P38α mitogen-activated protein kinase inhibitors

Abstract

Disclosed herein are p38a mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and methods of treatment using p38a mitogen-activated protein kinase inhibitors.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 026,466, filed May 18, 2020, pursuant to 35 USC § 119(e), the entire contents of which are incorporated herein by reference. Technical Field

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

[0003] MAPKs are serine / threonine protein kinases that process and regulate cellular properties in response to a wide range of extracellular stimuli. p38 MAPK comprises four isoforms (α, β, γ, and δ). p38α MAPK was the first p38 MAPK isoform identified and was initially recognized as a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. These enzymes phosphorylate the OH groups of serine or threonine residues in proteins and play important roles in the regulation of cell proliferation, differentiation, survival, and apoptosis. Several distinct MAPKs have been identified in mammalian cells, including p38MAPK.

[0004] p38 MAPKs are a class of MAPKs that respond to stress stimuli such as inflammatory cytokines and reactive oxygen species (ROS), and are involved in a wide range of signaling pathways that stimulate various biological functions. For example, p38 MAPKs have been found to play important roles in regulating pro-inflammatory signaling networks and the biosynthesis of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in immune cells.

[0005] Studies have shown that p38 MAPK contributes to the pathogenesis of chronic inflammation, prompting preclinical and clinical trials of p38 MAPK inhibitors for use in inflammatory diseases such as rheumatoid arthritis and asthma.

[0006] Many p38 MAPK catalytic inhibitors are inefficient, potentially due to their activity against non-inflammatory p38 and the loss of p38α-dependent counterregulatory responses, leading to toxicity. There is a need for p38α MAPK inhibitors that can selectively inhibit certain p38α MAPK functions and maintain key counterregulatory and homeostatic functions when used to treat inflammatory and oncological diseases. Inhibition of p38 MAPK has been shown to effectively alleviate inflammatory diseases such as rheumatoid arthritis, cardiovascular disease, and inflammatory pain. Summary of the Invention

[0007] According to the present invention, the compound has the structure of formula (1):

[0008] (1)

[0009] Or its pharmaceutically acceptable salt, wherein,

[0010] R 1 Selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0011] R 2 Selected from parts of equation (2a), parts of equation (2b), parts of equation (2c), and C 8-16 Heterocyclic alkyl and substituted C 8-16 Heterocyclic alkyl groups:

[0012] (2a) (2b) (2c)

[0013] in,

[0014] B 1 B 2 B 3 and B 4 Each of them is independently selected from –(CH(–R) 4 )) n -,in,

[0015] Each n is independently selected from 0, 1, 2, 3, and 4;

[0016] B 1 and B 2 Neither of them is 0;

[0017] B 3 and B 4 Neither of them is 0; and

[0018] Each R 4 Independently selected from hydrogen, –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl;

[0019] D is selected from methane-diyl and ethane-diyl; and

[0020] X is selected from –O–, –CH(–OH)–, –NR3 – and –SO2–, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatic compounds.

[0021] According to the present invention, the compound has the structure of formula (1):

[0022] (1)

[0023] Or its pharmaceutically acceptable salt, wherein,

[0024] R 1 Selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0025] R 2 This is part of equation (2d):

[0026] (2d)

[0027] in,

[0028] Each A 1 and A 2 Independently selected from –CH2–, –CH(–R) 5 ) – and –C(=O) –, where each R 5 Independently selected from –OH, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatics;

[0029] A 1and A 2 One or more independently selected from –CH(–R) 5 – and –C(=O) –;

[0030] Each n is independently selected from 1, 2, 3, and 4; and

[0031] X is selected from –O–, –CH(–OH)–, –NR 3 – and –SO2–, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 5-8 cycloalkyl, C6 aryl, C 6-12 cycloalkylalkyl, C 7-10 Arylalkyl, C 1-6 Heteroalkyl, C 5-8 Heterocyclic alkyl, C 5-6 heteroaryl, C 6-12 Heterocyclic alkyl, C 7-10 Heteroarylalkyl, substituted C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C6 aryl, substituted C 6-12 Cycloalkylalkyl, substituted C 7-10 arylalkyl, substituted C 1-6 Heteroalkyl, substituted C 5-8 Heterocyclic alkyl, substituted C 5-6 heteroaryl, substituted C 6-12 Heterocyclic alkyl alkyl and substituted C 7-10 Heteroarylalkyl.

[0032] According to the present invention, the pharmaceutical composition comprises a compound according to the present invention or a pharmaceutically acceptable salt thereof.

[0033] According to the present invention, a method for treating a patient's disease comprises administering to a patient in need a therapeutically effective amount of the compound according to the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is cancer, such as melanoma; inflammatory diseases, such as 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, rheumatoid arthritis, amyotrophic lateral sclerosis, cystic fibrosis; autoimmune diseases; age-related diseases, such as hearing loss, muscle degeneration, Werner syndrome, cellular senescence and Alzheimer's disease; or viral diseases, such as coronavirus infection, pneumonia associated with coronavirus infection, and human respiratory syndrome infection. Detailed Implementation

[0034] A dash ("-") not between two letters or symbols is used to indicate the connection point of a part or substituent. For example, –CONH2 is connected by a carbon atom.

[0035] "Alkyl" refers to a saturated, branched, or straight-chain monovalent hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of alkyl groups include methyl; ethyl, such as ethyl, vinyl, and ethynyl; and propyl, such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl, and prop-2-yn-1-yl. wait Butyl, such as 1-butyl, 2-butyl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, 1-en-1-yl, 1-en-2-yl, 2-methyl-prop-1-en-1-yl, 2-en-1-yl, 2-en-2-yl, 1,3-dien-1-yl, 1,3-dien-2-yl, 1-yn-1-yl, 1-yn-3-yl, 3-yn-1-yl wait ; etc. The term "alkyl" includes groups having any degree of saturation or level of saturation. Right now Groups having only 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 combinations of carbon-carbon single, double, and triple bonds. The terms alkyl, alkenyl, and ynyl are used when referring to a specific level of saturation. Alkyl groups can be C10, C20, C30, C40, C50, C60, C7 ... 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, ethyl, or methyl.

[0036] "Alkoxy" refers to the group –OR, where R is an alkyl group as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be C10, C2 ... 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkyl, ethoxy, or methoxy.

[0037] "Aryl" itself, or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups encompass 5- and 6-membered carbocyclic aromatic rings, such as benzene; bicyclic systems in which at least one ring is a carbocyclic and aromatic ring, such as naphthalene, indane, and naphthalene; and tricyclic systems in which at least one ring is a carbocyclic and aromatic ring, such as fluorene. Aryl groups also encompass polycyclic systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocyclic alkyl ring. For example, aryl groups include benzene rings fused to 5- to 7-membered heterocyclic alkyl rings containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic systems in which only one ring is a carbocyclic aromatic ring, the group carbon atom may be on the carbocyclic aromatic ring or on the heterocyclic alkyl ring. Examples of aryl groups include those derived from anthracene, acenaphthene, phenanthrene, anthracene, chamomile ring, benzene, phenanthrene, fluorene, benzoxene, hexaphenylene, hexaphenylene, hexaene, as-indacene, s-indacene, indene, indene, naphthalene, octaphenylene, octaphenylene, elliptylbenzene, pentacene, cyclopentadiene, pentaphenylene, perylene, phenatene, phenanthrene, heptaphenylene, pyrene, pinanthrene, rubicene, and triphenylene and trinaphthalene. The aryl group can be C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or phenyl. However, aryl does not encompass heteroaryl as defined herein or overlap with heteroaryl as defined herein in any way.

[0038] "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethenyl, 2-phenylvinyl, naphthylmethyl, 2-naphthylethenyl, 2-naphthylvinyl, naphthobenzyl, 2-naphthophenylethenyl, etc. When referring to a specific alkyl moiety, the terms nominate arylalkyl chain, arylalenyl, or arylynyl are used. An arylalkyl group can be C16-3 ... 7-16 Arylalkyl, For example The alkyl, alkenyl, or ynyl group of an arylalkyl group is C 1-6 The aryl moiety is C 6-10 Arylalkyl groups can be C 7-16 Arylalkyl, For example The alkyl, alkenyl, or ynyl group of an arylalkyl group is C 1-6 The aryl moiety is C 6-10 Arylalkyl groups can be C 7-9 arylalkyl, wherein the alkyl moiety is C 1-3 Alkyl group, where the aryl moiety is phenyl. Arylalkyl groups can be C10-32 ... 7-16 Arylalkyl, C 7-14 Arylalkyl, C 7-12 Arylalkyl, C7-10 Arylalkyl, C 7-8 Arylalkyl or benzyl.

[0039] Bioavailability refers to the rate and amount of a drug that reaches a patient's systemic circulation after administration of the drug or its prodrug, and can be determined by evaluating, for example, plasma or blood concentration-time curves. Parameters used to characterize plasma or blood concentration-time curves include the area under the curve (AUC) and the time to reach maximum concentration (T0). max ) and maximum drug concentration (C max ), where C max It is the maximum concentration of the drug in a patient's plasma or blood after a certain dose or form of drug has been administered to the patient, and T max The maximum concentration (C) of a drug in a patient's plasma or blood is reached after a certain dose or form of drug has been administered to the patient. max (Time)

[0040] "Oral bioavailability" (F%) refers to the fraction of an orally administered drug that reaches the systemic circulation. Oral bioavailability is the product of the absorption fraction, the fraction that escapes elimination from the intestinal wall, and the fraction that escapes elimination from the liver. Factors affecting bioavailability can be categorized into physiological factors, physicochemical factors, and biopharmaceutical factors.

[0041] The term "compound" disclosed herein includes any specific compound of the disclosed formula. Compounds can be identified by their chemical structure and / or chemical name. Compounds are named using the ChemBioDraw Ultra 14.0.0.117 nomenclature program (CambridgeSoft, Cambridge, MA). In the event of a conflict between chemical structure and chemical name, the chemical structure determines the identification of the compound. Compounds described herein may contain one or more stereocenters and / or double bonds, and therefore may exist as stereoisomers such as double bond isomers (…). Right now Geometric isomers, enantiomers, diastereomers, or transisomers are present. Therefore, any chemical structure within the scope of this specification having relative configurations, described in whole or in part, encompasses all possible enantiomers and stereoisomers of the compound shown, including the stereoisomeric pure form ( For example (Geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be separated into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0042] The compounds disclosed herein include, in part, optical isomers of the compounds and portions thereof, racemates thereof, and other mixtures thereof. In such embodiments, a single enantiomer or diastereomer may be obtained by asymmetric synthesis or by resolution of a racemate. Resolution of a racemate may be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or by chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column having a chiral stationary phase. Furthermore, the compounds include ( Z )-form and ( E )-form (or Cis -form and trans Compounds with double bonds (in the form of -), as a single geometric isomer or a mixture thereof.

[0043] Compounds and portions may also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures described herein encompass all possible tautomeric forms of the compounds shown. Compounds may exist in both non-solventized and solvated forms (including hydrated forms). Some compounds may exist in multiple crystalline, cocrystalline, or amorphous forms. Compounds include pharmaceutically acceptable salts of themselves, or pharmaceutically acceptable solvates of any of the aforementioned compounds in their free acid form, as well as crystalline forms of any of the aforementioned compounds.

[0044] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group. Cycloalkyl groups can be C16, C26, C36, C46, ​​C56, C6 ... 3-8 cycloalkyl, C 3-5 cycloalkyl, C 5-6 Cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. The cycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0045] “Cycloalkylalkyl” refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a cycloalkyl group as defined herein. When referring to a specific alkyl moiety, the nomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylynyl is used. A cycloalkylalkyl group can be C10-3 ... 4-30 cycloalkyl alkyl For example The alkyl, alkenyl, or ynyl moiety of a cycloalkyl group is C 1-10 Furthermore, the cycloalkyl group of the cycloalkyl group is C10. 3-20 . Cycloalkyl alkyl can be C 4-20 Cycloalkyl alkyl groups, for example, where the alkyl, alkenyl, or ynyl moiety of a cycloalkyl alkyl group is C10. 1-8 Furthermore, the cycloalkyl moiety of the cycloalkyl group is C10. 3-12 . Cycloalkyl alkyl can be C 4-9 Cycloalkylalkyl, wherein the alkyl moiety of the cycloalkylalkyl group is C10. 1-3 Alkyl, and the cycloalkyl moiety of cycloalkyl is C3-6 Cycloalkyl. Cycloalkyl groups can be C10-2000. 4-12 cycloalkylalkyl, C 4-10 cycloalkylalkyl, C 4-8 cycloalkyl alkyl and C 4-6 Cycloalkyl alkyl group. Cycloalkyl alkyl groups can be cyclopropylmethyl (–CH2–cyclo-C3H5), cyclopentylmethyl (–CH2–cyclo-C5H9), or cyclohexylmethyl (–CH2–hexyl-C6H5). 11 The cycloalkyl group can be cyclopropylvinyl (–CH=CH–cyclo-C3H5), cyclopentylethynyl (–C≡C–cyclo-C5H9), etc.

[0046] "Cycloalkylheteroalkyl" itself, or as part of another substituent, refers to a heteroalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of an alkyl group are independently replaced by one or more heteroatom groups of the same or different nature, and in which one hydrogen atom bonded to a carbon atom is replaced by a cycloalkyl group. When referring to a specific alkyl moiety, the nomenclature cycloalkylheteroalkyl, cycloalkylheteroalkenyl, or cycloalkylheterynyl is used. In cycloalkylheteroalkyl groups, the heteroatom groups may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatom groups may be selected from –O– and –NH–, or the heteroatom groups may be –O– or –NH–.

[0047] "Cycloalkoxy" refers to the group –OR, where R is a cycloalkyl group as defined herein. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. A cycloalkoxy group can be C 3-6 Cycloalkoxy, C 3-5 Cycloalkoxy, C 5-6 Cycloalkoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy.

[0048] "Disease" means any of the aforementioned diseases, symptoms, conditions, or signs.

[0049] According to 21 USC § 321(g)(1), “drug” means “(A) a product recognized in the Official United States Pharmacopeia, the Official United States Homeopathic Pharmacopeia, or the Official National Formulary or any supplement thereof; and (B) a product intended to diagnose, cure, alleviate, treat or prevent disease in a human or other animal; and (C) a product intended to affect the structure or any function of the body of a human or other animal (other than food)…”.

[0050] "Fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine, as defined herein. Fluoroalkyl groups can be C16-3 ... 1-6 fluoroalkyl, C 1-5 fluoroalkyl, C1-4 fluoroalkyl or C 1-3 Fluoroalkyl groups. Fluoroalkyl groups can be pentafluoroethyl (–CF2CF3) or trifluoromethyl (–CF3).

[0051] "Fluoroalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by fluorine, as defined herein. Fluoroalkoxy groups can be C10, C20, C30, C40, C50, C60, C7 ... 1-6 fluoroalkoxy, C 1-5 fluoroalkoxy, C 1-4 fluoroalkoxy, C 1-3 Fluoroalkoxy, –OCF2CF3, or –OCF3.

[0052] "Halogen" refers to fluorine, chlorine, bromine, or iodine groups.

[0053] "Heteroalkoxy" refers to an alkoxy group in which one or more carbon atoms are replaced by heteroatoms. Heteroalkoxy groups can be C10, C20, C30, C40, C50, C60, C7 ... 1-6 Zykaloxy, C 1-5 Zykaloxy, C 1-4 Hexaalkoxy or C 1-3 Heteroalkoxy groups. In heteroalkoxy groups, the heteroatom group can be selected from –O–, –S–, –NH–, –NR–, where R is C. 1-6 Alkyl groups, –SO–, –SO2–, –Si–, and –B–, or heteroatomic groups may be selected from –O– and –NH–, or heteroatomic groups may be –O– and –NH–. 1-6 Zykaloxy, C 1-5 Zykaloxy, C 1-4 Hexaalkoxy or C 1-3 Heteroalkoxy.

[0054] "Heteroalkyl" itself, or as part of another substituent, refers to an alkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced by one or more heteroatom groups, either the same or different. Examples of heteroatom groups include –O–, –S–, –Si–, –B–, –NH–, –NR–, –O–O–, –S–S–, =N–N=, –N=N–, –N=N–NR–, –PR–, –P(O)OR–, –P(O)R–, –POR–, –SO–, –SO2–, and –Sn(R)2–, where each R is independently selected from hydrogen, carbon ... 1-6 Alkyl, substituted C 1-6 Alkyl, C 6-12 Aryl, substituted C 6-12 Arylalkyl, C 7-18 arylalkyl, substituted C 7-18 Arylalkyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, C 3-7 Heterocyclic alkyl, substituted C3-7 Heterocyclic alkyl, 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 Heteroarylalkyl. Each R can be independently selected from hydrogen and C. 1-3 Alkyl group. For example, C10. 1-6 Heteroalkyl refers to a C-aryl group in which at least one carbon atom (and some associated hydrogen atoms) is replaced by a heteroatom. 1-6 Alkyl group. For example, C 1-6 Heteroalkyl groups include groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatoms, and so on. In heteroalkyl groups, the heteroatom group can be selected from O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, and –B–, or the heteroatom group can be selected from –O– and –NH–, or the heteroatom group can be –O– or –NH–. Heteroalkyl groups can be C… 1-6 Heteroalkyl, C 1-5 Heteroalkyl or C 1-4 Heteroalkyl or C 1-3 Heteroalkyl groups.

[0055] "Heteroaryl" itself, or as part of another substituent, refers to a monovalent heteroaryl group derived by removing a hydrogen atom from a single atom of a parent heteroaryl ring system. Heteroaryl encompasses polycyclic systems having at least one heteroaryl ring fused to at least one other ring, which can be aromatic or non-aromatic. For example, heteroaryl comprises bicyclic rings, one of which is heteroaryl and the second is a heterocyclic alkyl ring. For such fused bicyclic heteroaryl ring systems in which only one ring contains one or more heteroatoms, the group carbon may be on an aromatic ring or on a heterocyclic alkyl ring. When the total number of N, S, and O atoms in a heteroaryl exceeds 1, the heteroatoms may be adjacent to each other or not. The total number of heteroatoms in a heteroaryl does not exceed 2. In the heteroaryl group, the heteroatomic group can be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, and –B–, or the heteroatomic group can be selected from –O– and –NH–, or the heteroatomic group can be –O– or –NH–. The heteroaryl group can be selected from, for example, C. 5-10 heteroaryl, C 5-9 heteroaryl, C 5-8 heteroaryl, C 5-7 heteroaryl, C 5-6 Heteroaryl, C5 heteroaryl or C6 heteroaryl.

[0056] Examples of heteroaryl groups include those derived from acridine, arsinindole, carbazole, α-carboline, chromene, chromene, zoline, furan, imidazole, indazole, indole, dihydroindole, inazine, isobenzofuran, isochromene, isoindole, isodihydroindole, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, naphthalene-intercalated diazoxide, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthene, thiazoline, and oxazolline. Heteroaryl groups can be derived from, for example, thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, the heteroaryl group can be a C5 heteroaryl group, and can be selected from furanyl, thiophene, pyrrole, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. The heteroaryl group can also be a C6 heteroaryl group, and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0057] "Heteroarylalkyl" refers to an arylalkyl group in which one carbon atom (and some associated hydrogen atoms) is replaced by a heteroatom. Heteroarylalkyl groups can be C16-3 ... 6-16 Heteroarylalkyl, C 6-14 Heteroarylalkyl, C 6-12 Heteroarylalkyl, C 6-10 Heteroarylalkyl, C 6-8 Heteroarylalkyl or C7 heteroarylalkyl or C6 heteroarylalkyl. In heteroarylalkyl, the heteroatomic group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si– and –B–, or the heteroatomic group may be selected from –O– and –NH–, or the heteroatomic group may be –O– or –NH–.

[0058] "Heterocyclic alkyl" refers to a moiety having two heterocyclic alkyl groups. Heterocyclic alkyl groups can be fused ring or spirocyclic compounds.

[0059] "Heterocyclic alkyl" itself, or as part of another substituent, refers to a saturated or unsaturated cycloalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced by 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 by the same or different heteroatoms, such that the ring system violates Hückel's rule. Examples of heteroatoms that replace carbon atoms include N, P, O, S, B, and Si. Examples of heterocyclic alkyl groups include groups derived from epoxides, aziridines, thiaprothiocyclobenes, imidazolides, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, and quinine rings. Heterocyclic alkyl groups can be C5 heterocyclic alkyl groups and are selected from pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazoalkyl, oxazolylalkyl, thiazoalkyl, dioxopentyl, and dithiopentyl. The heterocyclic alkyl group can be a C6 heterocyclic alkyl group and can be selected from piperidinyl, tetrahydropyranyl, piperazinyl, oxazinyl, dithiaalkyl, and dioxaneyl. 3-8 Heterocyclic alkyl, C 3-8 Heterocyclic alkyl, C 3-5 Heterocyclic alkyl, C 5-6 Heterocyclic alkyl, C5 heterocyclic alkyl, or C6 heterocyclic alkyl. In heterocyclic alkyl, the heteroatom group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatom group may be selected from –O– and –NH–, or the heteroatom group may be –O– or –NH–.

[0060] "Heterocycloalkylalkyl" refers to a cycloalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are independently replaced by the same or different heteroatoms. Heterocycloalkylalkyl can be C 4-12 Heterocyclic alkyl, C 4-10 Heterocyclic alkyl, C 4-8 Heterocyclic alkyl, C 4-6 Heterocyclic alkyl, C 6-7 Heterocyclic alkyl alkyl or C6 heterocyclic alkyl alkyl or C7 heterocyclic alkyl alkyl. In heterocyclic alkyl alkyl, the heteroatomic group may be selected from –O–, –S–, –NH–, –N(–CH3)–, –SO–, –SO2–, –Si–, –B–, or the heteroatomic group may be selected from –O– and –NH–, or the heteroatomic group may be –O– or –NH–.

[0061] "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system with 4n+2 cyclic conjugated π (pi) electrons (Hückel's rule). The definition of "parent aromatic ring system" includes fused ring systems where one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indene, indene, and finasterene. Examples of parent aromatic ring systems include anthracene, acenaphthene, phenanthrene, anthracene, chamomile, benzene, phenanthrene, fluoranthene, phenanthene, hexaphenyl, hexaphenyl, hexaene, asymmetric indarene, symmetric indarene, indene, indene, naphthalene, octaphenyl, octaphenyl, octaene, elliptylbenzene, pentacene, cyclopentadiene, pentaphenyl, perylene, finasterene, phenanthrene, sepium, pyrene, pinanthrene, rubidium, triphenylene, and trinaphthalene.

[0062] "Hydrate" refers to an adduct formed by incorporating water into the crystal lattice of a compound described herein in a stoichiometric proportion. Methods for preparing hydrates include, for example, storage in an atmosphere containing water vapor, the use of water-containing dosage forms, or conventional pharmaceutical processing steps, such as crystallization. Right now Hydrates can be formed from water or a mixture of aqueous solvents (crystallized from water or a mixture of aqueous solvents), freeze-dried, wet granulated, coated with an aqueous film, or spray-dried. In some cases, hydrates can also form from crystalline solvates exposed to water vapor or anhydrous substances suspended in water. Hydrates can also crystallize in more than one form, resulting in polymorphic hydrates.

[0063] "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system with a conjugated π-electron system. Specifically, the definition of "parent aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indene, indene, and finasterene. Examples of parent aromatic ring systems include anthracene, acenaphthene, phenanthrene, anthracene, chamomile, benzene, phenanthrene, fluoranthene, phenanthene, hexaphenylene, hexaphenylene, asymmetric indarene, symmetric indarene, indene, indene, naphthalene, octaphenylene, octaphenylene, octaene, elliptylbenzene, pentadiene, pentacene, perylene, finasterene, phenanthrene, phenanthrene, heptaphenylene, pyrene, pinanthrene, rubidium, triphenylene, and trinaphthalene.

[0064] 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 by the same or different heteroatoms in a manner corresponding to Hückel’s rule (4n+2) to maintain the continuous π-electron system characteristic and multiple π electrons of the aromatic system. Examples of heteroatoms that replace carbon atoms include N, P, O, S, Si, and B. The definition of a “parent heteroaromatic ring system” specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as arsenoindene, benzene, benzofuran, chromene, indole, dihydroindole, and xanthracene. Examples of parent heteroaromatic ring systems include acridine, arsenindole, carbazole, β-carboline, chromene, chromene, zoline, furan, imidazole, indazole, indole, dihydroindole, inazine, isobenzofuran, isochromene, isoindole, isodihydroindole, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, naphthalene-intercalated diazoxide, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthane, thiazoline, and oxazolidine.

[0065] "Patient" refers to a mammal, such as a human.

[0066] "Pharmaceutical acceptable" means that a substance is approved or permitted by a federal or state government regulatory agency or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more specifically for humans.

[0067] A "pharmaceutically acceptable salt" is a salt of a compound that has the desired pharmacological activity of its parent compound. Such salts include acid addition salts formed with an inorganic acid and one or more protonable functional groups within the parent compound, such as primary, secondary, or tertiary amines. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. It can form salts with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic 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-hydroxyethylsulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc. When one or more acidic protons present in the parent compound are reacted with metal ions... For example When alkali metal ions, alkaline earth metal ions, or aluminum ions, or combinations thereof, are substituted, salts can be formed; or they can react with organic bases such as ethanolamine, diethanolamine, triethanolamine, and...N- Methylglucosamine coordination. Pharmaceutically acceptable salts can be hydrochloride salts. Pharmaceutically acceptable salts can be sodium salts. In compounds having two or more ionizable groups, pharmaceutically acceptable salts may contain one or more counterions, such as disalts, for example, dihydrochloride salts.

[0068] The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or amorphous forms. Where a specific pharmaceutically acceptable salt is disclosed, it should be understood that the specific salt ( For example Salts (such as hydrochlorides) are examples of salts, and other salts can be formed using techniques known to those skilled in the art. Furthermore, those skilled in the art will be able to convert pharmaceutically acceptable salts into corresponding compounds, free bases, and / or free acids using techniques generally known in the art.

[0069] "Pharmaceutically acceptable mediator" means a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, or any combination of the foregoing substances. The compounds provided in this disclosure can be administered to a patient together with the mediator, and the mediator does not impair its pharmacological activity and is non-toxic when administered in a dose sufficient to provide a therapeutically effective amount of the compound.

[0070] "Pharmaceutical composition" means a compound of formula (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, which is administered to a patient together with said at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known in the art.

[0071] "Prevention" refers to reducing the risk of acquiring a disease or condition. Right now To prevent at least one clinical symptom of a disease in patients who may be exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease. In some embodiments, “prevention” means to alleviate the symptoms of a disease by administering the compounds provided in this disclosure in a prophylactic manner. The application of a therapeutic agent for the prevention or avoidance of a disease is called prophylaxis. The compounds provided in this disclosure can provide excellent prophylaxis because of their low long-term side effects.

[0072] A "solvent" is a molecular complex of a compound with one or more solvent molecules in stoichiometric or non-stoichiometric amounts. These solvent molecules are those commonly used in the pharmaceutical industry and are known to be harmless to patients, such as water or ethanol. The compound or a portion of the compound's molecular complex with a solvent can be stabilized by non-covalent intramolecular forces such as electrostatic forces, van der Waals forces, or hydrogen bonds. The term "hydrate" refers to a solvate in which one or more solvent molecules are water. A "solvent" is an adduct formed by incorporating a solvent into the crystal lattice of the compound described herein in stoichiometric proportions. Methods for preparing solvates include, for example, storage in a solvent-containing atmosphere, solvent-containing dosage forms, or conventional pharmaceutical processing steps, such as crystallization. Right now Crystallization from solvent or mixed solvent) vapor diffusion 。 In some cases, solvates can also be formed from other crystalline solvates or hydrates when exposed to a solvent or when the material is suspended in a solvent. Solvates can crystallize in more than one form, resulting in solvate polymorphs.

[0073] "The compounds provided in this disclosure" refers to the compounds covered by formula (1) and their pharmaceutical salts. The compounds provided in this disclosure may further include compounds covered by formula (1), such as pharmaceutically acceptable salts, solvates, hydrates and / or prodrugs of any of the foregoing.

[0074] The compounds disclosed herein also include crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof. The terms "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0075] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Each substituent can be independently selected from, for example, deuterium, halogens, –OH, –CN, –CF3, –OCF3, =O, –NO2, C. 1-6 Alkoxy, C 1-6 Alkyl, –COOR, –NR2, and –CONR2; wherein each R is independently selected from hydrogen and C. 1-6 Alkyl group. Each substituent may be independently selected from, for example, deuterium, halogen, –NH2, –OH, C. 1-3 Alkoxy and C 1-3Alkyl, trifluoromethoxy, and trifluoromethyl. Each substituent may be independently selected from deuterium, –OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Each substituent may be selected from deuterium, C… 1-3 Alkyl, =O, C 1-3 Alkyl, C 1-3 Alkoxy and phenyl. Each substituent can be selected from, for example, deuterium, –OH, –NH2, C. 1-3 Alkyl and C 1-3 Alkyl group.

[0076] "Sustained release" refers to the release achieved relative to an immediately-release formulation of the same compound administered via the same route of administration, whereby the compound is released from a dosage form of the pharmaceutical composition into the patient's systemic circulation over an extended period of time at a rate that effectively achieves therapeutic or preventative concentrations of the compound or its active metabolites. In some embodiments, the release of the compound occurs over a period of at least about 4 hours, for example, 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.

[0077] "Treatment" of a disease refers to suppressing or improving at least one clinical symptom of the disease or condition, reducing the risk of acquiring at least one clinical symptom of the disease or condition, reducing the development of at least one clinical symptom of the disease or condition, or reducing the risk of developing at least one clinical symptom of the disease or condition. "Treatment" also refers to physical ( For example Stable and identifiable symptoms), physiologically ( For example "Treatment" also refers to the suppression of disease (either by stabilizing bodily parameters) or both, and specifically the suppression of at least one bodily parameter or manifestation, whether identifiable or indistinguishable to the patient. "Treatment" also refers to delaying the onset of a disease or condition in a patient who may be exposed to or susceptible to it, or delaying the onset of at least one or more symptoms of the disease, even if the patient has not yet experienced or exhibited symptoms of the disease.

[0078] "Therapeutic effective amount" means the amount of a compound that, when administered to a patient to treat a disease or at least one clinical symptom of a disease, is sufficient to affect the disease or its symptoms. "Therapeutic effective amount" can vary depending on, for example, the compound, the disease and / or its symptoms, the severity of the disease and / or the symptoms of the disease or condition, the age, weight, and / or health of the patient to be treated, and the judgment of the prescribing physician. In any given situation, the appropriate amount can be determined by those skilled in the art or can be determined through routine experiments.

[0079] "Therapeutic effective dose" refers to a dose that provides effective treatment for a patient's disease or condition. Therapeutic effective doses can vary between compounds and between patients, and can depend on factors such as the patient's condition and route of delivery. Therapeutic effective doses can be determined according to conventional pharmacological procedures known to those skilled in the art.

[0080] "Mediator" refers to a diluent, excipient, or carrier that is administered to a patient along with a compound. A mediator can be a pharmaceutically acceptable mediator. Pharmaceutically acceptable mediators are those known in the art.

[0081] Binding affinity refers to the strength of the binding interaction between a single biomolecule and its ligand / binding partner. Binding affinity is expressed as IC50. 50 The binding affinity can be determined by phage ELISA competitive assay.

[0082] "Modulate" refers to changes in the biological activity of a biomolecule (e.g., a protein, gene, peptide, or antibody). Such changes can involve an increase in the biological activity of the biomolecule, such as increased activity, activation, expression, upregulation, and / or increased expression, or a decrease in biological activity, such as decreased activity, antagonism, inhibition, inactivation, downregulation, and / or decreased expression.

[0083] For example, the compounds described herein can modulate, for example, the inhibition of the p38α MAPK protein. Compared to other MAPKs or p38MAPK isoforms, the compounds provided in this disclosure can selectively inhibit the p38α MAPK protein. Compared to other MAPKs or p38MAPK proteins, the compounds provided in this disclosure can selectively modulate, for example, the selective inhibition of the p38α MAPK protein.

[0084] A "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0085] Reference is now made to certain embodiments of the compounds, compositions, and methods. The disclosed embodiments are not intended to limit the claims. Rather, the claims are intended to cover all substitutions, modifications, and equivalents.

[0086] The compounds disclosed herein are selective inhibitors of the p38α MAPK protein. The pharmaceutical compositions disclosed herein include the compounds disclosed herein. The compounds and pharmaceutical compositions disclosed herein can be used to treat diseases, wherein the treatment involves inhibiting the p38α MAPK protein.

[0087] Inhibitors of the catalytic activity associated with p38α MAPK can not only block the expression of pro-inflammatory cytokines, but also block other p38α MAPK signaling pathways that are important for establishing and maintaining homeostasis.

[0088] The compounds disclosed herein target the substrate-binding groove of p38α MAPK, which extends between two acidic plaque CD and ED domains and differs from the DEF substrate-binding pocket. Downstream substrates, upstream activated kinases, and potential scaffold molecules interact with p38 MAPK through the CD and ED domains. The compounds disclosed herein can selectively bind to p38α MAPK without binding to p38β MAPK, stabilize endothelial barrier function in human pulmonary microvascular endothelial cells (HMVECL), and inhibit LPS-induced pro-inflammatory gene expression in THP1 cells.

[0089] The compounds disclosed herein include R. 2 Compounds containing fused rings having formula (1) and wherein R 2 Compounds containing a monocyclic ring having formula (1).

[0090] (1)

[0091] The compounds disclosed herein may have the structure of formula (1):

[0092] (1)

[0093] Or its pharmaceutically acceptable salt, wherein,

[0094] R 1 Can be selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0095] R 2 It can be selected from parts of equation (2a), parts of equation (2b), parts of equation (2c), and C. 8-16 Heterocyclic alkyl and substituted C 8-16 Heterocyclic alkyl groups:

[0096] (2a) (2b) (2c)

[0097] in,

[0098] B 1 B 2 B 3and B 4 Each of these can be independently selected from –(CH(–R) 4 )) n -,in,

[0099] Each n can be independently selected from 0, 1, 2, 3, and 4;

[0100] B 1 and B 2 Neither of them is 0;

[0101] B 3 and B 4 Neither of them is 0; and

[0102] Each R 4 It can be independently selected from hydrogen, –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl;

[0103] D can be selected from methane-diyl and ethane-diyl; and

[0104] X can be selected from –O–, –CH(–OH)–, –NR. 3 – and –SO2–, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatic compounds.

[0105] In the compound of formula (1), each of one or more substituents may be independently selected from –OH, =O, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6Mixed aromatic compounds.

[0106] In the compound of formula (1), each of one or more substituents may be independently selected from –OH, =O, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0107] In the compound of formula (1), each of one or more substituents may be independently selected from –OH, =O and C. 1-3 alkyl.

[0108] In the compound of formula (1), R 1 It can be C 1-4 Alkyl.

[0109] In the compound of formula (1), R 1 It can be ethylenedimethylamine.

[0110] In the compound of formula (1), R 1 It can be methanediol.

[0111] In the compound of formula (1), R 2 It can be a part of equation (2a):

[0112] (2a)

[0113] In part of equation (2a), B 1 B 2 B 3 and B 4 Each of these can be independently selected from –(CH2). n –

[0114] In part of equation (2a), B 1 and B 2 Each of these can be independently selected from –(CH2). n –

[0115] In part of equation (2a), B 1 B 2 and B 3 Each of these can be independently selected from –(CH2). n –

[0116] In part of equation (2a), B 1 B 2 and B 4 Each of these can be independently selected from –(CH2). n –

[0117] In part of equation (2a), B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0118] In part of equation (2a), B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0119] In part of equation (2a), B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0120] In part of equation (2a), B 1 B 2 B 3 and B 4 Each of them independently contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0121] In part of equation (2a), each n can be independently selected from 0, 1, 2 and 3.

[0122] In part of equation (2a), each n can be independently selected from 1, 2 and 3.

[0123] In part of equation (2a), B 1 and B 2 Each of the n values ​​can be independently chosen from 1 and 2; and B 3 and B 4 Each of them can have n = 2.

[0124] In part of equation (2a), B 1 and B 2 n in each case can be 1; and B 3 and B 4 Each of them can have n = 2.

[0125] In part of equation (2a), B 1 and B 2 In each case, n can be 2; and B 3 and B 4 Each of them can have n as 1.

[0126] In part of equation (2a), B 1 and B 2 In each case, n can be 2; and B 3 and B 4 Each of them can have n = 2.

[0127] In part of equation (2a), B 1 and B 2 n in each case can be 1; and B 3 and B 4 Each of them can have n as 1.

[0128] In part of equation (2a), X can be –O–.

[0129] In part of formula (2a), X can be –CH(–OH)–.

[0130] In part of equation (2a), X can be –SO2–.

[0131] In part of equation (2a), X can be –NR 3 –

[0132] In part of equation (2a), X can be –NR 3 – and R 3 It can be selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0133] In part of equation (2a), X can be –NR 3 – and R 3 It can be –C(=O)–CH3.

[0134] In part of equation (2a), X can be –NR 3 – and R 3 It can be –CH3.

[0135] In part of equation (2a), B 1 It could be –(CH2)2–; B 2 It can be –CH2–; B 3 It could be –(CH2) n – where n is selected from 0, 1, 2, and 3; B 3 It could be –(CH2) 3n –; and X is O.

[0136] A portion of equation (2a) may be selected from portions of equations (2a.1) to (2a.4):

[0137] (2d.1) (2d.2)

[0138] (2d.3) (2d.4)

[0139] Where R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 alkyl.

[0140] In the compound of formula (1), R 2 It can be a part of equation (2b):

[0141] (2b).

[0142] In part of equation (2b), B 1 B 2 B 3 and B 4 Each of these can be independently selected from –(CH2). n –

[0143] In part of equation (2b), B 1 and B 2 Each of these can be independently selected from –(CH2).n –

[0144] In part of equation (2b), B 1 B 2 and B 3 Each of these can be independently selected from –(CH2). n –

[0145] In part of equation (2b), B 1 B 2 and B 4 Each of these can be independently selected from –(CH2). n –

[0146] In part of equation (2b), B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0147] In part of equation (2b), B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 ), where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0148] In part of equation (2b), B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0149] In part of equation (2b), B 1 B2 B 3 and B 4 Each of them independently contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0150] In part of equation (2b), each n can be independently selected from 1 and 2.

[0151] In part of equation (2b), each n can be 1.

[0152] In part of equation (2b), B 1 and B 2 n in each case can be 1; and B 3 and B 4 Each of them can have n = 2.

[0153] In part of equation (2b), B 1 and B 2 In each case, n can be 2; and B 3 and B 4 Each of them can have n as 1.

[0154] In part of equation (2b), B 1 B 2 and B 3 In each case, n can be 1, and B 4 n can be 2.

[0155] In part of equation (2b), B 1 B 2 and B 3 In each case, n can be 2, and B 4 n can be 1.

[0156] In part of equation (2b), X can be –O–.

[0157] In part of equation (2b), X can be –CH(–OH)–.

[0158] In part of equation (2b), X can be –SO2–.

[0159] In part of equation (2b), X can be –NR 3 –

[0160] In part of equation (2b), X can be –NR 3– and R 3 It can be selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0161] In part of equation (2b), X can be –NR 3 – and R 3 It can be –C(=O)–CH3.

[0162] In part of equation (2b), X can be –NR 3 – and R 3 It can be –CH3.

[0163] In the compound of formula (1), R 2 It can be a part of equation (2c):

[0164] (2c).

[0165] In part of equation (2c), B 1 B 2 B 3 and B 4 Each of these can be independently selected from –(CH2). n –

[0166] In part of equation (2c), B 1 and B 2 Each of these can be independently selected from –(CH2). n –

[0167] In part of equation (2c), B 1 B 2 and B 3 Each of these can be independently selected from –(CH2). n –

[0168] In part of equation (2c), B 1 B 2 and B 4 Each of these can be independently selected from –(CH2). n –

[0169] In part of equation (2c), B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0170] In part of equation (2c), B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0171] In part of equation (2c), B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0172] In part of equation (2c), B 1 B 2 B 3 and B 4 Each of them independently contains –CH(–R) 4 )–, where R 4 It can be selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0173] In part of equation (2c), each n can be independently selected from 1 and 2.

[0174] In part of equation (2c), each n can be 1.

[0175] In part of equation (2c),

[0176] B 1 and B 2 In each case, n can be 1; and

[0177] B 3 and B 4 Each of them can have n = 2.

[0178] In part of equation (2c),

[0179] B 1 and B 2 In each case, n can be 2; and

[0180] B 3 and B 4 Each of them can have n as 1.

[0181] In part of equation (2c), each n can be 2.

[0182] In part of formula (2c), D can be methanediyl.

[0183] In part of formula (2c), D can be ethylenedimethyl.

[0184] In part of equation (2c), X can be –O–.

[0185] In part of formula (2c), X can be –CH(–OH)–.

[0186] In part of equation (2c), X can be –SO2–.

[0187] In part of equation (2c), X can be –NR 3 –

[0188] In part of equation (2c), X can be –NR 3 – and R 3 It can be selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0189] In part of equation (2c), X can be –NR 3 – and R 3 It can be –C(=O)–CH3.

[0190] In part of equation (2c), X can be –NR 3 – and R 3 It can be –CH3.

[0191] The compounds of formula (1) can be selected from:

[0192] N-(4-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-4-chlorobenzamide (3);

[0193] N -(4-((7-oxa-2-azaspiro[3.5]non-2-yl)methyl)phenyl)-4-chlorobenzamide (4);

[0194] N -(4-((8-oxa-2-azaspiro[4.5]dec-2-yl)methyl)phenyl)-4-chlorobenzamide (5);

[0195] N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6);

[0196] N -(4-(((1 R 5 S )-3-oxa-7-azabicyclo[3.3.1]non-7-yl)methyl)phenyl)-4-chlorobenzamide (9); and

[0197] 4-Chloro- N -(4-(((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)methyl)phenyl)benzamide (10);

[0198] Or a pharmaceutically acceptable salt of any of the foregoing.

[0199] The compounds disclosed herein may have the structure of formula (1):

[0200] (1)

[0201] Or its pharmaceutically acceptable salt, wherein,

[0202] R 1 Can be selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0203] R 2 It can be a part of equation (2d):

[0204] (2d)

[0205] in,

[0206] Each A 1 and A 2 It can be independently selected from –CH2–, –CH(–R) 5 ) – and –C(=O) –, where each R 5 It can be independently selected from –OH, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatics;

[0207] A 1 and A 2 One or more can be independently selected from –CH(–R) 5 – and –C(=O) –;

[0208] Each n can be independently selected from 1, 2, 3, and 4; and

[0209] X can be selected from –O–, –CH(–OH)–, –NR. 3 – and –SO2–, where R 3 It can be selected from hydrogen, C 1-6 Alkyl, C 5-8 cycloalkyl, C6 aryl, C 6-12 cycloalkylalkyl, C 7-10 Arylalkyl, C 1-6 Heteroalkyl, C 5-8 Heterocyclic alkyl, C 5-6 heteroaryl, C 6-12 Heterocyclic alkyl, C 7-10 Heteroarylalkyl, substituted C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C6 aryl, substituted C 6-12 Cycloalkylalkyl, substituted C 7-10 arylalkyl, substituted C 1-6 Heteroalkyl, substituted C 5-8 Heterocyclic alkyl, substituted C 5-6 heteroaryl, substituted C 6-12 Heterocyclic alkyl alkyl and substituted C 7-10 Heteroarylalkyl.

[0210] In part of equation (2d), R 1It can be C 1-4 Alkyl.

[0211] In part of equation (2d), R 1 It can be ethylenedimethylamine.

[0212] In part of equation (2d), R 1 It can be methanediol.

[0213] In part of equation (2d), each n can be independently selected from 1, 2, and 3.

[0214] In part of equation (2d), each n can be 2.

[0215] In part of equation (2d), each n can be 3.

[0216] In part of equation (2d), each n can be 4.

[0217] In part of equation (2d), A 1 and A 2 One or more of them can be independently selected from –CH(–R) 5 )–, where R 5 It can be C 1-3 Alkyl; and –C(=O)–.

[0218] In part of equation (2d), A 1 and A 2 One or more of them can be independently selected from –CH(–R) 5 )–, where R 5 It can be C 1-3 alkyl.

[0219] In part of equation (2d), A 1 and A 2 One or more of them can be –C(=O)–.

[0220] In part of equation (2d), X can be –O–.

[0221] In part of formula (2d), X can be –CH(–OH)–.

[0222] In part of equation (2d), X can be –SO2–.

[0223] In part of equation (2d), X can be –NR 3 –

[0224] In part of equation (2d), X can be –NR 3 – and R 3 It can be selected from hydrogen, C 1-3 Alkyl, C1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0225] In part of equation (2d), X can be –NR 3 – and R 3 It can be –C(=O)–CH3.

[0226] In part of equation (2d), X can be –NR 3 – and R 3 It can be –CH3.

[0227] The compounds of formula (1) can be selected from:

[0228] 2-Chloro- N -(4-(morpholinomethyl)phenyl)pyrimidine-5-carboxamide (1);

[0229] N -(4-((1,4-oxazacycloheptan-4-yl)methyl)phenyl)-4-chlorobenzamide (2);

[0230] 4-Chloro- N -(4-(((2 S 6 R )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (7);

[0231] 4-Chloro- N -(4-(((2 S 6 S )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (8);

[0232] 4-Chloro- N -(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (11);

[0233] 4-Chloro- N -(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (12);

[0234] 4-Chloro- N -(4-((3-hydroxypyrrolidone-1-yl)methyl)phenyl)benzamide (13);

[0235] N -(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-4-chlorobenzamide (14);

[0236] 4-Chloro- N-(4-((3-oxopiperazin-1-yl)methyl)phenyl)benzamide (15);

[0237] 4-Chloro- N -(4-((4-methyl-3-oxopirarin-1-yl)methyl)phenyl)benzamide (16); and

[0238] 4-Chloro- N -(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (17);

[0239] Or a pharmaceutically acceptable salt of any of the foregoing.

[0240] In part of equation (2d), A 1 It could be –(CH2) n – where n can be an integer from 1 to 4; A 2 It could be –(CH2) 5-n –; and X is O.

[0241] The part of equation (2d) can have the structure of equation (2d.1) or equation (2d.2):

[0242] (2d.1) (2d.2)

[0243] Where R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 alkyl.

[0244] In part of equation (2d), A 1 It could be –(CH2) n – where n is 1 or 2; A 2 It could be –(CH2) 3-n –; and X is –N(–C(=O)–R 6 )–, where R 6 Selected from.

[0245] The part of equation (2d) can be selected from parts of equations (2d.3) and (2d.4):

[0246] (2d.3) (2d.4)

[0247] in,

[0248] R 5The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0249] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0250] In part of equation (2d), A 1 It could be –(CH2) n – where n is 1 or 2; A 2 It could be –(CH2) 3-n –; and X can be O, and can contain one or two –CH3 substituents.

[0251] The part of equation (2d) can have the structure of equation (2d.5):

[0252] (2d.5).

[0253] The compounds disclosed herein may have the structure of formula (1):

[0254] (1)

[0255] Or its pharmaceutically acceptable salt, wherein,

[0256] R 1 Can be selected from C 1-4 Alkyl; and

[0257] R 2 The substituted or unsubstituted portion selected from any of formulas (2a.1) to (2a.4) and (2d.1) to (2d.5):

[0258] (2a.1) (2a.2)

[0259] (2a.3) (2a.4)

[0260] (2d.1) (2d.2)

[0261] (2d.3) (2d.4)

[0262] (2d.5)

[0263] in,

[0264] R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0265] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0266] In the compound of formula (1), R 1 Selected from methane-diyl, ethane-diyl, and n-propane-diyl.

[0267] In the compound of formula (1), R 1 It is methane-dimethyl.

[0268] In the compound of formula (1), R 2 The unsubstituted portion selected from any one of (2a.1) to (2a.4) and (2d.1) to (2d.5).

[0269] In the compound of formula (1), R 2 The portion selected from any of equations (2a.1) to (2a.4) and (2d.1) to (2d.5) that is substituted:

[0270] In compounds of formula (1), the substituted portion may have the structure of any of formulas (2a.1) to (2a.4) and (2d.1) to (2d.5):

[0271] (2a.1) (2a.2)

[0272] (2a.3) (2a.4)

[0273] (2d.1) (2d.2)

[0274] (2d.3) (2d.4)

[0275] (2d.5)

[0276] in,

[0277] R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0278] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0279] The compound of formula (1) may be a solvate, a pharmaceutically acceptable salt, or a combination thereof.

[0280] In the compound of formula (1), the pharmaceutically acceptable salt can be a hydrochloride salt.

[0281] In the compound of formula (1), the pharmaceutically acceptable salt can be a dihydrochloride.

[0282] The compound of formula (1) may be a pharmaceutically acceptable salt of the compound of formula (1), its hydrate or a solvate of any of the foregoing.

[0283] The compounds disclosed herein may be p38 MAPK inhibitors and / or p38α MAPK protein activity modulators.

[0284] The compounds disclosed herein selectively bind to p38α MAPK. The selective p38α MAPK inhibitors disclosed herein exhibit a higher binding affinity to the target pocket of p38α MAPK than to p38β MAPK. The compounds provided by this invention selectively inhibit p38α MAPK. The p38α MAPK inhibitors can bind to p38α MAPK near its substrate-binding groove, which extends between two acidic plaques termed the CD and ED domains. The binding pocket may be defined at least by residues R49, H107, L108, and K165 of p38α MAPK. The binding pocket may be defined at least by residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 of p38α MAPK.

[0285] The selective binding of the compounds disclosed herein to p38α MAPK was confirmed using complementary techniques. For example, selective p38α MAPK inhibitors exhibit a concentration-dependent increase in melting temperature for p38α but not p38β, as detected by differential scanning spectroscopy (DSF), which measures ligand-induced protein stabilization. STD-NMR pass The nonscalar magnetization transfer from protein to ligand protons is used to measure low-affinity protein / ligand binding, which can be used to confirm the binding of specific compounds to p38α and localize the interaction to its aromatic ring. p38α MAPK inhibitors induce a concentration-dependent increase in the p38α MAPK melting temperature. The melting temperature T can be measured at concentrations of p38α MAPK inhibitors from 1 nM to 1,000 μM (e.g., 100 μM). m The difference can be significant. For example, the difference in melting temperature can be 0.1°C to approximately 2°C.

[0286] The compounds disclosed herein can interact with pockets near the ED substrate docking sites of p38α MAPK.

[0287] The compounds disclosed herein can bind p38α MAPK near the substrate-binding groove of p38α MAPK, which extends between the CD and ED domains.

[0288] The compounds disclosed herein can inhibit MK2 phosphorylation by interacting with p38α MAPK.

[0289] The compounds disclosed herein are compatible with 4-chloro- N -(4-((1,1-dioxothiomorpholino)methyl)phenyl)benzamide competitively binds to p38α MAPK.

[0290] The compound disclosed herein binds to the p38α MAPK subunit via IC50. 50 It can be smaller than the IC that binds to the p38β MAPK subunit. 50 .

[0291] The p38α MAPK inhibitors disclosed herein may have logP values, such as -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, defined as the logarithm of the octanol / water partition coefficient of the compound.

[0292] Phosphorylation of MK2 requires binding to an ED site in the p38α MAPK adjacent to the target pocket. The target pocket can be defined by amino acids R49, H107, L108, and K165 in the p38α MAPK. The target pocket can also be defined by amino acids selected from R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in the p38α MAPK.

[0293] The p38α MAPK inhibitors disclosed herein can at least partially inhibit MK2 phosphorylation. For example, Western blotting can be used to measure the inhibition of MK2 phosphorylation in HeLa cells stimulated with anisin by the compounds disclosed herein.

[0294] The p38α MAPK inhibitors disclosed herein can stabilize endothelial or epithelial barrier function. Endothelial barrier permeability can be measured by exposure alone or in combination to TNFα and high temperature, followed by measurement of the permeability of 10 kDa dextran. For example, endothelial barrier stability can be assessed by pretreatment with the compounds disclosed herein, before and after permeability measurements, wherein stability can be expressed as a percentage reduction in the increase in permeability before and after pretreatment. The increase in permeability of 10 kDa dextran can be reduced from 5% to greater than 100%, for example, greater than 5%, greater than 10%, greater than 20%, greater than 40%, greater than 60%, greater than 80%, or greater than 100%.

[0295] The p38α MAPK inhibitors disclosed herein can modulate TNFα-induced gene expression in human lung microvascular endothelial cells (HMVECLs), as determined using, for example, RNASeq. For example, HMVECLs can be pretreated with an appropriate concentration of the p38α MAPK inhibitor for a period of time, followed by stimulation with TNFα for a period of time. The p38α MAPK inhibitors disclosed herein can inhibit genes such as PRRG4, TSLP, CCLI7, EXOC3L4, MMP9, IDOI, CXCL10, CD200, SLCI5A3, VDR, ILIB, GPR88, CD207, TCHH, HAS3, GBPIPI, MUC4, ELOVL7, CXCL11, GBP4, PLAIA, and / or CXCL5.

[0296] The effect of p38α MAPK inhibitors on the expression of inflammatory cytokines can be determined by pretreating PMA-differentiated THPI cells with p38α MAPK inhibitors, followed by LPS stimulation, and harvesting RNA after a period of time for PCR-based cytokine array analysis. p38α MAPK inhibitors can inhibit the expression of various genes, such as IL-1A, IL-8, TNFSF8, CXCL5, CCL7, CCLI7, TNFSF9, IL-1B, CXCL1, TNFSF5, CCL5, CCL4, CCL20, CXCL2, TNF, or BMP6. p38α MAPK inhibitors can also inhibit Smad3 expression, promote the differentiation of Foxp3 T-regulated cells, and inhibit interferon-γ expression. The reduction in inflammation can be measured by comparing the fold change in mRNA levels at various concentrations of p38α MAPK inhibitors with that of unstimulated PMA-differentiated THPI cells.

[0297] Compounds of formula (1) can be synthesized using methods known in the art.

[0298] To prepare the synthetic precursor 4-chloro- N -(4-(chloromethyl)phenyl)benzamide (B) can be prepared by adding 4-chlorobenzoyl chloride to a stirred solution of (4-aminophenyl)methanol and sodium acetate in THF (100 mL) at room temperature (23 °C) and reacting for 1.5 hours at room temperature.

[0299] The reaction mixture can be extracted, the organic extract dried, filtered, and concentrated to give 4-chloro-N- N -(4-(hydroxymethyl)phenyl)benzamide (A). At room temperature, methanesulfonyl chloride is added to a stirred solution of 4-chloro- N The reaction mixture (A) was added to a DCM solution and stirred at room temperature for 2 hours. The reaction mixture could then be extracted, washed, dried, and filtered to provide the precursor 4-chloro- N -(4-(chloromethyl)phenyl)benzamide (B).

[0300] Compound (1) can be obtained by adding anhydrous potassium carbonate to compound (A) (200 mg, 0.714 mmol) and the heterocyclic moiety (R in compound (1)). 2 The compound is prepared by reacting a stirred mixture in DMF at 50°C for 2 hours with stirring. The reaction mixture may be filtered and purified to provide the compound of formula (1).

[0301] The compounds of formula (1) provided herein can be incorporated into pharmaceutical compositions for administration to patients via any suitable route of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, oral, sublingual, intracerebral, intravaginal, percutaneous, rectal, inhalation, or local administration. The pharmaceutical compositions provided herein may be injectable formulations. The pharmaceutical compositions provided herein may be injectable intravenous formulations. The pharmaceutical compositions provided herein may be oral formulations. Oral formulations may be oral dosage forms. The pharmaceutical compositions may be formulated for intravenous or subcutaneous administration.

[0302] The pharmaceutical compositions provided in this disclosure may comprise a therapeutically effective amount of a compound of formula (1) and a suitable amount of one or more pharmaceutically acceptable carriers to provide a composition for appropriate administration to a patient. Suitable pharmaceutical carriers and methods for preparing pharmaceutical compositions are described in the art.

[0303] Assessing individual patient responses to treatment and determining eligibility for optimal treatment is one of the greatest challenges of modern healthcare and involves the trend toward personalized medicine. Compounds of formula (1) may have target selectivity, for example, for certain cancers and immune cells. Radiolabeled compounds of formula (1) used in positron emission tomography (PET) or single-photon emission computed tomography (SPECT) can be used in case-by-case patient analyses based on single studies to predict treatment targeting, thereby excluding patients who are not expected to benefit from treatment. Once concentration-dependent, PET / SPECT scans using compounds of formula (1) can provide a three-dimensional distribution map, which can then be used for macroscopic dose calculations.

[0304] Therefore, those skilled in the art are able to determine and use compounds of formula (1) and / or their pharmaceutical compositions for treatment.

[0305] Compounds of formula (1) and / or their pharmaceutical compositions may generally be used in an effective amount to achieve the intended purpose. For the treatment of diseases such as cancer, autoimmune diseases or inflammatory diseases, compounds of formula (1) and / or their pharmaceutical compositions may be administered or applied in a therapeutically effective amount.

[0306] The amount of compound (1) and / or any of the foregoing pharmaceutical compositions that are effective in treating the specific conditions or symptoms disclosed herein will depend in part on the nature of the condition or symptom and can be determined by standard clinical techniques known in the art. Additionally, optional use may be made. in vitro or in vivo Determination is used to help determine the optimal dosage range. The dosage of the compound of formula (1) and / or any of the aforementioned pharmaceutical compositions will depend on factors such as the patient being treated, the patient's weight, the severity of the pain, the route of administration, and the prescribing physician's judgment.

[0307] Before being used on humans, it was possible in vitro and in vivo Determine the desired therapeutic activity of the compound of formula (1). For example, body outside Assays can be used to determine whether the administration of a particular compound or combination of compounds is preferred. Animal model systems can also be used to demonstrate that a compound is effective and safe.

[0308] In some embodiments, a therapeutically effective dose of the compound of formula (1) and / or any of the foregoing pharmaceutical compositions will provide therapeutic benefit without causing significant toxicity. The toxicity of the compound of formula (1) and / or any of the foregoing pharmaceutical compositions can be determined using standard pharmaceutical methods and can be readily determined by those skilled in the art. The dose ratio between toxicity and therapeutic effect is the therapeutic index. The compound of formula (1) and / or any of the foregoing pharmaceutical compositions exhibits a particularly high therapeutic index in the treatment of diseases and conditions. The dose of the compound of formula (1) and / or any of the foregoing pharmaceutical compositions will be within a cyclic concentration range including the effective dose with minimal toxicity.

[0309] The compounds and pharmaceutical compositions provided in this disclosure may be included in a kit for administering the compounds to a patient for therapeutic purposes. The kit may include a pharmaceutical composition and instructions for administering the pharmaceutical composition to a patient, the pharmaceutical composition comprising the compounds provided in this disclosure suitable for administration to a patient. The kit may be suitable for treating cancer, autoimmune diseases, or inflammatory diseases. Kits for treating cancer, autoimmune diseases, or inflammatory diseases may contain the compounds or pharmaceutical compositions provided in this disclosure, and instructions for administering the compounds to a patient.

[0310] The compounds and pharmaceutical compositions disclosed herein may be included in containers, packages or dispensers together with instructions for use.

[0311] The instructions provided with the kit may be printed and / or provided as, for example, electronically readable media, videotapes, audiotapes, flash memory devices, or may be published on an Internet website or distributed as electronic communications to patients and / or healthcare providers.

[0312] The compounds and pharmaceutical compositions disclosed herein can be used to treat patients’ diseases.

[0313] The compounds and pharmaceutical compositions disclosed herein can be used to treat diseases in which the cause of the disease is associated with the upregulation and / or downregulation of the p38αMAPK protein.

[0314] The methods provided in this disclosure include treating a patient’s disease, comprising administering a therapeutically effective amount of the compound or composition provided in this disclosure to the patient in need, wherein the disease is treated by inhibiting the p38α MAPK protein.

[0315] The p38 mitogen-activated protein kinase (MAPK) family of activating kinases and cytokine-activated kinases is associated with the pathogenesis of many human diseases, including cancer, rheumatoid arthritis, amyotrophic lateral sclerosis, cystic fibrosis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI). In many important biological processes regulated by p38 MAPKs, the regulation of endothelial and epithelial barrier function, leukocyte transport, and cytokine expression are crucial for the pathogenesis of acute and chronic inflammatory diseases.

[0316] The compounds and pharmaceutical compositions disclosed herein can be used to treat cancer in patients. Cancer can be, for example, a solid tumor or a metastatic tumor.

[0317] The methods provided in this disclosure include methods for treating cancer in patients, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need.

[0318] Suitable examples of cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder tumor, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, and gastric cancer. Cancer), glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, sarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary gland carcinoma, pineal carcinoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer (sto (machcancer), sweat gland cancer, synovial tumour, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, nephroblastoma, blood cancer, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease.

[0319] Suitable examples of cancers include pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck tumors, breast tumors, ovarian tumors, lung tumors, small cell lung cancer, nephroblastoma, cervical tumors, testicular tumors, bladder tumors, pancreatic tumors, stomach tumors, colon tumors, prostate tumors, urogenital tract cancers, thyroid tumors, esophageal tumors, myeloma, multiple myeloma, adrenal cancer, renal cell carcinoma, and endometrial tumors. Tumors, adrenocortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid tumor, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical spondylosis, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, piloblastic leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, idiopathic thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia or retinoblastoma, etc. In other embodiments, the cancers are acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder tumor, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, and kidney cancer. Cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, sarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary gland carcinoma, papillary carcinoma, pineal tumor, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer (stomach) Cancer), sweat gland cancer, synovial sarcoma, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, nephroblastoma, blood cancer, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

[0320] The compounds and pharmaceutical compositions disclosed herein may be used to treat, for example, one or more of the following cancers: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma (non-melanoma), B-cell lymphoma, bladder cancer, bone cancer, brain and spinal cord tumors, brainstem cancer, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, head and neck tumors, embryonal tumors of the central nervous system, and cerebellar astrocytoma. Cytomas, astrocytomas / malignant gliomas, cervical cancer, chordomas, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, desmoplastic small round cell tumors, ductal carcinoma, chromosomal carcinoma, endocrine pancreatic tumors (islet cell tumors), endometrial cancer, ependymoblastoma, esophageal cancer, nasal glioma, Ewing family tumors, extracranial germ cell tumors, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer. Cancer), gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic tumors, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, heart cancer, lymphoid hematopoietic tumors, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway gliomas, ID-related lymphoma, intraocular melanoma, islet cell tumors, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, male breast cancer, malignant fibrous histiocytoma, malignant germ cell tumors, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer. Cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumors, low-potency ovarian tumors, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineal tumors and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasmacytoma / multiple myeloma, pleural pulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary liver cancer, primary metastatic occult squamous neck cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter, respiratory tract cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Cezari syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma (non-melanoma), gastric cancer (stomach)Cancer), supratentorial primitive neuroectodermal tumors, T-cell lymphomas, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma, urethral cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic gliomas, vulvar cancer, Waldenstome macroglobulinemia, nephroblastoma, and systemic and central metastases of any of the above.

[0321] The methods disclosed herein include methods for treating cancer, wherein the cancer is selected from breast cancer and melanoma.

[0322] The methods provided in this disclosure include methods for treating inflammatory diseases in patients, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need.

[0323] Examples of inflammatory diseases include allergies, Alzheimer's disease, anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma, autism, carpal tunnel syndrome, celiac disease, colitis, Crohn's disease, congestive heart failure, dermatitis, diabetes, diverticulitis, eczema, fibromyalgia, fibrosis, gallbladder disease, gastroesophageal reflux disease, Hashimoto's thyroiditis, heart attack, hepatitis, irritable bowel syndrome, kidney failure, lupus, multiple sclerosis, nephritis, neuropathy, pancreatitis, Parkinson's disease, psoriasis, polymyalgia rheumatica, rheumatoid arthritis, scleroderma, stroke, surgical complications, and ulcerative colitis.

[0324] The methods provided in this disclosure include methods for treating inflammatory diseases in patients, wherein the inflammatory diseases are selected from, for example, acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

[0325] The methods provided in this disclosure include methods for treating autoimmune diseases in patients, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need.

[0326] The compounds or pharmaceutical compositions disclosed herein may be used to treat autoimmune diseases. Autoimmune diseases can be defined as human diseases in which the immune system attacks its own proteins, cells, and / or tissues. A comprehensive list and review of autoimmune diseases can be found in, for example, […]. Autoimmune diseases 》, Rose and Mackay, 2014, Academic Press.

[0327] Examples of autoimmune diseases include Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBN nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Barlow's disease, Bechtel's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, allergic granulomatous vasculitis, cicatricial pemphigoid, and Cogan's disease. Syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dervec disease, discoid lupus, Deresler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpassuu syndrome, polyangiitis granuloma, Graves' disease, Graves-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura, herpes gestationis or pemphigoid of pregnancy, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis, immune thrombocytopenic purpura Inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus, juvenile myositis, Kawasaki disease, Lambert-Eton syndrome, leukocytosis, lichen planus, lichen sclerosis, woody conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mollen's keratitis, Mueller-Hacker disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, spinal neuritis, optic neuritis, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS, cerebellar paraneoplastic degeneration, paroxysmal nocturnal hemoglobinuria, manic-depressive syndrome, platysmitis, Barto syndrome, pemphigus, peripheral neuropathy, perivenous encephalopathy Myelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polygonatum syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis, SARS syndrome, sympathetic ophthalmia, high-ankle arteritis, temporal arteritis.Thrombocytopenic purpura, polycystic Hunt syndrome, transverse myelitis, type I diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vacuum inflammation, vitiligo, and Wegener's granulomatosis.

[0328] The compounds or pharmaceutical compositions disclosed herein can be used to treat autoimmune diseases such as lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, loss of pregnancy, atopic diseases, and inflammatory bowel disease.

[0329] The compounds or pharmaceutical compositions disclosed herein may be administered in combination with one or more other therapeutic agents for the treatment of autoimmune diseases. The compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with one or more immunosuppressants, including, for example, corticosteroids such as prednisone, budesonide, and prednisolone; Janus kinase inhibitors such as tofacitinib; calcineurin inhibitors such as cyclosporine and tacrolimus; mTOR inhibitors such as sirolimus and everolimus; and IMDH inhibitors such as azathioprine, leflunomide, and mycophenolate mofetil. 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.

[0330] The methods provided in this disclosure include methods for treating a patient’s disease, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need, wherein the disease is selected from 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.

[0331] The methods provided in this disclosure include methods for treating a patient’s disease, the methods comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need, wherein the disease is an age-related disease, such as hearing loss, muscle degeneration, Weiner syndrome, cellular senescence, or Alzheimer’s disease.

[0332] The methods provided in this disclosure include methods for treating a patient’s disease, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition provided in this disclosure to a patient in need, wherein the disease is selected from sudden idiopathic hearing loss, drug-induced hearing loss, age-related hearing loss, and Duchenne muscular dystrophy.

[0333] Compounds of formula (1) or pharmaceutical compositions thereof may be administered to patients to treat viral diseases.

[0334] Examples of suitable viral diseases include Acinetobacter infections, actinomycosis, African sleeping sickness (African trypanosomiasis), AIDS (Acquired Immunodeficiency Syndrome), amoebiasis, anaplasmosis, angiostrongylus infection, anisakiasis, anthrax, Cryptococcus hemolyticus infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial meningitis, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balanitis, Bartonella infection, Beliella bailey infection, non-sexually transmitted syphilis, syphilis, yaws, BK virus infection, trichomonas nigricans, blastomycosis, Bolivian hemorrhagic fever, botulism (and infant botulism), Brazilian hemorrhagic fever, brucellosis. Bacterial diseases, bubonic plague, Burkholderia infection, Burkholderia ulcer, calicivirus infection (norovirus and zarovirus), Campylobacteriosis, Candidiasis (candidiasis; thrush), Capillary nematode disease, Carrion disease, Cat scratch disease, Cellulitis, Chagas disease (American trypanosomiasis), Chancroid, Chickenpox, Chikungunya, Chlamydia, Chlamydia pneumoniae infection, Cholera, Chromomiasis, Chytriditis, Clonorchiasis, Clostridium difficile colitis, Coccidioidomycosis, Colorado tick fever (CTF), Common cold (acute viral nasopharyngitis), Acute nasal catarrh, Coronavirus infection such as MERS-CoV infection, SARS-CoV infection or SARS-CoV-2 infection, Coronavirus disease 2019 (COVID-19) 9) Coronavirus-associated pneumonia, human respiratory syndrome infection, Creutzfeldt-Jakob disease (CJD), Crimean-Congo hemorrhagic fever (CCHF), cryptococcosis, cryptosporidiosis, cutaneous larval migration syndrome (CLM), coccidioidomycosis, cysticercosis, cytomegalovirus infection, dengue fever, Demodex mite infection, binuclear amoebiasis, diphtheria, sparganosis, dracunculiasis, Ebola hemorrhagic fever, echinococcosis, ehrlichiosis, pinworm infection, enterococcal infection, enterovirus infection, epidemic typhus, Epstein-Barr virus infection, mononucleosis (Mono), erythema infectiosum (fifth disease), roseola infantum (sixth disease), fascioliasis, fascioliasis, fatal familial insomnia ( FFI), filariasis, Clostridium perfringens food poisoning, free-living amoeba infection, fusobacterium infection, gas gangrene (clostridium myonecrosis), dysphincosis, G. S.-S. syndrome (GSS), giardiasis, glanders, gnatostome disease, gonorrhea, granuloma inguinale (dunovan infection), group A streptococcal infection, group B streptococcal infection, Haemophilus infection, hand-foot-mouth disease (HFMD), Hantavirus [3] pulmonary syndrome (HPS), peritonitis virus disease, Helicobacter pylori infection, hemolytic uremic syndrome (HUS), hemorrhagic fever with renal syndrome (HFRS), Hendra virus infection, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworm infection, human bocavirus infectionHuman Ehrlich's disease, human granulocytic anaplasmosis (HGA), human metapneumovirus infection, human monocytic Ehrlich's disease, human papillomavirus (HPV) infection, human parainfluenza virus infection, hymenolepis taeniasis, influenza, isosporidioid coccidiosis, Kawasaki disease, keratitis, Kekinella infection, kuru, Lassa fever, Legionnaires' disease, leishmaniasis, leprosy, leptospirosis, Listeria infection, Lyme disease (Lamb's borreliosis), lymphatic filariasis (elephantiasis), lymphocytic choriomeningitis, malaria, Marburg hemorrhagic fever (MHF), measles, melioidosis (Whitmore's disease), meningitis, meningococcal disease, post- Paragonimiasis, Microsporidiosis, Middle East Respiratory Syndrome (MERS), Molluscum Contagiosum (MC), Monkeypox, Mumps, Murine Typhus (endemic typhus), Mycoplasmosis of the Foot, Genital Mycoplasma Infection, Mycoplasma Pneumonia, Myiasis, Neonatal Conjunctivitis (Neonatal Eye Infection), Nipah Virus Infection, Nocardiasis, Norovirus (Children and Infants), Onchocerciasis (River Blindness), Opisthocoidosis, Paracoccidioidomycosis (South American Blastomycosis), Paragonimiasis, Pasteurella Mitis, Head Lice, Body Lice, Pubic Lice, Pelvic Inflammatory Disease (PID), Pertussis (whooping cough) Cough, plague, pneumococcal infection, Pneumocystis pneumonia (PCP), pneumonia, poliomyelitis, wartyx fever, Prevotella infection, primary amoebic meningoencephalitis (PAM), progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, relapsing fever, respiratory syncytial virus infection, rhinocystis infection, rhinovirus infection, rickettsia infection, rickettsial pox, Rift Valley fever (RVF), Rocky Mountain spotted fever (RMSF), rotavirus infection, rubella, salmonellosis, SARS (Severe Acute Respiratory Syndrome), MERS-CoV, SARS-CoV, SARS-CoV-2, scabies, scarlet fever, schistosomiasis, sepsis, Shigella infection (bacterial dysentery), herpes zoster (shingles / herpes zoster). Zoster, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis, subacute sclerosing panencephalitis, tapeworm infection, tetanus (lockjaw disease), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), tinea corporis (ringworm of the body), tinea cruris (jock itch), tinea manum (ringworm of the hand), tinea pedis (athlete's foot), onychomycosis (nail fungus), tinea versicolor (pityriasis versicolor).Toxocariasis (ocular larval migration (OLM)), Toxocariasis (visceral larval migration (VLM)), Toxoplasmosis, Trachoma, Trichinosis, Trichomoniasis, Whipworm Infection, Tuberculosis, Tularemia, Typhoid Fever, Spotted Typhus, Ureaplasma Infection, Valley Fever, Venezuelan Equine Encephalitis, Venezuelan Hemorrhagic Fever, Vibrio Parahaemolyticus Enteritis, Vibrio vulnificus Infection, Viral Pneumonia, West Nile Fever, Trichophyton Ulva (Tinea Pedis), Yellow Fever, Pseutuberculosis Yersinia Infection, Yersiniasis, Zeaspora, Zika Fever, and Zygomycosis.

[0335] The effective therapeutic amount of the compound of formula (1) or its pharmaceutical composition provided in this disclosure for cancer treatment may depend at least in part on the nature of the disease and may be determined by standard clinical techniques known in the art. Furthermore, [the following methods may be used]. in vitro or in vivo Measurements are used to help determine the optimal dosing range. Dosing regimens and dosing intervals can also be determined by methods known to those skilled in the art. The dosage of the compound of formula (1) provided in this disclosure may depend on factors such as the patient being treated, the patient's weight, the severity of the disease, the route of administration, and the prescribing physician's judgment.

[0336] For systemic administration, the initial effective therapeutic dose can be from... iExtracorporeal Experimental estimation. Techniques known in the art can also be used from... in vivo data For example Animal models estimate the initial dose. This information can be used to more accurately determine the effective dose for humans. Those skilled in the art can optimize human administration based on animal data.

[0337] The dosage and appropriate dosing interval of the compound of formula (1) provided in this disclosure can be selected to maintain a sustained therapeutically effective concentration of the compound of formula (1) provided in this disclosure in the patient’s blood, and in some embodiments, not exceeding a minimum adverse concentration.

[0338] Pharmaceutical compositions comprising compounds of formula (1) provided in this disclosure may be administered, for example, once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. Administration may be provided alone or in combination with other drugs and may be effective for the duration required to treat the disease. Administration may be performed using continuous or semi-continuous administration over a period of time. Administration includes giving the pharmaceutical composition to mammals, such as humans, in a fed or fasted state.

[0339] The pharmaceutical composition may be administered in a single dosage form or in multiple dosage forms or as a continuous or cumulative dose over a period of time. When multiple dosage forms are used, the amount of the compound of formula (1) provided in this disclosure contained in each of the multiple dosage forms may be the same or different.

[0340] Suitable daily dose ranges for administration can be, for example, about 2 μg to about 200 mg per kilogram of body weight of the compounds of formula (1) provided in this disclosure.

[0341] Suitable daily dose ranges for application can be, for example, from about 1 μg to about 50 mg of the compound of formula (1) disclosed herein per square meter (m²). 2 Within the range of the body surface.

[0342] The compound of formula (1) provided in this disclosure can be administered to treat a patient’s cancer at a dose, for example, from 0.001 mg / day to 100 mg / day or at any other suitable daily dose. The dose can be, for example, from 0.01 μg / kg body weight / week to 100 μg / kg body weight / week or any other suitable dose.

[0343] A pharmaceutical composition comprising a compound of formula (1) provided in this disclosure may be administered to treat a patient’s cancer, thereby providing a therapeutically effective concentration of the compound of formula (1) provided in the patient’s blood or plasma. The therapeutically effective concentration of the compound of formula (1) provided in this disclosure in the patient’s blood may be, for example, from 0.01 μg / L to 1,000 μg / L, from 0.1 μg / L to 500 μg / L, from 1 μg / L to 250 μg / L, or from about 10 μg / L to about 100 μg / L. The therapeutically effective concentration of the compound of formula (1) provided in this disclosure in the patient’s blood may 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 (1) in the patient’s blood may be, for example, less than an amount that would cause unacceptable side effects, including side effects on homeostasis. The therapeutically effective concentration of the compound of formula (1) in the patient’s blood may be an amount sufficient to restore and / or maintain homeostasis in the patient.

[0344] The pharmaceutical composition provided in this disclosure can be administered to treat a patient’s disease, thereby providing a therapeutically effective concentration of the compound of formula (1) in the patient’s blood for a period of time, such as 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day or 2 days.

[0345] The dosage of the compound in formula (1) can be varied in the treatment regimen.

[0346] In addition to compounds of formula (1), the pharmaceutical compositions provided in this disclosure may also contain one or more pharmaceutically active compounds. Such compounds may be provided, for example, to treat cancer treated with compounds of formula (1) or to treat diseases, conditions or symptoms other than cancer treated with compounds of formula (1), to treat side effects caused by administration of compounds of formula (1), to increase the efficacy of compounds of formula (1), and / or to regulate the activity of compounds of formula (1).

[0347] The compound of formula (1) provided in this disclosure may be administered in combination with at least one other therapeutic agent. The compound of formula (1) may be administered to a patient together with another compound to treat the patient’s cancer. The at least one other therapeutic agent may be a second different compound of formula (1). The compound of formula (1) and at least one other therapeutic agent may act in combination with another compound of formula (1) or synergistically in some embodiments. At least one additional therapeutic agent may be included in the same pharmaceutical composition or medium comprising the compound of formula (1), or may be in a separate pharmaceutical composition or medium. Thus, in addition to administering the compound of formula (1), the method provided in this disclosure also includes administering one or more therapeutic agents effective in treating cancer or diseases, conditions or symptoms other than cancer. The method provided in this disclosure includes administering the compound of formula (1) and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic efficacy of the compound of formula (1) and / or does not produce an adverse combination effect.

[0348] A pharmaceutical composition containing a compound of formula (1) may be administered concurrently with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as the pharmaceutical composition containing formula (1) or in a different pharmaceutical composition. The compound of formula (1) may be administered before or after the administration of the other therapeutic agent. In some combination therapies, the combination therapy may be included in alternating administration of the compound of formula (1) with a composition containing another therapeutic agent. For example To minimize adverse drug effects associated with a particular drug. When a compound of formula (1) is administered concurrently with another therapeutic agent that may produce adverse drug effects (including, for example, toxicity), the other therapeutic agent may be administered at a dose below the threshold that would cause an adverse drug reaction.

[0349] Pharmaceutical compositions comprising compounds of formula (1) provided herein may be administered together with one or more substances, for example, to enhance, modulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of compounds of formula (1). For example, pharmaceutical compositions comprising compounds of formula (1) may be co-administered with an active agent having a pharmacological effect that enhances the therapeutic efficacy of compounds of formula (1).

[0350] The compound of formula (1) or a pharmaceutical composition thereof may be used in combination with an agent known or believed to be effective in treating a patient’s disease such as cancer, an autoimmune disease or an inflammatory disease, for example with the same disease treated with the compound of formula (1).

[0351] Compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with agents known or believed to interfere with cell proliferation.

[0352] Compounds of formula (1) or pharmaceutical compositions thereof may be used in combination with agents known or believed to interfere with cell metabolism, act as an antimetabolites, interfere with RNA transcription, interfere with RNA translation, interfere with cell protein synthesis, interfere with DNA synthesis and the synthesis of precursors for replication, interfere with purine synthesis, interfere with nucleoside synthesis, interact with mTOR, act as mTOR inhibitors, or interfere with cell cycle checkpoints.

[0353] Compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with checkpoint inhibitors, including CTLA-4 inhibitors such as ipilimumab, PD-1 inhibitors such as pembrolizumab and nivolumab, and / or PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab. Compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with immunomodulators such as CD137 / 4-1BB, CD27, GIYR, and / or OC40.

[0354] The compound of formula (1) or its pharmaceutical composition may be used in combination with agents known or believed to be cytotoxic, cause DNA damage, cause cell cycle arrest or cause mitotic catastrophe.

[0355] The compound of formula (1) or its pharmaceutical composition may be used in combination with agents known or believed to regulate glutathione concentration, regulate intracellular glutathione concentration, reduce intracellular glutathione concentration, reduce intracellular glutathione uptake, reduce glutathione synthesis or reduce intracellular glutathione synthesis.

[0356] Compounds of formula (1) or pharmaceutical compositions thereof may be used in combination with agents known or believed to interfere with, reduce or promote angiogenesis.

[0357] Compounds of formula (1) or pharmaceutical compositions thereof may be used in combination with agents known or believed to interfere with hormone homeostasis, hormone synthesis, hormone receptor binding or hormone signal transduction.

[0358] The compound of formula (1) or its pharmaceutical composition may be used in combination with agents known or believed to interfere with growth factor homeostasis, interfere with growth factor receptor expression, interfere with the binding of growth factors to growth factor receptors, interfere with growth factor receptor signal transduction, interfere with Hedgehog (Hh) signal transduction, inhibit Hedgehog pathway signal transduction, inhibit ALK (anaplastic lymphoma kinase) pathway signal transduction, or inhibit non-homologous end junction (NHEJ) pathway.

[0359] Compounds of formula (1) or pharmaceutical compositions thereof may be used in combination with one or more of the following known or believed agents: VEGFR (vascular endothelial growth factor receptor) inhibitors, RTK (receptor tyrosine kinase) inhibitors, sodium channel current blockers, FAK (focal adhesion kinase) inhibitors, GLI (glioma-associated oncogene) inhibitors, GLI1 inhibitors, GLI2 inhibitors, GLI3 inhibitors, MAPK (mitogen-activated protein kinase) inhibitors, MAPK / ERK pathway (also known as Ras-Raf-MEK-ERK pathway) inhibitors, MEK1 inhibitors, MEK2 inhibitors, MEK5 inhibitors, MEK5 / ERK5 inhibitors, RTA (renal tubular acidosis) inhibitors, ALK (anaplastic lymphoma kinase) inhibitors, Aa LK kinase inhibitors, nuclear translocation inhibitors, PORCN (porcupine) inhibitors, 5-ARI (5α-reductase inhibitors), topoisomerase inhibitors, Ras (rat sarcoma) inhibitors, K-ras inhibitors, CERK (ceramide kinase) inhibitors, PKB (protein kinase B, also known as AKT) inhibitors, AKT1 inhibitors, EZH2 (zeste homologue 2 enhancer) inhibitors, BET (bromodomain and outer domain motif) inhibitors, SYK (spleen tyrosine kinase) inhibitors, JAK (Janus kinase) inhibitors, SYK / JAK inhibitors, IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitors, IDO1 inhibitors, RXR (retinoic acid X receptor) activators, selective RXR activators, p-glycoprotein inhibitors, ERK inhibitors, PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors, BRD (bromine-containing domain protein) inhibitors, BRD2 inhibitors, BRD3 inhibitors, BRD4 inhibitors, BRDT (bromine-containing domain testis-specific protein) inhibitors, reverse transcriptase inhibitors, NRT (nucleoside analog reverse transcriptase) inhibitors, PIM (proviral integration of Moronni virus) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, photosensitizers, radiosensitizers, ROS (proto-oncogene, receptor tyrosine kinase) inhibitors, ROS1 (proto-oncogene 1) inhibitors, CK (casein kinase) inhibitors, CK2 inhibitors, bcr-abl (breakpoint cluster region-Abelson proto-oncogene) tyrosine kinase inhibitors such as dasatinib, microtubule stabilizers, microtubule depolymerization / decomposition inhibitors, DNA intercalation agents, androgen receptor antagonists, chemopreservatives, HDAC (histone deacetylase) inhibitors, DPP (dipeptide-dependent hydroxyl group) inhibitors. Peptidase inhibitors, DPP-4 inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, kinase inhibitors such as imatinib, tyrosine kinase inhibitors such as nilotinib, ARP (poly(ADP-ribose) polymerase) inhibitors, CDK (cyclin-dependent kinase) inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, HIF1α (hypoxia-inducible factor 1-α) inhibitors, DNA ligase inhibitors, DNA ligase IV inhibitors, NHEJ (non-homologous end joining) inhibitors, DNA ligase IV, NHEJ inhibitors and RAF inhibitors, TKIs and RAF inhibitors, TKIs and RAF inhibitors such as sorafenib, PDT (photodynamic therapy) sensitizers, ATR (ataxia-telangiectasia and Rad3-related protein kinase) inhibitors, or any combination of the foregoing.

[0360] Compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with one or more chemotherapeutic agents, such as VEGFR inhibitors, such as fruquintinib, motesanib / AMG-706, vatalanib; 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 brigstinib; bromopyruvate; DNA alkylating agents, such as thiotepa; nuclear translocation factors, such as JSH-23; PORCn inhibitors, such as W nt-C59; 5α-reductase inhibitors, such as dutasteride; topoisomerase inhibitors, such as carrubicin; RAS inhibitors, such as Kobe0065; CerK inhibitors, such as NVP-231; AKT inhibitors, such as uprosertib; 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 bexsrotene; PGP inhibitors, such as acotiamide or acotiamide hydrochloride. HCl); Erk inhibitors, such as SCH772984; PI3K inhibitors, such as gedatolisib; JAK inhibitors, such as ruxolitinib; AKT inhibitors, such as afuresertib or afuresertib hydrochloride; ALK1 inhibitors, such as ceritinib; HDAC inhibitors, such as abexitinib; DPP inhibitors, such as oamarigliptin; EGFR inhibitors, such as gefitinib; EZH2 inhibitors, such as GSK126; BTK inhibitors, such as ibrutinib; kinase inhibitors, such as imatinib hydrochloride; IDO inhibitors, such as INCB024360; DNA cross-linking agents, such as mitomycin C.Tyrosine kinase inhibitors, such as nilotinib; PARP inhibitors, such as olaparib; microtubule stabilizing agents, such as paclitaxel; CDK4 / 6 inhibitors, such as palbociclib; RTK inhibitors, such as sunitinib; PDT sensitizers, such as tslsporfin; 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; IDO inhibitors, such as INCB024360; or combinations of any of the foregoing.

[0361] The compound of formula (1) or its pharmaceutical composition may be administered in combination with another chemotherapeutic agent, such as... 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, fluxuridine, fludarabine, gemcitabine, interferon-alpha, ipilimumab, lenalidomide, leucovorin, melphalan, mycofenolate mofetil), paclitaxel, palifermin, panobinostat, pegfilrastim, prednisolone, prednisone, revlimid, rituximab, sirolimus, sodium 2-mercaptoethanesulfonate (MESNA), sodium thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, or any combination of the foregoing.

[0362] Compounds of formula (1) or pharmaceutical compositions thereof may be used in combination with other chemotherapeutic agents, including one or more antimetabolites, such as folic acid analogs; pyrimidine analogs, such as fluorouracil, fluorouridine, and cytarabine; purine analogs, such as mercaptopurine, thioguanine, and pentostatin; natural products, such as vincristine, vinblastine, etoposide, tertiposide, actinomycin D, daunorubicin, doxorubicin, bleomycin, mithamycin, and mitomycin C. C) L-asparaginase and interferon α; platinum coordination complexes, such as cisplatin and carboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists, such as prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, flumethasone, flutamide, and leuprolide; anti-angiogenic agents or inhibitors, such as angiostatin, retinoic acid, paclitaxel, estradiol derivatives, and thiazopyrimidine derivatives; apoptosis preventives; tripterygium wilfordii; colchicine; luliconazole; and radiation therapy.

[0363] Compounds of formula (1) or pharmaceutical compositions thereof may be co-administered with compounds that inhibit DNA repair, such as O6-benzylguanine (O6-BG).

[0364] Compounds of formula (1) or pharmaceutical compositions thereof may be administered in combination with one or more chemotherapeutic agents, such as abarelix, abemaciclib, abiraterone, abiraterone acetate, ABVD, ABVE, AC, acalabrutinib, aclarubicin hydrochloride, AC-T, ADE, adenine, ado-trastuzumab emtansine, adriamycin, afatinib, aldesleukin, alectinib, alemtuzumab, alendronate sodium, alitretinoin, and allopurinol. sodium, alpelisib, altretamine, aifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anastrozole, zoledronic acid, angiostatin, apalutamide, apremilast, aprepitant, arsenic trioxide, ascorbic acid, asparaginase erwinia chrysanthemi, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, azathioprine sodium, bazedoxifene (serm), BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bexarotene, bicalutamide, binimetinib, biricodarBleomycin sulfate, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib, brivudine, BuMel, buserelin, busulfan, buthionine sulfoxime, cabazitaxel, cabozantinib, CAF, calaspargase-MKNL pegol-mknl, capecitabine, caplacizumab-yhdp, CAPOX, carboplatin, carboquone, carfilzomib, carmofur, carmustine, CEM, cemipril-rwlc, ceritinib, cetuximab, CEV, chlorambucil, cisplatin, cladribine, clodronatedisodium, clofarabine, CMF, cobimetinib, copanlisib hydrochloride Hydrochloride, COPDAC, COPP, Crizotinib, CVP, Cyclophosphamide, Cyclosporine, Cytarabine, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin, Dalatumumab, Darbepoetin Alpha, Dasatinib, Datinomycin, Daunorubicin, Decitabine, Defribrotide, Degarelix, Denileukin DiftitoxDenosumab, dexamethasone, dexrazoxane hydrochloride, diaziquone, diethyl stilbestrol, dinutuximab, docetaxel, doxifluridine, doxorubicin, dromostanolone propionate, durvalumab, dutasteride, duvelisib, elotuzumab, eltrombopag, emapalumab-lzsg, enasidenib mesylate, encorafenib, enzalutamide, epirubicin hydrochloride, EPOCH, epoetin α, erdafitinib, eribulin mesylate, erlotinib hydrochloride, estramustine phosphate sodium, ethinyl estradiol, etoposide, everolimus, exemestane, FEC, fentanyl, filgrastim, fingolimod, fluxuridine, fludarabine phosphate Phosphate), fluorouracil, fluoxymesterone, flutamide, fofiri, fofirinox, fofox, formestane, formylmelphalan, fosaprepitant, fstamatinib disodium, fotemustine, FU-LV, fulvestrant, gefitinib, gemcitabineGemtuzumab ozogamicin, gilteritinib fumarate, glasdegib maleate, glucarpidase, glutathione, glyciphosphoramide, glyfosfin, goserelin acetate, granisetron, heptaplatin, hexyl 5-aminolevulinate, histrelin acetate, HPV bivalent vaccine, hydroxyprogesterone caproate, hydroxyurea, hyper-CVAD, ibandronate Sodium, ibrutinib, ICE, Icotinib, idarubicin hydrochloride, idelalisib, idoxuridine, ifosfamide, imatinib mesylate, imiquimod, ingenol mebutate, inotuzumabozogamicin, interferon alpha, iobenguane, ipilimumab, irinotecan hydrochloride, ivosidenib, ixabepilone, ixazomib citrate, JEB, lanreotide. Acetate, lapatinib, larotrectinib sulfate, lasofoxifene, L-asparaginase, lenalidomide, lenvatinib mesylate, letrozole.Leucovorin calcium, leuprolide acetate, levamisole hydrochloride, levoleucovorin calcium, lobaplatin, lomustine, lorlatinib, lutetium 177-dotatate, maropitant, masoprocol, mechlorethamine hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan, and mecaptoethanesulfonate. Sodium, mercaptopurine, mesna, methotrexate, methoxsalen, methylaminolevulinate, methylene blue, methylisoindigotin, methylnaltrexone bromide, midostaurin, mifamurtide, miltefosine, miriplatin, mithamycin, mitobronitol, mitomycin C, mitotane, mitoxantrone hydrochloride, mogamulizumab-kpkc, moxetumomab-tdfk pasudotox-tdfk), MVAC, mycophenolate mofetil, nabiximols, n-acetylcysteine, nafarelin, nandrolone, necitumumab, nedaplatin, nelarabineNeratinib maleate, netupitant, nilotinib, nilutamide, nimustine, nintedanib, niraparib tosylate monohydrate, nivolumab, nocodazole, O6-benzylguanine, obinutuzumab, octreotide, OEPA, ofatumumab, OFF, olaparib, olaratumab, omacetaxine mepesuccinate, ondansetron hydrochloride, OPPA, osimertinib mesylate mesylate, oxaliplatin, paclitaxel, PAD, palbociclib, palifermin, palonosetron hydrochloride, pamidronate disodium, panitumumab, panobinostat, pasireotide, pazopanib hydrochloride, PCV, PEB, pegaspargase, pegfilrastim, peginterferon α-2b, pembrolizumab, pemetrexed Disodium, pentostatin, peplomycin, pertuzumab, pipobroman, pirarubicin, plerixafor, plicamycin, polatuzumab vedotin-piiq, pomalidomide, ponatinib, ponatinib hydrochloride.Porfimer sodium, porfiromycin, pralatrexate, prednimustine, prednisolone, prednisone, procarbazine hydrochloride, propranolol hydrochloride, quinagolide hydrochloride, radium 223 dichloride, radotinib, raloxifene, raloxifene hydrochloride Hydrochloride, raltitrexed, ramucirumab, ranimustine, rasburicase, ravulizumab-cwvz, R-CHOP, R-CVP, recombinant HPV bivalent vaccine, regorafenib, R-EPOCH, retinoic acids, revlimide, ribociclib, R-ICE, rituximab, rolapitant hydrochloride, romidepsin, romiplostim, rucaparib camphor sulfonate Camsylate), ruxolitinib, semustine, siltuximab, sipuleucel-t, sirolimus, sodium thiosulfate, sonidegib, sorafenib free, STANFORD V, streptozocin, sufentanil, sunitinib, TAC, tacrolimus, tagraxofusp-erzs, talaporfin sodium, talazoparib tosylate, talc.Latamogene, aherparepvec, tamibarotene, tamoxifen, citrate, tapentadol, temoporfin, temozolomide, temsirolimus, teniposide, teriflunomide, tertiposide, testolactone, testosterone propionate osteronepropionate, thalidomide, thioguanine, thiotepa, thymalfasin, tisagenlecleucel, toceranib phosphate, tocilizumab, topotecan, hydrochloride, toremifene, TPF, trabectedin, trametinib metinib, trastuzumab, trastuzumab, tretinoin, trifluridine, ipiracil, ydrochloride, trilostane, triptorelin, tropisetron, uramustine, uridine, riacetate, VAC, valrubicin, VAMP, vandetanib, vitamin Vedotin, VeIP, Vemurafenib, Venetoclax, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinorelbinetartrate, VIP, Vismodegib, Vorinostat, XELIRI, XELOX, Ziv-afliberceptZoledronic acid, or any combination thereof.

[0365] The efficacy of a compound of formula (1) or a pharmaceutical composition thereof in treating cancer, inflammatory diseases or autoimmune diseases may be used. in vitro Evaluation will be conducted through animal studies and clinical trials.

[0366] The method for inhibiting p38α MAPK provided in this disclosure includes contacting the p38α MAPK with a compound provided in this disclosure in a pocket near the ED substrate docking site of the p38α MAPK.

[0367] The method for inhibiting p38α MAPK disclosed herein does not result in loss of the p38α-dependent counterregulatory response. The p38α-dependent counterregulatory response involves mitogens and stress-activated protein kinase-1 (MSK1) or MSK2. Within a pocket near the ED substrate docking site targeting p38α, the inhibitors disclosed herein avoid interference with CD-specific substrates, including MSK1 / 2, thereby limiting inflammation through the expression of IL-10 and DUSP2.

[0368] Various aspects of the present invention

[0369] The present invention is further defined by the following aspects.

[0370] Aspect 1. A compound having the structure of formula (1):

[0371] (1)

[0372] Or its pharmaceutically acceptable salt, wherein,

[0373] R 1 Selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0374] R 2 Selected from parts of equation (2a), parts of equation (2b), parts of equation (2c), and C 8-16 Heterocyclic alkyl and substituted C 8-16 Heterocyclic alkyl groups:

[0375] (2a) (2b) (2c)

[0376] in,

[0377] B 1 B2 B 3 and B 4 Each of them is independently selected from –(CH(–R) 4 )) n -,in,

[0378] Each n is independently selected from 0, 1, 2, 3, and 4;

[0379] B 1 and B 2 Neither of them is 0;

[0380] B 3 and B 4 Neither of them is 0; and

[0381] Each R 4 Independently selected from hydrogen, –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl;

[0382] D is selected from methane-diyl and ethane-diyl; and

[0383] X is selected from –O–, –CH(–OH)–, –NR 3 – and –SO2–, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatic compounds.

[0384] Aspect 2. The compound according to aspect 1, wherein each of one or more substituents is independently selected from –OH, =O, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6Heterocyclic alkyl and substituted C 5-6 Mixed aromatic compounds.

[0385] Aspect 3. The compound according to aspect 1, wherein each of one or more substituents is independently selected from –OH, =O, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0386] Aspect 4. The compound according to aspect 1, wherein each of one or more substituents may be independently selected from –OH, =O and C. 1-3 alkyl.

[0387] Aspect 5. The compound according to any one of Aspects 1 to 4, wherein R 1 C 1-4 Alkyl.

[0388] Aspect 6. The compound according to any one of Aspects 1 to 4, wherein R 1 It is ethanediyl.

[0389] Aspect 7. The compound according to any one of Aspects 1 to 4, wherein R 1 It is a dimethylmethane.

[0390] Aspect 8. The compound according to any one of Aspects 1 to 7, wherein R 2 For part of equation (2a):

[0391] (2a).

[0392] Aspect 9. The compound according to aspect 8, wherein B 1 B 2 B 3 and B 4 Each of these is independently selected from –(CH2). n –

[0393] Aspect 10. The compound according to aspect 8, wherein B 1 and B 2 Each of these is independently selected from –(CH2). n –

[0394] Aspect 11. The compound according to aspect 8, wherein B 1 B 2 and B 3 Each of these is independently selected from –(CH2). n –

[0395] Aspect 12. The compound according to aspect 8, wherein B 1 B 2 and B 4 Each of these is independently selected from –(CH2). n –

[0396] Aspect 13. The compound according to any one of Aspects 8 to 12, wherein B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0397] Aspect 14. The compound according to any one of Aspects 8 to 12, wherein B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0398] Aspect 15. The compound according to any one of Aspects 8 to 12, wherein B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0399] Aspect 16. The compound according to any one of Aspects 8 to 12, wherein B 1 B 2 B 3 and B 4 Each of them independently contains –CH(–R) 4)–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0400] Aspect 17. The compound according to any one of Aspects 8 to 16, wherein each n is independently selected from 0, 1, 2 and 3.

[0401] Aspect 18. The compound according to any one of aspects 8 to 16, wherein each n is independently selected from 1, 2 and 3.

[0402] Aspect 19. The compound according to any one of Aspects 8 to 16, wherein B 1 and B 2 Each of the n values ​​is independently chosen from 1 and 2; and B 3 and B 4 Each of them has an n of 2.

[0403] Aspect 20. The compound according to any one of Aspects 8 to 16, wherein B 1 and B 2 Each of them has n=1; and B 3 and B 4 Each of them has an n of 2.

[0404] Aspect 21. The compound according to any one of Aspects 8 to 16, wherein B 1 and B 2 Each of them has n as 2; and B 3 and B 4 Each of them has n=1.

[0405] Aspect 22. The compound according to any one of Aspects 8 to 16, wherein B 1 and B 2 Each of them has n=2; and B 3 and B 4 Each of them has an n of 2.

[0406] Aspect 23. The compound according to any one of Aspects 8 to 16, wherein B 1 and B 2 Each of them has n=1; and B 3 and B 4 Each of them has n=1.

[0407] Aspect 24. The compound according to any one of Aspects 8 to 24, wherein X is –O–.

[0408] Aspect 25. The compound according to any one of Aspects 8 to 24, wherein X is –CH(–OH)–.

[0409] Aspect 26. The compound according to any one of Aspects 8 to 24, wherein X is –SO2–.

[0410] Aspect 27. The compound according to any one of Aspects 8 to 24, wherein X is –NR 3 –

[0411] Aspect 28. The compound according to any one of Aspects 8 to 24, wherein X is –NR 3 – and R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0412] Aspect 29. The compound according to any one of Aspects 8 to 24, wherein X is –NR 3 – and R 3 It is –C(=O)–CH3.

[0413] Aspect 30. The compound according to any one of Aspects 8 to 24, wherein X is –NR 3 – and R 3 It is –CH3.

[0414] Aspect 31. The compound according to any one of Aspects 1 to 7, wherein R 2 For part of equation (2b):

[0415] (2b).

[0416] Aspect 32. The compound according to aspect 31, wherein B 1 B 2 B 3 and B 4 Each of these is independently selected from –(CH2). n –

[0417] Aspect 33. The compound according to aspect 31, wherein B 1 and B 2 Each of these is independently selected from –(CH2). n –

[0418] Aspect 34. The compound according to aspect 31, wherein B 1 B 2 and B 3Each of these is independently selected from –(CH2). n –

[0419] Aspect 35. The compound according to aspect 31, wherein B 1 B 2 and B 4 Each of these is independently selected from –(CH2). n –

[0420] Aspect 36. The compound according to any one of Aspects 31 to 35, wherein B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0421] Aspect 37. The compound according to any one of Aspects 31 to 35, wherein B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0422] Aspect 38. The compound according to any one of aspects 31 to 35, wherein B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0423] Aspect 39. The compound according to any one of aspects 31 to 35, wherein B 1 B 2 B3 and B 4 Each of them independently contains –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0424] Aspect 40. The compound according to any one of aspects 31 to 39, wherein each n is independently selected from 1 and 2.

[0425] Aspect 41. The compound according to any one of aspects 31 to 39, wherein each n is 1.

[0426] Aspect 42. The compound according to any one of aspects 31 to 39, wherein B 1 and B 2 Each of them has n=1; and B 3 and B 4 Each of them has an n of 2.

[0427] Aspect 43. The compound according to any one of aspects 31 to 39, wherein B 1 and B 2 Each of them has n as 2; and B 3 and B 4 Each of them has n=1.

[0428] Aspect 44. The compound according to any one of aspects 31 to 39, wherein B 1 B 2 and B 3 Each of them has n=1, and B 4 In this case, n is 2.

[0429] Aspect 45. The compound according to aspect 21, wherein B 1 B 2 and B 3 Each of them has n=2, and B 4 In this case, n is 1.

[0430] Aspect 46. The compound according to any one of Aspects 31 to 45, wherein X is –O–.

[0431] Aspect 47. The compound according to any one of Aspects 31 to 45, wherein X is –CH(–OH)–.

[0432] Aspect 48. The compound according to any one of aspects 31 to 45, wherein X is –SO2–.

[0433] Aspect 49. The compound according to any one of Aspects 31 to 45, wherein X is –NR 3 –

[0434] Aspect 50. The compound according to any one of Aspects 31 to 45, wherein X is –NR 3 – and R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0435] Aspect 51. The compound according to any one of Aspects 31 to 45, wherein X is –NR 3 – and R 3 It is –C(=O)–CH3.

[0436] Aspect 52. The compound according to any one of Aspects 31 to 45, wherein X is –NR 3 – and R 3 It is –CH3.

[0437] Aspect 53. The compound according to any one of Aspects 1 to 7, wherein R 2 For part of equation (2c):

[0438] (2c).

[0439] Aspect 54. The compound according to aspect 53, wherein B 1 B 2 B 3 and B 4 Each of these is independently selected from –(CH2). n –

[0440] Aspect 55. The compound according to aspect 53, wherein B 1 and B 2 Each of these is independently selected from –(CH2). n –

[0441] Aspect 56. The compound according to aspect 53, wherein B 1 B 2 and B 3 Each of these is independently selected from –(CH2). n –

[0442] Aspect 57. The compound according to aspect 53, wherein B 1 B 2 and B4 Each of these is independently selected from –(CH2). n –

[0443] Aspect 58. The compound according to any one of Aspects 53 to 57, wherein B 1 B 2 B 3 and B 4 One of them contains –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0444] Aspect 59. The compound according to any one of Aspects 53 to 57, wherein B 1 B 2 B 3 and B 4 The two independent components in the formula –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0445] Aspect 60. The compound according to any one of Aspects 53 to 57, wherein B 1 B 2 B 3 and B 4 The three independent components in the formula –CH (–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0446] Aspect 61. The compound according to any one of Aspects 53 to 57, wherein B 1 B 2 B 3 and B 4 Each of them independently contains –CH(–R) 4 )–, where R 4 Selected from –OH, –NH2, –NO2, C 1-3 Alkyl, C 1-3Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0447] Aspect 62. The compound according to any one of aspects 53 to 61, wherein each n is independently selected from 1 and 2.

[0448] Aspect 63. The compound according to any one of aspects 53 to 61, wherein each n is 1.

[0449] Aspect 64. The compound according to any one of Aspects 53 to 61, wherein B 1 and B 2 Each of them has n=1; and B 3 and B 4 Each of them has an n of 2.

[0450] Aspect 65. The compound according to any one of aspects 53 to 61, wherein B 1 and B 2 Each of them has n as 2; and B 3 and B 4 Each of them has n=1.

[0451] Aspect 66. The compound according to any one of aspects 53 to 61, wherein each n is 2.

[0452] Aspect 67. The compound according to any one of aspects 53 to 61, wherein each n is 1.

[0453] Aspect 68. The compound according to any one of Aspects 53 to 67, wherein D is methanediyl.

[0454] Aspect 69. The compound according to any one of Aspects 53 to 67, wherein D is ethanediyl.

[0455] Aspect 70. The compound according to any one of Aspects 53 to 67, wherein X is –O–.

[0456] Aspect 71. The compound according to any one of Aspects 53 to 67, wherein X is –CH(–OH)–.

[0457] Aspect 72. The compound according to any one of Aspects 53 to 67, wherein X is –SO2–.

[0458] Aspect 73. The compound according to any one of Aspects 53 to 67, wherein X is –NR 3 –

[0459] Aspect 74. The compound according to any one of Aspects 53 to 67, wherein X is –NR3 – and R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0460] Aspect 75. The compound according to any one of Aspects 53 to 67, wherein X is –NR 3 – and R 3 It is –C(=O)–CH3.

[0461] Aspect 76. The compound according to any one of Aspects 53 to 67, wherein X is –NR 3 – and R 3 It is –CH3.

[0462] Aspect 77. The compound according to aspect 53, wherein the compound is selected from:

[0463] N -(4-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-4-chlorobenzamide (3);

[0464] N -(4-((7-oxa-2-azaspiro[3.5]non-2-yl)methyl)phenyl)-4-chlorobenzamide (4);

[0465] N -(4-((8-oxa-2-azaspiro[4.5]dec-2-yl)methyl)phenyl)-4-chlorobenzamide (5);

[0466] N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6);

[0467] N -(4-(((1 R 5 S )-3-oxa-7-azabicyclo[3.3.1]non-7-yl)methyl)phenyl)-4-chlorobenzamide (9); and

[0468] 4-Chloro- N -(4-(((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)methyl)phenyl)benzamide (10);

[0469] Or a pharmaceutically acceptable salt of any of the foregoing.

[0470] Aspect 78. A compound having the structure of formula (1):

[0471] (1)

[0472] Or its pharmaceutically acceptable salt, wherein,

[0473] R 1 Selected from C 1-4 Alkyl, C 1-4 Zyrabendiyl, substituted C 1-4 Alkyl and substituted C 1-4 Zyrandiol; and

[0474] R 2 This is part of equation (2d):

[0475] (2d)

[0476] in,

[0477] Each A 1 and A 2 Independently selected from –CH2–, –CH(–R) 5 ) – and –C(=O) –, where each R 5 Independently selected from –OH, –NH2, –NO2, C 1-6 Alkyl, C 1-6 cycloalkyl, C6 aryl, C 1-6 Heteroalkyl, C 1-6 Heterocyclic alkyl, C 5-6 heteroaryl, substituted C 1-6 Alkyl, substituted C 1-6 Cycloalkyl, substituted C6 aryl, substituted C 1-6 Heteroalkyl, substituted C 1-6 Heterocyclic alkyl and substituted C 5-6 Mixed aromatics;

[0478] A 1 and A 2 One or more independently selected from –CH(–R) 5 – and –C(=O) –;

[0479] Each n is independently selected from 1, 2, 3, and 4; and

[0480] X is selected from –O–, –CH(–OH)–, –NR 3 – and –SO2–, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 5-8cycloalkyl, C6 aryl, C 6-12 cycloalkylalkyl, C 7-10 Arylalkyl, C 1-6 Heteroalkyl, C 5-8 Heterocyclic alkyl, C 5-6 heteroaryl, C 6-12 Heterocyclic alkyl, C 7-10 Heteroarylalkyl, substituted C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C6 aryl, substituted C 6-12 Cycloalkylalkyl, substituted C 7-10 arylalkyl, substituted C 1-6 Heteroalkyl, substituted C 5-8 Heterocyclic alkyl, substituted C 5-6 heteroaryl, substituted C 6-12 Heterocyclic alkyl alkyl and substituted C 7-10 Heteroarylalkyl.

[0481] Aspect 79. The compound according to aspect 78, wherein R 1 It is C 1-4 Alkyl.

[0482] Aspect 80. The compound according to aspect 78, wherein R 1 It is ethanediyl.

[0483] Aspect 81. The compound according to aspect 78, wherein R 1 It is a dimethylmethane.

[0484] Aspect 82. The compound according to any one of aspects 78 to 81, wherein each n is independently selected from 1, 2 and 3.

[0485] Aspect 83. The compound according to any one of aspects 78 to 81, wherein each n is 2.

[0486] Aspect 84. The compound according to any one of aspects 78 to 81, wherein each n is 3.

[0487] Aspect 85. The compound according to any one of aspects 78 to 81, wherein each n is 4.

[0488] Aspect 86. The compound according to any one of Aspects 78 to 81, wherein A 1 and A 2 One or more of them are independently selected from –CH(–R) 5 )–, where R 5 It is C 1-3 Alkyl; and –C(=O)–.

[0489] Aspect 87. The compound according to any one of Aspects 78 to 81, wherein A 1 and A 2 One or more of them are independently selected from –CH(–R) 5 )–, where R 5 It is C 1-3 alkyl.

[0490] Aspect 88. The compound according to any one of aspects 78 to 81, wherein A 1 and A 2 One or more of them are –C(=O)–.

[0491] Aspect 89. The compound according to any one of Aspects 78 to 88, wherein X is –O–.

[0492] Aspect 90. The compound according to any one of Aspects 78 to 88, wherein X is –CH(–OH)–.

[0493] Aspect 91. The compound according to any one of Aspects 78 to 88, wherein X is –SO2–.

[0494] Aspect 92. The compound according to any one of Aspects 78 to 88, wherein X is –NR 3 –

[0495] Aspect 93. The compound according to any one of Aspects 78 to 88, wherein X is –NR 3 – and R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, substituted C 1-3 Alkyl and substituted C 1-3 Heteroalkyl groups.

[0496] Aspect 94. The compound according to any one of Aspects 78 to 88, wherein X is –NR 3 – and R 3 It is –C(=O)–CH3.

[0497] Aspect 95. The compound according to any one of Aspects 78 to 88, wherein X is –NR 3 – and R 3 It is –CH3.

[0498] Aspect 96. The compound according to aspect 78, wherein the compound is selected from:

[0499] 2-Chloro- N -(4-(morpholinomethyl)phenyl)pyrimidine-5-carboxamide (1);

[0500] N -(4-((1,4-oxazacycloheptan-4-yl)methyl)phenyl)-4-chlorobenzamide (2);

[0501] 4-Chloro- N -(4-(((2 S 6 R )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (7);

[0502] 4-Chloro- N -(4-(((2 S 6 S )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (8);

[0503] 4-Chloro- N -(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (11);

[0504] 4-Chloro- N -(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (12);

[0505] 4-Chloro- N -(4-((3-hydroxypyrrolidone-1-yl)methyl)phenyl)benzamide (13);

[0506] N -(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-4-chlorobenzamide (14);

[0507] 4-Chloro- N -(4-((3-oxopiperazin-1-yl)methyl)phenyl)benzamide (15);

[0508] 4-Chloro- N -(4-((4-methyl-3-oxopirarin-1-yl)methyl)phenyl)benzamide (16); and

[0509] 4-Chloro- N -(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (17);

[0510] Or a pharmaceutically acceptable salt of any of the foregoing.

[0511] Aspect 97. The compound according to any one of Aspects 1 to 96, wherein the compound inhibits the p38α MAPK receptor.

[0512] Aspect 98. The compound according to any one of Aspects 1 to 96, wherein the compound selectively inhibits the p38αMAPK receptor.

[0513] Aspect 99. The compound according to any one of Aspects 1 to 96, wherein the compound has a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0514] Aspect 100. The compound according to any one of Aspects 1 to 96, wherein the compound binds to a selective binding site of p38α MAPK, wherein the binding pocket may be defined by a pocket defined at least by residues R49, H107, L108 and K165 of p38α MAPK.

[0515] Aspect 101. The compound according to any one of Aspects 1 to 96, wherein the compound is reacted with 4-chloro- N -(4-((1,1-dioxothiomorpholino)methyl)phenyl)benzamide competitively binds to selective binding sites.

[0516] Aspect 102. The compound of any one of Aspects 1 to 96, wherein the compound is derived by means of 4-chloro- N -(4-((1,1-dioxothiomorpholino)methyl)phenyl)benzamide inhibits MK2 phosphorylation in anisin-stimulated HeLa cells.

[0517] Aspect 103. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 96 or a pharmaceutically acceptable salt thereof.

[0518] Aspect 104. The pharmaceutical composition according to aspect 99, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 96, for treating a patient's disease.

[0519] Aspect 105. The pharmaceutical composition according to aspect 104, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0520] Aspect 106. The pharmaceutical composition according to aspect 104, wherein the disease is cancer.

[0521] Aspect 107. The pharmaceutical composition according to aspect 104, wherein the disease is an inflammatory disease.

[0522] Aspect 108. The pharmaceutical composition according to aspect 104, wherein the disease is an autoimmune disease.

[0523] Aspect 109. The pharmaceutical composition according to aspect 104, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0524] Aspect 110. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0525] Aspect 111. A method for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is cancer.

[0526] Aspect 112. The method according to aspect 111, wherein the cancer is selected from breast cancer and melanoma.

[0527] Aspect 113. A method for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is an inflammatory disease.

[0528] Aspect 114. The method according to aspect 113, 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.

[0529] Aspect 115. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is an autoimmune disease.

[0530] Aspect 116. A method for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is an age-related disease.

[0531] Aspect 117. The method according to aspect 116, wherein the age-related disease is selected from hearing loss, muscle degeneration, Weiner syndrome, cellular senescence, and Alzheimer's disease.

[0532] Aspect 118. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 96, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0533] Aspect 119. A method for inhibiting p38α MAPK receptor, the method comprising contacting the p38α MAPK receptor with a compound according to any one of aspects 1 to 96 or a pharmaceutically acceptable salt thereof.

[0534] Aspect 120. A method for inhibiting p38α MAPK receptors in a patient, the method comprising administering to the patient a pharmacologically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 96.

[0535] Aspect 121. The method according to aspect 120, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

[0536] Aspect 122. The method according to aspect 121, wherein inhibition of the p38α MAPK receptor does not result in loss of the p38α-dependent counterregulatory response.

[0537] Aspect 123. The method according to aspect 122, wherein the p38α-dependent counterregulatory response involves a mitogen and an activated protein kinase-1 (MSK1) or MSK2.

[0538] Aspect 124. The method according to any one of Aspects 119 to 123, wherein inhibiting the p38α MAPK receptor stabilizes endothelial or epithelial barrier function.

[0539] Aspect 125. The method according to any one of aspects 119 to 124, wherein inhibiting the p38α MAPK receptor reduces inflammation.

[0540] Aspect 126. The method according to any one of aspects 119 to 125, wherein inhibiting the p38α MAPK receptor alleviates KPS-induced lung injury.

[0541] Aspect 127. The method according to any one of aspects 119 to 126, wherein the p38α MAPK receptor is inhibited to regulate leukocyte transport.

[0542] Aspect 128. The method according to any one of aspects 119 to 127, wherein the p38α MAPK receptor is inhibited to regulate cytokine expression.

[0543] Aspect 1A. The compound according to aspect 8, wherein B 1 It is –(CH2)2–; B 2 It is –CH2–; B 3 It is –(CH2) n – where n is selected from 0, 1, 2, and 3; B 3 It is –(CH2) 3n –; and X is O.

[0544] Aspect 2A. The compound according to aspect 8, wherein the portion of formula (2a) is selected from the portions of formulas (2a.1) to (2a.4):

[0545] (2d.1) (2d.2)

[0546] (2d.3) (2d.4)

[0547] Where R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 alkyl.

[0548] Aspect 3A. The compound according to aspect 78, wherein A 1 It is –(CH2) n – where n is an integer from 1 to 4; A 2 It is –(CH2) 5-n –; and X is O.

[0549] Aspect 4A. The compound according to aspect 78, wherein the portion of formula (2d) may have the structure of formula (2d.1) or formula (2d.2):

[0550] (2d.1) (2d.2)

[0551] Where R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 alkyl.

[0552] Aspect 5A. The compound according to aspect 78, wherein A 1 It is –(CH2) n – where n is 1 or 2; A 2 It is –(CH2) 3-n –; and X is –N(–C(=O)–R 6 )–, where R 6 Selected from.

[0553] Aspect 6A. The compound according to aspect 78, wherein the portion of formula (2d) is selected from portions of formulas (2d.3) and (2d.4):

[0554] (2d.3) (2d.4)

[0555] in,

[0556] R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0557] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0558] Aspect 7A. The compound according to aspect 78, wherein A 1 It is –(CH2) n – where n is 1 or 2; A 2 It is –(CH2) 3-n –; and X is O, and contains one or two –CH3 substituents.

[0559] Aspect 8A. The compound according to aspect 78, wherein the portion of formula (2d) may have the structure of formula (2d.5):

[0560] (2d.5).

[0561] Aspect 9A. A compound having the structure of formula (1):

[0562] (1)

[0563] Or its pharmaceutically acceptable salt, wherein,

[0564] R 1 Selected from C 1-4 Alkyl; and

[0565] R 2 The substituted or unsubstituted portion selected from any of formulas (2a.1) to (2a.4) and (2d.1) to (2d.5):

[0566] (2a.1) (2a.2)

[0567] (2a.3) (2a.4)

[0568] (2d.1) (2d.2)

[0569] (2d.3) (2d.4)

[0570] (2d.5)

[0571] in,

[0572] R 5 The R is selected from hydrogen (unsubstituted), –OH, –NH2, –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0573] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0574] Aspect 10A. The compound according to aspect 9A, wherein R 1 Selected from methane-diyl, ethane-diyl, and n-propane-diyl.

[0575] Aspect 11A. The compound according to aspect 9A, wherein R 1 It is methane-diyl.

[0576] Aspect 12A. The compound according to any one of aspects 9A to 11A, wherein R 2 The unsubstituted portion is selected from any one of equations (2a.1) to (2a.4) and equations (2d.1) to (2d.5).

[0577] Aspect 13A. The compound according to any one of aspects 9A to 11A, wherein R 2 The substitution portion is selected from any one of equations (2a.1) to (2a.4) and equations (2d.1) to (2d.5).

[0578] Aspect 14A. The compound according to any one of Aspects 9A to 11A, wherein the substituted portion may have the structure of any one of formulas (2a.1) to (2a.4) and (2d.1) to (2d.5):

[0579] (2a.1) (2a.2)

[0580] (2a.3) (2a.4)

[0581] (2d.1) (2d.2)

[0582] (2d.3) (2d.4)

[0583] (2d.5)

[0584] in,

[0585] R 5 The derivatives are selected from –OH, –NH2, and –NR2, where each R is independently selected from hydrogen and C. 1-3 Alkyl, –NO2, =O, C 1-3 Alkyl group and C(=O)–R, where R is C 1-3 Alkyl groups; and

[0586] R 6 Selected from C 1-6 Alkyl and C 1-6 Alkyl group.

[0587] Aspect 15A. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1A to 14A.

[0588] Aspect 16A. The pharmaceutical composition according to aspect 15A, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1A to 14A, for treating a patient’s disease.

[0589] Aspect 17A. The pharmaceutical composition according to aspect 16A, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0590] Aspect 18A. The pharmaceutical composition according to aspect 16A, wherein the disease is cancer.

[0591] Aspect 19A. The pharmaceutical composition according to aspect 16A, wherein the disease is an inflammatory disease.

[0592] Aspect 20A. The pharmaceutical composition according to aspect 16A, wherein the disease is an autoimmune disease.

[0593] Aspect 21A. The pharmaceutical composition according to aspect 16A, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

[0594] Aspect 22A. The pharmaceutical composition according to aspect 16A, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0595] Aspect 23A. The pharmaceutical composition according to aspect 16A, wherein the disease is a viral disease.

[0596] Aspect 24A. The pharmaceutical composition according to aspect 16A, wherein the viral disease is selected from coronavirus infections such as MERS-CoV infection, SARS-CoV infection or SARS-CoV-2 infection, coronavirus infection-associated pneumonia and human respiratory syndrome infection.

[0597] Aspect 25A. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0598] Aspect 26A. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is cancer.

[0599] Aspect 27A. The method according to aspect 26A, wherein the cancer is selected from breast cancer and melanoma.

[0600] Aspect 28A. A method for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is an inflammatory disease.

[0601] Aspect 29A. The method according to aspect 28A, 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.

[0602] Aspect 30A. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is an autoimmune disease.

[0603] Aspect 31A. A method for treating a patient’s disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is an age-related disease.

[0604] Aspect 32A. The method according to aspect 31A, wherein the age-related disease is selected from hearing loss, muscle degeneration, Weiner syndrome, cellular senescence and Alzheimer's disease.

[0605] Aspect 33A. A method for treating a patient’s disease, comprising administering to a patient in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1A to 14A, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

[0606] Aspect 34A. A method for inhibiting a p38α MAPK receptor, the method comprising contacting the p38α MAPK receptor with a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1A to 14A.

[0607] Aspect 35A. A method for inhibiting p38α MAPK receptors in a patient, the method comprising administering to the patient a pharmacologically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects A1A to 14A.

[0608] Aspect 36A. The method according to aspect 35A, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

[0609] Aspect 37A. The method according to aspect 36A, wherein inhibition of the p38α MAPK receptor does not result in loss of the p38α-dependent counterregulatory response.

[0610] Aspect 38A. The method according to aspect 37A, wherein the p38α-dependent counterregulatory response involves a mitogen and an activated protein kinase-1 (MSK1) or MSK2.

[0611] Aspect 39A. The method according to any one of aspects 34A to 38A, wherein inhibiting the p38α MAPK receptor stabilizes endothelial or epithelial barrier function.

[0612] Aspect 40A. The method according to any one of aspects 34A to 39A, wherein inhibiting the p38α MAPK receptor reduces inflammation.

[0613] Aspect 41A. The method according to any one of aspects 34A to 40A, wherein inhibition of the p38α MAPK receptor alleviates KPS-induced lung injury.

[0614] Aspect 42A. The method according to any one of aspects 34A to 41A, wherein the p38α MAPK receptor is inhibited to regulate leukocyte transport.

[0615] Aspect 43A. The method according to any one of aspects 34A to 42A, wherein inhibiting the p38α MAPK receptor reduces inflammation.

[0616] Aspect 44A. The pharmaceutical composition according to any one of aspects 103 to 104, wherein the disease is a viral disease.

[0617] Aspect 45A. The pharmaceutical composition according to aspect 44A, wherein the viral disease is selected from coronavirus infections such as MERS-CoV infection, SARS-CoV infection or SARS-CoV-2 infection.

[0618] Aspect 46A. The method described in aspect 111, wherein the disease is a viral disease.

[0619] Aspect 47A. The method according to aspect 46A, wherein the viral disease is selected from coronavirus infections such as MERS-CoV infection, SARS-CoV infection or SARS-CoV-2 infection.

[0620] Example

[0621] The following examples describe in detail the synthesis, characterization, and use of compounds of formula (1). It will be apparent to those skilled in the art that many modifications can be made to the materials and methods without departing from the scope of this disclosure.

[0622] Example A

[0623] Synthesis of 4-chloro- N -(4-(hydroxymethyl)phenyl)benzamide (A)

[0624]

[0625] 4-Chlorobenzoyl chloride (15.63 g, 89.32 mmol) was slowly added to a stirred solution of (4-aminophenyl)methanol (10 g, 81.2 mmol) and sodium acetate (10 g, 121.8 mmol) in THF (100 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with water (100 mL × 2) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM:MeOH = 50:1, v / v) to give 4-chloro- N 4-(hydroxymethyl)phenyl)benzamide (A) (19.53 g, 91.9% yield), is a white solid. LCMS (Agilent Technologies): R t = 1.47 minutes; m / z calculated value [M+H] + 262.1, measured value 262.1. 1 H-NMR(400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.99-7.96 (m, 2H), 7.70 (d, J = 8.4 Hz,2H), 7.62-7.58 (m, 2H), 7.29 (dd, J = 6.4, 2.0 Hz, 2H), 5.12 (t, J = 5.2 Hz, 1H), 4.46 (d, J = 5.2 Hz, 2H).

[0626] Example B

[0627] Synthesis of 4-chloro- N -(4-(chloromethyl)phenyl)benzamide (B)

[0628]

[0629] At room temperature, methanesulfonyl chloride (1.75 g, 15.28 mmol) was added dropwise to 4-chloro- N-(4-(hydroxymethyl)phenyl)benzamide (A) (2.00 g, 7.64 mmol) and triethylamine (1.53 g, 15.28 mmol) were added to a stirred solution in DCM (25 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL × 3). The combined organic extracts were washed with H2O (30 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (B) (627 mg, 29.3% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.4 (Silicone, PE / EtOAc = 3 / 1, v / v). LCMS (Agilent Technologies): Rt = 2.30 min; m / z calculated [M+H] + 280.0, measured value 280.0 / 282.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.98 (dd, J = 6.4, 2.0Hz, 2H), 7.77 (dd, J = 6.4, 2.0 Hz, 2H), 7.61 (dd, J = 6.8, 2.0 Hz, 2H), 7.42(dd, J = 6.8, 2.0 Hz, 2H), 4.75 (s, 2H).

[0630] Example 1

[0631] synthesis N -(4-((1,4-oxazacycloheptan-4-yl)methyl)phenyl)-4-chlorobenzamide (1)

[0632]

[0633]

[0634] Anhydrous potassium carbonate (99 mg, 0.71 mmol) was added in a single addition to compound (B) (100 mg, 0.36 mmol) and 1,4-oxazacycloheptane (44 mg, 0.45 mmol) in a stirred solution of DMF (2 mL) at 50 °C. After the addition was complete, the reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with H₂O (10 mL) and filtered. The resulting solid filter cake was washed with a small volume of DCM and dried under reduced pressure to give a crude product. The crude product was then acidified with 0.5 M HCl (aq) and concentrated to dryness to give the title compound (1) (100 mg, 81.1% yield) as a white solid. The product was analyzed by LC-MS and... 1 The structure was confirmed by H-NMR. TLC:R f =0.6 (Silica gel; DCM / MeOH=20 / 1, v / v). LCMS (Agilent): Rt =0.86 min; m / z calculated value [M+H]+ 345.1, measured value 345.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.95 (s,1H), 10.51 (s, 1H), 8.1 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.63-7.60 (m, 4H), 4.33 (d, J = 5.2 Hz, 2H), 3.81-3.86 (m, 2H), 3.64-3.75 (m, 2H), 3.41 - 3.46 (m, 1H), 3.29 - 3.45 (m, 1H), 3.08-3.21 (m, 2H), 2.29-3.32 (m,1H), 1.96-2.03 (m,1H).

[0635] Example 2

[0636] synthesis N -(4-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-4-chlorobenzamide (2)

[0637]

[0638]

[0639] Anhydrous potassium carbonate (197.39 mg, 1.428 mmol) was added in a single addition to a stirred mixture of compound (B) (200 mg, 0.714 mmol) and 2-oxa-6-azaspiro[3.3]heptane (84.95 mg, 0.857 mmol) in DMF (4 mL) at room temperature, and the mixture was heated to 50 °C. After stirring at 50 °C for 2 h, the reaction mixture was diluted with H2O (10 mL) and filtered. The collected solid was purified by preparative C18 reversed-phase HPLC (eluting with 10% to 95% MeCN / H2O) to give title compound (2) (109 mg, 44.5% yield) as a white solid. The final product was purified by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.2 (Silicone; MeOH:DCM = 1:10). LCMS (Agilent Technologies): Rt = 0.81 min; m / z calculated [M+H] + 343.1, measured value 343.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.01-7.97 (m, 2H), 7.77(d, J = 8.4 Hz, 2H), 7.63-7.59 (m, 2H), 7.35 (d, J = 8 Hz, 2H), 4.63 (s, 4H), 3.85 (d, J = 42.4 Hz (4H), 3.33 (s, 2H).

[0640] Example 3

[0641] Synthesis of 2-chloro- N -(4-(morpholinomethyl)phenyl)pyrimidine-5-carboxamide (3)

[0642]

[0643]

[0644] At room temperature, EEDQ (257 mg, 1.0 mmol) was added in a single addition to a stirred solution of 4-(morpholinomethyl)aniline (200 mg, 1.0 mmol) and 2-chloropyrimidine-5-carboxylic acid (164 mg, 1.0 mmol) in DMF (4 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 40 hours and diluted with H2O (10 mL). The resulting slurry was extracted with EtOAc (30 mL × 3) and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative C18 reversed-phase HPLC to give the title compound (3) (130 mg, 37.6% yield) as a white solid. The final product was determined by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f =0.3 (silica gel, MeOH / DCM = 1 / 15, v / v). LCMS (Agilent Technologies): Rt = 0.49 min; m / z calculated [M+Na] + 333.1, measured value 333.0. 1 H-NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.92 (s, 1H), 9.27 (s, 2H), 7.88 - 7.81 (m, 2H), 7.61 (d, J = 8.3 Hz, 2H), 4.30 (d, J = 5.1Hz, 2H), 3.94 (dd, J = 13.0, 3.3 Hz, 2H), 3.78 (t, J = 12.0 Hz, 2H), 3.22 (d, J = 12.4 Hz, 2H), 3.07 (d, J = 11.5 Hz, 2H).

[0645] Example 4

[0646] synthesis N -(4-((7-oxa-2-azaspiro[3.5]non-2-yl)methyl)phenyl)-4-chlorobenzamide (4)

[0647]

[0648]

[0649] Anhydrous potassium carbonate (621 mg, 4.49 mmol) was added to a stirred solution of compound (A) (430 mg, 1.5 mmol) and 7-oxa-2-azaspiro[3.5]nonane (191 mg, 1.5 mmol) in DMF (5 mL) at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was diluted with H2O (10 mL) and filtered. The resulting solid was dissolved in 2N HCl (2 mL) and DMSO (2 mL) and then purified by reversed-phase Biotage® column chromatography (C18 column, eluted with 10% to 95% MeCN / H2O containing 0.1% hydrochloric acid) to give the title compound (4) (80 mg, 14.4% yield) as a white solid. The final product was obtained by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.40 (Silicone, PE:EtOAc = 1:1, v / v). LCMS (Agilent Technologies): Rt = 2.00 min; m / z calculated [M+H] + 371.2, measured value 371.2. 1 H-NMR (400 MHz, DMSO-d6) δ 10.43(s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.6Hz, 2H), 7.50 (s, 2H), 4.19 (s, 2H), 3.69 (s, 4H), 3.48 (s, 4H), 1.77 (s, 4H).

[0650] Example 5

[0651] synthesis N -(4-((8-oxa-2-azaspiro[4.5]dec-2-yl)methyl)phenyl)-4-chlorobenzamide (5)

[0652]

[0653]

[0654] Anhydrous potassium carbonate (230 mg, 1.66 mmol) was added in a single addition to compound (B) (280 mg, 0.83 mmol) and 8-oxa-2-azaspiro[4.5]decane (142 mg, 1.0 mmol) in a stirred solution of DMF (6 mL) at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was diluted with H2O (10 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure. The residue was then purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v). The key fraction was concentrated under reduced pressure, and the resulting solid was treated with 0.5 N HCl (aq) and evaporated to dryness under reduced pressure to give title compound (5) (144.2 mg, 45.1% yield) as a white solid. The results were analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f =0.4% silica gel; DCM:MeOH = 20:1. LCMS (Agilent Technologies): Rt = 1.96 minutes; m / z calculated value [M+H] + 385.1, measured value 385.1. 1 H-NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.51 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.63-7.60 (m, 4H), 4.35-4.25 (m, 2H), 3.58-3.47 (m, 4H), 4.45-3.37 (m, 1H), 3.25-3.14 (m, 2H), 2.95-2.89 (m, 1H), 2.01-1.95 (m, 1H), 1.91-1.84 (m, 1H), 1.67-1.80 (m, 3H), 1.55-1.50 (m, 1H).

[0655] Example 6

[0656] synthesis N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6)

[0657]

[0658]

[0659] Anhydrous potassium carbonate (444 mg, 3.21 mmol) was added in a single addition to a solution of compound (B) (300 mg, 1.07 mmol) and 1-oxa-7-azaspiro[4.4]nonane (210 mg, 1.28 mmol) in DMF (5.6 mL) at 50 °C. After stirring at 50 °C for 1 hour, the reaction mixture was diluted with H2O (20 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v), and the desired fraction was evaporated under reduced pressure. The resulting residue was acidified with 0.5 M HCl (aq) and concentrated under reduced pressure to give the title compound (6) (100 mg, 25.2% yield) as a white solid. The final product was obtained by LCMS and... 1 Structure confirmed by H-NMR. LCMS (Agilent Technologies): Rt = 1.93 minutes; calculated m / z values ​​[M+H] + = 371.1, measured value [M+H] + = 371.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.55 (d, J = 13.6 Hz, 1H), 8.01-8.04 (m, 2H), 7.87-7.83 (m, 2H), 7.62-7.57 (m, 4H), 4.34-4.26 (m, 2H), 3.80-3.68 (m, 2H), 3.47-3.08 (m, 4H), 2.02-1.86 (m, 6H).

[0660] Examples 7 and 8

[0661] Synthesis of 4-chloro- N -(4-(((2 S 6 R )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (7)

[0662]

[0663] Synthesis of 4-chloro- N -(4-(((2 S 6 S )-2,6-Dimethylmorpholino)methyl)phenyl)benzamide (8)

[0664]

[0665]

[0666] Anhydrous potassium carbonate (296 mg, 2.14 mmol) was added in a single addition to a stirred solution of compound (B) (300 mg, 1.07 mmol) and 2,6-dimethylmorpholine (147 mg, 1.28 mmol) in DMF (5 mL) at 50 °C. After stirring at 50 °C for 1 hour, the reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (30 mL × 4). The combined extracts were concentrated to dryness. The residues were purified by C18 reversed-phase preparative HPLC (eluting with 10% to 95% MeCN / H₂O). The key fraction was concentrated under reduced pressure, and the resulting solid was treated with 0.5 N HCl (aq) and evaporated to dryness under reduced pressure to provide Shun Mode Isomer (7) (105 mg, 27.3%) and trans Isomer (8) (40 mg, 10.4%). Analyzed by LCMS and... 1 The structure was confirmed by H-NMR.

[0667] Cis Isomer (7). TLC:R f = 0.4% silica gel; pure EtOAc. LCMS (Agilent Technologies): Rt = 1.92 minutes; m / z calculated [M+H] + = 359.1, measured value [M+H] + = 359.1. 1 H-NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 8.02-7.99 (m, 2H), 7.87-7.85 (m, 2H), 7.63-7.58 (m, 4H), 4.26-4.25 (m, 2H), 4.02-3.98 (m, 2H), 3.23-3.20 (m, 2H), 2.66-2.58 (m, 2H), 1.11(d, J = 6.0 Hz, 6H).

[0668] trans Isomer (8). TLC:R f = 0.5% silicone; pure EtOAc. LCMS (Agilent Technologies): Rt = 1.92 minutes; m / z calculated value [M+H] + = 359.1, measured value [M+H] + = 359.1. 1H-NMR (400 MHz, DMSO-d6) δ10.95 (s, 1H), 10.52 (s, 1H), 8.01-7.99 (m, 2H), 7.87-7.85 (m, 2H), 7.64-7.61(m, 4H), 4.34-4.12 (m, 4H), 3.28-3.25 (m, 1H), 3.08-2.93 (m, 2H), 2.67-2.59(m, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H).

[0669] Example 9

[0670] synthesis N -(4-(((1 R 5 S )-3-oxa-7-azabicyclo[3.3.1]non-7-yl)methyl)phenyl)-4-chlorobenzene Formamide (9)

[0671]

[0672]

[0673] Anhydrous potassium carbonate (625 mg, 4.52 mmol) was added in a single addition to compound (B) (512 mg, 1.81 mmol) and 3-oxa-7-azabicyclo[3.3.1]nonane (230 mg, 1.81 mmol) in a stirred solution of DMF (6 mL) at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was treated with H2O (30 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure. The residue was acidified with 0.5 N HCl (aq) and concentrated to dryness to give title compound (9) (437 mg, 78.2% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f =0.4% silicone; PE:EtOAc = 1:1. LCMS (Shimadzu Corporation): Rt = 2.32 minutes; m / z calculated value [M+H] + = 371.2, measured value [M+H] + = 371.2. 1 H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.65 (s, 1H), 8.04-8.00 (m, 2H), 7.92-7.88 (m, 2H), 7.64-7.57 (m, 4H), 4.22 (d, J= 5.3 Hz, 2H), 3.97 (d, J = 11.3 Hz, 2H), 3.69-3.64 (m, 2H), 3.48-3.42 (m, 2H), 3.27(t, J = 11.2 Hz, 2H), 2.01 (s, 2H), 1.94-1.78 (m, 2H).

[0674] Example 10

[0675] Synthesis of 4-chloro- N -(4-(((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)methyl)benzene (10) Benzoamide

[0676]

[0677]

[0678] At room temperature, anhydrous potassium carbonate (531 mg, 3.84 mmol) was added in a single addition to compounds (B) (435 mg, 1.28 mmol) and (3a). R ,6a S 1,3-hexahydro-1H-furano[3,4-c]pyrrole (230 mg, 1.54 mmol) was added to a stirred solution in DMF (6.5 mL). The reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was treated with H2O (60 mL), filtered, and the resulting solid was washed with petroleum ether / ethyl acetate = 3 / 1 and purified by C18 reversed-phase preparative HPLC (eluting with 10% to 95% MeCN / H2O). The key fraction was concentrated under reduced pressure, and the resulting solid was treated with 0.5 N HCl (aq) and evaporated to dryness under reduced pressure to give the title compound (10) (194.5 mg, 42.6% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.30 (Silica gel, DCM / MeOH = 20 / 1, v / v). LCMS (Shimadzu Corporation): Rt = 2.25 min; m / z calculated [M+H] + = 357.2, measured value [M+H] + = 357.2. 1 H-NMR (400MHz, DMSO-d6) δ 10.95 (d, J = 78.2 Hz, 1H), 10.51 (d, J = 6.3 Hz, 1H), 8.04-7.98 (m, 2H), 7.85 (dd,J = 8.5, 6.2 Hz, 2H), 7.65-7.52 (m, 4H), 4.28 (dd, J = 21.3, 5.6 Hz, 2H), 3.75 (t, J = 9.5 Hz, 2H), 3.67-3.55 (m, 2H), 3.37 (ddd, J = 38.9, 11.0, 5.8 Hz, 2H), 3.20-2.91 (m, 3H), 2.73-2.67 (m, 1H).

[0679] Example 11

[0680] Synthesis of 4-chloro- N -(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (11)

[0681]

[0682]

[0683] Anhydrous potassium carbonate (50.2 mg, 0.363 mmol) was added in a single addition to compound (B) (100.0 mg, 0.29 mmol) and piperidine-4-ol (35.4 mg, 0.35 mmol) in a stirred solution of DMF (2 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was diluted with H2O (10 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure to give a crude product. The crude product was acidified with 0.5 M HCl and then concentrated under reduced pressure to give the title compound (11) (90 mg, 90.0% yield) as a white solid. The product was analyzed by LC-MS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.1 silica gel; DCM:MeOH = 10:1. LCMS (Agilent Technologies): Rt = 1.72 minutes; m / z calculated value [M+H] + = 345.1, measured value [M+H] + =345.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.54 (s, 1H), 8.02 (d, J =8.4 Hz, 2H), 7.84 (d, 1 H-NMR = 8.8 Hz (2H), 7.60 (m, J = 4.5 Hz, 4H), 4.22(m,J = 5.2 Hz, 2H), 3.92 (s, 1H), 3.61 (m, J = 5.6 Hz, 1H), 3.26 (d, J =12.4 Hz, 1H), 3.08 (m, J = 6.8 Hz, 2H), 2.89 (m, J = 8.2 Hz, 1H), 1.95 (m, J = 14.0 Hz, 2H), 1.73 (m, J = 14.0 Hz, 2H).

[0684] Example 12

[0685] Synthesis of 4-chloro- N -(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (12)

[0686]

[0687]

[0688] Anhydrous potassium carbonate (160.4 mg, 1.16 mmol) was added in a single addition to a stirred solution of compound (B) (200 mg, 0.58 mmol) and piperidine-3-ol (70.8 mg, 0.70 mmol) in DMF (4 mL) at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was diluted with H2O (20 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure to give a crude product. The crude product was acidified with 0.5 M HCl (aqueous solution) and concentrated to dryness under reduced pressure to give the title compound (12) (122.5 mg, 61.25% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.2% silica gel; DCM:MeOH = 10:1. LCMS (Agilent Technologies): Rt = 1.77 minutes; m / z calculated value [M+H] + = 345.1, measured value [M+H] + = 345.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.99 (s, 0.57H),10.55 (d, J= 11.6 Hz, 1H), 9.59 (s, 0.35H), 8.04-8.00 (m, 2H), 7.88-7.85 (m,2H), 7.64-7.52 (m, 4H), 4.30-4.12 (m, 2H), 4.01 (s, 0.39H), 3.86 (s, 0.59H),3.34-3.16 (m, 2H), 3.00 2.87 (m, 1H), 2.72 (s, 0.69H), 2.08-2.01 (m, 0.47H),1.92-1.81 (m, 2H), 1.69-1.51 (m, 1H), 1.28-1.18 (m, 1H).

[0689] Example 13

[0690] Synthesis of 4-chloro- N -(4-((3-hydroxypyrrolidone-1-yl)methyl)phenyl)benzamide (13)

[0691]

[0692]

[0693] Anhydrous potassium carbonate (197.4 mg, 1.428 mmol) was added in a single addition to a stirred solution of compound (B) (200 mg, 0.72 mmol) and pyrrolidine-3-ol (74.6 mg, 0.86 mmol) in DMF (4 mL) at room temperature. After stirring at 50 °C for 6 hours, the reaction mixture was diluted with H₂O (20 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under reduced pressure to give a crude product. The crude product was acidified with 0.5 M HCl (aqueous solution) and concentrated to dryness under reduced pressure to give the title compound (13) (230 mg, 87.71% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.25 silica gel; DCM:MeOH = 10:1. LCMS (Agilent Technologies): Rt = 1.82 minutes; m / z calculated value [M+H] + = 333.1, measured value [M+H] + = 333.1. 1 H-NMR (400 MHz, DMSO-d6) δ 11.79 (s, 0.45H), 10.78 (s, 0.40H), 10.51 (d, J= 7.6 Hz, 1H), 8.02-7.99 (m, 2H), 7.86-7.93 (m,2H), 7.63-7.55 (m, 4H), 4.45-4.24 (m, 3H), 3.50-3.44 (m, 1H), 3.40-3.33 (m,0.52H), 3.27-3.09 (m, 2H), 2.98-2.93 (m, 0.50H), 2.33-2.23 (m, 0.44H), 2.07-1.81 (m, 1.61H).

[0694] Example 14

[0695] synthesis N -(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-4-chlorobenzamide (14)

[0696]

[0697]

[0698] Anhydrous potassium carbonate (414 mg, 2.99 mmol) was added in a single addition to a stirred solution of compound (B) (340 mg, 1.0 mmol) and 1-(piperazin-1-yl)ethyl-1-one (128 mg, 1.0 mmol) in DMF (4 mL). After stirring at room temperature for 6 hours, the reaction mixture was diluted with H2O (20 mL) and filtered. The resulting solid was dissolved in 2N HCl (2 mL) and DMSO (2 mL) and purified by reversed-phase Biotage® chromatography (C18 column, eluted with 10% to 95% MeCN / H2O containing 0.1% hydrochloric acid) to give the title compound (14) (130 mg, 35.0% yield) as a white solid. The final product was obtained by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.4% silica gel; DCM:MeOH = 10:1. LCMS (Agilent Technologies): Rt = 0.87 minutes; m / z calculated value [M+H] + = 372.0, measured value [M+H] + = 372.0. 1 H-NMR (400 MHz, DMSO-d6) δ11.58 (s, 1H), 10.55 (s, 1H), 8.05-7.98 (m, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 8.8 Hz, 4H), 4.41 (d,J = 14.1 Hz, 1H), 4.27 (d, J = 4.3 Hz, 2H), 3.98 (d, J = 14.4 Hz, 1H), 3.59 (t, J = 13.3 Hz, 1H), 3.28 (d, J = 12.1Hz, 2H), 3.06 (dt, J = 20.9, 12.0 Hz, 2H), 2.87 (d, J = 11.6 Hz, 1H), 2.03 (s, 3H).

[0699] Example 15

[0700] Synthesis of 4-chloro- N -(4-((3-oxopiperazin-1-yl)methyl)phenyl)benzamide (15)

[0701]

[0702]

[0703] Anhydrous potassium carbonate (414 mg, 2.88 mmol) was added in a single addition to a stirred solution of compound (B) (280 mg, 1.0 mmol) and piperazine-2-one (100 mg, 1.0 mmol) in DMF (4 mL) at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was diluted with H2O (20 mL) and filtered. The resulting solid was dissolved in 2N HCl (2 mL) and DMSO (2 mL), and then purified by Biotage® reversed-phase column chromatography (C18 column, eluted with 10% to 95% MeCN / H2O containing 0.1% hydrochloric acid) to give the title compound (15) (108 mg, 31.5% yield) as a white solid. The final product was obtained by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.3% silicone; PE:EtOAc = 1:1. LCMS (Agilent Technologies): Rt = 0.85 minutes; m / z calculated value [M+H] + = 344.1, measured value [M+H] + = 344.1. 1H-NMR (400 MHz, DMSO-d6) δ 11.93 (s,1H), 10.55 (s, 1H), 8.39 (s, 1H), 8.06-7.98 (m, 2H), 7.92-7.83 (m, 2H), 7.61(dd, J = 8.4, 6.0 Hz, 4H), 4.34 (s, 2H), 3.78-3.40 (m, 5H), 3.19 (d, J = 21.8Hz, 1H).

[0704] Example 16

[0705] Synthesis of 4-chloro- N -(4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)benzamide (16)

[0706]

[0707]

[0708] Anhydrous potassium (296 mg, 2.14 mmol) was added in a single addition to a stirred solution of compound (B) (300 mg, 1.07 mmol) and 1-methylpiperazin-2-one (146 mg, 1.28 mmol) in DMF (5 mL) at 50 °C. After stirring at 50 °C for 1 hour, the reaction mixture was diluted with H2O (10 mL) and filtered. The resulting filter cake was washed with a small volume of DCM and dried under pressure to give a crude product. The crude product was acidified with 0.5 M HCl and concentrated to dryness under reduced pressure to give the title compound (16) (121 mg, 31.6% yield) as a white solid. The product was analyzed by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.4% silica gel; DCM:MeOH = 20:1. LCMS (Agilent Technologies): Rt = 1.81 minutes; m / z calculated value [M+H] + = 358.1, measured value [M+H] + = 358.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.01-7.99 (m,2H), 7.75 (d, J = 8.0 Hz, 2H), 7.62-7.59 (m, 2H), 7.30-7.28 (m, 2H), 3.50 (s,1H), 3.25 (t, J= 5.6 Hz, 2H), 2.94 (s, 2H), 2.81 (s, 3H), 2.83-2.62 (m, 2H).

[0709] Example 17

[0710] Synthesis of 4-chloro- N -(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (17)

[0711]

[0712]

[0713] Anhydrous potassium carbonate (290 mg, 2.1 mmol) was added in a single addition to compound (B) (200 mg, 0.7 mmol) and 1-methylpiperazine (74 mg, 0.7 mmol) in a stirred solution of DMF (4 mL) at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was diluted with H2O (10 mL) and filtered. The resulting filter cake was purified by C18 reversed-phase preparative HPLC (eluting with 10% to 95% MeCN / H2O containing 0.1% hydrochloric acid) to give the title compound (17) as a white solid (110 mg, 43.4% yield). The final product was further purified by LCMS and... 1 The structure was confirmed by H-NMR. TLC:R f = 0.3% silica gel; MeOH:DCM = 1:15. LCMS (Agilent Technologies): Rt = 0.83 minutes; m / z calculated value [M+H] + = 344.1, measured value [M+H] + = 344.1. 1 H-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.03-7.95 (m, 2H), 7.80 (d, J = 8.5Hz, 2H), 7.66-7.56 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 5.75 (s, 2H), 3.91 (s,2H), 3.29 (d, J = 97.6 Hz, 6H), 2.80 (s, 3H).

[0714] Example 18

[0715] Expression and purification of pf p38 MAPK protein

[0716] Human p38α and β MAP kinase isoforms were expressed in E. coli and were used with Shah et al. , Journal of Immunology (Journal of Immunology)》 Purification was performed according to the protocol described in , 2017, 198, 3296-3306.

[0717] Mouse anti-human p38α and rabbit anti-phospho-MK2 (T222) and anti-phospho-STAT-1 (S727) were obtained from Cell Signaling Technologies, Danvers, MA. The coding sequences for human p38α variant 2 and p38β (with an N-terminal hemagglutinin tag) were amplified by PCR and cloned into pRSetA (Thermo Fisher Scientific, Waltham, MA). Mutations were introduced into p38α using Quikchange® (Stratagene) and confirmed by bidirectional sequencing. To generate [the desired product / product / etc.]... in vitro Activated diphosphorylated p38α, as determined by kinase assay, was amplified by PCR into p38α variant 2 and cloned into the first multiple cloning site of pETDuet™ (EMD-Millipore) with an N-terminal His-tagged sequence. A gene block containing an optimized sequence of the constitutively active human MKK6 S207G / T211G mutant was synthesized (Genscript, Piscataway, NJ) and cloned into the second multiple cloning site of pETDuet™-p38α. The plasmid was transformed into *E. coli* BL21 and confirmed using a cobalt column (TALON; Clontech Laboratories, Mountain View, CA) by SDS-PAGE and Western blotting. MALDI assay confirmed that approximately 80% of the p38α protein expressed by the pETDuet™ plasmid was diphosphorylated.

[0718] Example 19

[0719] Differential scanning fluorescence (DSF) assay

[0720] Differential scanning fluorescence (DSF) was used to evaluate the binding of certain compounds of formula (1) to p38α MAPK and p38β MAPK isoforms. DSF was also used to evaluate the target protein melting temperature (ΔT) resulting from the interaction with the test compounds. m The changes in SYPRO Orange (Thermo Fischer Scientific) diluted 1:1000 in 10 mM HEPES, 150 mM NaCl (pH 7.5), and 1 μM unphosphorylated recombinant human p38α were added to a 96-well PCR plate. The test compound (50 nm to 200 nM) dissolved in 100% DMSO (2% final DMSO concentration) was added, the plate was mixed, sealed, and centrifuged at 1,000 rpm for 1 minute. The melting curve was determined using the StepOne™ Real-Time PCR instrument from Applied Biosystems. The melting point was determined by the first derivative curve.

[0721] The interactions of all compounds with p38α or p38β were initially tested at 100 μM using DSF. Control ATP-competitive p38 inhibitors were then tested at 10 μM. The dose-response of compounds showing selectivity for p38α was then retested (1 μM, 3, 10 μM, 30 μM, 100 μM). Each experiment was repeated three times for each compound using three different techniques.

[0722] Compounds 1, 6, 8, and 14 exhibited a ΔTm greater than 0.1 at a concentration of 100 μM. SB203580 exhibited a ΔTm greater than 10 at a concentration of 10 μM.

[0723] Example 20

[0724] Surface plasmon resonance (SPR) measurement

[0725] The binding affinity of compounds selective for p38α was demonstrated in DSF assays using an SPR assay with a Biacore T200 instrument. Binding affinity (KD) for either p38α or p38β was determined by various doses of the test compound (e.g., 1 μM, 3 μM, 10 μM, 30 μM, 100 μM). Controls were used to confirm the binding of ATP-competitive p38 inhibitors. Each experiment was repeated three times.

[0726] Compounds (1), (6), (8) and (14) exhibited a Kt of less than 1E-8 M for binding p38β at pH 4. D .

[0727] Example 21

[0728] Plasma stability test

[0729] Human, mouse, rat, and monkey plasma (K2 EDTA by default) were obtained from Bioreclamation. Each test compound was incubated at 10 μM at 37°C in the presence of plasma. Samples were quenched with organic solvents at 0, 30, 60, and 240 minutes, vortexed, and centrifuged. The supernatant was transferred to fresh plates and analyzed by LC / MS / MS using an ABSciex API 4000™ instrument connected to a Shimadzu LC-20AD LC pump system. Samples were separated and analyzed using a Waters Atlantis T3 C18 reversed-phase HPLC column (20 mm × 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consisted of a solution of 0.1% formic acid in water (solvent A) and a solution of 0.1% formic acid in 100% acetonitrile (solvent B).

[0730] The degree of metabolism was calculated as the disappearance of the test compound compared to a 0-minute control reaction incubation. Propylamine was included as a positive control to validate the assay performance.

[0731] Compounds 1, 6, 8, 10 and 14 were stable in human, monkey and rat plasma for at least 4 hours.

[0732] Example 22

[0733] Antiviral efficacy against SARS-CoV-19

[0734] A549-ACE2 cells were cultured in DMEM supplemented with 10% FBS and maintained at 37°C and 5% CO2. HEK293T-ACE2 cells (ATCC, CRL-3216) were maintained in DMEM (Corning) supplemented with 10% FB (peak serum) and penicillin / streptomycin (Corning) at 37°C and 5% CO2. Cells ectopically expressing hACE2 were generated by transduction with a lentiviral vector expressing human ACE2. Puromycin-resistant cells expressing hACE2 were sorted after staining with Alexa Fluor® 647-conjugated goat anti-hACE2 antibody. Cells were then single-cell cloned and screened for their ability to support SARS-CoV-2 replication. Mycoplasma contamination was periodically screened for in all cell lines used in this study using a universal detection kit (ATCC, 30-1012K).

[0735] The SARS-CoV-2 isolate BetaCoV / France / IDF0372 / 2020 (SARS-CoV-2 Paris) was provided by the National Reference Centre for Respiratory Viruses, hosted by the Pasteur Institute, Paris, France. The isolate was provided through the European Virus Archive goes Global (EVAg) platform. Viral stock solutions were prepared by propagation in Vero E6 cells in DMEM supplemented with 2% FBS. Viral titer was determined by plaque assay in minimum essential medium (MEM) supplemented with 2% (v / v) FBS (Invitrogen) and 0.05% agarose. All experiments involving live SARS-CoV-2 were performed in an approved laboratory in accordance with the Pasteur Institute's guidelines for Biosafety Level 3 (BSL-3).

[0736] The SARS-CoV-2 isolate USA-WA1 / 2020 (NR-52281) (SARS-CoV-2 New York) shares 99.983% sequence identity with the BetaCoV / France / IDF0372 / 2020 isolate. It was deposited with the Centers for Disease Control and Prevention and obtained through BEI Resources (BEI Resources, NIAID, NIH) at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. SARS-CoV-2 was propagated in Vero E6 cells in DMEM supplemented with 2% FBS, 4.5 g / L D-glucose, 4 mM L-glutamine, 10 mM non-essential amino acids, 1 mM sodium pyruvate, and 10 mM HEPES. All work involving live SARS-CoV-2 was conducted in accordance with institutional biosafety requirements at the CDC / USDA-approved BSL-3 facility of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai.

[0737] Two hours prior to infection, the culture medium was replaced with DMEM (2% FBS) containing the target compound (including the DMSO control) at a concentration 50% higher than indicated. The plates were then transferred to a BSL-3 instrument, and the same volume of SARS-CoV-2 was added to the DMEM (2% FBS) to achieve the indicated compound concentration. The plates were then incubated at 37°C for 48 hours. All assays were performed biologically independent in triplicate.

[0738] Viral genome detection was performed directly from the inactivated supernatant via 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) Applied Biosystems The virus was used in the company's QuantStudio™ 7 thermal cycler with 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 is expressed as PFU equivalents / mL and calculated using a standard curve with RNA from a viral stock solution with a known viral titer.

[0739] Virus quantification was performed in Paris using plaque assay. Cells were loaded at 7.5 × 10⁻⁶. 4 Cells / well were inoculated at a concentration of [number] cells / well in 24-well plates. The next day, serial dilutions were performed in serum-free MEM medium. After 1 hour, the inoculum was absorbed at 37°C, and 2× covering medium was added to achieve a final concentration of 2% (v / v) FBS / MEM medium and 0.05% (w / v) agarose (all from Thermo Fisher Scientific) for semi-solid coverage. Plaque assays were incubated at 37°C for 3 days. Samples were fixed using 4% formalin (Sigma Aldrich), and plaques were visualized using crystal violet solution (Sigma Aldrich).

[0740] Cell viability, Paris. Cell viability was measured using the CellTiter-Glo® luminescence viability assay (Promega) according to the manufacturer's instructions, and luminescence was measured in a Tecan Infinite® 2000 plate reader. Cytotoxicity assays were performed in uninfected cells with the same compound dilution, along with virus replication assays. Percentage viability was calculated relative to untreated cells (100% viability) and cells lysed with 20% ethanol (0% viability).

[0741] Viral quantification was performed in New York using N-protein staining. After infection, the supernatant was removed, and cells were fixed with 4% formaldehyde for 24 hours before being removed from the BSL-3 system. Cells were then immunostained with DAPI counterstain for viral NP protein (1:10,000). Infected cells (488 nM) and total cells (DAPI) were quantified using a Celigo (Nexcelcom) imaging cytometer. Infectivity was measured by the accumulation of viral NP protein in the cell nucleus (fluorescence accumulation). The percentage of infection was quantified as ((infected cells / total cells) - background) × 100, with a DMSO control set as 100% infection for analysis.

[0742] Cell viability, New York. Cytotoxicity was also assessed using the MTT assay (Roche) according to the manufacturer's instructions. Cytotoxicity was measured in uninfected cells with the same compound dilution, along with viral replication assays. Percentage viability was calculated relative to untreated cells (100% viability).

[0743] Data analysis and IC50 calculation. The Hill function was fitted to each dose-response curve using the lsqcurvefit function in MATLAB (R2018a). The IC50 (virus) value was defined as the concentration at which a percentage measurement (virus or cell viability quantification) crosses with a 50% marker. If the fitted curve did not start above 50% and crossed below 50% throughout the dose-response period, the IC50 value was marked as greater than the maximum tested concentration.

[0744] Compounds (1), (2), (3), (4), (6), (8), (1), (11), (13) and (17) exhibited IC50 values ​​of less than 1E-5 M for anti-SARS-CoVID-19 activity. The results are shown in Table 1.

[0745] Table 1. Antiviral activity

[0746]

[0747] 1 Not measured.

[0748] Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein. Therefore, these embodiments are to be considered illustrative rather than restrictive, and the claims are not limited to the details given herein, but may be modified within their scope and equivalents.

Claims

1. A compound, wherein the compound is selected from: N -(4-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-4-chlorobenzamide (2); N -(4-((7-oxa-2-azaspiro[3.5]non-2-yl)methyl)phenyl)-4-chlorobenzamide (4); N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6); N -(4-(((1 R 5 S )-3-oxa-7-azabicyclo[3.3.1]non-7-yl)methyl)phenyl)-4-chlorobenzamide (9); and 4-Chloro- N -(4-(((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)methyl)phenyl)benzamide (10); Or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound according to claim 1, wherein the compound is selected from: N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6); Or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound according to claim 1, wherein the compound is selected from: N -(4-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-4-chlorobenzamide (2); N -(4-((7-oxa-2-azaspiro[3.5]non-2-yl)methyl)phenyl)-4-chlorobenzamide (4); N -(4-((1-oxa-7-azaspiro[4.4]non-7-yl)methyl)phenyl)-4-chlorobenzamide (6); and 4-Chloro- N -(4-(((3a R ,6a S )-Tetrahydro-1 H -furano[3,4-c]pyrrole-5(3) H )-yl)methyl)phenyl)benzamide (10); Or a pharmaceutically acceptable salt of any of the foregoing.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, for the treatment of cancer, inflammatory diseases, autoimmune diseases and viral diseases.

6. The pharmaceutical composition according to claim 5, wherein, The viral diseases mentioned are selected from coronavirus infection, coronavirus infection-associated pneumonia, and human respiratory syndrome infection; The cancers mentioned are selected from breast cancer and melanoma; and The inflammatory diseases mentioned are 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 and pain in hypercholesterolemia, diabetes, and rheumatoid arthritis.

7. The pharmaceutical composition according to claim 6, wherein the coronavirus infection is MERS-CoV infection, SARS-CoV infection, or SARS-CoV-2 infection.

8. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, for the treatment of acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, or cystic fibrosis.

9. Use of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, inflammatory diseases, autoimmune diseases or viral diseases.

10. The use according to claim 9, wherein, The viral diseases mentioned are selected from coronavirus infection, coronavirus infection-associated pneumonia, and human respiratory syndrome infection; The cancers mentioned are selected from breast cancer and melanoma; and The inflammatory diseases mentioned are 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 and pain in hypercholesterolemia, diabetes, and rheumatoid arthritis.

11. The use according to claim 10, wherein the coronavirus infection is MERS-CoV infection, SARS-CoV infection, or SARS-CoV-2 infection.

12. Use of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis or cystic fibrosis.

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