Isoquinolinone derivative, pharmaceutical composition containing isoquinolinone derivative and application of isoquinolinone derivative and pharmaceutical composition

Abstract

The invention discloses an isoquinolinone derivative with aquaporin (AQP), particularly AQP4 regulating activity, and particularly discloses a compound shown as a formula (A) or pharmaceutically acceptable salt of the compound, and application of the compound and a pharmaceutical composition of the compound in prevention and treatment of AQP4-mediated diseases or symptoms. The invention also discloses application of the compound or the composition thereof in preparation of drugs for inhibiting aquaporin AQP4. # imgabs0 #

Description

Isoquinolinone derivatives, pharmaceutical compositions containing the same, and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202210663930.X filed with the State Intellectual Property Office of China on June 10, 2022, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of medicine and specifically relates to novel isoquinolinone derivatives having aquaporin (AQP), particularly AQP4, modulating activity, pharmaceutical compositions containing the same, and the use of such compounds or pharmaceutical compositions in preventing and treating AQP4-mediated diseases or conditions (e.g., edema). The present application also relates to the use of such compounds or pharmaceutical compositions in the preparation of medicaments for inhibiting the aquaporin AQP4. Background Art

[0004] Aquaporins (such as AQP4) are cell membrane proteins that act as molecular water channels that mediate water flow in and out of cells. Although there is a certain degree of passive diffusion of water or infiltration through the cell membrane, water is fast and selectively in and out of cells and relates to aquaporins. These water channels selectively guide water molecules in and out of cells, while blocking ions and other solutes to pass through, thus protecting the membrane potential of cells. Aquaporins are actually found in all life forms, from bacteria to plants, and then to animals. In the human body, they are found in cells throughout the body.

[0005] AQP4 abnormalities are associated with a variety of diseases. It is of great significance to develop new AQP4 regulators and study their effects on the prevention and treatment of AQP4-mediated diseases or conditions.

[0006] Summary of the Invention

[0007] In one aspect, the present application provides a compound of formula A or a pharmaceutically acceptable salt thereof:

[0008] in:

[0009] X is selected from -(C=O)- and -CH2-

[0010] R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino, optionally substituted by one or more alkyl or haloalkyl, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;

[0011] R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl;

[0012] R2 is independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino;

[0013] each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;

[0014] n is an integer selected from 0, 1, 2, 3 or 4.

[0015] In another aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0016] in:

[0017] R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino, optionally substituted by one or more alkyl or haloalkyl, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;

[0018] R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl;

[0019] R2 is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino;

[0020] each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;

[0021] n is an integer selected from 0, 1, 2, 3 or 4.

[0022] In another aspect, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0023] In another aspect, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0024] In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0025] In another aspect, the present application provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease or condition mediated by aquaporin AQP4.

[0026] In another aspect, the present application provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for inhibiting aquaporin AQP4. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figures 1A, 1B, 1D, and 1E respectively show the cell survival of astrocytes cultured under hypotonic conditions with the addition of different doses of the compounds of Examples 1 to 4 and DMSO (solvent control). Figure 1C shows the fitted curve of the protective effect of the compound of Example 1 on astrocytes under hypotonic conditions.

[0028] Figures 2A and 2B show the animal survival curve and 24-hour balance beam score of the compound of Example 1 in a mouse water intoxication model, respectively. Figures 2C and 2D show the animal survival curve of the compound of Example 3 and the compound of Example 4 in a mouse water intoxication model, respectively.

[0029] 3A-3C show the infarct volume observed by TTC staining in rat tMACO-1h model with the compound of Example 1. DETAILED DESCRIPTION

[0030] In one aspect, the present application provides a compound of formula A or a pharmaceutically acceptable salt thereof:

[0031] in:

[0032] X is selected from -(C=O)- and -CH2-

[0033] R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino, optionally substituted by one or more alkyl or haloalkyl, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;

[0034] R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl;

[0035] R2 is independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino;

[0036] each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;

[0037] n is an integer selected from 0, 1, 2, 3 or 4.

[0038] In another aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0039] in:

[0040] R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino, optionally substituted by one or more alkyl or haloalkyl, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;

[0041] R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl;

[0042] R2 is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino;

[0043] each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;

[0044] n is an integer selected from 0, 1, 2, 3 or 4.

[0045] In some embodiments, R0 is independently selected from: C 1-6 alkyl, C each optionally substituted by an amino group 6- 18 Aryl and C 2-18 Heteroaryl; wherein the C 1-6 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-6 Alkyl or C 1-6 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-6 Alkyl and C 1-6 One or more substituents in the haloalkyl group are optionally substituted with 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2-18 Heteroaryl.

[0046] In some embodiments, R0 is independently selected from: C 1-4 alkyl, C each optionally substituted by an amino group6- 12 Aryl and C 2-12 Heteroaryl; wherein the C 1-4 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-4 Alkyl or C 1-4 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-4 Alkyl and C 1-4 One or more substituents in the haloalkyl group are optionally substituted with 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 Heteroaryl.

[0047] In some embodiments, C 2-3 alkyl, C each optionally substituted by an amino group 6-12 Aryl and C 2-12 Heteroaryl; wherein the C 2-3 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-2 Alkyl or C 1-2 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-2 Alkyl and C 1-2 One or more substituents in the haloalkyl group are optionally substituted with 6-10 membered cycloalkyl, 6-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 Heteroaryl.

[0048] In some embodiments, R0 is independently selected from: a ring group formed by condensing an aromatic ring with a cycloalkyl group and a ring group formed by condensing a heteroaromatic ring with a cycloalkyl group, each of which is optionally substituted with an amino group.

[0049] In some embodiments, R0 is independently selected from: C 6-10 Aromatic ring and 3-8 membered cycloalkyl fused ring group and C 2-10 A ring group formed by condensing a heteroaromatic ring with a 3-8 membered cycloalkyl, each of which is optionally substituted with an amino group. In some embodiments, the ring group is connected to the rest of the compound of formula A or formula I via a connection site on the cycloalkyl portion.

[0050] In some embodiments, R0 is independently selected from the group consisting of tetrahydronaphthyl, indanyl, pyridocyclopentanyl, and thiazolocyclohexanyl, each of which is optionally substituted with amino.

[0051] In some embodiments, R 0 is independently selected from the group consisting of tetrahydronaphthyl, indanyl, pyridocyclopentanyl, and thiazolocyclohexanyl substituted with NH 2 .

[0052] In some embodiments, R0 is an alkyl group substituted with a group selected from the group consisting of: each optionally substituted with one or more C 1-6 Alkyl or C 1-6 amino substituted with haloalkyl, and cycloalkyl, N-heterocycloalkyl, aryl and heteroaryl each optionally substituted with one or more substituents selected from hydroxy, halogen, amino and haloalkyl.

[0053] In some embodiments, R0 is C substituted with a group selected from 1-6 Alkyl: -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, and each is selected from hydroxy, halogen, amino and C 1-6 One or more substituents in the haloalkyl group are optionally substituted with 3-12 membered cycloalkyl, 3-12 membered N-heterocycloalkyl, C 6-12 Aryl and C 2-12 Heteroaryl.

[0054] In some embodiments, R0 is C substituted with a group selected from 1-4 Alkyl: cyclohexyl, piperidinyl, phenyl, each optionally substituted by one or more substituents selected from hydroxy, -NH2, F, Cl and CF3

[0055] In some embodiments, R0 is alkyl substituted with a group selected from the group consisting of cycloalkyl; N-heterocycloalkyl optionally substituted with one or more halogens; aryl optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, and haloalkyl; and heteroaryl.

[0056] In some embodiments, R0 is alkyl substituted with a group selected from the group consisting of aryl optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, and haloalkyl.

[0057] In some embodiments, R0 is aryl-substituted alkyl.

[0058] In some embodiments, R0 is C 6-10 Aryl-substituted C 1-4 alkyl.

[0059] In some embodiments, R0 is independently selected from:

[0060] In some embodiments, R0 is independently selected from:

[0061] In some embodiments, R2 is independently selected from the group consisting of: hydrogen, hydroxy, halogen, C 1-6Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, cyano and amino groups.

[0062] In some embodiments, R2 is independently selected from: hydrogen, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, cyano and amino groups.

[0063] In some embodiments, R2 is independently selected from the group consisting of: hydrogen, hydroxy, and halogen.

[0064] In some embodiments, R2 is independently selected from the group consisting of: hydrogen and halogen.

[0065] In some embodiments, R2 is independently selected from the group consisting of: hydrogen, hydroxy, F, Cl, and Br.

[0066] In some embodiments, R2 is independently selected from the group consisting of: hydrogen, F, Cl, and Br.

[0067] In some embodiments, R2 is independently selected from the group consisting of: hydroxy and Cl.

[0068] In some embodiments, R2 is Cl.

[0069] In some embodiments, R1, R3 and R4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2-18 Heteroaryl.

[0070] In some embodiments, R1, R3 and R4 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, 3-10 membered cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, hydroxy, nitro, cyano, 3-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 Heteroaryl.

[0071] In some embodiments, R1, R3, and R4 are each independently selected from the group consisting of: hydrogen, hydroxy, and halogen.

[0072] In some embodiments, R1, R3, and R4 are each independently selected from the group consisting of: hydrogen and halogen.

[0073] In some embodiments, R1, R3, and R4 are each independently selected from the group consisting of hydrogen, hydroxy, F, Cl, and Br.

[0074] In some embodiments, R1, R3, and R4 are each independently selected from the group consisting of: hydrogen, F, Cl, and Br.

[0075] In some embodiments, R1, R3 and R4 are each independently selected from: hydrogen and F.

[0076] In some embodiments, R1, R3, and R4 are each independently selected from the group consisting of: hydrogen and hydroxy.

[0077] In some embodiments, R1 and R4 are both hydrogen, and R3 is hydroxy.

[0078] In some embodiments, R1, R3, and R4 are all hydrogen.

[0079] In some embodiments, each R5 is independently selected from: halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2-18 Heteroaryl.

[0080] In some embodiments, each R5 is independently selected from: halogen, C 1-4 Alkyl, 3-10 membered cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, hydroxy, nitro, cyano, 3-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 Heteroaryl.

[0081] In some embodiments, each R5 is independently selected from halogen.

[0082] In some embodiments, each R5 is independently selected from F.

[0083] In some embodiments, n is an integer selected from 0, 1, or 2.

[0084] In some embodiments, n is 0.

[0085] In the absence of conflict, it should be understood that the above embodiments can be combined to form a technical solution including the features of the combined embodiments. Such a combined technical solution is within the scope of the present disclosure.

[0086] In another aspect, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0087] In another aspect, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0088] In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0090] In another aspect, the present application provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease or condition mediated by aquaporin AQP4.

[0091] In another aspect, the present application provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for inhibiting aquaporin AQP4.

[0092] In another aspect, the present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating diseases mediated by aquaporin AQP4.

[0093] In another aspect, the present application also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in inhibiting aquaporin AQP4.

[0094] In another aspect, the present application also provides a method for preventing or treating diseases or conditions mediated by aquaporin AQP4, comprising administering a therapeutically effective amount of the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof.

[0095] In another aspect, the present application also provides a method for inhibiting aquaporin AQP4, comprising administering the above-mentioned compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a therapeutically effective amount.

[0096] In another aspect, the present application also provides the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease or condition mediated by aquaporin AQP4.

[0097] In another aspect, the present application also provides the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for inhibiting aquaporin AQP4.

[0098] In some embodiments of any of the aforementioned aspects, the aquaporin AQP4-mediated disease is a disease or condition associated with aquaporin AQP4 inhibition.

[0099] In some embodiments of any of the foregoing aspects, the disease or condition comprises edema, cerebral ischemia, cerebral infarction, hydrocephalus, water imbalance disease, hyponatremia, excessive fluid retention, epilepsy, cerebral small vessel disease, retinal ischemia, other eye diseases associated with abnormal intraocular pressure and / or tissue hydration, myocardial ischemia, myocardial ischemia / reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis optica, migraine, and neurodegenerative disease.

[0100] In some embodiments, the edema comprises cytotoxic brain edema, spinal cord edema, retinal edema, optic nerve edema, and cardiac edema.

[0101] In some embodiments, the neurodegenerative disease includes Parkinson's disease and Alzheimer's disease.

[0102] In some embodiments of any of the aforementioned aspects, the subject is a mammal. In some embodiments of any of the aforementioned aspects, the subject is a human.

[0103] The above-mentioned compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof disclosed herein has excellent AQP4 inhibitory activity and can be used as an AQP4 inhibitor for preventing or treating diseases or conditions mediated by aquaporin AQP4.

[0104] definition

[0105] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0106] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0107] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, or an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0108] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0109] The term "membered" refers to the number of backbone atoms constituting the ring. For example, "3-membered to 12-membered" refers to the number of backbone atoms constituting the ring being 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0110] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0111] When the number of a substituent is 0, for example, -(R5)0, it means that the substituent R5 does not exist.

[0112] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0113] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0114] The term "hydroxy" refers to an -OH group.

[0115] The term "cyano" refers to a -CN group.

[0116] The term "nitro" refers to a -NO2 group.

[0117] The term "amino" refers to a -NH2 group, -NH(C 1-6 alkyl) group or -N(C 1-6Specific examples of amino groups include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, -NHC2H5, -N(C2H5)2, -N(C3H7)2, -N(CH3)C2H5, and the like.

[0118] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, alkoxy, haloalkyl, and the alkyl portion of haloalkoxy (i.e., alkyl) have the same definition as above.

[0119] The term "alkoxy" refers to an -O-alkyl group.

[0120] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. The carbocyclic ring can be a 3- to 12-membered ring (e.g., a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]penta-1-yl, etc.

[0121] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. The heterocycle can be a 3-12 membered ring, such as a 3 to 8 membered ring, containing 1 to 5 heteroatoms (e.g., 1, 2, 3, 4, or 5 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioranyl, and aziridinyl groups. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups. Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups. Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Examples of 8-membered heterocycloalkyl groups include, but are not limited to, azabicyclo[3.2.1]octanyl groups.

[0122] The term "N-heterocycloalkyl" refers to a group having the following structure:

[0123] wherein Ring A is a heterocycloalkyl ring as defined above containing said nitrogen, i.e., a heterocycloalkyl ring containing N as the site of attachment.

[0124] The term "aryl" refers to a monocyclic or fused polycyclic ring system consisting only of carbon atoms as ring atoms and having at least one aromatic ring. 6-18 "Aryl" refers to an aromatic group as defined above having 6 to 18 (e.g., 6 to 15, 6 to 12, 6 to 10, 6 to 8) carbon atoms. The aryl group includes a ring system formed by fusion of an aromatic ring with an aromatic ring, or an aromatic ring with a non-aromatic carbocyclic ring (e.g., cycloalkane, cycloalkene or cycloalkyne). Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like.

[0125] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1 to 5, such as 1, 2, 3, 4, or 5) ring atom selected from N, O, S, with the remaining ring atoms being carbon, and having at least one aromatic ring. The ring carbon atoms and heteroatoms may be substituted with oxo or thio groups. The term "C 2-18 "Heteroaryl" refers to a heteroaryl group as defined above having 2-18 (e.g., 2 to 15, 2 to 12, 2 to 10, 2 to 8) carbon atoms. The heteroaryl group includes a ring system formed by condensing a heteroaromatic ring with an aromatic ring, a heteroaromatic ring with a heteroaromatic ring, or a heteroaromatic ring with a non-aromatic carbocyclic ring (e.g., cycloalkane, cycloalkene or cycloalkyne) or a heterocyclic ring (e.g., heterocycloalkane, heterocycloalkene or heterocycloalkyne). Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, wait.

[0126] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0127] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0128] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0129] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes:

[0130] Preventing a disease or disease state from occurring in a subject (eg, a mammal) is particularly useful when such subject is susceptible to having the disease state but has not yet been diagnosed as having the disease state.

[0131] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0132] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0133] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0134] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0135] In this disclosure, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish.

[0136] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0137] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0138] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0139] Certain compounds of the present invention may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included within the scope of the present invention.

[0140] When the compounds herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0141] The compound of the present application can exist in specific geometric isomer or stereoisomer form.The application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application. Other asymmetric carbon atoms can exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0142] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0143] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0144] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0145] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of this application.

[0146] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0147] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0148] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0149] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0150] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0151] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0152] The therapeutic dose of the compounds of the present invention may depend, for example, on the specific therapeutic application, the manner in which the compound is administered, the patient's health and condition, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present invention in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In certain embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.

[0153] The compounds of the present application can be prepared by a variety of synthetic methods, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0154] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0155] An important consideration in synthetic route planning in this field is the selection of a suitable protecting group for a reactive functional group (such as the amino group in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein in their entirety.

[0156] In some embodiments, the compounds of the general formula (I) of the present application can be prepared by those skilled in the art of organic synthesis by the following routes using general or conventional methods in the art:

[0157] Synthesis route:

[0158] For the sake of clarity, the present disclosure is further illustrated by examples, but the examples are not intended to limit the scope of the present application. All reagents used in this application are commercially available and can be used without further purification.

[0159] This application uses the following abbreviations:

[0160] THF: tetrahydrofuran; TBAB: tetrabutylammonium bromide; DMF: N,N-dimethylformamide; NBS: N-bromosuccinimide; DCM: dichloromethane; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; (Boc)2O: di-tert-butyl dicarbonate; DMSO: dimethyl sulfoxide; PE: petroleum ether; EA: ethyl acetate; t-BuOK: potassium tert-butoxide; TTC: 2,3,5-triphenyltetrazolium chloride; HEPES: 4-hydroxyethylpiperazineethanesulfonic acid; K-Aspartic: potassium aspartate; EGTA: ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; Na2-ATP: disodium adenosine triphosphate.

[0161] Example

[0162] Example 1: 7-chloro-2-phenethyl-3,4-dihydroisoquinolin-1(2H)-one

[0163] Synthesis route:

[0164] Procedure: Weigh 7-chloro-3,4-dihydroisoquinolin-1(2H)-one (1.0 g) into a 100 mL single-necked flask. Dissolve in tetrahydrofuran (THF) (10.0 mL). Slowly add tetrabutylammonium bromide (TBAB) (0.2 g), 3 mL of 50% NaOH solution, and then slowly add (2-bromoethyl)benzene (1.2 g). Stir the reaction at 70°C for 4 h. Post-processing and purification: TLC indicates completion of the reaction. Concentrate to remove the tetrahydrofuran. Add an appropriate amount of water to the reaction system, extract the aqueous layer three times with ethyl acetate, combine the organic phases, wash three times with saturated brine, dry, and concentrate. Purify by a normal phase silica gel column (petroleum ether / ethyl acetate as eluent) to obtain 900 mg of the product as a white solid with a purity of 98.68%. 1 H NMR (400MHz, DMSO-d6) δ7.79 (d, J=2.3Hz, 1H), 7.52 (dd, J=8.1, 2.3Hz, 1H), 7.35-7. 17(m,6H),3.74-3.66(m,2H),3.46(t,J=6.6Hz,2H),2.89-2.79(m,4H).MS:286[M+H] + .

[0165] Example 2: 7-chloro-2-(3-phenylpropyl)-3,4-dihydroisoquinolin-1(2H)-one

[0166] The compound of Example 2 was synthesized in the same manner as Example 1, except that (3-bromopropyl)benzene was used instead of (2-bromoethyl)benzene in Example 1. The compound of Example 2 was obtained with a purity of 97.42%. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=2.3Hz,1H),7.52(dd,J=8.1,2.3Hz,1H),7.34(d,J=8.1Hz,1H),7.30-7.21(m,4H ),7.20-7.14(m,1H),3.59-3.46(m,4H),2.94(t,J=6.6Hz,2H),2.64–2.56(m,2H),1.91-1.80(m,2H).MS:300[M+H] + .

[0167] Example 3: 7-chloro-2-(3,4-diamino-5-fluorophenethyl)-3,4-dihydroisoquinolin-1(2H)-one

[0168] Synthesis route:

[0169] Step 1: 4-Bromo-2-fluoro-6-nitroaniline

[0170] Weigh 6.0 g of 2-fluoro-6-nitroaniline into a 250 ml single-necked flask, then add 50 ml of DMF. Dissolve 8.2 g of NBS in 40 mL of DMF and add the resulting mixture dropwise to the single-necked flask using a constant pressure dropping funnel at room temperature. Stir at room temperature for 4 hours. LCMS indicates the formation of the title compound. Post-processing and purification: Pour the reaction mixture into an appropriate amount of ice water, extract twice with ethyl acetate, wash the organic phase three times with water, then with saturated brine, and dry and evaporate to obtain 8 g of the crude title compound as a yellow solid.

[0171] Step 2: tert-Butyl (4-bromo-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate

[0172] 4-Bromo-2-fluoro-6-nitroaniline (8g) was weighed into a 500ml single-necked flask, followed by the addition of DCM (100ml), TEA (18g), and DMAP (0.85g). (Boc)2O (22g) was dissolved in DCM (50ml) and added dropwise to the flask at room temperature. Stirring was continued overnight at room temperature. LCMS indicated the formation of the title compound. Post-processing and purification: The reaction mixture was poured into an appropriate amount of ice water, separated, and extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried, and then purified by rotary evaporation. Purification by flash column chromatography (PE / EA) afforded 14g of the title compound as a pale yellow solid.

[0173] Step 3: tert-Butyl (tert-Butoxycarbonyl)(2-fluoro-6-nitro-4-vinylphenyl)carboxylate

[0174] Weigh tert-butyl (4-bromo-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate (3.5 g) into a 100 ml single-necked flask and add 1,4-dioxane (40 ml) and water (8 ml). Add vinylboronic acid pinacol ester (2.5 g), K2CO3 (3.5 g), and Pd(PPh3)4 (0.95 g) under nitrogen. Replace the nitrogen atmosphere three times, heat the reaction to 90°C for 4 h, and LCMS confirms the formation of the target compound. Post-processing and purification: Add an appropriate amount of water to the system, extract the aqueous layer three times with DCM, and combine the organic phases. Wash twice with saturated brine, dry, and concentrate. Purify by flash column chromatography (petroleum ether / ethyl acetate) to obtain 2.5 g of the target compound as a yellow solid.

[0175] Step 4: tert-Butyl (tert-butoxycarbonyl)(4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-fluoro-6-nitrophenyl)carboxylate

[0176] 7-Chloro-3,4-dihydroisoquinolin-1(2H)-one (250 mg) was weighed into a 40 ml single-necked flask, DMSO (5 ml) was added, and t-BuOK (250 mg) was added portionwise at room temperature and stirred for 1 hour. Tert-butyl (tert-butyloxycarbonyl)(2-fluoro-6-nitro-4-vinylphenyl)carboxylate (1.8 g) was dissolved in THF (5 ml) and added dropwise to the reaction flask at room temperature. The reaction was allowed to proceed for 4 hours. LCMS confirmed the formation of the target compound. Post-treatment and purification: Saturated aqueous ammonium chloride was added to the system under an ice bath, diluted with water, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated. Purification by flash column chromatography (petroleum ether / ethyl acetate) afforded 125 mg of the target compound as a pale yellow solid.

[0177] Step 5: tert-Butyl (2-amino-4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-fluorophenyl)(tert-butoxycarbonyl)carboxylate

[0178] Tert-butyl (tert-butoxycarbonyl)(4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-fluoro-6-nitrophenyl)carboxylate (125 mg) was dissolved in ethanol / water (2:1) (6 ml). Zinc powder (15 eq.) and ammonium chloride (5 eq.) were added with stirring at room temperature. After addition, the reaction mixture was heated to 65°C and allowed to react for 4 h. LCMS confirmed the formation of the target compound and complete reaction of the starting material. Post-processing and purification: The reaction mixture was filtered through Celite. The filter cake was rinsed with water and ethyl acetate, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated to yield 115 mg of a crude pale yellow solid.

[0179] Step 6: 7-Chloro-2-(3,4-diamino-5-fluorophenylethyl)-3,4-dihydroisoquinolin-1(2H)-one

[0180] Tert-butyl (2-amino-4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-fluorophenyl)(tert-butoxycarbonyl)carboxylate (115 mg) was placed in a 25 ml single-necked flask, ethyl acetate (4 ml) was added, and HCl (4 M in EA, 2 ml) was added dropwise with stirring at room temperature. After completion of the addition, the mixture was stirred at room temperature for 1 hour. LCMS confirmed the formation of the target compound and the complete reaction of the starting material. Post-processing and purification: Concentrate, dissolve in a small amount of water and acetonitrile, purify by flash column chromatography (0.2‰ HCl), and lyophilize to obtain the target compound hydrochloride as a white solid (30 mg). MS: 334 [M+H] + . 1 H NMR (400MHz, DMSO-d6+D2O) δ7.78(d,J=2.2Hz,1H),7.50-7.56(m,1H),7.34(d,J=8.2Hz,1H),6.89(d,J=11.4H z,1H),6.80(s,1H),3.70(t,J=7.0Hz,2H),3.48(t,J=6.6Hz,2H),2.88(t,J=6.5Hz,2H),2.80(t,J=7.1Hz,2H).

[0181] Example 4: 2-phenylethyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol

[0182] Synthesis route:

[0183] Step 1: 1,2,3,4-Tetrahydroisoquinoline-6,7-diol

[0184] Weigh 2.0 g of dopamine into a 100 mL single-necked flask and dissolve it in 15 mL of water. Then, weigh 5 mL of 37% formaldehyde solution and add it to the reaction mixture. Stir and react at room temperature overnight. Post-processing and purification: LC-MS indicated completion of the reaction. The solvent was removed by vortexing, and the mixture was concentrated to dryness to obtain the crude title compound, which was used directly in the next step.

[0185] Step 2: tert-Butyl 6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0186] Weigh 1,2,3,4-tetrahydroisoquinoline-6,7-diol (1.66 g) into a 100 mL single-necked flask and dissolve in 20 mL of water. Then, add di-tert-butyl dicarbonate (3.27 g) and 20 mL of dioxane to the reaction mixture. Add triethylamine (1.5 g) and stir at room temperature for 3 hours. Post-processing and purification: LCMS indicated completion of the reaction. Remove the dioxane by evaporation, extract with EA, and purify the EA layer by column chromatography to yield 1.1 g of the title compound.

[0187] Step 3: tert-Butyl 6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0188] Weigh 1.0 g of tert-butyl 6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate into a 100 mL single-necked flask and dissolve in 10 mL of DMF. Then, add 1.56 g of KCO and 5 mL of dioxane. Add CHCl (1.6 g) and stir at room temperature for 3 hours. After LCMS indicated completion, add 80 mL of water, extract with EA, concentrate the EA layer, and purify by column chromatography to yield 1.0 g of the title compound.

[0189] Step 4: 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline

[0190] Weigh 1.0 g of tert-butyl 6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate into a 100 mL single-necked vial and dissolve in a small amount of EA. Then, add 10 mL of 4N HCl / EA and stir at room temperature for 3 hours. Post-processing and purification: LCMS indicated completion of the reaction. Filter the crude target compound and use it directly in the next step.

[0191] Step 5: 6,7-Dimethoxy-2-phenylethyl-1,2,3,4-tetrahydroisoquinoline

[0192] Weigh 200 mg of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline into a 100 mL single-necked flask and dissolve in an appropriate amount of THF. Then, add 370 mg of ethyl bromide. Add 2 mL of 50% NaOH solution to the reaction mixture and stir at 60°C for 3 hours. Post-processing and purification: LCMS indicated completion of the reaction. Remove the THF and extract with EA. The EA layer was concentrated and purified by column chromatography to yield 200 mg of the title compound.

[0193] Step 6: 2-Phenylethyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol

[0194] 6,7-Dimethoxy-2-phenylethyl-1,2,3,4-tetrahydroisoquinoline (250 mg) was weighed into a 100 mL single-necked vial and dissolved in DCM. BBr (630 mg) was then added and stirred at room temperature for 30 minutes. Post-processing and purification: LCMS indicated the reaction was complete. The product was filtered and purified by RP-HPLC to yield 42 mg of a white solid with a purity of 96.91%. MS: 270 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.03(s,1H),9.09(s,1H),7.37-7.25(m,5H),6.59(s,1H),6.55(s,1H),4.43(d,J=14.76Hz,1H),4 .24-4.15(dd,J=14.6,7.04Hz,1H),3.70(m,1H),3.41-3.22(m,3H),3.10-3.07(m,2H),2.98-2.94(m,1H),2.88-2.84(m,1H).

[0195] Synthesis methods of compounds other than the compounds synthesized in Example 1, Example 2, Example 3, and Example 4 can be easily recognized by those skilled in the art by referring to the synthesis routes and source materials and synthesizing other compounds.

[0196] Biological evaluation

[0197] Study on the anti-edema efficacy of the compounds disclosed herein

[0198] Experimental content

[0199] 1) Primary astrocytes that naturally overexpress AQP4 were used as experimental subjects. The compounds of the present disclosure were added and cultured overnight under hypotonic conditions. The protective effect and half-maximal effect concentration of the drug were determined based on the survival rate of astrocytes treated with different drug concentrations.

[0200] 2) C57BL / 6J mice were used as experimental subjects, and pure water containing the compound of the present disclosure was injected intraperitoneally. The mortality rate and balance beam score of the mice were observed for 24 hours to determine the protective effect of the drug in the animal model.

[0201] 3) The tMACO-1h model was established in male SD rats. The drug was administered three times after embolization. The protective effect of the drug in this model was determined by detecting animal mortality, 24h neurological function mNNS score, and TTC staining.

[0202] The results of Experimental Contents 1)-3) show that the compounds of Formula A and Formula I disclosed herein have at least one of the following effects:

[0203] The EC of the compounds of formula A and formula I disclosed herein 50 The range may be below 100 μM, below 20 μM, below 10 μM, or even below 7 μM;

[0204] The compounds of formula A and formula I disclosed herein can effectively increase the survival rate of experimental animals and reduce neurobehavioral damage to animals. After administration of the compounds disclosed herein, the survival rate of animals can be increased by more than 5%, more than 10%, or even more than 20%; and

[0205] The compounds of formula A and formula I disclosed herein have significant protective effects in a rat cerebral ischemia model.

[0206] Experimental Example 1

[0207] Relationship between drug activity and AQP4 structure

[0208] Astrocytes isolated and cultured from the cortex of newborn (P2) rats were seeded into 24-well plates and cultured for 2 days (cell confluence 100%) before hypotonic treatment.

[0209] Experimental groups: DMSO control group, compound experimental group.

[0210] First, pretreat the cells with different doses of drugs or DMSO (solvent control) under isotonic conditions for 30 minutes. Then, aspirate the culture medium (as dry as possible) and add hypotonic culture medium (diluted with water to 25% of the normal culture medium osmotic pressure). Add the corresponding dose of DMSO or drug to each well, and culture the cells in an incubator overnight.

[0211] After approximately 18-22 hours of hypotonic treatment, cell survival was observed under a microscope. Cells were stained with Calcein AM, photographed (three random fields per well), and the number of surviving cells in each field was counted.

[0212] Experimental results

[0213] Because primary astrocytes highly express AQP4 water channels on their surface, a large amount of water flows into the cells under a hypotonic environment, causing the cells to absorb water and burst. This bursting can be alleviated by the inhibitor compounds of the present disclosure that inhibit AQP4 channels, as shown in Figures 1A-1E.

[0214] The results showed that cells treated with DMSO solvent control died in large numbers, while the compounds disclosed herein could inhibit cell death caused by hypotonicity.

[0215] As shown in Figures 1A-1E, the compound of Example 1 has excellent pharmacological efficacy, starting to take effect at 1 μM and achieving a cell protection effect of more than 80% at 30 μM. The EC value of the compound of Example 1 was calculated by measuring the proportion of surviving cells using software. 50 The compound of Example 2 also has excellent cell protection effect, starting to take effect at 1 μM and reaching maximum protection at 10 μM. Its EC 50 The drug effect of Example 3 is the best at 30 μM, and it starts to decrease gradually at 10 μM, and has almost no effect at 0.3 μM. 50 Slightly lower than 3 μM. Example 4 has a cell protection effect of more than 85% at 10 μM and about 40% at 1 μM.

[0216] Experimental Example 2

[0217] Mouse water intoxication model—survival curve and 24-hour balance beam score

[0218] Male C57BL / 6J mice aged 8-12 weeks were randomly divided into 10 groups. The blank control group was intraperitoneally injected with 20-23.5% of body weight of pure water containing 0.1% DMSO. The drug-treated group was intraperitoneally injected with 20-23.5% of body weight of pure water containing a certain dose of the disclosed compound / 0.1% DMSO. The survival of the animals was observed, and after 24 hours, the surviving animals were scored for balance beam behavior.

[0219] Experimental results

[0220] As shown in Figures 2A-2B, the results showed that intraperitoneal injection of 20-23.5% body weight of the compound of Example 1 in pure water containing 1.75 mg / kg or 0.88 mg / kg of 0.1% DMSO effectively increased the survival rate of experimental animals and alleviated neurobehavioral damage to the animals. In terms of the number of animals surviving, the survival rate of animals increased from 30.56% (0.88 mg / kg group) to 46.43% (1.75 mg / kg group) and 52.78% (0.88 mg / kg group), with the 1.75 mg / kg dose having a greater effect. In terms of balance beam behavioral scores, both dose groups showed significant differences compared to the DMSO control group, with the 1.75 mg / kg group showing a more pronounced effect, with a p-value of 0.0044 (**).

[0221] As shown in FIG2C , the compound of Example 3 at a dose of 5 mg / kg improved the survival rate of experimental animals. The survival rate of animals increased from 10% to 30% after administration.

[0222] As shown in FIG2D , the compound of Example 4 at a dose of 5 mg / kg improved both the survival rate and the death rate of the experimental animals. After administration, the survival rate of the animals increased from 13.3% to 23.3%.

[0223] Experimental Example 3

[0224] Rat tMACO-1h Model—Mortality, 24h Neurological Function mNNS Score, and TTC Staining

[0225] Male SD rats weighing 220-250 g were randomly divided into two groups and subjected to a tMACO-1h surgical model. A suture was inserted into the external carotid artery, and the observation endpoint was 24 hours. Three intraperitoneal injections were administered at 10 minutes, 2 hours, and 4 hours after thrombus removal. The vehicle control group received an intraperitoneal injection of cyclodextrin injection solvent, while the drug-treated group received 1.2 mg / kg of the disclosed compound cyclodextrin injection. TTC staining (infarct volume, excluding unsuccessful modeling) was performed 24 hours later.

[0226] Experimental results

[0227] The experimental results of the compound of Example 1 tested according to the above method are shown in Figures 3A-3C. The results show that, in terms of the index of cerebral infarction volume calculated by TTC staining, the group receiving the compound of Example 1 can significantly reduce the infarction volume, with a p-value of 0.0014 (**), indicating that the compounds of the present disclosure, such as the compound of Example 1, have a significant protective effect in the rat cerebral ischemia model.

[0228] Experimental Example 4

[0229] Determination of hERG inhibition

[0230] Cell culture

[0231] HEK-293 cells stably expressing hERG potassium channel were used. hERG potassium channel cells were purchased from Creacell (Cat. No. A-0320). The cell culture method is as follows:

[0232] HEK-293 cells stably expressing hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at a temperature of 37° C. and a carbon dioxide concentration of 5%.

[0233] Cell passaging: Remove old culture medium and wash once with PBS, then add 1 mL of TrypLE TM Express solution, incubate at 37°C for about 1 minute. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, seed the cells in a 10 cm cell culture dish with 6 × 10 cells seeded per dish. 5 cells (final volume: 5 mL).

[0234] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0235] Before patch clamp testing, cells were stained with TrypLE TM Express separation, add culture medium to terminate digestion, centrifuge, resuspend cells and count, adjust the cell density to 2×10 6 cells / mL to 3×10 6 cells / mL, and then gently mix the cells on a balanced shaker at room temperature for 15-20 minutes before testing on the instrument.

[0236] Electrophysiological recordings

[0237] 4.2.1. Record the liquid used

[0238] Extracellular fluid: K-007-1

[0239] 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, NaOH adjusted to pH = 7.4.

[0240] Intracellular fluid: K-002-2

[0241] 20mM KCl, 115mM K-Aspartic, 1mM MgCl2·6H2O, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, KOH adjust pH=7.2.

[0242] The extracellular solution should be stored for one week. After preparing the intracellular solution, aliquot into 10 mL tubes and store frozen at -20°C. Use freshly thawed intracellular solution each day. Use all intracellular solution within one week. If the solution has been used for more than one week, discard the old solution and prepare fresh.

[0243] 4.2.2. Patch clamp assay

[0244] Electrophysiological measurements were performed using a fully automated patch clamp instrument, QPatch 48X (Sophion).

[0245] First, the prepared cells are placed in the centrifuge of the Qpatch workstation. The cells are washed using multiple centrifugation / suspension cycles, and the cell culture medium is replaced with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. A QPlate chip is removed and placed in the QPlate source position. A robotic arm scans the barcodes on the MTP-96 plate and QPlate chip and grabs them to the measurement station. Intracellular and extracellular fluids are drawn from the liquid reservoirs and added to the intracellular fluid reservoir and cell and compound reservoirs of the QPlate chip, respectively. At the measurement station, all measurement sites on the QPlate undergo initial quality control. This quality control process involves aspirating the cell suspension from the cell container in the centrifuge and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal and establish whole-cell recording mode. Once a stable control current baseline is achieved, the test drugs are sequentially drawn from the test MTP-96 plate in order of concentration and applied to the cells.

[0246] The voltage stimulation protocol for whole-cell patch clamp recording of hERG currents is as follows: After forming a whole-cell seal, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV for 0.5 s (to detect leakage current), then stepped to 30 mV for 2.5 s, and then quickly restored to -50 mV for 4 s to stimulate the hERG channel tail current. Data are collected repeatedly every 10 s to observe the effects of drugs on hERG tail current. Experimental data are collected by the QPatch screening workstation and stored in the database server.

[0247] Each drug concentration was administered twice, with a duration of at least 5 minutes. The current measured in the external solution without compound served as a control for each cell, and the measurements were performed in duplicate. All electrophysiological experiments were performed at room temperature.

[0248] 4.3. Data Quality Standards

[0249] The following criteria are used to determine whether the data is acceptable:

[0250] (1) Sealing resistance>1GΩ

[0251] (2) The initial access resistance is less than 15MΩ

[0252] (3) Access resistance ends <15MΩ

[0253] (4) Initial tail current peak > 200pA

[0254] (5) The peak value of the initial tail current is greater than the peak value of the activation current

[0255] (6) There is no obvious spontaneous decay of tail current

[0256] (7) No significant leakage current at a membrane potential of -80 mV (absolute value ≤ 25% of the maximum current peak)

[0257] Data Analysis

[0258] The second of the two dosings was used for data analysis. For each drug concentration, the average of the last three data points before the next dosing concentration was taken to represent the current value after the action of that concentration. The current value representing each drug concentration was normalized to the reference current value used as the blank control. The inhibition rate corresponding to each drug concentration was then calculated (1-). The mean (mean), standard deviation (SD), and standard error (SE) of the inhibition rate were calculated for each concentration.

[0259] Experimental results

[0260] The hERG inhibition rate of the disclosed compound at 1 μM and 10 μM was tested using the above method and compared with the active ingredient of the clinical drug AER-270 for cerebral edema (structure shown in the table below). The results are shown in the table below.

[0261] The above results indicate that Example 1 and Example 3 have significantly lower toxicity than AER-270 in terms of toxicity associated with hERG inhibition.

[0262] While the present disclosure has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications or improvements may be made based on the present disclosure. Therefore, such modifications or improvements, without departing from the spirit of the present disclosure, are intended to be within the scope of protection claimed in this application.

Claims

1. A compound of formula A or a pharmaceutically acceptable salt thereof: in: X is selected from -(C=O)- and -CH2- R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino, optionally substituted by one or more alkyl or haloalkyl, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl; R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl; R2 is independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino; each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl; n is an integer selected from 0, 1, 2, 3 or 4.

2. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R0 is independently selected from: alkyl, aryl and heteroaryl, each of which is optionally substituted by amino; wherein the alkyl is substituted by a group selected from the following: amino optionally substituted by one or more alkyl or haloalkyl, and each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups; R1, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl and heteroaryl; R2 is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cyano, and amino; each R5 is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl; n is an integer selected from 0, 1, 2, 3 or 4.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R0 is independently selected from: C 1-6 alkyl, C each optionally substituted by an amino group 6-18 Aryl and C 2-18 Heteroaryl; wherein the C 1-6 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-6 Alkyl or C 1-6 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-6 Alkyl and C 1-6 One or more substituents in the haloalkyl group are optionally substituted with 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2-18 heteroaryl; or R0 is independently selected from: C 1-4 alkyl, C each optionally substituted by an amino group 6-12 Aryl and C 2-12 Heteroaryl; wherein the C 1-4 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-4 Alkyl or C 1-4 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-4 Alkyl and C 1-4 One or more substituents in the haloalkyl group are optionally substituted with 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 heteroaryl; or R0 is independently selected from: C 2-3 alkyl, C each optionally substituted by an amino group 6-12 Aryl and C 2-12 Heteroaryl; wherein the C 2-3 The alkyl group is substituted with a group selected from the group consisting of: optionally with one or more C 1-2 Alkyl or C 1-2 amino substituted with haloalkyl, and each selected from hydroxy, halogen, amino, C 1-2 Alkyl and C 1-2 One or more substituents in the haloalkyl group are optionally substituted with 6-10 membered cycloalkyl, 6-10 membered heterocycloalkyl, C 6-12 Aryl and C 2-12 heteroaryl; or R0 is independently selected from: a ring group formed by condensing an aromatic ring and a cycloalkyl group and a ring group formed by condensing a heteroaromatic ring and a cycloalkyl group, each of which is optionally substituted by an amino group; or R0 is independently selected from: tetrahydronaphthyl, indanyl, pyridocyclopentanyl and thiazolocyclohexanyl, each of which is optionally substituted with an amino group; or R0 is independently selected from the group consisting of tetrahydronaphthyl, indanyl, pyridocyclopentyl and thiazolocyclohexyl substituted with NH2; or R0 is an alkyl group substituted by a group selected from the following: each optionally substituted by one or more C 1-6 Alkyl or C 1-6 amino substituted with haloalkyl, and cycloalkyl, N-heterocycloalkyl, aryl and heteroaryl each optionally substituted with one or more substituents selected from hydroxy, halogen, amino and haloalkyl; or R0 is C substituted by a group selected from the following 1-4 Alkyl: cyclohexyl, piperidinyl, phenyl, each optionally substituted by one or more substituents selected from hydroxy, -NH2, F, Cl and CF3 or R0 is an alkyl group substituted by a group selected from the following: cycloalkyl; N-heterocycloalkyl optionally substituted by one or more halogens; aryl optionally substituted by one or more substituents selected from hydroxy, amino, halogen and haloalkyl; and heteroaryl; or R0 is an alkyl group substituted by a group selected from the following: an aryl group optionally substituted by one or more substituents selected from hydroxy, amino, halogen and haloalkyl; or R0 is an alkyl group substituted with an aryl group; or R0 is C 6-10 Aryl-substituted C 1-4 Alkyl; or R0 is independently selected from:

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: R2 is independently selected from: hydrogen, hydroxy, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, cyano and amino; or R2 is independently selected from: hydrogen, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, cyano and amino; or R2 is independently selected from: hydrogen, hydroxy and halogen; or R2 is independently selected from: hydrogen and halogen; or R2 is independently selected from the group consisting of hydrogen, hydroxy, F, Cl and Br; or R2 is independently selected from: hydrogen, F, Cl and Br; or R2 is independently selected from: hydroxyl and Cl; or R2 is Cl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: R1, R3 and R4 are each independently selected from: hydrogen, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2-18 heteroaryl; or R1, R3 and R4 are each independently selected from: hydrogen, hydroxy and halogen; or R1, R3 and R4 are each independently selected from: hydrogen and halogen; or R1, R3 and R4 are each independently selected from: hydrogen, hydroxy, F, Cl and Br; or R1, R3 and R4 are each independently selected from: hydrogen, F, Cl and Br; or R1, R3 and R4 are each independently selected from: hydrogen and F; or R1, R3 and R4 are each independently selected from: hydrogen and hydroxy; or R1 and R4 are both hydrogen, and R3 is hydroxy; or R1, R3 and R4 are all hydrogen.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: Each R5 is independently selected from: halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 Aryl and C 2- 18 heteroaryl; or each R5 is independently selected from halogen; or Each R5 is independently selected from F; or n is an integer selected from 0, 1 or 2; or n is 0.

7. The following compound or a pharmaceutically acceptable salt thereof:

8. The following compound or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for preventing or treating a disease or condition mediated by aquaporin AQP4, or in the preparation of a medicament for inhibiting aquaporin AQP4.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in preventing or treating diseases mediated by aquaporin AQP4 or in inhibiting aquaporin AQP4.

12. A method for preventing or treating a disease or condition mediated by aquaporin AQP4, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9.

13. A method for inhibiting aquaporin AQP4, comprising administering the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9 to a subject in need thereof.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, for use in preventing or treating diseases or conditions mediated by aquaporin AQP4.

15. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, for inhibiting aquaporin AQP4.

16. The use according to claim 10 or 11, or the method according to claim 12, or the compound or pharmaceutically acceptable salt or pharmaceutical composition for use according to claim 14, wherein: The aquaporin AQP4-mediated disease is a disease or condition associated with the inhibition of aquaporin AQP4; or Such diseases or conditions include edema, cerebral ischemia, cerebral infarction, hydrocephalus, water imbalance diseases, hyponatremia, excessive fluid retention, epilepsy, cerebral small vessel disease, retinal ischemia, other eye diseases associated with abnormal intraocular pressure and / or tissue hydration, myocardial ischemia, myocardial ischemia-reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis optica, migraine, and neurodegenerative diseases; Preferably, the edema includes cytotoxic brain edema, spinal cord edema, retinal edema, optic nerve edema and cardiac edema; Preferably, the neurodegenerative diseases include Parkinson's disease and Alzheimer's disease.

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