N-phenyl-2-azacyclo-acetamide derivative as well as preparation method and application thereof

Abstract

The invention provides the N-phenyl-2-azacyclo-acetamide derivative which can enhance the physical strength of mice and coordinate the biological activity of behaviors, so that the N-phenyl-2-azacyclo-acetamide derivative has anti-fatigue activity and provides a new thought and direction for developing efficient and safe anti-fatigue drugs.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an N-phenyl-2-azacycloacetamide derivative and a preparation method and application thereof. Background Art

[0002] With the accelerated pace of work and life and the increase in pressure among contemporary people, unhealthy diet, lack of rest, insufficient physical activity, unreasonable exercise, high-intensity work, mental stress, and long-term negative emotions are becoming more and more common. As a result, a large number of people are in a sub-healthy state (a special state between health and disease) and experience "unexplained fatigue". One-third of the world's population suffers from chronic fatigue for six months or even longer. Fatigue often leads to anxiety and depression, and is related to cognitive dysfunction, sleep quality, physical dysfunction, and energy balance. In severe cases, fatigue can cause a variety of diseases related to biological regulation and the immune system. For example, long-term fatigue can lead to aging, depression, cancer, multiple sclerosis, and Parkinson's disease, seriously affecting the patient's life and work.

[0003] The use of anti-fatigue drugs is an important and effective way to prevent, reduce and eliminate fatigue. After taking the ideal anti-fatigue drug, the mental workers will become more active, and the discomfort of the physical workers can be eliminated, which can extend the working time and improve the work efficiency. Moreover, it is easy to take, will not interfere with normal sleep, and will not have any side effects. Therefore, it is very important to find anti-fatigue drugs or preparations with definite efficacy and few side effects.

[0004] AMPA receptor is a central excitatory ionotropic glutamate receptor. Glutamate neurotransmitters are important excitatory neurotransmitters in the mammalian central nervous system and are involved in a variety of neural activity processes, including neuronal development, synaptic plasticity and neurotoxicity. AMPA receptor modulators have unique effects in relieving fatigue symptoms caused by sleep deprivation and have the potential to be a drug for relieving fatigue and improving sleep deprivation symptoms. However, existing AMPA receptor modulators such as aniracetam have defects such as short half-life and low anti-fatigue efficacy. 1-BCP is an AMPA receptor positive allosteric modulator containing a benzamide structure and has entered the Phase II clinical trial stage. In vitro experiments have confirmed that 1-BCP can regulate the gated current of AMPA receptors and increase the current intensity flowing into glutamate gated ion channels. In vivo experiments have confirmed that 1-BCP can pass through the blood-brain barrier, regulate excitatory postsynaptic potentials, and regulate the long-term potentiation effect of rat hippocampal synaptic activity. Based on the above research status, finding AMPA receptor modulators with high anti-fatigue efficiency provides more options for anti-fatigue drugs. Summary of the invention

[0005] The purpose of the present invention is to address the technical defects existing in the prior art and to provide an N-phenyl-2-azacycloacetamide derivative shown in formula I, or its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate compound, wherein the formula I is as follows:

[0006]

[0007] R1 is independently selected from a halogen atom, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O )-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N(C1-6 alkyl)2, -S(O)2-(C1-6 alkyl), -OS(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), - N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2, C2-12 heterocycloalkyl, or C5-12 heteroaryl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl; wherein the number of substitutions by R1 is 1-3, and the substitution position of R1 is the meta or para position of the 2-(4-substituted acylpiperazin-1-yl)acetamide group; when the number of R1 is 2 or more, the R1 connected to the adjacent carbon atoms are optionally combined to form a condensed ring selected from C3-12 heterocycloalkyl, wherein each condensed ring is optionally substituted by one or more substituents selected from R2;

[0008] A is a 5-membered ring or a 6-membered ring which may be substituted or unsubstituted by R2, and X is selected from O, S or N; when the A ring is substituted, the number of R2 substitutions is 1-3, wherein R2 is independently selected from hydrogen, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), - NH-(C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O)-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N( C1-6 alkyl)2, -S(O)2-(C1-6 alkyl), -OS(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2 , C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, -C(O)-(C5-12 aryl), -C(O)-(C5-12 heteroaryl), C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl. Wherein, R2 is optionally substituted by R3, for example, the C1-6 alkyl, C1-6 cycloalkyl, C5-12 aryl, C5-12 heteroaryl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy can be optionally substituted by R3.

[0009] Further, A is a 6-membered ring which may be substituted by R2, and X is selected from O or N; when the A ring is substituted, the number of R2 substitutions is 1, wherein R2 is independently selected from -C(O)-N(C1-3 alkyl)2, -C(O)-(C5-6 aryl), and -C(O)-(C5-6 heteroaryl).

[0010] Optionally, the N-phenyl-2-azacycloacetamide derivative is as shown in Formula II,

[0011]

[0012] The number of R3 substitutions is 0-4; when the number of R3 is 2 or more, the R3 connected to adjacent carbon atoms may optionally combine to form a condensed ring selected from C5-12 aryl, C5-12 heteroaryl, C3-12 cycloalkyl and C3-12 heterocycloalkyl, wherein each condensed ring may be optionally substituted by 1 or more substituents selected from R2 or may not be substituted;

[0013] R3 is independently selected from hydrogen, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O)-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N(C1-6 alkyl)2, -S(O)2-(C1-6 alkyl), -O S(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, -C(O)-(C5-12 aryl), -C(O)-(C5-12 heteroaryl), C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

[0014] In another optional embodiment, R1 is independently selected from -OH, -NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

[0015] In another optional embodiment, R3 is independently selected from hydrogen, a halogen atom, -OH, -NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

[0016] In another alternative embodiment, R3 is independently selected from hydrogen, a halogen atom, -OH, -NH2, -O-(C1-3 alkyl), C1-3 alkyl, C2-6 alkenyl, C1-6 haloalkyl.

[0017] In another alternative embodiment, the number of R1 is 2, and the R1 attached to adjacent carbon atoms combine to form a C3-6 heterocycloalkyl group.

[0018] The number of heteroatoms in the heterocycle or heteroaromatic ring may be 1, 2, 3 or more and may be selected from O, S and N. When the number of heteroatoms is 2 or more, each heteroatom may be the same or different.

[0019] In another alternative embodiment, the number of R1 is 2, and R1 attached to adjacent carbon atoms are combined to form 1,3-dioxole.

[0020] In another alternative embodiment, the number of R1 is 2 or 3, selected from -O-(C1-6 alkyl), preferably -OCH3.

[0021] The present invention provides an N-phenyl-2-azacycloacetamide derivative, an isomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, characterized in that it comprises any one of the following:

[0022] N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-benzoylpiperazin-1-yl)acetamide

[0023] N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(4-methylbenzoyl)piperazin-1-yl)acetamide

[0024] N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(2-methylbenzoyl)piperazin-1-yl)acetamide

[0025] N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-(2-ethylbenzoyl)piperazin-1-yl)acetamide

[0026] 2-(4-Benzoylpiperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0027] 2-(4-(4-Methylbenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0028] 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0029] 2-(4-(4-(Trifluoromethyl)benzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0030] 4-(2-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxoethyl)-N,N-diethylpiperazine-1-carboxamide

[0031] N,N-Diethyl-4-(2-oxo-2-((3,4,5-trimethoxyphenyl)amino)ethyl)piperazine-1-carboxamide

[0032] N-(Benzo[d][1,3]dioxol-5-yl)-2-morpholinoacetamide

[0033] (4-Benzoylpiperazin-1-yl)(quinolin-2-yl)methanone

[0034] (4-(4-Methylbenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone

[0035] (4-(4-Methoxybenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone

[0036] Quinolin-2-yl(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)methanone

[0037] (4-(4-(Chloromethyl)benzoyl)piperazin-1-yl)(4-methoxyphenyl)methanone

[0038] (4-(Chloromethyl)benzoyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone.

[0039] The present invention also provides a composition comprising any of the above-mentioned N-phenyl-2-azacycloacetamide derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof, and a pharmaceutically acceptable carrier or excipient.

[0040] Specifically, the composition is selected from the group consisting of enteral and parenteral dosage forms, wherein the parenteral dosage forms include injection dosage forms, skin dosage forms, respiratory dosage forms, mucosal dosage forms, and cavity dosage forms. Among them, the injection dosage form can be an injection, an intravenous injection dosage form, an intramuscular injection dosage form, a subcutaneous injection dosage form, an intradermal injection dosage form, and an acupoint injection dosage form; the respiratory administration can be an inhalation agent or an aerosol; the skin administration can be a local effect-external solution, lotion, liniment, plaster, ointment, paste, and a systemic effect-transdermal absorption plaster; the mucosal administration can be an eye drop, a nasal drop, a gargle, a sublingual tablet, a buccal tablet, a suppository, and an oral film. The gastrointestinal dosage form can be a solution, a syrup, an emulsion, a suspension, a powder, an granule, a pill, a tablet, a capsule, and an enema and a suppository for rectal administration. Preferably, it is a subcutaneous injection dosage form.

[0041] The present invention also proposes a use of any of the above-mentioned N-phenyl-2-azacycloacetamide derivatives, their isomers, their prodrugs, their pharmaceutically acceptable salts, their hydrates or their solvates, characterized in that they are used for (1) preparing anti-fatigue drugs; (2) preparing AMPA modulators.

[0042] The present invention also provides an active ingredient combination, which comprises the following components:

[0043] (1) any one of the above-mentioned N-phenyl-2-azacycloacetamide derivatives, isomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; and

[0044] (2) Anti-fatigue drugs; drugs that improve cognitive impairment; antidepressant drugs.

[0045] The present invention uses AMPA receptor modulators to combat the adverse effects of fatigue, designs a compound with a completely new structure, and can enhance the biological activity of physical strength and coordinated behavior of mice, thus having anti-fatigue activity, and provides a new idea and direction for the development of efficient and safe anti-fatigue drugs. DETAILED DESCRIPTION

[0046] As used herein, the terms "comprise", "include", and "contain" are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

[0047] It should be understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be synthesized by techniques known in the art and the methods described below. If substituted with more than one substituent group, it should be understood that the multiple groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0048] As used herein, the term "substituted" or "substituted" means that a hydrogen atom on a group is replaced by a non-hydrogen atom group, but the valence requirement is satisfied and the substitution generates a chemically stable compound, i.e., a compound that does not spontaneously undergo transformations such as cyclization, elimination, etc.

[0049] As used herein, the term "alkyl" refers to a straight chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. For example, C1-C4 alkyl refers to an alkyl group containing 1-4 carbon atoms, representative examples of which include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0050] The term "alkenyl" refers to a monovalent group of a branched or unbranched unsaturated hydrocarbon group, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. Preferred alkenyl groups include vinyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), etc.

[0051] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0052] In the present invention, the term "halogenated" means substituted by halogen, and the halogenated group may be substituted by 1, 2 or 3 halogens.

[0053] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated unit ring, a bicyclic or polycyclic (condensed ring, bridged ring or spirocyclic) ring system group. When a cycloalkyl group is preceded by a carbon atom number limit (such as C3-C8), it means that the cycloalkyl group has 3-8 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group with 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. "Condensed cycloalkyl" refers to a full carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, these may contain one or more double bonds, but neither ring has a completely conjugated pi electron system.

[0054] The term "alkoxy" refers to a RO-group, where R is an alkyl group, and the alkyl group is as defined herein above, and when the alkoxy group is preceded by a carbon atom number, such as a C1-C6 alkoxy group, the alkyl group in the alkoxy group has 1-6 carbon atoms. Representative examples of alkoxy groups include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0055] As used herein, the term "alkylthio" refers to a RO-group, wherein R is an alkyl group, and the alkyl group is as defined herein above, and when the alkylthio group is preceded by a carbon atom number, such as C1-C6 alkylthio, the alkyl group in the alkoxy group has 1-6 carbon atoms. Representative examples of alkylthio groups include (but are not limited to): methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or the like.

[0056] As used herein, the term "haloalkoxy" refers to a haloalkyl-O- group, wherein the haloalkyl group is as defined above, for example, a haloC1-C4alkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, representative examples of which include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or the like.

[0057] As used herein, the term "haloalkylthio" refers to a haloalkyl-S- group, wherein the haloalkyl group is as defined above, for example, a haloC1-C4alkylthio group refers to a haloalkylthio group containing 1 to 4 carbon atoms, representative examples of which include but are not limited to, monofluoromethylthio, monofluoroethylthio, bisfluorobutylthio, or the like.

[0058] The term "heterocycloalkyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 4-7 membered monocyclic ring, a 7-11 membered bicyclic ring, or an 8-16 membered tricyclic ring system), wherein at least one heteroatom is present in a ring having at least one carbon atom. When there is a number limit before the heterocycloalkyl group, it refers to the number of ring atoms of the heterocycloalkyl group, for example, a 3-12 membered heterocycloalkyl group refers to a heterocycloalkyl group having 3-12 ring atoms, each heterocyclic ring containing a heteroatom may carry one or more (such as 1, 2, 3 or 4) heteroatoms, and these heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen atoms or sulfur atoms may be oxidized, and the nitrogen atoms may also be quaternized. The heterocycloalkyl group may be connected to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocycloalkyl groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0059] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, and is an aromatic cyclic hydrocarbon compound group. When the aryl group is preceded by a carbon atom number limit, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system.

[0060] The term "heteroaryl" refers to an aromatic heterocyclic group having one to multiple (preferably 1, 2, 3 or 4) heteroatoms, which may be a single ring (monocyclic) or a polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and each heterocyclic ring containing a heteroatom may carry one or more (such as 1, 2, 3, 4) heteroatoms independently selected from the following group: oxygen, sulfur and nitrogen. When there is a number limit before the heteroaryl, it refers to the number of ring atoms of the heteroaryl. For example, a 5-12-membered heteroaryl refers to a heteroaryl having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazolyl and tetrazolyl.

[0061] As used herein, the term "nitro" by itself or as part of another substituent means -NO2.

[0062] As used herein, the term "cyano" when used alone or as part of another substituent means -CN

[0063] As used herein, the term "hydroxy" by itself or as part of another substituent means -OH.

[0064] isomers or hydrates, such as optical isomers or racemic compounds; pharmaceutically acceptable salts, which may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, bromides, iodides, acetates, propionates, octanoates, acrylates, formates, isobutyrates, heptanoates, decanoates, propiolates, oxalates, malonates, succinates, suberates, decanoates, Diacids, fumarates, maleates, 2-butyne-1,4-dioates, 3-cyclohexyne-2,5-dioates, benzoates, chlorobenzoates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, hippurates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, glutamates, arginates, lysine salts, and the like, preferably hydrochlorides and phosphates.

[0065] In this specification, all substituents are interpreted as being unsubstituted unless explicitly described as "substituted" in this document. The term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position.

[0066] The present invention provides a method for (1) preparing an anti-fatigue, cognitive impairment improvement, and anti-depressant drug; (2) preparing an AMPA modulator. In the present invention, the method for treating or preventing refers to treatment, and the term "prevention" refers to a method for preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. "Prevention" as used herein also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the risk of a subject acquiring a disease.

[0067] In the present invention, the term "treatment" refers to any treatment of a disease in a mammal, including (but not limited to): (a) inhibiting the disease, i.e., slowing or preventing the development of clinical symptoms; and / or (b) alleviating the disease, i.e., causing regression of clinical symptoms, and / or (c) alleviating or eliminating the disease and / or its attendant symptoms.

[0068] Typically, the composition is a pharmaceutical composition, which comprises the compound of formula I according to the present invention, or its isomer, or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

[0069] In the composition of the present invention, the amount of the compound of formula I is a therapeutically effective amount, wherein "therapeutically effective amount" refers to an amount that produces a function or activity on humans and / or animals and can be accepted by humans and / or animals. It should be understood by those of ordinary skill in the art that the "therapeutically effective amount" may vary depending on the form of the pharmaceutical composition, the route of administration, the adjuvants of the drug used, the severity of the disease, and the combination with other drugs.

[0070] In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.

[0071] Representative examples include (but are not limited to): tablets, injections, infusions, ointments, gels, solutions, microspheres, and films. The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semisolid, liquid or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the components of the pharmaceutical composition and the active ingredients of the drug and their mutual blending without significantly reducing the efficacy of the drug.

[0072] Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, skin penetration enhancers, colorants, flavorings, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-free water, etc.

[0073] Typically, in addition to the active pharmaceutical ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents.

[0074] The pharmaceutical preparation should be matched with the mode of administration. The medicament of the present invention can also be used with other synergistic therapeutic agents (including before, during or after use). When using a pharmaceutical composition or preparation, a safe and effective amount of the drug is applied to the desired object (such as a human or non-human mammal), and the safe and effective amount is usually at least about 10 micrograms / kg body weight, and in most cases does not exceed about 8 milligrams / kg body weight, preferably the dosage is about 10 micrograms / kg body weight-about 1 milligram / kg body weight. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0075] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0076] Synthesis of target compounds

[0077] Synthesis of N-(Benzo[d][1,3]dioxol-5-yl)-2-chloroacetamide (M1)

[0078] Under anhydrous and oxygen-free conditions, benzo[d][1,3]dioxol-5-amine was dissolved in dichloromethane, triethylamine was added, and chloroacetyl chloride was added at 0°C, and the reaction was carried out at room temperature for 3 hours. 30 mL of water was added to the reaction mixture for washing, and the organic phase was dried over anhydrous sodium sulfate for 3 hours, the solvent was evaporated under reduced pressure, and a brown solid was obtained by column chromatography separation and purification with a yield of 80%.

[0079] Synthesis of 2-chloro-N-(3,4,5-trimethoxyphenyl)acetamide (M2)

[0080] According to the preparation method of M1, a light yellow solid was obtained from 3,4,5-trimethoxyaniline and chloroacetyl chloride with a yield of 75%.

[0081] Synthesis of Phenyl(Piperazine-1-yl)Methanone(N1)

[0082] 1-tert-Butyloxycarbonylpiperazine was dissolved in dichloromethane, N,N-diisopropylethylamine was added under stirring at room temperature, benzoyl chloride was added dropwise under stirring at 0°C, and the mixture was reacted at room temperature for 2 h. The reaction mixture was washed once with 1N hydrochloric acid, saturated sodium bicarbonate and water, respectively. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane:trifluoroacetic acid (1:1), and the mixture was reacted at room temperature for 2 h. The pH was adjusted to 8-9 with saturated sodium carbonate, and the mixture was extracted with dichloromethane 3 times. The organic phase was dried over anhydrous sodium sulfate for 3 h, and the solvent was evaporated under reduced pressure. The mixture was used directly in the subsequent synthesis steps without purification.

[0083] Synthesis of Piperazine-1-yl(p-tolyl)methanone(N2)

[0084] According to the preparation method of N1, it was prepared from 1-BOC-piperazine and 4-methylbenzoyl chloride.

[0085] Synthesis of Piperazine-1-yl(o-tolyl)methanone(N3)

[0086] According to the preparation method of N1, it was prepared from 1-BOC-piperazine and 2-methylbenzoyl chloride.

[0087] Synthesis of Piperazine-1-yl(2-ethylphenyl)methanone(N4)

[0088] According to the preparation method of N1, it was prepared from 1-BOC-piperazine and 2-ethylbenzoyl chloride.

[0089] Synthesis of (4-methoxyphenyl)(piperazine-1-yl)methanone (N5)

[0090] According to the preparation method of N1, it was prepared from 1-BOC-piperazine and 4-methoxybenzoyl chloride.

[0091] Synthesis of Piperazine-1-yl(4-(trifluoromethyl)phenyl)methanone(N6)

[0092] According to the preparation method of N1, it was prepared from 1-BOC-piperazine and p-trifluoromethylbenzoyl chloride.

[0093] Synthesis of N,N-diethylpiperazine-1-carboxamide (N7)

[0094] According to the preparation method of N1, it can be prepared from 1-BOC-piperazine and N,N-diethylchloroformamide.

[0095] Example 1: Synthesis of N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-benzoylpiperazin-1-yl)acetamide (Comp#1)

[0096] M1 was placed in an eggplant-shaped bottle, and N,N-dimethylformamide was added as solvent. Triethylamine and N1 were added under stirring at room temperature, and the reaction was heated at 100°C for about 3 hours. After the reaction was completed, water was added to the reaction mixture, and ethyl acetate was extracted 5 times. The organic phase was dried with anhydrous sodium sulfate for 3 hours, and the solvent was evaporated under reduced pressure. A brown-yellow solid was obtained by column chromatography separation and purification, with a yield of 56% and a melting range of 142.9-144°C. 1 H NMR(400MHz,Chloroform-d)δ8.85(s,1H),7.42(s,5H),7.29(d,J=2.1Hz,1H),6.82(dd,J=8.3,2.1Hz,1H) ,6.75(d,J=8.3Hz,1H),5.95(s,2H),3.68(d,J=100.3Hz,4H),3.16(s,2H),2.63(s,4H).HRMS(ESI):exact mass calculated forC 20 H 21 N3O4[M+H] + ,368.1610.Found:368.1605.

[0097] Example 2: Synthesis of N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(4-methylbenzoyl)piperazin-1-yl)acetamide (Comp#2)

[0098] According to the preparation method of Comp#1, a brown-gray solid was obtained from M1 and N2 with a yield of 57%; the melting range was 164.4-165.3℃. 1HNMR(400MHz,Chloroform-d)δ8.86(s,1H),7.33–7.24(m,4H),7.21(d,J=7.8Hz,2H),6.82(dd,J=8.3,2.1Hz, 1H),6.75(d,J=8.3Hz,1H),5.95(s,2H),3.68(s,4H),3.16(s,2H),2.63(s,4H),2.38(s,3H).HRMS(ESI):exact mass calculated for C 21 H 23 N3O4[M+H] + ,382.1767.Found:382.1762.

[0099] Example 3: Synthesis of N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(2-methylbenzoyl)piperazin-1-yl)acetamide (Comp#3)

[0100] According to the preparation method of Comp#1, a light brown solid was obtained from M1 and N3 with a yield of %; the melting range was 130.1-131.3℃. 1 HNMR(600MHz,Chloroform-d)δ8.85(s,1H),7.31–7.27(m,2H),7.24–7.20(m,2H),7.16(dd,J=7.6,1.5Hz,1H),6.82(dd,J=8.3,2.1Hz,1 H),6.75(d,J=8.3Hz,1H),5.95(s,2H),3.92(s,2H),3.25(d,J=96.0Hz,4H),2.62(d,J=115.8Hz,4H),2.32(s,3H).HRMS(ESI):exactmass calculated for C 21 H 23 N3O4[M+H] + ,382.1767.Found:382.1762.

[0101] Example 4: Synthesis of N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-(2-ethylbenzoyl)piperazin-1-yl)acetamide (Comp#4)

[0102] According to the preparation method of Comp#1, a light brown solid was obtained from M1 and N4; the melting range is 241-242.2℃. 1H NMR (600MHz, DMSO-d6) δ10.85(s,1H),7.41–7.37(m,1H),7.34(d,J=7.7Hz,1H),7.31(d,J=2.1Hz,1H),7.30–7.21(m,2H),7.02(dd,J=8.4 ,2.1Hz,1H),6.90(d,J=8.4Hz,1H),6.01(s,2H),4.85–3.91(m,4H),3.63(s,1H),3.31(s,3H),2.58(s,2H),1.15(s,3H).HRMS(ESI):exact mass calculated for C 22 H 25 N3O4[M+H] + ,396.1924,found:396.1920.

[0103] Example 5: Synthesis of 2-(4-benzoylpiperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Comp#5)

[0104] According to the preparation method of Comp#1, a white solid was obtained from M2 and N1 with a yield of 56%; the melting range was 158.6-160℃. 1 HNMR(600MHz,Chloroform-d)δ8.85(s,1H),7.46–7.39(m,5H),6.85(s,2H),3.84(d,J=31.4Hz,13H),3.20(s,2H),2.67(s,4H).HRMS(ESI):exact mass calculated forC 22 H 27 N3O5[M+H] + ,414.2029,found:414.2023.

[0105] Example 6: Synthesis of 2-(4-(4-methylbenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Comp#6)

[0106] According to the preparation method of Comp#1, a brown solid was obtained from M2 and N2 with a yield of 64%; the melting range was 146.8-148℃. 1HNMR(600MHz,Chloroform-d)δ8.79(s,1H),7.24(d,J=8.0Hz,2H),7.15(d,J=7.8Hz,2H),6. 78(s,2H),3.77(d,J=30.6Hz,13H),3.12(s,2H),2.58(s,4H),2.31(s,3H).HRMS(ESI):exact mass calculated for C 23 H 29 N3O5[M+H] + ,428.2185,found:428.2183.

[0107] Example 7: Synthesis of 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Comp#7)

[0108] According to the preparation method of Comp#1, a brown solid was obtained from M2 and N5 with a yield of 53%; the melting range was 132.6-133.9℃. 1 HNMR(500MHz,Chloroform-d)δ8.89(s,1H),7.41(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H),6. 87(s,2H),3.89–3.83(m,12H),3.74(s,4H),3.21(s,2H),2.68(s,4H).HRMS(ESI):exactmass calculated for C 23 H 29 N3O6[M+H] + ,444.2135,found:444.2129.

[0109] Example 8: Synthesis of 2-(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Comp#8)

[0110] According to the preparation method of Comp#1, a brown solid was obtained from M2 and N6 with a yield of 62%; the melting range was 135.2-135.8℃. 1HNMR(600MHz,Chloroform-d)δ8.72(s,1H),7.63(d,J=8.0Hz,2H),7.46(d,J=8.3Hz,2H),6.78(s,2H),3 .80(s,6H),3.75(s,3H),3.53(d,J=108.3Hz,4H),3.14(s,2H),2.61(d,J=71.3Hz,4H).HRMS(ESI):exact mass calculated for C 18 H 26 N4O4[M+H] + ,482.1903,found:482.1898.

[0111] Example 9: Synthesis of 4-(2-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxoethyl)-N,N-diethylpiperazine-1-carboxamide (Comp#9)

[0112] According to the preparation method of Comp#1, a brown solid was obtained from M1 and N7 with a yield of 40%; the melting range was 133.7-135.0℃. 1 HNMR (600MHz, Chloroform-d) δ8.96 (s, 1H), 7.31 (d, J = 2.1Hz, 1H), 6.83 (d, J = 8.4Hz, 1H), 6.76 (d, J = 8. 3Hz,1H),5.95(s,2H),3.30–3.14(m,10H),2.71–2.58(m,4H),1.13(t,J=7.1Hz,6H).HRMS(ESI):exact mass calculated for C 18 H 26 N4O4[M+H] + ,363.2033.Found:363.2031.

[0113] Example 10: Synthesis of N,N-diethyl-4-(2-oxo-2-((3,4,5-trimethoxyphenyl)amino)ethyl)piperazine-1-carboxamide (Comp#10)

[0114] According to the preparation method of Comp#1, a light yellow solid was obtained from M2 and N7 with a yield of 30%; the melting range was 157.8-159.2℃. 1HNMR(500MHz,Chloroform-d)δ9.01(s,1H),6.87(s,2H),3.89(s,6H),3.82(s,3H),3.30(s,4 H),3.24(q,J=7.1Hz,4H),3.18(s,2H),2.67(s,4H),1.14(t,J=7.1Hz,6H).HRMS(ESI):exact mass calculated for C 20 H 32 N2O5[M+H] + ,409.2451.Found:409.2447.

[0115] Example 11: Synthesis of N-(Benzo[d][1,3]dioxol-5-yl)-2-morpholinoacetamide (Comp#11)

[0116] According to the preparation method of Comp#1, M1 was reacted with morpholine to obtain a brown solid with a melting range of 120.5-121.3°C. 1 H NMR(600MHz,Chloroform-d)δ8.95(s,1H),7.31(d,J=2.1Hz,1H),6.84(d,J=8.3Hz,1H),6.76(d ,J=8.3Hz,1H),5.95(s,2H),3.78(t,J=4.6Hz,4H),3.13(s,2H),2.63(s,4H).HRMS(ESI):exact mass calculated for C 13 H 16 N2O4[M+H] + ,265.1188.Found:265.1186.

[0117] Example 12: Synthesis of (4-benzoylpiperazin-1-yl)(quinolin-2-yl)methanone (Comp#12)

[0118] Quinaldic acid (6mmol) was placed in a 100mL eggplant-shaped bottle, and N,N-dimethylformamide (5mL) was added. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and hydroxybenzotriazine were added to the stirred solution. After stirring for 30min, N1 was added to the mixture and stirred at room temperature for 4h. After the reaction was completed, the mixture was poured into water (50mL). The mixture was extracted with ethyl acetate (20mL) 3 times. The organic phase was collected and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and water in sequence. The organic phase was dried with anhydrous sodium sulfate for 3h, the solvent was evaporated under reduced pressure, and the white solid was separated and purified by column chromatography with a yield of 84%; the melting range was 129.3-131.2℃. 1H NMR(600MHz,Chloroform-d)δ8.29(d,J=8.5Hz,1H),8.09(s,1H),7.87(d,J=8.2Hz,1H),7.7 8(d,J=8.4Hz,2H),7.63(t,J=7.6Hz,1H),7.44(s,5H),4.14–3.52(m,8H).HRMS(ESI):exact mass calculated for C 21 H 19 N3O2[M+H] + ,346.1556.Found:346.1550.

[0119] Example 13: Synthesis of (4-(4-methylbenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone (Comp#13)

[0120] According to the preparation method of Comp#12, a white solid was obtained from quinaldine acid and N2 with a yield of 62%; the melting range was 181.0-182.6℃. 1 H NMR(600MHz,Chloroform-d)δ8.31(d,J=8.4Hz,1H),8.11(s,1H),7.89(d,J=8.1Hz,1H),7.80(d,J=8.4Hz,2H),7 .65(t,J=7.5Hz,1H),7.36(d,J=7.6Hz,2H),7.26(s,2H),3.76(d,J=91.1Hz,8H),2.40(s,3H).HRMS(ESI):exact mass calculated forC 22 H 21 N3O2[M+H] + ,360.1712,found:360.1707.

[0121] Example 14: Synthesis of (4-(4-methoxybenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone (Comp#14)

[0122] According to the preparation method of Comp#12, a white solid was prepared from quinaldine acid and N5 with a yield of 37%; the melting range was 165.4-166.6℃. 1H NMR(600MHz,Chloroform-d)δ8.30(d,J=8.4Hz,1H),8.10(d,J=8.5Hz,1H),7.87(d,J=6.8Hz,1H),7.81–7.74(m,2 H),7.63(t,J=6.9Hz,1H),7.42(d,J=8.7Hz,2H),6.93(d,J=8.2Hz,2H),3.82(m,J=23.8Hz,11H).HRMS(ESI):exact mass calculated forC 22 H 21 N3O3[M+H] + ,376.1661.Found:376.1655.

[0123] Example 15: Synthesis of Quinolin-2-yl(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)methanone (Comp#15)

[0124] According to the preparation method of Comp#12, it is prepared from 4-chloromethylbenzoic acid and N6, and purified by column chromatography to obtain a milky white solid with a yield of 40%; the melting range is 175.8-177℃. 1 H NMR(600MHz,Chloroform-d)δ8.31(s,1H),8.10(d,J=52.5Hz,1H),7.93–7.49(m,8H),4.04–3.50(m,8H).HRMS(ESI):exact masscalculated for C 22 H 18 F3N3O2[M+H] + ,414.1429.Found:414.1425.

[0125] Example 16: Synthesis of (4-(4-(chloromethyl)benzoyl)piperazin-1-yl)(4-methoxyphenyl)methanone (Comp#16)

[0126] According to the preparation method of Comp#12, it is prepared from 4-chloromethylbenzoic acid and N5. A small amount of methanol is added and allowed to stand. Solid precipitates and is filtered to obtain a white solid with a yield of 47%. The melting range is 199.2-200.8℃. 1 H NMR(600MHz,Chloroform-d)δ7.27–7.19(m,6H),6.73(d,J=8.3Hz,2H),4.40(s,2H),3.64(s,12H).HRMS(ESI):exactmass calculated for C 20 H21 N2O3Cl[M+H] + ,373.1319,found:373.1314.

[0127] Example 17: Synthesis of (4-(chloromethyl)benzoyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone (Comp#17)

[0128] According to the preparation method of Comp#12, a light yellow solid was obtained from 4-chloromethylbenzoic acid and N6 with a yield of 43%; the melting range was 177-178.2℃. 1 H NMR(600MHz,Chloroform-d)δ7.71(d,J=7.9Hz,2H),7.54(d,J=7.8Hz,2H),7.49–7.34(m,4H),4.60(s,2H),3.63(d,J=168.8Hz,8H).HRMS(ESI):exact masscalculated for C 20 H 18 F3N2O2Cl[M+H] + ,411.1088.Found:411.1088. The target compound structure is shown in Table 1

[0129] Table 1 Structure of target compounds

[0130]

[0131] Anti-fatigue activity evaluation experiment

[0132] 1. Weighted swimming test

[0133] After three days of adaptive feeding, KM mice were randomly divided into model group and compound group according to body weight, with 10 mice in each group, half male and half female. Standard feeding conditions, 12 hours of light environment adaptation, 12 hours of dark environment adaptation, room temperature 25±1℃, relative humidity 55%-60%. The compound group was dissolved with 0.5% CMC-Na in saline, with a concentration of 0.02mmol / mL. The drug administration method of this experiment was 7 consecutive days, with a dose of 0.1

[0134] mL / 10g. Corresponding adaptive training was performed on the 4th, 5th, and 6th days of administration, and the experiment was performed 30 minutes after administration on the 7th day.

[0135] KM mice were subjected to adaptive learning on the 4th, 5th and 6th days of drug administration, and swam for 10 minutes each time. 30 minutes after the last drug administration, 5% of the body weight was placed on the 1 / 3 of the mouse's tail and placed in a 40 cm deep smooth swimming pool with a water temperature of 35-28°C, 5 mice per pool, to prevent trampling. If the mouse did not float to the surface for 10 seconds, it was considered to be exhausted. The mouse was fished out and the time was recorded. If it exceeded 1800 seconds, it was recorded as 1800 seconds.

[0136]

[0137] In the experiment, several compounds with different structures were designed based on the structural characteristics of 1-BCP. The results showed that compared with the model group, all compounds prolonged the swimming time of mice, and the swimming time of some mice was close to or even exceeded 20 minutes, and the improvement percentage relative to the model group exceeded 15%.

[0138] 0%, showing strong activity. It is speculated that the reason may be the extension of the main chain modification, which can form a stronger interaction with the amino acid residues in the protein, thereby promoting the binding with the receptor and enhancing its biological activity. Compared with the model group, the improvement of compounds 18 and 19 was 125% and 135% respectively.

[0139] and 113%.

[0140] The compounds with better activity will be selected for further verification.

[0141] 2. Rotarod test

[0142] After three days of adaptive feeding, KM mice were randomly divided into model group and compound group according to body weight, with 10 mice in each group, half male and half female. Standard feeding conditions, 12 hours of light environment adaptation, 12 hours of dark environment adaptation, room temperature 25±1℃, relative humidity 55%-60%. The compound group was dissolved with 0.5% CMC-Na in saline, with a concentration of 0.02mmol / mL. The drug administration method of this experiment was 7 consecutive days, with a dose of 0.1

[0143] mL / 10g. Corresponding adaptive training was performed on the 4th, 5th and 6th days of administration, and the experiment was performed 30 minutes after administration on the 7th day. KM mice were subjected to adaptive training at 30, 40 and 50 r / min for 5 minutes on the 4th, 5th and 6th days of administration, respectively. 30 minutes after the last administration, the mice were placed on the rotarod fatigue instrument, the speed was set to 60 r / min, the acceleration time was 1 minute, and the time when the mice fell from the rotarod was recorded. If it exceeded 1800s, it was recorded as 1800s.

[0144]

[0145] The experiment showed that the falling time of mice in the compound 1, 4, 7, and 11 groups was significantly longer than that in the model group, indicating that each compound has the biological activity of enhancing the physical strength and coordinated behavior of mice, thereby exerting anti-fatigue activity.

[0146] 3. Determination of biochemical indexes

[0147] According to the results of behavioral experiments, the biochemical index content of compounds with relatively strong anti-fatigue activity was determined. After three days of adaptive feeding, KM mice were randomly divided into a blank group, a model group and each compound group according to body weight, with 10 mice in each group, half male and half female. Standard feeding conditions, 12 hours of light environment adaptation, 12 hours of dark environment adaptation, room temperature 25±1℃, relative humidity 55%-60%. The compound groups were all treated with 0.5%

[0148] CMC-Na was dissolved in saline solution at a concentration of 0.02mmol / mL.

[0149] The dosage was 0.1 mL / 10 g. Adaptive learning was conducted on the 4th, 5th, and 6th days of administration.

[0150] 10min. 30min after the last administration, place the mice in a 40cm deep smooth swimming pool with a water temperature of 35-40℃. After the mice swam for 120min without weight, they were taken out, rested for 30min, dried, and blood was collected from the eyeballs, liver tissue and gastrocnemius muscle tissue. The whole blood was left to stand, centrifuged at 3500r / min for 15min, and the serum was collected and packaged for the detection of relevant indicators.

[0151] Table 2 Biochemical index content

[0152]

[0153] Lactic acid (LD) and urea nitrogen (BUN) are the metabolites of sugar and protein in the body, respectively. Glycogen is the main functional substance in the body. The accumulation of metabolites or the consumption of energy supply substances will cause fatigue symptoms. Therefore, the content of these related indicators is inseparable from fatigue. The results of fatigue-related index content showed that compound 1, 4, 11, and 17 groups can reduce the LD and BUN content in serum, that is, reduce the accumulation of glucose and protein metabolites in the body after exercise, and increase the LG and MG content, that is, reduce the consumption of energy supply substances, which indirectly proves the anti-fatigue activity of the compound.

[0154] 4. Safety Experiment

[0155] ① Take HaCaT cells in the logarithmic growth phase, digest them with trypsin, count them, and add complete culture medium.

[0156] Dilute the medium and adjust the cell density to 1.3×10 4Pieces / mL;

[0157] ② Use a multichannel pipette to inoculate cells into a 96-well plate, 100 μL per well, containing 5,000 cells. Set up a blank group, a negative control group, and a test compound group, with 3 replicate wells in each group. Fill the surrounding blank wells with pure water, and culture the cells in a 5% CO2, 37°C incubator;

[0158] ③ Compound preparation: Weigh the compound to be tested and dissolve it in DMSO with an initial concentration of 40 mmol / L. Extract 1 μL of the DMSO solution and dilute it in 0.5 mL of complete culture medium to obtain a compound solution with a concentration of 80 μM.

[0159] ④ Adding drugs: After 24 hours of cell culture, 100 μL of compound solution was added to each replicate well.

[0160] Place in an incubator and continue culturing for 24 hours;

[0161] ⑤After the incubation, add 10 μL CCK-8 colorimetric reagent to each well and continue incubation for 3 hours.

[0162] ⑥ Colorimetry: After incubation, measure the OD value of each well with an enzyme-labeled instrument, and the selected wavelength is 450nm;

[0163] ⑦Data processing: Use the formula to calculate the cell viability and the standard deviation.

[0164] Survival rate (%) = (OD compound - OD blank) / (OD negative - OD blank) × 100%

[0165] Based on behavioral experiments and the determination of fatigue-related biological indicators, two preferred compounds, Compound 1 and Compound 4, were screened out and further biosafety evaluation was performed. In the HaCaT cell model, under the high-dose treatment condition of 80 μmol / L, the cell survival rate of Compound 1 was 13.6%, while the cell survival rate of Compound 4 reached 140.3%. Compared with Compound 1, Compound 4 showed superior biosafety.

[0166] Table 3 OD values ​​of each group

[0167]

[0168] The above is only a preferred embodiment of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An N-phenyl-2-azacycloacetamide derivative, an isomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, characterized in that: The formula I is as follows, R1 is independently selected from a halogen atom, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O)-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N (C1-6 alkyl)2, -S(O)2-(C1-6 alkyl), -OS(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2, C2-12 heterocycloalkyl, or C5-12 heteroaryl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl; wherein the number of R1 substitutions is 1-3, and the R1 substitution position is the meta or para position of the 2-(4-substituted acylpiperazin-1-yl)acetamide group; when the number of R1 is 2 or more, the R1 connected to the adjacent carbon atoms may optionally combine to form a condensed ring selected from C3-12 heterocycloalkyl, wherein each condensed ring may optionally be substituted by one or more substituents selected from R2; A is a 5-membered ring or a 6-membered ring optionally substituted by R2, X is selected from O, S or N; when the A ring is substituted, the number of R2 substitutions is 1-3, wherein R2 is independently selected from hydrogen, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), -NH- -C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O)-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N(C1-6 alkyl) -6 alkyl), -S(O)2-(C1-6 alkyl), -OS(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, -C(O)-(C5-12 aryl), -C(O)-(C5-12 heteroaryl), C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

2. The N-phenyl-2-azacycloacetamide derivative according to claim 1, characterized in that: The 2-(4-benzoylpiperazine-1-yl)-N-phenylacetamide is as shown in Formula II, The number of R3 substitutions is 0-4; when the number of R3 is 2 or more, the R3 connected to adjacent carbon atoms may optionally combine to form a condensed ring selected from C5-12 aryl, C5-12 heteroaryl, C3-12 cycloalkyl and C3-12 heterocycloalkyl, wherein each condensed ring may be optionally substituted by 1 or more substituents selected from R2; wherein, R3 is independently selected from hydrogen, a halogen atom, -CN, a nitro group, -OH, -NH2, -C(O)H, -OC(O)H, -C(O)-OH, -NH-C(O)H, -C(O)-NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, -C(O)-(C1-6 alkyl), -OC(O)-(C1-6 alkyl), -NH-C(O)-(C1-6 alkyl), -N(C1-6 alkyl)-C(O)-(C1-6 alkyl), -C(O)-O-(C1-6 alkyl), -C(O)-NH-(C1-6 alkyl), -C(O)-N(C1-6 alkyl)2, -S(O)2-(C1-6 alkyl), -O S(O)2-(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -S(O)2-O-(C1-6 alkyl), -S(O)2-NH-(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, -C(O)-(C5-12 aryl), -C(O)-(C5-12 heteroaryl), C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

3. The N-phenyl-2-azacycloacetamide derivative according to claim 1, characterized in that: R1 is selected from -OH, -NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

4. The N-phenyl-2-azacycloacetamide derivative according to claim 1, characterized in that: R3 is selected from hydrogen, a halogen atom, -OH, -NH2, -O-(C1-6 alkyl), -NH-(C1-6 alkyl), -N(C1-6 alkyl)2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C5-12 aryl, or C5-12 heteroaryl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C2-6 haloalkenyl, C1-6 haloalkoxy, C2-6 haloalkenyloxy, or (C1-6 alkoxy)-C1-6 alkyl.

5. The N-phenyl-2-azacycloacetamide derivative according to claim 1, characterized in that: The number of R1 is 2, and R1 connected to adjacent carbon atoms combines to form a C3-6 heterocyclic group condensed ring, preferably a 1,3-dioxole condensed ring.

6. The N-phenyl-2-azacycloacetamide derivative according to claim 1, characterized in that: The number of R1 is 2 or 3, selected from -O-(C1-6 alkyl), preferably -OCH3.

7. An N-phenyl-2-azacyclic acetamide derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate, characterized in that: Includes any of the following: N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-benzoylpiperazin-1-yl)acetamide N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(4-methylbenzoyl)piperazin-1-yl)acetamide N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(2-methylbenzoyl)piperazin-1-yl)acetamide N-(Benzo[d][1,3]dioxolan-5-yl)-2-(4-(2-ethylbenzoyl)piperazin-1-yl)acetamide 2-(4-Benzoylpiperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide 2-(4-(4-Methylbenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide 2-(4-(4-(Trifluoromethyl)benzoyl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)acetamide 4-(2-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxoethyl)-N,N-diethylpiperazine-1-carboxamide N,N-diethyl-4-(2-oxo-2-((3,4,5-trimethoxyphenyl)amino)ethyl)piperazine-1-carboxamide N-(Benzo[d][1,3]dioxol-5-yl)-2-morpholinoacetamide (4-Benzoylpiperazin-1-yl)(quinolin-2-yl)methanone (4-(4-Methylbenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone (4-(4-Methoxybenzoyl)piperazin-1-yl)(quinolin-2-yl)methanone Quinolin-2-yl(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)methanone (4-(4-(Chloromethyl)benzoyl)piperazin-1-yl)(4-methoxyphenyl)methanone (4-(Chloromethyl)benzoyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone.

8. A composition comprising the N-phenyl-2-azacycloacetamide derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier or excipient.

9. Use of the N-phenyl-2-azacycloacetamide derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate according to any one of claims 1 to 7, characterized in that: Used for (1) preparing anti-fatigue drugs; (2) preparing AMPA receptor regulators.

10. An active ingredient combination, comprising the following components: (1) The N-phenyl-2-azacycloacetamide derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate according to any one of claims 1 to 7; and (2) Anti-fatigue drugs.

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