-2-yl, and 2-methyl-propan-1-yl. , 2-methyl-propan-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, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, butyl; and the like. The term "alkyl" includes groups having any degree or level of saturation, i.e., groups having exclusively carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having a combination of carbon-carbon single, double, and triple bonds. When specific levels of saturation are intended, the terms alkanyl, alkenyl, and alkynyl are used. Alkyl groups include those having C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 It can be alkyl, ethyl, or methyl.

[0016] "Alkoxy" refers to the radical -OR where R is alkyl as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. An alkoxy group is a C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 It can be alkoxy, ethoxy, or methoxy.

[0017] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes five- and six-membered carbocyclic aromatic rings, such as benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane, and tetralin; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as fluorene. Aryl includes multiple ring systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes a phenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic ring systems in which only one of the rings is a carbocyclic aromatic ring, the radical carbon atom can be in the carbocyclic aromatic ring or the heterocycloalkyl ring. Examples of aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl may be aryl, or phenyl. However, aryl does not in any way encompass or overlap with heteroaryl, which is defined separately herein.

[0018] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. Where a specific alkyl moiety is intended, the nomenclature arylalkanyl, arylalkenyl, or arylalkynyl is used. An arylalkyl group is a C 7-16 It can be an arylalkyl, for example, the alkanyl, alkenyl, or alkynyl portion of the arylalkyl group can be C 1-6 and the aryl moiety is C 6-10 The arylalkyl group is C 7-16 It can be an arylalkyl, for example, the alkanyl, alkenyl, or alkynyl portion of the arylalkyl group can be C 1-6 and the aryl moiety is C 6-10 The arylalkyl group is C 7-9 arylalkyl, wherein the alkyl portion is C 1-3 The aryl alkyl group can be C 7-16 Aryl alkyl, C 7-14 Aryl alkyl, C 7-12 Aryl alkyl, C 7-10 Aryl alkyl, C 7-8 It may be aryl, alkyl, or benzyl.

[0019] "Bioavailability" refers to the rate and amount of drug that reaches a patient's systemic circulation following administration of the drug or its prodrug to the patient, and can be determined, for example, by assessing the plasma or blood concentration versus time profile of the drug. Parameters useful for characterizing the plasma or blood concentration versus time curve include the area under the curve (AUC), time to maximum concentration (T), and the like. max ), and maximum drug concentration (C max ) and C maxis the maximum concentration of the drug in the patient's plasma or blood after administration of a dose of the drug or form of the drug to the patient, and T max is the maximum concentration (C) of a drug in a patient's plasma or blood after administration of a dose of the drug or form of the drug to the patient. max ) is the time until

[0020] "Oral bioavailability" (F%) refers to the fraction of an orally administered drug that reaches the systemic circulation. Oral bioavailability is the product of the fraction absorbed, the fraction that escapes intestinal elimination, and the fraction that escapes hepatic elimination, and factors that affect bioavailability can be divided into physiological, biochemical, and biopharmaceutical factors.

[0021] "Compounds" and moieties disclosed herein include any specific compound within the disclosed formula. Compounds may be identified by either chemical structure and / or 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 the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity. Compounds described herein may contain one or more stereoisomeric centers and / or double bonds and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, or atropisomers. Therefore, any chemical structure within the scope of this specification, depicted in whole or in part in a relative configuration, encompasses all possible enantiomers and stereoisomers of the depicted compound, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art.

[0022] The compounds and moieties disclosed herein include optical isomers of the compounds and moieties, their racemates, and other mixtures thereof. In such embodiments, single enantiomers or diastereomers can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished by conventional methods such as, for example, crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column having a chiral stationary phase. In addition, the compounds include (Z)- and (E)-forms (or cis- and trans-forms) of compounds with double bonds, either as single geometric isomers or mixtures thereof.

[0023] Compounds and moieties may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the depicted compounds. Compounds may exist in solvated forms, including unsolvated and hydrated forms. Certain compounds may exist in multiple crystalline, co-crystalline, or amorphous forms. Compounds include pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates of any of the foregoing free acid forms, and any of the foregoing crystalline forms.

[0024] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl radical. A cycloalkyl group is a C 3-8 Cycloalkyl, C 3-5 Cycloalkyl, C 5-6 It may be cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. Cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl, and cyclooctyl.

[0025] "Cycloalkylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group, as defined herein. Where a specific alkyl moiety is intended, the nomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl is used. A cycloalkylalkyl group is a C 4-30 It can be a cycloalkylalkyl, for example, the alkanyl, alkenyl, or alkynyl portion of the cycloalkylalkyl group can be C 1-10 and the cycloalkyl portion of the cycloalkylalkyl moiety is C 3-20 The cycloalkylalkyl group is C 4-20 It can be a cycloalkylalkyl, for example, the alkanyl, alkenyl, or alkynyl portion of the cycloalkylalkyl group can be C 1-8 and the cycloalkyl portion of the cycloalkylalkyl group is C 3-12 Cycloalkylalkyl is a cycloalkyl group in which the alkyl portion is C 1-3 The cycloalkyl group is C 3-6 cycloalkyl, C 4-9 The cycloalkylalkyl group can be C 4-12 Cycloalkylalkyl, C 4-10 Cycloalkylalkyl, C 4-8 Cycloalkylalkyl, and C 4-6 The cycloalkylalkyl group can be cyclopropylmethyl (-CH2-cyclo-C3H5), cyclopentylmethyl (-CH2-cyclo-C5H9), or cyclohexylmethyl (-CH2-cyclo-C6H 11 The cycloalkylalkyl group can be cyclopropylethenyl (-CH=CH-cyclo-C3H5), cyclopentylethynyl (-C≡C-cyclo-C5H9), and the like.

[0026] "Cycloalkylheteroalkyl" by itself or as part of another substituent refers to a heteroalkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) of the alkyl group are independently replaced with the same or different heteroatom group, and one of the hydrogen atoms bonded to the carbon atom is replaced with a cycloalkyl group. Where a specific alkyl moiety is intended, the nomenclature cycloalkylheteroalkanyl, cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl are used. In cycloalkylheteroalkyl, the heteroatom group can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, -SO2-, -Si-, -B-, or the heteroatom group can be selected from -O- and -NH-, or the heteroatom group is -O- or -NH-.

[0027] "Cycloalkyloxy" refers to the radical -OR where R is cycloalkyl as defined herein. Examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. A cycloalkyloxy group is a C 3-6 Cycloalkyloxy, C 3-5 Cycloalkyloxy, C 5-6 It may be cycloalkyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0028] "Disease" refers to any of the diseases, disorders, conditions, or symptoms described above.

[0029] "Drug," as defined under 21 U.S.C. § 321(g)(1), means "(A) any article recognized in the United States Pharmacopoeia, the United States Homeopathic Pharmacopoeia, or the National Formulary, or any supplement thereto, and (B) any article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, and (C) any article (other than food) intended to affect the structure or any function of the body of humans or other animals..."

[0030] "Halogen" refers to a fluoro, chloro, bromo, or iodo group.

[0031] "Heteroalkoxy" refers to an alkoxy group in which one or more of the carbon atoms is replaced with a heteroatom. A heteroalkoxy group is a C 1-6 Heteroalkoxy, C 1-5 Heteroalkoxy, C 1-4 Heteroalkoxy, or C 1-3 In the heteroalkoxy, the heteroatom group can be selected from -O-, -S-, -NH-, -NR-, where R is C 1-6 The heteroatom groups may be selected from alkyl, -SO-, -SO2-, -Si-, and -B-, or the heteroatom groups are -O- and -NH-. Heteroalkoxy groups include C 1-6 Heteroalkoxy, C 1-5 Heteroalkoxy, C 1-4 Heteroalkoxy, or C 1-3 It may be heteroalkoxy.

[0032] "Heteroalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Examples of heteroatomic groups include -O-, -S-, -Si-, -B-, -NH-, -NR-, -OO-, -SS-, =NN=, -N=N-, -N=N-NR-, -PR-, -P(O)OR-, -P(O)R-, -POR-, -SO-, -SO2-, and -Sn(R)2-, where each R is independently hydrogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 6-12 Aryl, substituted C 6-12 Aryl, C 7-18 Aryl alkyl 、 substitution C 7-18 Aryl alkyl, C 3-7 Cycloalkyl, substituted C 3-7 cycloalkyl 、 C 3-7Heterocycloalkyl, substituted C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 6-12 Heteroaryl, substituted C 6-12 Heteroaryl, C 7-18 Heteroarylalkyl and substituted C 7-18 Each R is independently selected from hydrogen and C 1-3 alkyl, for example, C 1-6 Reference to heteroalkyl refers to a C alkyl group in which at least one of the carbon atoms (and certain associated hydrogen atoms) has been replaced with a heteroatom. 1-6 It means an alkyl group. For example, C 1-6 Heteroalkyl includes groups having 5 carbon atoms and 1 heteroatom, and groups having 4 carbon atoms and 2 heteroatoms. In heteroalkyl, 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-. Heteroalkyl groups include C 1-6 Heteroalkyl, C 1-5 Heteroalkyl, or C 1-4 Heteroalkyl, or C 1-3 It can be heteroalkyl.

[0033] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses multiple ring systems having at least one heteroaromatic ring fused to at least one other ring, which may be aromatic or non-aromatic. For example, heteroaryl encompasses bicyclic rings in which one ring is heteroaromatic and the second ring is a heterocycloalkyl ring. For such fused bicyclic heteroaryl ring systems, if only one of the rings contains one or more heteroatoms, the radical carbon can be in the aromatic ring or the heterocycloalkyl ring. If the total number of N, S, and O atoms in the heteroaryl group exceeds one, the heteroatoms may or may not be adjacent to one another. The total number of heteroatoms in a heteroaryl group is two or less. In heteroaryl, 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-. Heteroaryl groups include, for example, C 5-10 Heteroaryl, C 5-9 Heteroaryl, C 5-8 Heteroaryl, C 5-7 Heteroaryl, C 5-6 It may be selected from heteroaryl, C5 heteroaryl, or C6 heteroaryl.

[0034] Examples of heteroaryl groups include groups derived from acridine, arsindole, carbazole, α-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine, and oxazolidine. Heteroaryl groups can be derived from, for example, thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, heteroaryl can be C5 heteroaryl and can be selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. Heteroaryl can be C6 heteroaryl and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0035] "Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and certain associated hydrogen atoms) has been replaced with a heteroatom. 6-16 Heteroarylalkyl, C 6-14 Heteroarylalkyl, C 6-12 Heteroarylalkyl, C 6-10 Heteroarylalkyl, C 6-8It may be a heteroarylalkyl, or a C7 heteroarylalkyl, or a C6 heteroarylalkyl. In the heteroarylalkyl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, -SO2-, -Si-, and -B-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-.

[0036] "Heterobicycloalkyl" refers to a moiety having two heterocycloalkyl groups. Heterobicyclycloalkyl groups can be fused ring or spiro compounds.

[0037] "Heterocycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatoms, or to a parent aromatic ring system in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatoms, such that the ring system violates the Hückel rule. Examples of heteroatoms replacing carbon atoms include N, P, O, S, B, and Si. Examples of heterocycloalkyl groups include groups derived from epoxides, azirines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, and quinuclidines. Heterocycloalkyls can be C5 heterocycloalkyls and are selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. The heterocycloalkyl may be a C6 heterocycloalkyl and may be selected from piperidinyl, tetrahydropyranyl, piperidinyl, oxazinyl, dithianyl, and dioxanyl. 3-8 Heterocycloalkyl, C 3-8 Heterocycloalkyl, C 3-5 Heterocycloalkyl, C 5-6It can be a heterocycloalkyl, a C5 heterocycloalkyl, or a C6 heterocycloalkyl. In the heterocycloalkyl, the heteroatom group can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, -SO2-, -Si-, -B-, or the heteroatom group can be selected from -O- and -NH-, or the heteroatom group can be -O- or -NH-.

[0038] "Heterocycloalkylalkyl" refers to a cycloalkylalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are independently replaced with the same or different heteroatoms. 4-12 Heterocycloalkylalkyl, C 4-10 Heterocycloalkylalkyl, C 4-8 Heterocycloalkylalkyl, C 4-6 Heterocycloalkylalkyl, C 6-7 Heterocycloalkylalkyl, or C6 heterocycloalkylalkyl or C7 heterocycloalkylalkyl. In heterocycloalkylalkyl, the heteroatom group can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, -SO2-, -Si-, -B-, or the heteroatom group can be selected from -O- and -NH-, or the heteroatom group can be -O- or -NH-.

[0039] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugated π (pi) electron system with 4n+2 electrons (Hückel's rule). Included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0040] "Hydrate" refers to the incorporation of water into the crystal lattice of a compound described herein in a stoichiometric proportion, resulting in the formation of an adduct. Methods for producing hydrates include, but are not limited to, storage in an atmosphere containing water vapor, a dosage form containing water, or routine pharmaceutical processing steps, such as crystallization (i.e., from water or a mixed aqueous solvent), lyophilization, wet granulation, aqueous film coating, or spray drying. Hydrates can also form from crystalline solvates under certain circumstances upon exposure to water vapor or upon suspension of anhydrous materials in water. Hydrates can also crystallize in more than one form, resulting in hydrate polymorphs.

[0041] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0042] A "parent heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms in a manner that maintains the contiguous π-electron system characteristic of an aromatic system and the number of π-electrons corresponding to Hückel's rule (4n+2). Examples of heteroatoms for replacing carbon atoms include N, P, O, S, Si, and B. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, arsindole, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Examples of parent heteroaromatic ring systems include arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thiazolidine, oxazolidine.

[0043] "Patient" refers to a mammal, for example, a human.

[0044] "Pharmaceutically acceptable" refers to that which is listed, approved, or approvable by a regulatory agency of the Federal or State government, or in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0045] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include inorganic acids as well as acid addition salts formed with one or more protonatable functional groups, such as primary, secondary, or tertiary amines, in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can also be formed with 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, and benzenesulfonic acid. Salts may be formed with 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Salts may be formed when one or more acidic protons present in the parent compound are replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a combination thereof, or by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts may be hydrochlorides. Pharmaceutically acceptable salts may be sodium salts. For compounds with two or more ionizable groups, a pharmaceutically acceptable salt can include one or more counterions, such as a disalt, e.g., a dihydrochloride salt.

[0046] The term "pharmaceutically acceptable salts" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is understood that the specific salt (e.g., hydrochloride) is an example of a salt, and that other salts may be formed using techniques known to those skilled in the art. Additionally, using techniques generally known in the art, those skilled in the art will be able to convert a pharmaceutically acceptable salt to the corresponding compound, free base, and / or free acid.

[0047] A "pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or a combination of any of the foregoing, with which a compound provided by the present disclosure may be administered to a patient, which does not destroy its pharmacological activity, and which is non-toxic when administered in a dosage sufficient to provide a therapeutically effective amount of the compound.

[0048] A "pharmaceutical composition" refers to a compound provided by the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle administered to a patient together with a compound provided by the present disclosure, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable vehicles are known in the art.

[0049] "Preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., preventing at least one of the clinical symptoms of the disease from developing in a patient who may be exposed to or susceptible to the disease, but who does not yet experience or display symptoms of the disease). In some embodiments, "preventing" or "prevention" refers to reducing the symptoms of the disease by prophylactically administering a compound provided by the present disclosure. The application of a therapeutic agent to prevent or prevent a disease or disorder is known as prophylaxis. The compounds provided by the present disclosure can provide superior prevention due to lower long-term side effects over a long period of time.

[0050] A "solvate" refers to a molecular complex of a compound with one or more solvent molecules in stoichiometric or non-stoichiometric amounts. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to patients, such as water or ethanol. A molecular complex of a compound or a portion of a compound with a solvent can be stabilized by non-covalent intramolecular forces, such as electrostatic forces, van der Waals forces, or hydrogen bonding. The term "hydrate" refers to a solvate in which one or more solvent molecules are water.

[0051] "Solvate" refers to the incorporation of a solvent into the crystal lattice of a compound described herein in a stoichiometric proportion, resulting in the formation of an adduct. Methods for creating solvates include, for example, storage in a solvent-containing atmosphere, a dosage form containing a solvent, or routine pharmaceutical processing steps such as, for example, vapor diffusion crystallization (i.e., from a solvent or a mixture of solvents). Solvates can also form from other crystalline solvates or hydrates under certain circumstances when exposed to a solvent or when suspending a material in a solvent. Solvates can crystallize in more than one form, resulting in solvate polymorphs.

[0052] "Compounds provided by the present disclosure" refers to compounds encompassed by Formula (6) and pharmaceutical salts thereof. In certain embodiments, compounds provided by the present disclosure can further include compounds encompassed by Formula (6), pharmaceutical salts, solvates, hydrates, and / or prodrugs of any of the foregoing.

[0053] The compounds provided by the present disclosure also include crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referenced.

[0054] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituents. Each substituent is independently selected from deuterium, halogen, -OH, -CN, -CF3, -OCF3, =O, -NO2, C 1-6 Alkoxy, C 1-6 alkyl, -COOR, -NR2, and -CONR2, where each R is independently selected from hydrogen and C 1-6 Each substituent is independently selected from deuterium, halogen, —NH, —OH, C 1-3 Alkoxy, and C 1-3 Each substituent may be independently selected from deuterium, —OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Each substituent may be independently selected from deuterium, C 1-3 Alkyl, =O, C 1-3 Alkyl, C 1-3 Each substituent may be independently selected from deuterium, —OH, —NH, C 1-3 Alkyl, and C 1-3 It may be selected from alkoxy.

[0055] "Sustained release" refers to the release of a compound from a dosage form of a pharmaceutical composition at a rate effective to achieve therapeutic or prophylactic concentrations of the compound or its active metabolite in a patient's systemic circulation over a period of time relative to that achieved by administration of an immediate release formulation of the same compound by the same route of administration. In some embodiments, the release of the compound occurs over a period of at least about 4 hours, e.g., 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.

[0056] "Treating" or "treatment" of a disease refers to arresting or alleviating the disease or at least one clinical symptom of the disease or disorder, reducing the risk of acquiring the disease or at least one clinical symptom of the disorder, reducing the onset of the disease or at least one clinical symptom of the disorder, or reducing or reducing the risk of developing the disease or at least one clinical symptom of the disorder. "Treating" or "treatment" also refers to inhibiting the disease either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both, as well as inhibiting at least one physical parameter or manifestation, which may or may not be discernible to the patient. "Treating" or "treatment" also refers to delaying the onset of the disease, or delaying the onset of at least one or more symptoms thereof, in a patient who may be exposed to or susceptible to the disease or disorder, even if the patient has not yet experienced or exhibited symptoms of the disease.

[0057] A "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient for treating a disease, or at least one clinical symptom of the disease, is sufficient to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" can vary depending, for example, on the compound, the disease and / or symptoms of the disease, the severity of the disease, and / or symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. An appropriate amount in any given case can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0058] A "therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. A therapeutically effective dose may vary from compound to compound and from patient to patient, and may depend on factors such as the condition of the patient and the route of delivery. A therapeutically effective dose may be determined according to routine pharmacological procedures known to those skilled in the art.

[0059] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. The vehicle can be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0060] "Binding affinity" refers to the strength of the binding interaction between a single biomolecule and its ligand / binding partner. Binding affinity is measured by the IC 50 The binding affinity can be determined by phage ELISA competition assay.

[0061] "Modulate" and "modulation" refer to a change in the biological activity of a biological molecule, e.g., a protein, gene, peptide, or antibody, where such a change may relate to an increase in biological activity, e.g., increased activity, agonism, activation, expression, up-regulation, and / or increased expression, or a decrease in biological activity, e.g., decreased activity, antagonism, inhibition, deactivation, down-regulation, and / or decreased expression, for the biological molecule.

[0062] For example, the compounds described herein can inhibit, e.g., modulate, p38α MAPK protein. The compounds provided by the present disclosure can selectively inhibit, e.g., selectively modulate, p38α MAPK protein relative to other MAPK or p38 MAPK proteins. The compounds provided by the present disclosure can selectively inhibit, e.g., selectively modulate, p38α MAPK protein relative to other MAPK or p38 MAPK proteins.

[0063] "Moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0064] Reference will now be made in detail to certain compounds, compositions, and methods. The disclosed compounds, compositions, and methods are not intended to limit the scope of the claims. On the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

[0065] The compounds provided by the present disclosure are selective inhibitors of the p38α MAPK protein. The pharmaceutical compositions provided by the present disclosure include the compounds provided by the present disclosure. The compounds and pharmaceutical compositions provided by the present disclosure can be used to treat diseases, which are treated by inhibiting the p38α MAPK protein.

[0066] Catalytic inhibitors of p38α MAPK can block the expression of proinflammatory cytokines and other p38α MAPK signaling pathways that are important for establishing and maintaining homeostasis.

[0067] As an alternative to catalytic inhibitors, compounds provided by the present disclosure target the substrate-binding groove of p38α MAPK, which extends between two acidic patches called the CD and ED domains of the MAPK receptor and is distinct from the DEF substrate-binding pocket. Downstream substrates, upstream activating kinases, and possibly scaffolding molecules interact with p38 MAPK through these sites. Compounds provided by the present disclosure can selectively bind to p38α MAPK but not p38β MAPK, stabilize endothelial barrier function in human pulmonary microvascular endothelial cells (HMVECL), and / or inhibit lipopolysaccharide (LPS)-induced pro-inflammatory gene expression in THP-1 cells.

[0068] Compounds provided by the present disclosure include those having R 2 a compound of formula (6) containing a substituted fused ring, and R 2 The compounds provided by the present disclosure include compounds of formula (6) having the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But C 1-4 Alkanediyl, C 1-4 Heteroalkanediyl, substituted C 1-4 Alkanediyl and substituted C 1-4 heteroalkanediyl; R 2 But substitution C 5-12 may be heterocycloalkyl, R 3 may be selected from -C=O and -S(=O)2; R 4 But -N(R 5 ) 2 can be selected, each R 5 are independently hydrogen and C 1-4 It can be selected from alkyl.

[0069] In the compound of formula (6), each of the one or more substituents may independently be, for example, —OH, ═O, —NH, —NO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heteroalkoxy, C 1-6 Heterocycloalkyl, C 5-6 Heteroaryl, 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 heteroalkoxy, substituted C 1-6 Heterocycloalkyl and substituted C 5-6 Heteroaryl may be selected from:

[0070] In the compound of formula (6), each of the one or more substituents is independently -OH, ═O, -NH, -NO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Heteroalkyl, 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.

[0071] In the compound of formula (6), each of the one or more substituents is independently —OH, ═O, C 1-3 Alkyl, and C 1-3 It may be selected from alkoxy.

[0072] In compounds of formula (6), each of the one or more substituents can be =O.

[0073] In the compound of formula (6), each of the one or more heteroatoms may be independently selected from N and O.

[0074] In the compound of formula (6), R 1 is C 1-4 It may be an alkanediyl.

[0075] In the compound of formula (6), R 1 can be ethanediyl.

[0076] In the compound of formula (6), R 1 can be methanediyl.

[0077] In the compound of formula (6), R 2 can be a C6 heterocycloalkyl.

[0078] In the compound of formula (6), each of the one or more heteroatoms may be selected from O and N.

[0079] In the compound of formula (6), R 2 can be 4-morpholinyl.

[0080] In the compound of formula (6), R 2can be a substituted 4-morpholinyl.

[0081] In the compound of formula (6), R 2 can be a 3-substituted 4-morpholinyl.

[0082] In the compound of formula (6), R 2 can be a C5 heterocycloalkyl, a C6 heterocycloalkyl, a C7 heterocycloalkyl, a C8 heterocycloalkyl, or a C9 heterocycloalkyl.

[0083] In the compound of formula (6), R 2 is C 5-12 R through the nitrogen heteroatom of the heterocycloalkyl moiety 1 can be combined with

[0084] In the compound of formula (6), R 2 is a ring nitrogen heteroatom R 1 Monocyclic C bonded to 5-12 It may be a heteroalkyl ring.

[0085] In the compound of formula (6), R 2 is a ring nitrogen heteroatom R 1 and having at least one ring oxygen heteroatom, 5-12 It may be a heteroalkyl ring.

[0086] In the compound of formula (6), R 2 is a ring nitrogen heteroatom R 1 and having at least one ring oxygen heteroatom and at least one oxo (=O) substituent, 5-12 It may be a heteroalkyl ring.

[0087] In the compound of formula (6), R 2 is a ring nitrogen heteroatom R 1 Bicyclic C bonded to 5-12 It may be a heteroalkyl ring.

[0088] In the compound of formula (6), R2 is a ring nitrogen heteroatom R 1 and having at least one ring oxygen heteroatom, 5-12 It may be a heteroalkyl ring.

[0089] In the compound of formula (6), R 2 is a ring nitrogen heteroatom R 1 and having at least one ring oxygen heteroatom and at least one oxo (=O) substituent. 5-12 It may be a heteroalkyl ring.

[0090] In the compound of formula (6), R 2 is 4λ 2 -morpholin-3-one, 4λ 2 -morpholin-2-one, 1,3λ 2 -Oxazinan-4-one, 1,3λ 2 -Oxazinan-5-one, 1,3λ 2 -oxazinan-6-one, 3λ 2 -oxazolidin-2-one, 3λ 2 -oxazolidin-4-one, and 3λ 2 -oxazolidin-5-one.

[0091] In the compound of formula (6), each of the one or more substituents is selected from the group consisting of —OH, ═O, and —N(R 5 ) 2 can be selected, each R 5 are independently hydrogen and C 1-3 It can be selected from alkyl.

[0092] In the compound of formula (6), each of the one or more substituents can be -OH.

[0093] In compounds of formula (6), each of the one or more substituents can be =O.

[0094] In the compound of formula (6), each of the one or more substituents is —N(R 5 )2, and each R 5 are independently hydrogen and C1-3 It may be selected from alkyl.

[0095] In the compound of formula (6), R 3 may be selected from C(=O) and S(O)2.

[0096] In the compound of formula (6), R 3 can be C(=O).

[0097] In the compound of formula (6), R 3 can be S(O)2.

[0098] In the compound of formula (6), R 4 can be attached to the 3-, 4-, 5-, 6-, or 7-position of the naphthyl moiety.

[0099] In the compound of formula (6), R 4 can be attached to the 5-position of the naphthyl moiety.

[0100] In the compound of formula (6), R 1 is C 1-3 may be an alkanediyl; R 2 can be a substituted 4-morpholinyl; R 3 can be selected from C(=O) and S(O)2; R 4 is -N(R 5 ) 2 can be selected, each R 5 are independently hydrogen and C 1-3 It can be selected from alkyl.

[0101] In the compound of formula (6), R 1 may be methane-diyl; R 2 can be a substituted 4-morpholinyl; R 3 may be S(O)2, R 4 is -N(R5 )2, and each R 5 may be independently selected from hydrogen and methyl.

[0102] In the compound of formula (6), R 1 may be methane-diyl; R 2 can be a substituted 4-morpholinyl; R 3 can be C(=O), R 4 is -N(R 5 )2, and each R 5 may be independently selected from hydrogen and methyl.

[0103] In the compound of formula (6), R 2 can be a 3-substituted 4-morpholinyl.

[0104] In the compound of formula (6), R 2 In the moiety, the substituent may be =O.

[0105] In the compound of formula (6), R 4 may be selected from -NH(-CH3) and -N(-CH3)2.

[0106] In the compound of formula (6), R 4 can be -NH(-CH3).

[0107] In the compound of formula (6), R 4 can be —N(—CH 3 ) 2 .

[0108] The compound of formula (6) 4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, and 6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, or a pharmaceutically acceptable salt of any of the foregoing.

[0109] 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: [ka]

[0110] 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: [ka]

[0111] 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: [ka]

[0112] The compound of formula (6) can be a solvate, a pharmaceutically acceptable salt, or a combination thereof.

[0113] In the compound of formula (6), the pharmaceutically acceptable salt may be a hydrochloride salt.

[0114] The compound of formula (6) can be a pharmaceutically acceptable salt of the compound of formula (6), a hydrate thereof, or a solvate of any of the foregoing.

[0115] In certain embodiments, the compound provided by the present disclosure is not a compound of formula (1) (5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide). [ka]

[0116] Compounds provided by the present disclosure can be p38α MAPK inhibitors, such as selective p38 MAPK inhibitors, and / or modulators of p38α MAPK protein activity.

[0117] The compounds provided by the present disclosure can be selective inhibitors of p38α MAPK. The selective p38α MAPK inhibitors provided by the present disclosure have a higher binding affinity (lower IC) for the target pocket of p38α MAPK than for the catalytic binding site of p38α MAPK. 50). Compounds provided by the present disclosure can selectively inhibit p38α MAPK. p38α MAPK inhibitors can bind to p38α MAPK near the substrate-binding groove of p38α MAPK, which extends between two acidic patches called the CD and ED domains. The binding pocket can be defined by at least residues R49, H107, L108, and K165 of p38α MAPK. The binding pocket can be defined by at least residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 of p38α MAPK. Binding pockets and methods for determining selective binding to selective binding pockets are described, for example, in U.S. Application Nos. 2020 / 0331874 A1 and 2019 / 0151324 A1.

[0118] The selective binding of compounds provided by the present disclosure to p38α MAPK can be confirmed using complementary techniques. For example, selective p38α MAPK inhibitors can exhibit a concentration-dependent increase in the melting temperature of p38α but not p38P, as determined using differential scanning fluorometry (DSF) to detect ligand-induced protein stabilization. STD-NMR, which measures low-affinity protein / ligand binding via non-scalar magnetization transfer from protein to ligand protons, can be used to confirm specific compound binding to p38α and localize the interaction to the aromatic ring of the binding site. p38α MAPK inhibitors can cause a concentration-dependent increase in the melting temperature of p38α MAPK. Melting temperature T m The difference in melting temperature can be measured at p38α MAPK inhibitor concentrations of 1 nM to 1,000 μM, such as at a concentration of 100 μM. For example, the difference in melting temperature can be from 0.1°C to about 2°C.

[0119] The compounds provided by the present disclosure can interact with a pocket near the ED substrate docking site of p38 MAPK.

[0120] Compounds provided by the present disclosure can bind to p38α MAPK near the substrate binding groove of p38α MAPK, which extends between the CD and ED domains.

[0121] The compounds provided by the present disclosure can inhibit MK2 phosphorylation through interaction with p38α MAPK.

[0122] The compounds provided by the present disclosure can bind to p38α MAPK competitively with 4-chloro-N-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)benzamide.

[0123] Compounds provided by the present disclosure can have a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0124] The p38α MAPK inhibitors provided by the present disclosure may have a logP, for example, of -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.

[0125] Phosphorylation of MK2 can involve binding to an ED site adjacent to a target pocket in p38α MAPK. The target pocket can be defined by amino acids R49, H107, L108, and K165 in p38α MAPK. The target pocket can be defined by amino acids selected from R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK. The target pocket can be defined by amino acids R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK.

[0126] The p38α MAPK inhibitors provided by the present disclosure can at least partially inhibit MK2 phosphorylation. For example, Western blotting can be used to measure the inhibition of MK2 phosphorylation in anisomycin-stimulated HeLa cells by compounds provided by the present disclosure.

[0127] The p38α MAPK inhibitors provided by the present disclosure can stabilize endothelial or epithelial barrier function. Endothelial barrier permeability can be measured by separate or combined exposure to TNFα and hyperthermia, followed by measurement of permeability to 10 kDa dextran. For example, endothelial barrier stabilization can be assessed by pretreatment with a compound provided by the present disclosure, with permeability measurements taken before and after, and stabilization can be expressed as a percentage reduction in permeability increase before and after pretreatment. The permeability increase caused by 10 kDa dextran can be reduced by 5% to more than 100%, for example, by more than 5%, more than 10%, more than 20%, more than 40%, more than 60%, more than 80%, or more than 100%.

[0128] The p38α MAPK inhibitors provided by the present disclosure can regulate TNFα-induced gene expression in human pulmonary microvascular endothelial cells (HMVECL), for example, as determined using RNA Seq. For example, HMVECL can be pretreated with an appropriate concentration of a p38α MAPK inhibitor for a certain period of time, and then stimulated with TNFα for a certain period of time. The p38α MAPK inhibitors provided by the present disclosure can inhibit genes such as PRRG4, TSLP, CCLI 7, EXOC3L4, MMP9, IDOI, CXCL1O, CD200, SLCI5A3, VDR, ILIB, GPR88, CD207, TCHH, HAS3, GBPIPI, MUC4, ELOVL7, CXCL11, GBP4, PLAIA, and / or CXCL5.

[0129] The effect of p38α MAPK inhibitors on inflammatory cytokine expression can be determined by pretreating PMA-differentiated THPI cells with p38α MAPK inhibitors, then stimulating them with LPS, and collecting RNA at later time points for analysis by PCR-based cytokine array. p38α MAPK inhibitors can inhibit the expression of various genes, such as IL-1A, IL-8, TNFSF8, CXCL5, CCL7, CCLI7, TNFSF9, IL-1B, CXCL1, TNFSFI5, CCL5, CCL4, CCL20, CXCL2, TNF, and BMP6. p38α MAPK inhibitors can inhibit the expression of Smad3, which drives the differentiation of Foxp3 T regulatory cells and suppresses interferon-γ. Inflammation reduction can be measured by comparing the fold change in mRNA levels at various concentrations of p38α MAPK inhibitors with those of unstimulated PMA-differentiated THPI cells.

[0130] Certain compounds of formula (6) may be metabolites of the corresponding compound, N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide, which has an amine substituent on the naphthyl moiety. For example, a compound of formula (2) (5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; Compound 2) and a compound of formula (3) (5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; Compound 3) may be metabolites of compound (4) (5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide; Compound (4)): [ka] [ka] [ka]

[0131] Following administration of compound (4) to a subject, compound (4) can be metabolized in vivo to provide a compound of formula (3), a compound of formula (2), and a compound of formula (1) (5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (Compound 1)): [ka]

[0132] Compounds of formula (6) can be synthesized using methods known in the art.

[0133] For example, (4-aminophenyl)methanol (A) can be reacted with BocO in CHCl to give the Boc-protected compound tert-butyl(4-(hydroxymethyl)phenyl)carbamate (B). The Boc-protected intermediate (B) can be reacted with PDC in CHCl to give tert-butyl(4-acetylphenyl)carbamate (C). Intermediate (C) can be reacted with a suitable substituted morpholine in the presence of NaBH(OAc) in an organic solvent such as 1,2-dichloroethane (DCE) to give the corresponding substituted tert-butyl(4-(morpholinomethyl)phenyl)carbamate (D). Intermediate (D) can be deprotected in the presence of 4 M HCl in methanol to give the corresponding substituted 4-(morpholinomethyl)aniline dihydrochloride (E). Salt (E) can be reacted with a suitable substituted S-(naphthalen-1-yl)chlorothioate (F) in the presence of N,N-diisopropylethylamine (DIPEA) in dimethylformamide (DMF) to give the corresponding compound of formula (6).

[0134] The compounds provided by the present disclosure can be incorporated into pharmaceutical compositions that are administered to patients by any suitable route of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, peroral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical. The pharmaceutical compositions provided by the present disclosure can be injectable formulations. The pharmaceutical compositions provided by the present disclosure can be injectable intravenous formulations. The pharmaceutical compositions provided by the present disclosure can be oral formulations. The oral formulations can be oral dosage forms. The pharmaceutical compositions can be formulated for intravenous or subcutaneous administration.

[0135] Pharmaceutical compositions provided by the present disclosure may comprise a therapeutically effective amount of a compound of Formula (6) together with a suitable amount of one or more pharmaceutically acceptable vehicles to provide the composition for proper administration to a patient. Methods for preparing suitable pharmaceutical vehicles and pharmaceutical compositions are described in the art.

[0136] Evaluating a single patient's response to treatment and qualifying them for optimal therapy is one of the greatest challenges in modern medicine, stimulating the movement toward personalized medicine. Compounds of formula (6) can have target selectivity, for example, for specific cancers and immune cells. Using compounds of formula (6) radiolabeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT), treatment targeting can be predicted based on single-trial, case-by-case patient analysis, thereby excluding patients who are not expected to benefit from treatment. PET / SPECT scans using compounds of formula (6) can provide three-dimensional distribution maps, when correlated with concentration, which can then be used for macroscopic dose calculations.

[0137] The compound of formula (6) and / or its pharmaceutical composition can generally be used in an amount effective to achieve the intended purpose. For use in treating diseases such as cancer, autoimmune diseases, or inflammatory diseases, the compound of formula (6) and / or its pharmaceutical composition can be administered or applied in a therapeutically effective amount.

[0138] The amount of the compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions that will be effective in treating a particular disorder or condition will depend, in part, on the nature of the disease or condition, and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The amount of the compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions administered will depend, among other factors, on the patient being treated, the patient's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0139] The compounds of formula (6) can be assayed in vitro and in vivo for the desired therapeutic activity before use in humans. For example, in vitro assays can be used to determine whether administration of a particular compound or combination of compounds is preferred. Compounds can also be demonstrated to be effective and safe using animal model systems.

[0140] In certain embodiments, a therapeutically effective dose of the compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions will provide a therapeutic benefit without causing substantial toxicity. The toxicity of the compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions can be determined using standard pharmaceutical procedures and can be readily ascertained by one of ordinary skill in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index. The compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions exhibit a particularly high therapeutic index in treating diseases and disorders. The dose of the compound of Formula (6) and / or any of the aforementioned pharmaceutical compositions will be within a range of circulating concentrations that includes an effective dose with minimal toxicity.

[0141] The compounds and pharmaceutical compositions provided by the present disclosure can be included in kits that can be used to administer the compounds to a patient for therapeutic purposes. The kits can include a pharmaceutical composition comprising a compound provided by the present disclosure suitable for administration to a patient, and instructions for administering the pharmaceutical composition to a patient. The kits can be suitable for treating cancer, treating an autoimmune disease, or treating an inflammatory disease. Kits for use in treating cancer, treating an autoimmune disease, or treating an inflammatory disease can include a compound or pharmaceutical composition provided by the present disclosure and instructions for administering the compound to a patient.

[0142] The compounds and pharmaceutical compositions provided by the present disclosure can be included in a container, pack, or dispenser together with instructions for administration.

[0143] The instructions supplied with the kit may be printed and / or supplied, for example, as an electronically readable medium, video cassette, audio tape, flash memory device, or may be published on an internet website or distributed as an electronic communication to the patient and / or healthcare provider.

[0144] The compounds and pharmaceutical compositions provided by the present disclosure can be used to treat a disease in a patient.

[0145] The compounds and pharmaceutical compositions provided by the present disclosure can be used to treat diseases whose pathogenesis is associated with upregulation and / or downregulation of p38α MAPK protein.

[0146] Methods provided by the present disclosure include treating a disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition provided by the present disclosure, wherein the disease is treated by inhibiting p38α MAPK protein.

[0147] The p38 mitogen-activated protein kinase (MAPK) family of stress- and cytokine-activated kinases has been implicated 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 p38 MAPK, regulation of endothelial and epithelial barrier function, leukocyte trafficking, and cytokine expression is central to the pathogenesis of acute and chronic inflammatory disorders.

[0148] The compounds and pharmaceutical compositions provided by the present disclosure can be used to treat cancer in a patient. The cancer can be, for example, a solid tumor or a metastasis.

[0149] Methods provided by the present disclosure include a method of treating cancer in a patient comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0150] Examples of suitable cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, liver cancer, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myosarcoma, nasal cavity cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, and prostate Cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, and Hodgkin's disease.

[0151] 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 carcinoma, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, gastric carcinoma, colon carcinoma, prostate carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, and renal cell carcinoma. , endometrial carcinoma, adrenocortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma.Cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, liver cancer, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myosinoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, and retinal cancer. The cancer may be blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or primary macroglobulinemia.

[0152] The compounds and pharmaceutical compositions provided by the present disclosure may be used to treat, for example, the following cancers: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, appendix cancer, astrocytoma, atypical teratoid / rhabdomyoid tumor, basal cell carcinoma (non-melanoma), B-cell lymphoma, bladder cancer, bone cancer, brain and spinal cord tumors, brain stem cancer, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, head and neck cancer, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, and the like. Alveolar lymphoma, desmoplastic small round cell tumor, ductal carcinoma, pigmented carcinoma, endocrine pancreatic tumor (islet cell tumor), endometrial cancer, ependymoblastoma, esophageal cancer, nasal neuroblastoma, Ewing family tumor, extracranial germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic tumor, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, lymphoid hematopoietic tumor, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and optic tract glioma, IDs-related lymphoma, intraocular melanoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, Langerhans lymphoma Hans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, male breast cancer, malignant fibrous histiocytoma, malignant germ cell tumors, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplasia, myeloproliferative neoplasms, nasal and paranasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low-grade malignant potential tumors, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinuses and nasal cavity Cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary liver cancer, primary metastatic squamous cell carcinoma of the neck with occult features, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter, respiratory tract cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma (non-melanoma), gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma,It can be used to treat one or more of testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma, urethral cancer, uterine sarcoma, vaginal cancer, optic tract and hypothalamic glioma, vulvar cancer, primary macroglobulinemia, Wilms' tumor, and systemic and central metastases of any of the foregoing.

[0153] Methods provided by the present disclosure include methods of treating cancer, wherein the cancer is selected from breast cancer and melanoma.

[0154] Methods provided by the present disclosure include a method of treating an inflammatory disease in a patient comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0155] Examples of inflammatory diseases include allergies, Alzheimer's disease, anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma, autism, arthritis, 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, rheumatism, rheumatoid arthritis, sclerodermatitis, stroke, surgical complications, and ulcerative colitis.

[0156] Methods provided by the present disclosure include methods of treating an inflammatory disease in a patient, where the inflammatory disease is 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 in hypercholesterolemia, pain, diabetes, including type 1 diabetes and type 2 diabetes, and rheumatoid arthritis.

[0157] Methods provided by the present disclosure include a method of treating an autoimmune disease in a patient comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0158] The compounds or pharmaceutical compositions provided by the present disclosure may be useful for treating autoimmune diseases. Autoimmune diseases can be defined as human diseases in which the immune system attacks its own proteins, cells, and / or tissues. A comprehensive list and review of autoimmune diseases can be found, for example, in The Autoimmune Diseases, Rose and Mackay, 2014, Academic Press.

[0159] Examples of autoimmune diseases include Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBN nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Baro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss disease, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, and Coxcackie's myocarditis. myocarditis), CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Gulllain-Barré syndromesyndrome), Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis or pemphigoid of gestationis, hypogammaglobulinemia, IgA nephropathy, IgG4-related 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, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mukka-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, PANDAS, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever , rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0160] The compounds or pharmaceutical compositions provided by the present disclosure can 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 pregnancy loss, atopic diseases, and inflammatory bowel disease.

[0161] The compounds or pharmaceutical compositions provided by the present disclosure can be administered with one or more additional therapeutic agents for treating autoimmune diseases. The compound of formula (6) or a pharmaceutical composition 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; biologics such as abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and vedolizumab; and monoclonal antibodies such as basiliximab and daclizumab.

[0162] Methods provided by the present disclosure include methods of treating a disease in a patient comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present 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.

[0163] The compounds or pharmaceutical compositions provided by the present disclosure can be administered with one or more additional therapeutic agents for treating age-related diseases such as hearing loss, muscle regeneration, Werner's syndrome, etc.

[0164] Methods provided by the present disclosure include methods of treating a disease in a patient comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure, the disease being, for example, hearing loss, muscle degeneration, Werner's syndrome, cellular senescence, or an age-related disease such as Alzheimer's disease.

[0165] Methods provided by the present disclosure include methods of treating a disease in a patient, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure, wherein the disease is selected from sudden hearing loss, drug-induced hearing loss, age-related hearing loss, and Duchenne muscular dystrophy.

[0166] Methods provided by the present disclosure include methods of treating a viral disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure. The viral disease can be SARS-CoV-19 or SARS-CoV-2.

[0167] The amount of the compound of formula (6) provided by the present disclosure, or a pharmaceutical composition thereof, that will be effective in treating a disease will depend, at least in part, on the nature of the disease and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may be used to help identify optimal dosage ranges. Dosage regimens and intervals can also be determined by methods known to those skilled in the art. The amount of the compound of formula (6) provided by the present disclosure administered will depend, among other factors, 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.

[0168] For systemic administration, the therapeutically effective amount can be initially estimated from in vitro assays. The initial dose can also be estimated from in vivo data, for example, animal models, using techniques known in the art. Such information can be used to more accurately determine the useful dosage in humans. Those skilled in the art can optimize human administration based on animal data.

[0169] The dose and appropriate dosing interval of the compound of formula (6) provided by the present disclosure may be selected to maintain a sustained therapeutically effective concentration of the compound of formula (6) provided by the present disclosure in the patient's blood, in certain embodiments, without exceeding minimal harmful concentrations.

[0170] The pharmaceutical composition comprising the compound of formula (6) provided by the present disclosure can be administered, for example, once every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. The administration can be provided alone or in combination with other drugs and can continue as long as necessary for effective treatment of the disease. The administration can also be carried out using continuous or semi-continuous administration over a period of time. The administration includes administering the pharmaceutical composition to a mammal, such as a human, in a fed or fasted state.

[0171] The pharmaceutical composition may be administered in a single dosage form or multiple dosage forms, or as sequential or cumulative doses over a period of time. When multiple dosage forms are used, the amount of the compound of formula (6) provided by the present disclosure contained within each of the multiple dosage forms may be the same or different.

[0172] A suitable daily dose range for administration can be, for example, in the range of about 2 μg to about 200 mg of a compound of formula (6) provided by the present disclosure per kilogram of body weight.

[0173] Suitable daily dose ranges for administration are, for example, measured in square metres of body surface (m 2 The amount of the compound of formula (6) provided by the present disclosure can range from about 1 μg to about 50 mg per 100 mg of the compound of formula (6).

[0174] The compound of formula (6) provided by the present disclosure can be administered to treat cancer in a patient in an amount of, for example, 0.001 mg / day to 100 mg / day, or any other suitable daily dose, for example, 0.01 μg / kg body weight / week to 100 μg / kg body weight / week, or any other suitable dose.

[0175] A pharmaceutical composition comprising a compound of Formula (6) provided by the present disclosure can be administered to a patient to provide a therapeutically effective concentration of the compound of Formula (6) provided by the present disclosure in the patient's blood or plasma to treat cancer. The therapeutically effective concentration of the compound of Formula (6) provided by the present disclosure in the patient's blood can be, for example, 0.01 μg / L to 1,000 μg / L, 0.1 μg / L to 500 μg / L, 1 μg / L to 250 μg / L, or about 10 μg / L to about 100 μg / L. The therapeutically effective concentration of the compound of Formula (6) provided by the present 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 below an amount that causes unacceptable adverse effects, including, for example, adverse effects on homeostasis. A therapeutically effective concentration of a compound of formula (6) in the blood of a patient may be an amount sufficient to restore and / or maintain homeostasis in the patient.

[0176] The pharmaceutical compositions provided by the present disclosure can be administered to provide a therapeutically effective concentration of a compound of Formula (6) in the blood of a patient for a period of time such as, for example, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, or 2 days to treat a disease in the patient.

[0177] The amount of the compound of formula (6) administered may vary during the treatment regimen.

[0178] The pharmaceutical compositions provided by the present disclosure may further comprise one or more pharmaceutically active compounds in addition to the compound of Formula (6). Such compounds may be provided, for example, to treat a cancer being treated with the compound of Formula (6), or to treat a disease, disorder, or condition other than cancer being treated with the compound of Formula (6), to treat a side effect caused by administering the compound of Formula (6), to enhance the efficacy of the compound of Formula (6), and / or to modulate the activity of the compound of Formula (6).

[0179] The compound of Formula (6) provided by the present disclosure can be administered in combination with at least one other therapeutic agent. The compound of Formula (6) can be administered to a patient together with another compound for treating cancer in the patient. The at least one other therapeutic agent can be a second, different compound of Formula (6). The compound of Formula (6) and the at least one other therapeutic agent can act additively, or in certain embodiments, synergistically with another compound of Formula (6). The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle containing the compound of Formula (6), or can be included in a separate pharmaceutical composition or vehicle. Thus, the methods provided by the present disclosure can further include, in addition to administering a compound of Formula (6), administering one or more therapeutic agents effective to treat cancer or a disease, disorder, or condition other than cancer. The methods provided by the present disclosure can include administering a compound of Formula (6) and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic effectiveness of the compound of Formula (6) and / or does not result in adverse combined effects.

[0180] A pharmaceutical composition comprising a compound of Formula (6) can be administered simultaneously with the administration of another therapeutic agent, which can be part of the same pharmaceutical composition as the pharmaceutical composition comprising the compound of Formula (6) or can be a different pharmaceutical composition. The compound of Formula (6) can be administered before or after the administration of the other therapeutic agent. In certain combination therapies, the combination therapy can include alternating the administration of a composition comprising a compound of Formula (6) and another therapeutic agent, for example, to minimize adverse drug effects associated with a particular drug. When a compound of Formula (6) is administered simultaneously with another therapeutic agent that could potentially cause adverse drug effects, including, for example, toxicity, the other therapeutic agent can be administered at a dose below the threshold at which an adverse drug reaction is elicited.

[0181] Pharmaceutical compositions comprising a compound of Formula (6) provided by the present disclosure can be administered with one or more substances, for example, to enhance, modulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of the compound of Formula (6). For example, a pharmaceutical composition comprising a compound of Formula (6) can be co-administered with an active agent that has a pharmacological effect that enhances the therapeutic efficacy of the compound of Formula (6).

[0182] The compound of formula (6), or a pharmaceutical composition thereof, may be administered in conjunction with an agent known or believed to be effective in treating a disease, such as cancer, an autoimmune disease, or an inflammatory disease in a patient, such as the same disease being treated with the compound of formula (6).

[0183] A compound of formula (6), or a pharmaceutical composition thereof, may be administered in conjunction with an agent known or thought to interfere with cell proliferation.

[0184] The compounds of formula (6), or pharmaceutical compositions thereof, may be administered in conjunction with agents known or thought to interfere with cellular metabolism, be anti-metabolites, interfere with RNA transcription, interfere with RNA translation, interfere with cellular protein synthesis, interfere with the synthesis of precursors for DNA synthesis and replication, interfere with purine synthesis, interfere with nucleoside synthesis, interact with mTOR, be mTOR inhibitors, or interfere with cell cycle checkpoints.

[0185] The compound of formula (6) or a pharmaceutical composition thereof may be administered in combination with a checkpoint inhibitor, including a CTLA-4 inhibitor such as ipilimumab, a PD-1 inhibitor such as pembrolizumab and nivolumab, and / or a PD-LI inhibitor such as atezolizumab, avelumab, and durvalumab. The compound of formula (6) or a pharmaceutical composition thereof may be administered in combination with an immunomodulatory agent such as CD137 / 4-1BB, CD27, GIYR, and / or OC40.

[0186] The compounds of formula (6) or pharmaceutical compositions thereof may be administered in conjunction with agents known or thought to be cytotoxic, cause DNA damage, cause cell cycle arrest, or cause mitotic cell death.

[0187] The compound of formula (6) or a pharmaceutical composition thereof may be administered in conjunction with an agent known or believed to regulate glutathione levels, regulate intracellular glutathione levels, decrease intracellular glutathione levels, reduce glutathione uptake into cells, reduce glutathione synthesis, or reduce intracellular glutathione synthesis.

[0188] The compound of formula (6) or a pharmaceutical composition thereof may be administered in conjunction with an agent known or believed to interfere with, reduce, or promote neovascularization.

[0189] The compound of formula (6) or a pharmaceutical composition thereof may be administered in conjunction with an agent known or thought to interfere with hormone homeostasis, interfere with hormone synthesis, interfere with hormone receptor binding, or interfere with hormone signaling.

[0190] The compound of formula (6) or a pharmaceutical composition thereof may be administered in conjunction with an agent known or believed to interfere with growth factor homeostasis, interfere with growth factor receptor expression, interfere with growth factor binding to growth factor receptors, interfere with growth factor receptor signaling, interfere with Hedgehog (Hh) signaling, inhibit Hedgehog pathway signaling, inhibit ALK (anaplastic lymphoma kinase) pathway signaling, or inhibit the non-homologous end joining (NHEJ) pathway.

[0191] The compound of formula (6) or a pharmaceutical composition thereof is useful for treating or preventing inflammatory bowel disease, such as rheumatoid arthritis, ... 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 (enhancer of zeste homolog 2) inhibitors, BET (bromodomain and extraterminal 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 (bromodomain-containing protein) inhibitors, BRD2 inhibitors, BRD3 inhibitors, BRD4 inhibitors, BRDT (bromodomain testis-specific protein) inhibitors, reverse transcriptase inhibitors, NRT (nucleoside analogue reverse transcriptase) inhibitors, PIM (moloney 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, e.g., dasatinib, microtubule stabilizers, microtubule depolymerization / disassembly inhibitors, DNA intercalators, androgen receptor antagonists, chemoprotectants, HDAC (histone deacetylase) inhibitors, DPP ( The therapeutic agent may be administered in combination with one or more agents known or believed to be dipeptidyl peptidase (DPP-4) 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 of any of the foregoing.

[0192] The compound of formula (6) or a pharmaceutical composition thereof can be used in, for example, VEGFR inhibitors such as fruquintinib, motesanib / AMG-706, vatalanib, etc.; RTK inhibitors such as ponatinib; sodium channel blockers such as GS967; FAK inhibitors such as TAE226; GLI1 and GLI2 inhibitors such as GANT61; MEK inhibitors such as binimetinib; RTA inhibitors such as linifanib; ALK inhibitors such as brigustinib; bromopyruvate; DNA alkylating agents such as thiotepa; nuclear translocation factors such as JSH-23; and PORCn inhibitors such as Wnt-C59. agents; 5α-reductase inhibitors such as dutasteride; topoisomerase inhibitors such as carubicin; RAS inhibitors such as Kobe0065; CerK inhibitors such as NVP-231; AKT inhibitors such as aprosertib; EZH2 inhibitors such as GSK-503; BET bromodomain inhibitors such as OTX015; MEK5 / ERK5 inhibitors such as BIX02189; Syl / JAK inhibitors such as cerdulatinib; IDO1 inhibitors such as NLG919; retinoic acid X receptor activators such as bexsulotene; acotiamide or actotiamide HCl, etc. PGP inhibitors; Erk inhibitors such as SCH772984; PI3K inhibitors such as gedatolisib; JAK inhibitors such as ruxolitinib; AKT inhibitors such as afuresertib or afuresertib HCl; ALK1 inhibitors such as ceritinib; HDAC inhibitors such as abexinostat; DPP inhibitors such as omarigliptin; EGFR inhibitors such as gefitinib; EZH2 inhibitors such as GSK126; BTK inhibitors such as ibrutinib; kinase inhibitors such as imatinin HCl; IDO inhibitors such as INCB024360; and mitomycin C. DNA crosslinkers; tyrosine kinase inhibitors such as nilotinib; PARP inhibitors such as olaparib; tubulin stabilizing promoters such as paclitaxel; CDK4 / 6 inhibitors such as palbociclib; RTK inhibitors such as sunitinib; PDT sensitizers such as tursporfin; p-glycoprotein inhibitors such as tariquidar; ATR inhibitors such as VE-822; HDAC inhibitors such as PCI-24781; DPP inhibitors such as omarigliptin; EGFR inhibitors such as gefinib; EZH2 inhibitors such as GSK126; BTK inhibitors such as irbrutinib;It may be administered in conjunction with one or more chemotherapeutic agents, such as an IDO inhibitor, such as INCB024360; or a combination of any of the foregoing.

[0193] The compound of formula (6) or a pharmaceutical composition thereof can be used in combination with, for example, N-acetylcysteine ​​(NAC), adriamycin, alemtuzumab, amifostine, arsenic trioxide, ascorbic acid, bendamustine, bevacizumab, bortezomib, busulfan, buthionine sulfoxime, carfilzomib, carmustine, clofarabine, cyclophosphamide, cyclosporine, cytarabine, dasatinib, datinomycin, defibrotide, dexamethasone, docetaxel, doxorubicin, etoposide, filgrastim, floxidine, fludarabine, gemcitabine, or the like. It may be administered in conjunction with another chemotherapeutic agent, such as fluconazole, interferon alpha, ipilimumab, lenalidomide, leucovorin, melphalan, mycophenolate mofetil, paclitaxel, palifermin, panobinostat, pegfillastim, prednisolone, prednisone, Revlimid, rituximab, sirolimus, 2-mercaptoethane sodium sulfate (MESNA), sodium thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, or a combination of any of the foregoing.

[0194] The compound of formula (6) or a pharmaceutical composition thereof may be administered in combination with one or more antimetabolites, such as folic acid analogs; pyrimidine analogs, such as fluorouracil, floxuridine, and cytosine arabinoside; purine analogs, such as mercaptopurine, thiognine, and pentostatin; natural products, such as vinblastine, vincristine, etoposide, tertiposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, mitamycin, mitomycin C, L-asparaginase, and interferon alpha; platinum coordination complexes, such as cis-platinum and carboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists such as prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and leuprolide; anti-angiogenic agents or inhibitors such as angiostatin, retinoic acid, paclitaxel, estradiol derivatives, and thiazolopyrimidine derivatives; anti-apoptotic agents; triptolide; colchicine; luliconazole; and radiation therapy.

[0195] A compound of formula (6) or a pharmaceutical composition thereof may be co-administered with a compound that inhibits DNA repair, such as, for example, O6-benzylguanine (O6-BG).

[0196] The compound of formula (6) or a pharmaceutical composition thereof can be used in combination with other compounds, such as abarelix, abiraterone, abiraterone acetate, n-acetylcysteine, aclarubicin hydrochloride, adriamycin, adenine, afatinib, afatinib dimaleate, alemtuzumab, alendronate sodium, alitretinoin, allopurinol sodium, altretamine, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anastrozole, angiostatin, apremilast, aprepitant, arsenic trioxide, ascorbic acid, l-asparagine, benzodiazepine, benzocaine, benzophenone, benzocaine ... Ginase, azacitidine, azathioprine sodium, bazedoxifene (serum), belinstat, bendamustine HCl, O6-benzylguanine, bevacizumab, bexarotene, bicalutamide, biricodar, bleomycin sulfate, bortezomib, bosutinib, brivudine, buserelin, busulfan, buthionine sulfoxime, cabazitaxel, cabozantinib, capecitabine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, ceritinib, chlorambucil, cisplatin, cladribine, clodronate Thorium, clofarabine, crizotinib, cyclophosphamide, cyclosporine, cytarabine, cytosine arabinoside, dabrafenib, dacarbazine, dactinomycin, dasatinib, datinomycin, daunorubicin, decitabine, deflibrotide, degarelix acetate, dexamethasone, dexrazoxane hydrochloride, diaziquone, diethylstilbestrol, docetaxel, doxifluridine, doxorubicin hydrochloride, doxorubicin free base, drostanolone propionate, dutasteride, eltrombopag, enzalutamide, epirubicin hydrochloride , eribulin mesylate, erlotinib hydrochloride, estramustine sodium phosphate, ethinyl estradiol, etoposide phosphate, etoposide, everolimus, exemestane, fentanyl, filgrastim, fingolimod, floxuridine, fludarabine phosphate, fluorouracil, fluoxymesterone, flutamide, formestane, formylmelphalan, fosaprepitant, fotemustine, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine free base, glutathione, glycyphosphoramide, glyphosphine,Goserelin acetate, granisetron hydrochloride, heptaplatin, hexyl 5-aminolevulinate, histrelin acetate, hydroxyprogesterone caproate, hydroxyurea, ibandronate sodium, ibrutinib, icotinib, idarubicin HCl, idelalisib, idoxuridine, ifosfamide, interferon alfa, imatinib mesylate, imiquimod, ingenol mebutate, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib free base, lapatinib ditosylate, lasofoxifene, lenalidomide Iodide, letrozole, leucovorin calcium, leuprolide acetate, levamisole hydrochloride, levofolinate calcium, iobenguane, lobaplatin, lomustine, maropitant, masoprocol, mechlorethamine hydrochloride, megestrol acetate, medroxyprogesterone acetate, melphalan hydrochloride, mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, methoxsalen, methyl aminolevulinate, methylene blue, methylisoindigotine, mifamurtide, miltefosine, miriplatin, mitamycin, mitobronitol, mycobacterial Tomycin C, mitotane, mitoxantrone hydrochloride, mycophenolate mofetil, nabiximols, nafarelin, nandrolone, nedaplatin, nelarabine, netupitant, nilotinib, nilutamide, nimustine, nintedanib, nocodazole, octreotide, olaparib, omacetaxine mepesuccinate, ondansetron hydrochloride, oxaliplatin, paclitaxel, palbociclib, palifermin, palonosetron hydrochloride, pamidronate disodium, panobinostat, pasireotide, pazopanib hydrochloride, pegfilastim, pemetrexed disodium, pentostatin, peplomycin, pipobroman, pirarubicin, plerixafor, plicamycin, pomalidomide, ponatinib, porfimer sodium, porfiromycin, pralatrexate, prednimustine, prednisolone, prednisone, procarbazine hydrochloride, quinagolide hydrochloride, raloxifene, raltitrexed, radotinib, ranimustine, retinoic acid, revlimid, rituxinab, romidepsin, ruxolitinib, ruxolitinib phosphate, semustine, sirolimus, sodium thiosulfate, sorafenib free base,Sorafenib tosylate, streptozocin, sufentanil, sunitinib, tacrolimus, talaporfin sodium, tamibarotene, tamoxifen citrate, tapentadol, temoporfin, temozolomide, temsirolimus, teniposide, teriflunomide, tertiposide, testolactone, testosterone propionate, thalidomide, thioguanine, thiotepa, thymalfasin, toceranib phosphate, topoisomerase hydrochloride It may be administered in conjunction with one or more chemotherapeutic agents, such as tecan, toremifene citrate, trabectedin, trametinib, tretinoin, trilostane, triptorelin, tropisetron, uramustine, valrubicin, vandetanib, vedotin, vemurafenib, verteporfin, vinblastine, vincristine sulfate, vincristine free base, vindesine, vinorelbine tartrate, vorinostat, and zoledronic acid.

[0197] The compound of formula (6) or a pharmaceutical composition thereof can be used in combination with, for example, abemaciclib, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, ADE, adotrastuzumab emtansine, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, alpelisib, amifostine, aminolevulinic acid hydrochloride, anastrozole, apalutamide, aprepitant, arsenic trioxide, asparaginase erwinia chrysanthemi, atezolizumab, avelumab, axicarbagene ciloleucel, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bexarotene, bicalutamide, binimetinib, bleomycin sulfate, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib, BuMel, busulfan, cabazitaxel, cabozantinib-s -malic acid, CAF, calaspargase pegol-mknl, capecitabine, capracitabine-yhdp, CAPOX, carboplatin, carboplatin-taxol, carfilzomib, carmustine, carmustine implant, CEM, cemiplimab-rwlc, ceritinib, cetuximab, CEV, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, cladribine, clofarabine, CMF, cobimetinib, Copanlisib hydrochloride, COPDAC, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, cytarabine liposome, dabrafenib mesylate, dacarbazine, dacomitinib, dactinomycin, daratumumab, darbepoetin alfa, dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride and cytarabine liposome, decitabine, defibrotide sodium, degarelix, denileukin diftitoc s, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, durvalumab, duvelisib, elotuzumab, eltrombopag olamine, emapalumab-lzsg, enasidenib mesylate, encorafenib, enzalutamide, epirubicin hydrochloride, EPOCH, epoetin alfa, erdafitinib, eribulin mesylate, erlotinib hydrochloride, etoposide,Etoposide phosphate, everolimus, exemestane, fec, filgrastim, fludarabine phosphate, fluorouracil injection, fluorouracil-topical, flutamide, forfili, forfili-bevacizumab, forfili-cetuximab, forfirinox, forfox, fostamatinib disodium, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, gilteritinib fumarate, glaucoma maleate Degib, glucarpidase, goserelin acetate, granisetron, HPV bivalent vaccine, HPV bivalent vaccine, recombinant HPV nonvalent vaccine, HPV nonvalent vaccine, HPV nonvalent vaccine recombinant, HPV quadrivalent vaccine, HPV uadrivalent vaccine recombinant, hydroxyurea, hyper-CVAD, ibrituzumab tiuxetan, ibrutinib, ICE, idarubicin hydrochloride, idelalisib, ifosfamide, imatinib mesylate, imiquimod, inotuzumab ozogamicin, interferon α-2b recombinant, iobenguane, 131I, ipilimumab, irinotecan hydrochloride, irinotecan liposomal hydrochloride, ivosidenib, ixabepilone, ixazomib citrate, JEB, lanreotide acetate, lapatinib ditosylate, larotrectinib sulfate, lenalidomide, lenvatinib mesylate, letrozole, leucovorin calcium, leuprolide acetate, lomustine, loratinib, lutetium Lu177-dotatate, mechlorethamine hydrochloride, megestrol acetate, melphalan, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methylnaltrexone bromide, midostauri , mitomycin c, mitoxantrone hydrochloride, mogamulizumab-kpkc, moxetumomab-pasudotox-tdfk, MVAC, necitumumab, nelarabine, neratinib maleate, netupitant and palonosetron hydrochloride, nilotinib, nilutamide, niraparib tosylate monohydrate, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, olaratumab, omacetaxine mepesuccinate, ondansetron hydrochloride, OPPA, osimertinib mesylate, oxaliplatin, paclitaxel, paclitaxel albumin stabilized Nanoparticle formulation, PAD, palbociclib, palifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupitant, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, PCV, PEB, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, polatuzumab vedotin-piiq, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, propranolol hydrochloride, laminin hydrochloride Zinc-223, raloxifene hydrochloride, ramucirumab, rasburicase, ravulizumab-cwvz, R-CHOP, R-CVP, recombinant HPV bivalent vaccine, recombinant HPV nonvalent vaccine, recombinant HPV quadrivalent vaccine, recombinant interferon alpha-2b, regorafenib, R-EPOCH, ribociclib, R-ICE, rituximab, rituximab and hyaluronidase human, lorafenib hydrochloride, romidepsin, romiplostim, rucaparib camsylate, ruxolitinib phosphate, siltuximab, sipuleucel-t, sonitinib, sorafenib tosylate,Stanford V, sunitinib malate, TAC, tagraxofusp-erzs, talazoparib tosylate, talc, talimogene laherparepvec, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa, tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, TPF, trabectedin, trametinib, trastuzumab, trastuzumab and hyaluronidase-oysk, trif It may be administered in combination with one or more chemotherapeutic agents, such as uridine and tipiracil hydrochloride, uridine triacetate, VAC, valrubicin, VAMP, vandetanib, VeIP, vemurafenib, venetoclax, vinblastine sulfate, vincristine sulfate liposomal, vinorelbine tartrate, vip, vismodegib, vorinostat, XELIRI, XELOX, Ziv-aflibercept, zoledronic acid, and combinations of any of the foregoing.

[0198] The compounds provided by the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered to a patient in conjunction with another compound known to be useful in treating the inflammatory disease, autoimmune disease, or age-related disease being treated by the compounds provided by the present disclosure.

[0199] The effectiveness of administering a compound of formula (6) or a pharmaceutical composition thereof to treat cancer, an inflammatory disease, or an autoimmune disease can be evaluated using in vitro and animal tests and in clinical trials.

[0200] A method of inhibiting p38α MAPK provided by the present disclosure includes contacting p38α MAPK with a compound provided by the present disclosure in a pocket near the ED substrate docking site of p38α MAPK.

[0201] The method of inhibiting p38α MAPK provided by the present disclosure does not result in a loss of p38α-dependent counterregulatory responses, which involve mitogen- and stress-activated protein kinase-I (MSKl) or MSK2. By targeting a pocket near the ED substrate docking site of p38α, the inhibitors provided by the present disclosure avoid interfering with CD4+-specific substrates, including MSKl / 2, thereby limiting inflammation through the expression of IL-10 and DUSP2.

[0202] Aspects of the present invention Aspect 1. A compound having a structure of formula (6): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But C 1-4 Alkanediyl, C 1-4 Heteroalkanediyl, substituted C 1-4 Alkanediyl and substituted C 1-4 heteroalkanediyl; R 2 But substitution C 5-12 is heterocycloalkyl, R 3 is selected from -C(=O)- and -S(=O)-; R 4 But -N(R 5 )2, and each R 5 are independently hydrogen and C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

[0203] Embodiment 2. Each of the one or more substituents is independently —OH, ═O, —NH, —NO, C 1-6 Alkyl, C 1-6 Cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocycloalkyl, and C 5-6 The compound of embodiment 1, wherein the compound is selected from heteroaryl.

[0204] Embodiment 3. Each of the one or more substituents is independently —OH, ═O, —NH, —NO, C 1-3 Alkyl, and C 1-3 The compound of embodiment 1, wherein the alkyl is selected from heteroalkyl.

[0205] Aspect 4. One or more substituents are each independently selected from -OH, =O, and C 1-3 The compound of embodiment 1, wherein the alkyl is selected from:

[0206] Embodiment 5. The compound of embodiment 1, wherein each of the one or more substituents is =0.

[0207] Aspect 6.R 1 But C 1-4 The compound of any one of embodiments 1 to 5, wherein the compound is an alkanediyl.

[0208] Aspect 7.R 1 The compound of any one of embodiments 1-5, wherein is ethanediyl.

[0209] Aspect 8.R 1 The compound of any one of embodiments 1-5, wherein is methanediyl.

[0210] Aspect 9.R 2 The compound of any one of embodiments 1-5, wherein is substituted C6 heterocycloalkyl.

[0211] Embodiment 10. The compound of embodiment 9, wherein each of the one or more heteroatoms is independently selected from O and N.

[0212] Aspect 11.R 2 The compound of any one of embodiments 1 to 10, wherein is morpholin-4-yl.

[0213] Aspect 12.R 2 The compound of any one of embodiments 1 to 10, wherein is mono-substituted morpholin-4-yl.

[0214] Aspect 13.R 2The compound of any one of embodiments 1 to 10, wherein is 3-substituted morpholin-4-yl.

[0215] Embodiment 14. Each of the one or more substituents is independently —OH, ═O, —N(R 5 )2, and each R 5 are independently hydrogen and C 1-3 14. The compound of embodiment 12 or 13, wherein the alkyl is selected from alkyl.

[0216] Embodiment 15. The compound of embodiment 12 or 13, wherein each of the one or more substituents is -OH.

[0217] Embodiment 16. The compound of embodiment 12 or 13, wherein each of the one or more substituents is =0.

[0218] Embodiment 17. Each of the one or more substituents is —N(R 5 )2, and each R 5 are independently hydrogen and C 1-3 14. The compound of embodiment 12 or 13, wherein the alkyl is selected from alkyl.

[0219] Aspect 18.R 3 The compound of any one of embodiments 1 to 17, wherein is selected from —C(═O)— and —S(O) 2 —.

[0220] Aspect 19.R 3 The compound of any one of embodiments 1 to 17, wherein is —C(═O)—.

[0221] Aspect 20.R 3 The compound of any one of embodiments 1 to 17, wherein is —S(O) 2 —.

[0222] Aspect 21.R 4 is attached to the 3-, 4-, 5-, 6-, or 7-position of the naphthyl moiety.

[0223] Aspect 22.R 4 is attached to the 5-position of the naphthyl moiety.

[0224] Aspect 23. R 1 But C 1-3 is an alkanediyl, R 2 is a substituted 4-morpholinyl; R 3 is selected from —C(═O)— and —S(O)—; R 4 But -N(R 5 )2, and each R 5 are independently hydrogen and C 1-3 The compound of embodiment 1, wherein the alkyl is selected from:

[0225] Aspect 24. R 1 is methane-diyl, R 2 is a substituted 4-morpholinyl; R 3 is -S(O)2-, R 4 But -N(R 5 )2, and each R 5 The compound of embodiment 1, wherein is independently selected from hydrogen and methyl.

[0226] Aspect 25.R 2 25. A compound of embodiment 23 or 24, wherein is 3-substituted 4-morpholinyl.

[0227] Aspect 26.R 2 The compound of any one of embodiments 23 to 25, wherein the substituent is ═O.

[0228] Aspect 27.R 4 is selected from —NH(—CH 3 ) and —N(—CH 3 ) 2 .

[0229] Aspect 28. The compound is 4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, 6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, and 6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide, or a pharmaceutically acceptable salt of any of the foregoing.

[0230] Embodiment 29. The compound of embodiment 1, wherein the compound is 5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (compound 5), or a pharmaceutically acceptable salt thereof: [ka]

[0231] Embodiment 30. The compound of embodiment 1, wherein the compound is 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2), or a pharmaceutically acceptable salt thereof: [ka]

[0232] Embodiment 31. The compound of embodiment 1, wherein the compound is 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3), or a pharmaceutically acceptable salt thereof: [ka]

[0233] Embodiment 32 The compound of any one of embodiments 1 to 31, wherein the compound inhibits the p38α MAPK receptor.

[0234] Embodiment 33 The compound of any one of embodiments 1 to 32, wherein the compound selectively inhibits the p38α MAPK receptor.

[0235] Embodiment 34 The compound of any one of embodiments 1 to 33, wherein the compound has a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0236] Embodiment 35. The compound of any one of embodiments 1 to 34, wherein the compound binds to a selective binding site of p38α MAPK, the binding pocket being defined by a pocket and defined by at least residues R49, H107, L108, and K165 of p38α MAPK.

[0237] Embodiment 36. The compound of embodiment 35, wherein the compound binds to the selective binding site competitively with 4-chloro-N-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)benzamide.

[0238] Embodiment 37. The compound of any one of embodiments 1 to 36, wherein the compound inhibits MK2 phosphorylation induced by 4-chloro-N-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)benzamide in anisomycin-stimulated HeLa cells.

[0239] Embodiment 38. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0240] Embodiment 39. The pharmaceutical composition of embodiment 38, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, for treating a disease in a patient.

[0241] Embodiment 40 The pharmaceutical composition of embodiment 39, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0242] Embodiment 41 The pharmaceutical composition of embodiment 39, wherein the disease is cancer.

[0243] Embodiment 42 The pharmaceutical composition of embodiment 39, wherein the disease is an inflammatory disease.

[0244] Embodiment 43 The pharmaceutical composition of embodiment 39, wherein the disease is an autoimmune disease.

[0245] Embodiment 44. The pharmaceutical composition of embodiment 39, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0246] Embodiment 45. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0247] Embodiment 46. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is cancer.

[0248] Embodiment 47 The method of embodiment 46, wherein the cancer is selected from breast cancer and melanoma.

[0249] Embodiment 48. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is an inflammatory disease.

[0250] Embodiment 49. The method of embodiment 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 in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

[0251] Embodiment 50. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of Embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is an autoimmune disease.

[0252] Embodiment 51 The method of embodiment 50, wherein the autoimmune disease is selected from lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous loss of pregnancy, atopic disease, and inflammatory bowel disease.

[0253] Embodiment 52. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of Embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is an age-related disease.

[0254] Embodiment 53 The method of embodiment 52, wherein the age-related disease is selected from hearing loss, muscle degeneration, Werner's syndrome, cellular senescence, and Alzheimer's disease.

[0255] Embodiment 54. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of Embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0256] Embodiment 55. A method of inhibiting a p38α MAPK receptor, comprising contacting the p38α MAPK receptor with a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0257] Embodiment 56. A method of inhibiting a p38α MAPK receptor in a patient, comprising administering to the patient a pharmacologically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0258] Embodiment 57 The method of embodiment 56, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

[0259] Embodiment 58 The method of embodiment 57, wherein inhibiting the p38α MAPK receptor does not result in a loss of the p38α-dependent counterregulatory response.

[0260] Embodiment 59 The method of embodiment 58, wherein the p38α-dependent counterregulatory response involves mitogen-activated and stress-activated protein kinase-1 (MSK1) or MSK2.

[0261] Embodiment 60. The method of any one of embodiments 57-59, wherein selectively inhibiting the p38α MAPK receptor stabilizes endothelial or epithelial barrier function.

[0262] Embodiment 61 The method of any one of embodiments 57-60, wherein selectively inhibiting the p38α MAPK receptor reduces inflammation.

[0263] Embodiment 62 The method of any one of embodiments 57-61, wherein selectively inhibiting the p38α MAPK receptor reduces KPS-induced lung injury.

[0264] Embodiment 63 The method of any one of embodiments 57 to 62, wherein selectively inhibiting the p38α MAPK receptor modulates leukocyte trafficking.

[0265] Embodiment 64 The method of any one of embodiments 57 to 63, wherein selectively inhibiting the p38α MAPK receptor modulates cytokine expression. [Example]

[0266] The following examples detail the synthesis of compounds of formula (6), the characterization of compounds of formula (6), and the use of compounds of formula (6). It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

[0267] Example 1 Synthesis of 5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1) [ka] Step 1: 5-((benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b). [ka]

[0268] To a solution of 5-aminonaphthalene-1-sulfonic acid (1a) (50.2 g, 0.2249 mol) in 0.1 M NaHCO (40 mL) was added 2 M NaOH until the pH was adjusted to 10. Benzyl chloroformate (57.54 g, 0.3373 mol) was added to the stirred solution at 0 °C. The temperature was raised to 25 °C, and stirring was continued for 3 h. LCMS showed a major peak as the target molecule. The reaction mixture was adjusted to pH 2 with 4 M HCl, concentrated under reduced pressure, and purified by Biotage® Isolera One chromatography (C18 column, eluting with 10% to 95% MeCN / HO 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] - .

[0269] Step 2: 5-((((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1c). [ka]

[0270] To a solution of 5-(((benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b) (30.5 g, 0.08534 mol) in dry DMF (300 mL) was added sodium hydride (60% in mineral oil, 4.5 g, 0.1109 mol) at 0 °C. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 30 min, and iodomethane (15.7 g, 0.1109 mol) was added dropwise. Upon completion of the addition, the resulting solution was stirred at 23 °C for 2 h before being quenched with water. LCMS showed a major peak as the desired target molecule. The mixture was purified by Biotage® Isolera One chromatography (C18 column, eluting with 10% to 95% MeCN / HO containing 0.1% HCOOH) to give 5((((benzyloxy)carbonyl)(methyl)amino)-naphthalene-1-sulfonic acid (1c) (12 g) as an oil. LCMS: m / z 369.9 [M+H] - .

[0271] Step 3: Benzyl (5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate (1d). [ka]

[0272] 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 h. TLC showed that a new spot had formed. The reaction mixture was cooled to 23 °C and concentrated in vacuo to give crude benzyl (5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate (1d) (16.17 g, approximately 80% pure by TLC), which was used in the next step without further purification. LCMS: m / z 427.1 [M+H] + .

[0273] Step 4: Benzyl methyl (5-(N-(4-(morpholinomethyl)phenyl)sulfamoyl)naphthalen-1-yl)carbamate (1e). [ka]

[0274] To a stirred solution of 4-(morpholinomethyl)aniline (3.66 g, 0.01731 mol) in dichloromethane (60 mL) was added triethylamine (7.00 g, 0.06926 mol) at 0 °C. After stirring at the same temperature for 30 min, benzyl (5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate (1d) (6.75 g, 0.01731 mol) was added. The resulting solution was stirred at 45 °C overnight, cooled to room temperature, and quenched with water. LCMS showed the major peak as the desired target molecule. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The obtained crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=10 / 1) to give benzyl methyl (5-(N-(4-(morpholinomethyl)phenyl)sulfamoyl)naphthalen-1-yl)-carbamate (1e) (4.6 g) as a yellow solid. LCMS: m / z 546.1 [M+H] + .

[0275] Step 5: 5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1). [ka]

[0276] To a stirred solution of 8 (4.6 g, 0.00843 mol) in ethyl acetate (50 mL) was added 5% Pd / C (8 g). The reaction mixture was stirred at 23 °C under an atmosphere of H (balloon) for 24 h. LCMS indicated that the starting material had been consumed. The reaction mixture was filtered through a Celite® plug, and the resulting filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase Biotage® column chromatography (40 g C18 column), ACN / water (0.1% HCOOH) 0-100% to afford the title compound (1), 5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (1.12 g), as a green-yellow solid. LCMS Rt=1.25 min; m / z calculated for [M+H]+ 412.0. 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.43(d,J=8.5Hz,1H),8.26-8.16(m,1H),7.94(d,J=8.6Hz,1H),7.59-7.44(m,2H) ,7.13(s,2H),7.02(s,2H),6.65(d,J=4.9Hz,1H),6.59(d,J=7.8Hz,1H),3.57(s,4H),2.88(d,J=4.6Hz,3H),2.28(s,3H).

[0277] Example 2 Synthesis of 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2) [ka] Step 6: 4-(4-nitrobenzyl)morpholin-3-one (2a). [ka]

[0278] A stirred mixture of morpholin-3-one (20 g, 0.1978 mol), 1-(bromomethyl)-4-nitrobenzene (38.89 g, 0.1800 mol), and CsCO (116.65 g, 0.3580 mol) in acetonitrile (300 mL) was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a plug of Celite®, and the filtrate was concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to give 4-(4-nitrobenzyl)morpholin-3-one (2a) (24.83 g) as a yellow solid. LCMS: m / z 237.1 [M+H] + .

[0279] Step 7: 4-(4-aminobenzyl)morpholin-3-one (2b). [ka]

[0280] To a stirred solution of 4-(4-nitrobenzyl)morpholin-3-one 2b (24.8 g, 0.1050 mol) in MeOH (5 mL) was added 10% Pd / C (6 g). The resulting mixture was stirred at room temperature under an atmosphere of H (balloon) for 1 hour. LCMS indicated that the major peak was the target molecule. The mixture was filtered through a bed of Celite®, the filtrate was concentrated in vacuo, and crude 4-(4-aminobenzyl)morpholin-3-one 2b (18.4 g) was used in the next step without further purification. LCMS: m / z 207.1 [M+H] + Step 8: Benzyl methyl (5-(N-(4-((3-oxomorpholino)methyl)phenyl)sulfamoyl)naphthalen-1-yl)carbamate (2c). [ka]

[0281] 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, triethylamine TEA (8.89 g, 0.02416 mol) was added, and the temperature was maintained at 0 °C during the course of the addition. Upon completion of the addition, the reaction mixture was stirred at 0 °C for an additional 30 min. Benzyl (5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate 1d (9.42 g, 0.02416 mol) was added over several minutes. The resulting solution was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature and quenched with H2O. LCMS indicated that the major peak was the target molecule. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=10 / 1) to give benzyl methyl (5-(N-(4-((3-oxomorpholino)methyl)phenyl)-sulfamoyl)-naphthalen-1-yl)carbamate (2c) (5.3 g) as a yellow solid. LCMS: m / z 558.1 [M+H] - .

[0282] Step 9: 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2). [ka]

[0283] To a stirred solution of benzyl methyl (5-(N-(4-((3-oxomorpholino)methyl)phenyl)-sulfamoyl)-naphthalen-1-yl)carbamate (2c) (5.3 g, 9.47 mmol) in ethyl acetate (50 mL) was added 10% Pd / C (10 g). The mixture was then stirred under H (balloon) at 23 °C for 24 h. LCMS showed that SM was consumed. The reaction was filtered through a plug of Celite, and the resulting filtrate was concentrated in vacuo. The crude residue was purified by Biotage® reverse-phase column chromatography (40 g C18 column), acetonitrile / HO (0.1% HCOOH) 0-100% to give 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide (2) (1.02 g) as a green-yellow solid. LCMS (Shimadzu 2020): Rt = 1.81 min; m / z calculated for [M+H] + 426.15. 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.36(d,J=8.6Hz,1H),8.13(dd,J=7.4,1. 1Hz,1H),7.87(d,J=8.6Hz,1H),7.50-7.39(m,2H),7.00(d,J=8.7Hz,2H),6.98-6 .92(m,2H),6.58(d,J=4.9Hz,1H),6.52(d,J=7.8Hz,1H),4.32(s,2H),4.01(s,2 H),3.71(t,J=5.9,4.4Hz,2H),3.09(t,J=5.9,4.4Hz,2H),2.81(d,J=4.6Hz,3H).

[0284] Example 3 Synthesis of 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3) [ka] To a stirred solution of 4-(4-aminobenzyl)morpholin-3-one (2b) (7 g, 0.03394 mol) in dichloromethane (70 mL) at 0 °C, TEA (13.74 g, 0.1358 mol) was added, and the reaction was maintained at 0 °C. Upon completion of the addition, 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 at 45 °C overnight. The reaction mixture was then cooled to room temperature and quenched with water. LCMS showed a major peak as the desired target molecule. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and the resulting filtrate was concentrated in vacuo. The resulting crude product was purified by prep-HPLC (eluting with 30%-100% HO / MeCN containing 0.1% HCOOH acid) and neutralized with 2 M aqueous NaOH to give 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide (3) as a green solid. LCMS [M+H] 440.0.1. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.44(d,J=8.5Hz,1H),8.35(d,J=8.7H z,1H),8.21(dd,J=7.4,1.2Hz,1H),7.60(ddd,J=8.6,7.5,2.4Hz,2H),7.25( d,J=7.6Hz,1H),7.05(d,J=8.6Hz,2H),7.00(d,J=8.6Hz,2H),4.36(s,2H),4 .04(s,2H),3.73(dd,J=5.9,4.4Hz,2H),3.12(t,J=5.2Hz,2H),2.80(s,6H).

[0285] Example 4 Synthesis of 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (4) [ka] The synthesis of compound (4) is disclosed in Example 9 of U.S. Application Publication No. 2020 / 0331874 A1.

[0286] Example 5 Bioanalytical procedures for toxicology and clinical samples The following methods are used for the bioanalysis of samples for the 2-week toxicity study and clinical samples.

[0287] Bioanalysis of samples is performed according to validated methods. Monkey plasma samples are extracted by protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC with an ACE® Excel® 2 C18 column (50 × 3.0 mm, 2 μm particle size) and an API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada). Acquisition and chromatographic peak integration are performed using Analyst® Software 1.6.3 (AB Sciex). Peak areas for analytes and internal standards are imported into Watson LIMS® software version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) for standard curve regression analysis and quantification of analytes in samples. All analytical instruments and software are validated using appropriate procedures.

[0288] Example 6 Bioanalytical Procedures for Non-GLP Pharmacokinetic Studies The following methods are used for bioanalysis of samples for non-GLP pharmacokinetic studies.

[0289] Bioanalysis of samples is performed according to validated methods. Plasma samples are extracted by protein precipitation and analyzed by UPLC-MSMS using a Shimadzu UPLC with a Waters Acquity UPLC BEH C18 column (50 mm x 2.1 mm, 1.7 μm particle size) and an API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada). Acquisition and chromatographic peak integration are performed using Analyst® Software 1.6.3 (AB Sciex). Peak areas for analytes and internal standards are imported into Watson LIMS® software version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) for standard curve regression analysis and quantification of analytes in samples. All analytical equipment and software are validated using appropriate procedures.

[0290] Example 7 p38MAPK substrate phosphorylation profile To evaluate whether compounds provided by the present disclosure can selectively inhibit phosphorylation of their corresponding targets, HeLa cells were pretreated with 10 μM SB203580, 50 μM test compound, or 0.1% DMSO vehicle control for 30 minutes, and then analyzed by immunoblotting for p38 activator, anisomycin (25 μg / mL), and phosphorylated test compound and Stat-I.

[0291] Example 8 Specific binding to p38α MAPK DSF was used to analyze the concentration-specific binding of the compound of formula (6) to p38α MAPK and p38β MAPK. To confirm that the test compound binds to the CADD target pocket, DSF was used to compare compound binding to SB203580 binding to wild-type p38α MAPK and a p38α MAPK mutant with four of the ten target pocket amino acids substituted (R49K / HL107-8TF / KI65R). The mutant exhibited identical SB203580 binding to wild-type p38α MAPK, but failed to exhibit test compound binding.

[0292] Selective binding of test compounds to the CADD target pocket in p38α MAPK is confirmed using saturation transfer.

[0293] Example 9 Pharmacokinetics The pharmacokinetics of compounds (1)-(4) were determined in mice, rats, and monkeys.

[0294] Mouse studies.

[0295] Female CD-1 mice (n=9) received a single intraperitoneal dose of Compound (4) at 1 mg / mouse. The dosing formulation was prepared with Compound (4) at 2 mg / mL in 4% DMSO and 96% PBS prior to dosing. Blood samples were collected from the mice at the designated time points. After collection, the samples were centrifuged (2500 rpm, 4°C for 10 minutes), and the resulting plasma was collected and stored frozen (-60°C).

[0296] Bioanalysis of plasma samples was performed for compounds (1)-(4). Mouse plasma samples were extracted by protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC with a Waters Acquity® UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 μm particle size) and an API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada). Acquisition and chromatographic peak integration were performed using Analyst® 1.7 software. Standard curve regression and quantification of the analytes in the samples were performed using Analyst® software.

[0297] Pharmacokinetic parameters were calculated based on the plasma concentration data for Compound (4) and metabolite Compounds (1)-(3) by noncompartmental methods using WinNonlin® software, version 8.1 (Certara®, Inc.). For Compounds (1)-(4), the area under the concentration-time curve (AUC inf The percent AUC for each metabolite was calculated. inf (%AUC inf ) for each metabolite, inf AUC for compound (4) inf It was calculated as a ratio divided by

[0298] Rat studies. Male Sprague-Dawley rats (n=3) received a single intravenous bolus dose of 10 mg / kg of Compound (4). The dosing formulation was prepared prior to dosing by dissolving Compound (4) in 14% sulfobutylether-β-cyclodextrin (SBECD) at 5 mg / mL in deionized water (w / v). Blood samples were collected from each rat at the designated time points. After collection, the samples were centrifuged (2500 rpm, approximately 4°C for 10 minutes), and the resulting plasma was collected and stored frozen (-60°C).

[0299] Bioanalysis of samples was performed for compounds (1)-(4). Rat plasma samples were extracted by protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC with a Waters Acquity® UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 μm particle size) and an API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada). Acquisition and chromatographic peak integration were performed using Analyst® 1.7 software. Standard curve regression and quantification of the analytes in the samples were performed using Analyst® software.

[0300] Pharmacokinetic parameters were calculated from the plasma concentration data for Compound (4) and metabolite Compounds (1)-(3) by noncompartmental methods using WinNonlin® software, version 8.1 (Certara®, Inc.). For Compounds (1)-(4), the area under the concentration-time curve (AUC inf The percent AUC for each metabolite was calculated. inf and the AUC for each metabolite. inf AUC for compound (4) inf It was calculated as a ratio divided by

[0301] Monkey studies: Male cynomolgus monkeys (n = 3) received a single intravenous infusion of 5 mg / kg of Compound 4 (2.5 mL / kg / h) over a 2-hour period. The dosing formulation was prepared with 1 mg / mL of Compound 4 in 14% sulfobutylether-β-cyclodextrin (SBECD) in deionized water (w / v) prior to dosing. Blood samples were collected from each monkey at the designated time points. After collection, the samples were centrifuged (2500 rpm, 4°C for 10 minutes), and the resulting plasma was collected and stored frozen (-60°C).

[0302] Bioanalysis of samples for compounds (1)-(4) was performed. Monkey plasma samples were extracted by protein precipitation and analyzed by UPLC-MSMS using a Waters UPLC with an ACE® Excel® 2 C18 column (50 mm × 3.0 mm, 2 μm particle size) or a Waters Acquity® UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 μm) and an API 5000® triple quadrupole mass spectrometer (AB Sciex, Toronto, Canada). Acquisition and chromatographic peak integration were performed using Analyst® software, version 1.6.3. Standard curve regression and quantification of analytes in the samples were performed using Watson LIMS® software, version 7.4.1 (Thermo Fisher Scientific, Philadelphia, USA) or Analyst® software.

[0303] Pharmacokinetic parameters were calculated from the plasma concentration data for compound (4) and its metabolites by noncompartmental methods using WinNonlin® software, version 8.1 (Certara®, Inc.). For compounds (1) to (4), the area under the concentration-time curve (AUC inf ) was calculated. The percent AUC for each of the metabolites inf and the AUC of each metabolite inf The AUC of compound (4) inf It was calculated as a ratio divided by

[0304] After oral administration of compound (2) to mammals, metabolites having the structure of formula (1), (2), or (3) exhibited a % AUC inf (100×AUC 代謝物 / AUC 化合物(4) ) was shown. [Table 1]

[0305] Example 10 Antiviral effects in SARS-CoV-2 infected cell lines A549-ACE2 cells (Institut Pasteur, Paris, France) were cultured in DMEM (Corning) supplemented with 10% FBS (Peak Serum) and maintained at 37°C with 5% CO2. HEK293T-ACE2 cells (ATCC, CRL-3216) were maintained in DMEM (Corning) supplemented with 10% FBS (Peak Serum) and penicillin / streptomycin (Corning) at 37°C and 5% CO2. Ectopic hACE2-expressing cells were generated by transduction with 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 single-cell cloned and screened for their ability to support SARS-CoV-2 replication. All cell lines used were routinely screened for mycoplasma contamination using the Universal Mycoplasma Detection Kit (ATCC, 30-1012K).

[0306] The SARS-CoV-2 isolate BetaCoV / France / IDF0372 / 2020 was provided by the National Reference Centre for Respiratory Viruses, hosted by the Institut Pasteur (Paris, France). The isolate originated from a human sample and was provided through the European Virus Archive Goes Global (EVAg) platform. Virus stocks were prepared by propagation in Vero E6 cells in DMEM supplemented with 2% FBS. Virus titers were determined by plaque assay in minimal essential medium (MEM) supplemented with 2% (v / v) FBS (Invitrogen) and 0.05% agarose.

[0307] All experiments involving live SARS-CoV-2 were performed in an approved laboratory in compliance with the guidelines for biosafety level 3 (BSL-3) containment procedures of the Institut Pasteur Paris.

[0308] Two hours before infection, the medium was replaced with DMEM (2% FBS) containing the compound of interest at a concentration 50% higher than the indicated concentration, including the DMSO control. The plates were then transferred to a BSL-3 facility, and the same volume of SARS-CoV-2 was added to DMEM (2% FBS) to achieve the desired final compound concentration. The plates were then incubated at 37°C / 5% CO2 for 48 hours. All assays were performed in biologically independent triplicates.

[0309] Viral genome detection was performed directly from the inactivated supernatant by RT-qPCR. SARS-CoV-2-specific primers targeting the N gene region: 5'-TAATCAGACAAGGAACTGATTA-3' (SEQ ID NO: 1) (forward) and 5'-CGAAGGTGTGACTTCCATG-3' (SEQ ID NO: 2) (reverse) were used with the Luna® Universal One-Step RT-qPCR Kit (NEB) in an Applied Biosystems QuantStudio® 7 thermocycler under the following cycling conditions: 55°C for 10 minutes, 95°C for 1 minute, and 40 cycles of 95°C for 10 seconds, followed by 60°C for 1 minute. The number of viral genomes was expressed as PFU equivalents / mL and calculated by performing a standard curve with RNA derived from a viral stock with a known viral titer.

[0310] Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer's instructions, and luminescence was measured on a Tecan Infinite® 2000 plate reader. Cytotoxicity was performed in parallel with the viral replication assay on uninfected cells at the same compound dilutions. Percent viability was calculated relative to untreated cells (100% viability) and cells lysed with 20% ethanol (0% viability).

[0311] A 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 the percent measurement (virus or cell viability quantification) exceeded the 50% mark. If the fitted curve did not begin above 50% or cross below 50% throughout the dose-response, the IC50 value was marked as greater than the highest concentration tested.

[0312] The cell viability (black) and IC50 (red) curves for SARS-CoV-2 cell lines treated with compounds (4), (1), or (2) are shown in Figures 1-3, respectively.

[0313] Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein, and therefore the present embodiments are illustrative and not limiting, and the claims are not to be limited to the details given herein, but may be modified within the scope and equivalents thereof.

Claims

1. A compound having a structure of formula (6): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ But C １－４ Alkanediyl, C １－４ Heteroalkanediyl, substituted C １－４ Alkanediyl and substituted C １－４ heteroalkanediyl; R ２ But substitution C ５－１２ heterocycloalkyl, R 2 is bonded to R 1 through the nitrogen heteroatom of the substituted C 5-12 heterocycloalkyl moiety, and R 2 contains a heteroatom group selected from —S—, —NH—, —N(—CH 3 )—, —S(═O)—, and —SO 2 —; R ３ is selected from —C(═O)— and —SO 2 —; R ４ But -N(R ５ ) ２ and each R ５ are independently hydrogen and C １－４ alkyl, A compound, or a pharmaceutically acceptable salt thereof, wherein each substituent is independently selected from -OH, =O, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 cycloalkyl, C 6 aryl, C 1-6 heteroalkyl, C 1-6 heterocycloalkyl, and C 5-6 heteroaryl.

2. R １ But C １－４ The compound of claim 1 which is an alkanediyl.

3. The compound of claim 1, wherein the substituted C 5-12 heterocycloalkyl is a substituted C 6 heterocycloalkyl.

4. The compound of claim 1, wherein R 2 contains the heteroatom group —SO 2 —.

5. The compound of claim 1, wherein each R 2 substituent is independently selected from —OH, ═O, and —NH 2 .

6. The compound of claim 1, wherein each R 2 substituent is ═O.

7. R ３ The compound of claim 1, wherein is -C(=O)-.

8. R ３ The compound of claim 1, wherein is —SO 2 —.

9. R ４ The compound of claim 1 , wherein is attached to the 5-position of the naphthyl moiety.

10. R １ is methane-diyl, R ２ contains the heteroatom group —SO 2 —; R ３ is —SO 2 —; R ４ But -N(R ５ ) ２ and each R ５ 10. The compound of claim 1, wherein is independently selected from hydrogen and methyl.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. 12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, the disease being selected from cancer, an inflammatory disease, an autoimmune disease, and an age-related disease.

13. The method of claim 12, wherein the cancer is selected from breast cancer, melanoma, and polycythemia vera; 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 in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis; the autoimmune disease is selected from lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous pregnancy loss, atopic disease, and inflammatory bowel disease; and 12. The pharmaceutical composition of claim 11, wherein the age-related disease is selected from hearing loss, muscle degeneration, Werner's syndrome, cellular senescence, and Alzheimer's disease.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical for the treatment of a disease responsive to a p38α MAPK inhibitor.

15. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical for the treatment of cancer.

16. The use described in claim 15, wherein the cancer is selected from breast cancer, melanoma, and polycythemia vera.

17. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical for the treatment of an inflammatory disease, wherein the inflammatory disease is selected from acute respiratory distress syndrome, acute lung injury, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

18. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of an autoimmune disease, wherein the autoimmune disease is selected from lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous loss of pregnancy, atopic disease, and inflammatory bowel disease.

19. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical for the treatment of an age-related disease, wherein the age-related disease is selected from hearing loss, muscle degeneration, Werner's syndrome, cellular senescence, and Alzheimer's disease.

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