Isoquinoline derivative and pharmaceutical composition comprising same, and uses of isoquinoline derivative and pharmaceutical composition

Abstract

The present application relates to a novel isoquinoline derivative having cell protection activity against edema or nervous system diseases, and in particular to a compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof, and uses of the compound and a pharmaceutical composition comprising same in preparation of drugs for preventing and treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiac edema and diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiac edema, or uses thereof in preparation of drugs for cell protection in nervous system diseases.

Description

Isoquinoline derivatives, pharmaceutical compositions containing the same, and their uses

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202310868474.7 filed with the State Intellectual Property Office of China on July 14, 2023, 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 isoquinoline derivatives having anti-edema or neurological disease cytoprotective activity, pharmaceutical compositions containing the same, and the use of such compounds or pharmaceutical compositions in preventing and treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema, and cardiogenic edema, as well as diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema, and cardiogenic edema. The application also relates to the use of such compounds or pharmaceutical compositions for cytoprotection in neurological diseases. Background Art

[0004] Suppressing the swelling of nerve cells under hypotonic conditions is conducive to the treatment of edema such as cerebral edema related diseases, and developing new nerve cell hypotonic protective agents is of great significance to the prevention and treatment of edema related conditions. For example, 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 quickly and selectively enters and exits cells and relates to aquaporins. These water channels selectively guide water molecules in and out of cells, and simultaneously block 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. Effective nerve cell hypotonic protective effects can be achieved by suppressing aquaporins.

[0005] Summary of the Invention

[0006] In one aspect, the present application provides a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof:

[0007] in:

[0008] Indicates a single bond or a double bond;

[0009] Each R1 is independently selected from: halogen, -CN, amino, alkyl and -OH;

[0010] R2 is absent or is R'2, wherein R'2 is selected from:

[0011] heterocycloalkyl optionally substituted with alkyl; and

[0012] alkyl substituted with a group selected from: heterocycloalkyl or cycloalkyl, each optionally substituted with oxo, alkyl, halogen, -OH; aryl or heteroaryl, each optionally substituted with one or more groups independently selected from -NH2, halogen, -OH, and oxo; and dialkylamino;

[0013] The conditions are:

[0014] when When it represents a single bond, R2 is R'2 and R3 is oxo;

[0015] when When represents a double bond, R2 is absent and R3 is independently selected from:

[0016] Alkoxy substituted with a group selected from the group consisting of: amino optionally substituted with one or two groups independently selected from alkyl, cycloalkyl, alkoxyalkyl, haloalkyl; heterocycloalkyl or heterocycloalkenyl each optionally substituted with one or more groups independently selected from oxo, alkyl, halogen, -OH, -CN, alkoxy, -NH2; and aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH;

[0017] -OR c , where R c Selected from: heterocycloalkyl optionally substituted with alkyl;

[0018] an alkenyl group substituted with a heterocycloalkyl group;

[0019] Alkyl substituted with a group selected from the group consisting of heterocycloalkyl; aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH; and amino optionally substituted with one or two groups independently selected from alkyl and arylalkyl, wherein the amino is substituted with at least one arylalkyl group, and wherein the aryl group in the arylalkyl is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and

[0020] Alkylamino, wherein the alkyl portion of the alkylamino is optionally substituted with a group selected from the group consisting of heterocycloalkyl, alkylamino, dialkylamino, and aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH;

[0021] Each R4 is independently selected from halogen;

[0022] n is an integer selected from 0, 1, 2, 3 or 4; and

[0023] m is an integer selected from 0, 1 and 2.

[0024] In another aspect, the present application provides a pharmaceutical composition comprising the compound of formula I of the present application, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0025] In another aspect, the present application provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of a medicament for preventing or treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, as well as diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, or in the preparation of a medicament for cell protection in nervous system diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figures 1 to 53 respectively show the cell survival of astrocytes cultured with different doses of the example compounds and DMSO (solvent control) under hypotonic conditions and the fitting curves of the protective effect of the example compounds on astrocytes under hypotonic conditions.

[0027] Figures 54 to 61 respectively show the animal survival curves of the example compounds in the mouse water intoxication model.

[0028] FIG62 to FIG64 show the infarct volume observed by TTC staining of the Example compounds in the rat tMACO-1h model. DETAILED DESCRIPTION

[0029] In a first aspect, the present application provides a compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0030] in:

[0031] Indicates a single bond or a double bond;

[0032] Each R1 is independently selected from: halogen, -CN, amino, alkyl and -OH;

[0033] R2 is absent or is R'2, wherein R'2 is selected from:

[0034] heterocycloalkyl optionally substituted with alkyl; and

[0035] alkyl substituted with a group selected from: heterocycloalkyl or cycloalkyl, each optionally substituted with oxo, alkyl, halogen, -OH; aryl or heteroaryl, each optionally substituted with one or more groups independently selected from -NH2, halogen, -OH, and oxo; and dialkylamino;

[0036] The conditions are:

[0037] when When it represents a single bond, R2 is R'2 and R3 is oxo;

[0038] when When represents a double bond, R2 is absent and R3 is independently selected from:

[0039] 1) alkoxy substituted by a group selected from the following: amino optionally substituted by one or two groups independently selected from alkyl, cycloalkyl, alkoxyalkyl, haloalkyl; heterocycloalkyl or heterocycloalkenyl each optionally substituted by one or more groups independently selected from oxo, alkyl, halogen, -OH, -CN, alkoxy, -NH2; and aryl optionally substituted by one or more groups independently selected from halogen, -NH2, -OH;

[0040] 2)-OR c , where R c Selected from: heterocycloalkyl optionally substituted with alkyl;

[0041] 3) alkenyl substituted with heterocycloalkyl;

[0042] 4) alkyl substituted with a group selected from the group consisting of heterocycloalkyl; aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH; and amino optionally substituted with one or two groups independently selected from alkyl and arylalkyl, wherein the amino is substituted with at least one arylalkyl group, and wherein the aryl group in the arylalkyl is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and

[0043] 5) alkylamino, wherein the alkyl portion of the alkylamino is optionally substituted by a group selected from the group consisting of heterocycloalkyl, alkylamino, dialkylamino, and aryl optionally substituted by one or more groups independently selected from halogen, -NH2, and -OH;

[0044] Each R4 is independently selected from halogen;

[0045] n is an integer selected from 0, 1, 2, 3 or 4; and

[0046] m is an integer selected from 0, 1 and 2.

[0047] In some embodiments, each R1 is independently selected from: halogen, -CN, amino, C 1-6 Alkyl and -OH.

[0048] In some embodiments, each R1 is independently selected from the group consisting of: Cl, Br, -CN, -NH2, methyl, and -OH.

[0049] In some embodiments, each R 1 is independently selected from halogen, —NH 2 , and —OH.

[0050] In some embodiments, each R1 is independently selected from the group consisting of: halogen and -OH.

[0051] In some embodiments, each R1 is independently selected from: halogen.

[0052] In some embodiments, each R1 is independently selected from: Cl and -OH.

[0053] In some embodiments, R1 is Cl, and n is 1.

[0054] In some embodiments, R1 is -OH, and n is 1 or 2.

[0055] In some embodiments, R1 is -OH, and n is 2.

[0056] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0057] Optional C 1-4 Alkyl-substituted 5-12 membered heterocycloalkyl; and

[0058] C substituted by a group selected from the following 1-4 Alkyl: each optionally substituted with oxo, C 1-4 alkyl, halogen, -OH substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; each optionally substituted by one or more groups independently selected from -NH2, halogen, -OH and oxo 6-12 Aryl or C 2-12 Heteroaryl; and amino (C 1-4 Alkyl)2.

[0059] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from: 1-4 In some embodiments, the 5-12 membered heterocycloalkyl group is a 5-12 membered heterocycloalkyl group containing nitrogen as a ring heteroatom. In some embodiments, the R'2 is selected from: optionally substituted by C 1-4 Alkyl substituted 5-10 membered heterocycloalkyl, in some embodiments, the C 1-4 The alkyl group is substituted on a nitrogen heteroatom forming a ring of a 5-10 membered heterocycloalkyl group.

[0060] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is substituted by a group selected from the group consisting of: each optionally substituted by oxo, C 1-4alkyl, halogen, -OH substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; each optionally substituted by one or more groups independently selected from -NH2, halogen, -OH and oxo 6-12 Aryl or C 2-12 Heteroaryl; and amino (C 1-4 In some embodiments, the 5-10 membered heterocycloalkyl group is a 5-8 membered heterocycloalkyl group containing nitrogen as a ring heteroatom.

[0061] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is substituted by a group selected from the group consisting of: each optionally substituted by oxo, C 1-4 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl substituted with alkyl, halogen or -OH.

[0062] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is substituted by a group selected from the group consisting of: each optionally substituted by oxo, C 1-4 5-10 membered heterocycloalkyl substituted with alkyl, halogen or -OH.

[0063] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a group selected from the group consisting of: C 2 , ... 6-12 Aryl or C 2-12 Heteroaryl.

[0064] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0065] Optional C 1-2 Alkyl-substituted 5-10 membered heterocycloalkyl; and

[0066] C substituted by a group selected from the following 1-3 alkyl:

[0067] Each optionally substituted with oxo, C 1-2 Alkyl, halogen, -OH substituted 5-8 membered heterocycloalkyl or 3-8 membered cycloalkyl;

[0068] C each optionally substituted with two or three groups independently selected from -NH2, halogen, -OH 6-10 Aryl or C 2- 10 heteroaryl;

[0069] C substituted by oxo 2-10 heteroaryl; and

[0070] Amino (C 1-4 Alkyl)2.

[0071] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0072] C substituted by a group selected from the following 1-4 Alkyl: each optionally replaced by C 1-4 Alkyl-substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; each optionally substituted by one or more groups independently selected from -NH2, -OH and oxo 6-12 Aryl or C2- 12 Heteroaryl.

[0073] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0074] C substituted by a group selected from the following 1-4 Alkyl: each optionally replaced by C 1-4 alkyl-substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; C optionally substituted by one or more groups independently selected from -NH2 and -OH 6-12 Aryl; and C optionally substituted by one or more groups independently selected from -NH2, -OH and oxo 2-12 Heteroaryl.

[0075] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0076] C substituted by a group selected from the following 1-4 Alkyl: optionally replaced by C 1-4 Alkyl-substituted 5-10 membered heterocycloalkyl, C 6-12 Aryl or C optionally substituted by oxo 2-12 Heteroaryl.

[0077] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0078] C substituted by a group selected from the following 1-4Alkyl: C 6-12 Aryl or C optionally substituted by oxo 2-12 Heteroaryl.

[0079] In some embodiments, the C 6-10 Aryl or C 2-10 Substituents on the heteroaryl group are substituted at the meta and para positions.

[0080] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0081] octahydroquinolizinyl, piperidinyl substituted with methyl, and pyrrolyl substituted with methyl; and

[0082] C substituted by a group selected from the following 2-3 Alkyl: cyclohexyl; piperidinyl optionally substituted with methyl or F; morpholinyl; thiomorpholinyl; 1,1-dioxothiomorpholinyl; 3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl; 8-azabicyclo[3.2.1]octanyl optionally substituted with -OH; phenyl optionally substituted with two or three groups independently selected from -NH2, F, Cl, -OH; pyridinyl substituted with two -NH2; and -N(CH2CH3)2.

[0083] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from octahydroquinolizinyl, piperidinyl substituted by methyl, and pyrrolyl substituted by methyl.

[0084] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from: C substituted by a group selected from the following 2-3 Alkyl: cyclohexyl; piperidinyl optionally substituted by methyl or F; morpholinyl; thiomorpholinyl; 1,1-dioxothiomorpholinyl; 3,8-diazabicyclo[3.2.1]octanyl optionally substituted by methyl; 8-azabicyclo[3.2.1]octanyl optionally substituted by -OH.

[0085] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from: C substituted by a group selected from the following 2-3 Alkyl: phenyl or pyridyl, each optionally substituted by two or three groups independently selected from -NH2, F, Cl, -OH;

[0086] In some embodiments, when When it represents a single bond, R2 is R'2, wherein R'2 is selected from: C substituted by a group selected from the following 2-3 Alkyl: phenyl optionally substituted by two or three groups independently selected from -NH2, F, Cl, -OH; pyridyl substituted by two -NH2;

[0087] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0088] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0089] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0090] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0091] In some embodiments, when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

[0092] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0093] 1) C substituted by a group selected from the following 1-6 Alkoxy: optionally substituted by one or two independently selected from C 1-6 Alkyl, 3-10 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 amino substituted by a haloalkyl group; each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted by an alkoxy group, -NH2; and C6- optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 12 aryl;

[0094] 2)-OR c , where R c Select from: Optional C 1-6Alkyl-substituted 3-10 membered heterocycloalkyl;

[0095] 3) C substituted by 3-10 membered heterocycloalkyl 2-6 alkenyl;

[0096] 4) C substituted by a group selected from the following 1-6 Alkyl: 3-10 membered heterocycloalkyl; C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl; and optionally one or two independently selected from C 1-6 Alkyl and C6- 12 Aryl C 1-6 an amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-12 Aryl C 1-6 alkyl group, and wherein the C 6-12 Aryl C 1-6 C in the alkyl group 6-12 Aryl is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and

[0097] 5) C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6 The alkyl portion is optionally substituted by a group selected from the group consisting of 5-10 membered heterocycloalkyl, amino (C 1-6 alkyl), amino (C 1-6 alkyl) 2, and C optionally substituted by one or more groups independently selected from halogen, -NH 2 , -OH 6-10 Aryl.

[0098] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0099] 1) C substituted by a group selected from the following 1-3 Alkoxy: optionally substituted by one or two independently selected from C 1-4 Alkyl, 3-7 membered cycloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 amino substituted by a haloalkyl group; each optionally substituted by one or more independently selected from oxo, C 1-4 Alkyl, halogen, -OH, -CN, C 1-4 5-10 membered heterocycloalkyl or 5-10 membered heterocycloalkenyl substituted by an alkoxy group, -NH2; and C6- optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 10 aryl;

[0100] 2)-OR c , where R c Select from: Optional C 1-4 Alkyl-substituted 3-10 membered heterocycloalkyl;

[0101] 3) C substituted by 5-10 membered heterocycloalkyl 2-4 alkenyl;

[0102] 4) C substituted by a group selected from the following 1-4 Alkyl: 5-10 membered heterocycloalkyl; C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl; and optionally one or two independently selected from C 1-4 Alkyl and C6- 10 Aryl C 1-4 an amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-10 Aryl C 1-4 alkyl group, and wherein the C 6-10 Aryl C 1-4 C in the alkyl group 6-10 Aryl is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and

[0103] 5) C 1-4 Alkylamino, wherein the C 1-4 C in alkylamino 1-4 The alkyl portion is optionally substituted by a group selected from the group consisting of 5-10 membered heterocycloalkyl, amino (C 1-4 alkyl), amino (C 1-4 alkyl) 2, and C optionally substituted by one or more groups independently selected from halogen, -NH 2 , -OH 6-10 Aryl.

[0104] when When represents a double bond, R2 is absent and R3 is independently selected from:

[0105] C substituted by a group selected from the following 1-6 Alkoxy: optionally substituted by one or two independently selected from C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 amino substituted by a haloalkyl group; each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with an alkoxy group; and C 6-12 aryl;

[0106] -OR c , where R c Select from: Optional C 1-6 Alkyl-substituted 3-10 membered heterocycloalkyl;

[0107] C substituted by 3-10 membered heterocycloalkyl 1-6 Alkyl; and

[0108] C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6 The alkyl portion is optionally replaced by C 6-10 Aryl substitution.

[0109] when When represents a double bond, R2 is absent and R3 is independently selected from:

[0110] C substituted by a group selected from the following 1-6 Alkoxy: optionally substituted with one or two C 1-6 alkyl-substituted amino; 3-10 membered heterocycloalkyl optionally substituted by one or more halogens.

[0111] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0112] 1) C substituted by a group selected from the following 1-3 Alkoxy: amino optionally substituted by one or two groups independently selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, methoxyethyl, -CH2CF3, -CH2CHF2; piperidinyl or tetrahydropyridinyl, each optionally substituted by one or more groups independently selected from methyl, F, -OH, -CN, methoxy, -NH2; morpholinyl; thiomorpholine; 1,1-dioxothiomorpholinyl; 2-oxa-6-aza-spiro[3,3]heptyl; 8-azabicyclo[3.2.1]octanyl; pyrrolyl optionally substituted by methyl; azepanyl; hexahydropyrrolazinyl optionally substituted by F; piperazinyl optionally substituted by methyl; and phenyl optionally substituted by one or more groups selected from F, -NH2, -OH;

[0113] 2)-OR c , where R c is selected from the group consisting of: pyrrolyl, azetidinyl, octahydroquinolizinyl, and piperidinyl optionally substituted with methyl;

[0114] 3) a propenyl group substituted with a morpholinyl group; and

[0115] 4) C substituted by a group selected from the following 1-3Alkyl: benzylamino, methyl(benzyl)amino, (phenethyl)amino, and methyl(phenethyl)amino, wherein the phenyl group is optionally substituted with one or more groups independently selected from -NH2, -OH, and F; morpholinyl; piperidinyl; and diaminofluorophenyl; and

[0116] 5) C 2-3 Alkylamino, wherein the C 2-3 C in alkylamino 2-3 The alkyl portion is optionally substituted with a group selected from piperidinyl, morpholinyl, -NH(CH2CH3), -N(CH2CH3)2 and phenyl.

[0117] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0118] 1) C substituted by a group selected from the following 1-6 Alkoxy: optionally substituted by one or two independently selected from C 1-6 Alkyl, 3-10 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 amino substituted by a haloalkyl group; each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted by an alkoxy group, -NH2; and C6- optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 12 aryl; and

[0119] 4) C substituted by a group selected from the following 1-6 Alkyl: 3-10 membered heterocycloalkyl; C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl; and optionally one or two independently selected from C 1-6 Alkyl and C6- 12 Aryl C 1-6 an amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-12 Aryl C 1-6 alkyl group, and wherein the C 6-12 Aryl C 1-6 C in the alkyl group 6-12 The aryl group is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen.

[0120] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C1-6 Alkoxy, the C 1-6 The alkoxy group is substituted with a group selected from:

[0121] Optionally, one or two independently selected from C 1-6 Alkyl, 3-10 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 an amino group substituted with a haloalkyl group;

[0122] Each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with alkoxy or -NH2; and

[0123] C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-12 Aryl.

[0124] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is substituted with a group selected from:

[0125] Optionally, one or two independently selected from C 1-6 Alkyl, 3-10 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 An amino group substituted with a haloalkyl group.

[0126] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is substituted with a group selected from:

[0127] Each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with alkoxy or -NH2.

[0128] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is substituted with a group selected from:

[0129] C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-12 Aryl.

[0130] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from -OR c , where R c Select from: Optional C 1-6 Alkyl-substituted 3- to 10-membered heterocycloalkyl.

[0131] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from: C substituted by 3-10 membered heterocycloalkyl 2-6 Alkenyl.

[0132] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a group selected from:

[0133] 3-10 membered heterocycloalkyl;

[0134] C substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 aryl; and

[0135] One or two independently selected from C 1-6 Alkyl and C 6-12 Aryl C 1-6 an amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-12 Aryl C 1-6 alkyl group, and wherein the C 6-12 Aryl C 1-6 C in the alkyl group 6-12 The aryl group is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen.

[0136] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a 3-10 membered heterocycloalkyl group.

[0137] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a group selected from:

[0138] C substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl.

[0139] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a group selected from:

[0140] One or two independently selected from C 1-6 Alkyl and C 6-12 Aryl C 1-6 an amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-12 Aryl C 1-6 alkyl group, and wherein the C 6-12 Aryl C 1-6 C in the alkyl group 6-12 The aryl group is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen.

[0141] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0142] C substituted by a group A selected from the following 1-3 alkyl:

[0143] In the above group A, R a Selected from H and C 1-4 Alkyl, each R b is independently selected from -NH2, -OH and halogen, x is an integer from 1 to 4, and y is an integer from 0 to 4. In some embodiments, x is an integer from 1 to 2. In some embodiments, y is an integer from 1 to 3. In some embodiments, R a In some embodiments, each R b Independently selected from -NH2, -OH and F.

[0144] In some embodiments, in some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0145] C substituted by a group A-1 selected from the following 1-3 alkyl:

[0146] In the above group A-1, R a 、R b and x are as defined in group A above.

[0147] In some embodiments, in some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0148] C substituted by a group A-2 selected from the following 1-3 alkyl:

[0149] In the above group A-2, R a 、R b and x are as defined in group A above.

[0150] In some embodiments, in some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0151] C substituted by a group A-3 selected from the following 1-3 alkyl:

[0152] In the above group A-3, R a 、R b and x are as defined in group A above.

[0153] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from the following groups B:

[0154] In the above group B, L is a direct bond, an oxygen atom or N(R a ), R a Selected from H and C 1-4 Alkyl, each R b is independently selected from -NH2, -OH and halogen, x is an integer from 1 to 4, and y is an integer from 0 to 4. In some embodiments, x is an integer from 1 to 2. In some embodiments, y is an integer from 0 to 3. In some embodiments, R a In some embodiments, each R b In some embodiments, L is a direct bond or an oxygen atom, and y is an integer from 1 to 3. In some embodiments, L is a direct bond. In some embodiments, L is an oxygen atom.

[0155] In some embodiments, when When a double bond is represented, R2 is absent and R3 is a group C as follows:

[0156] In the above group C:

[0157] L is selected from a direct bond, an oxygen atom, a C 2-6 Alkenylene and N(R a );

[0158] Cy1 is each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with alkoxy, halogen, -OH, -CN, or -NH2;

[0159] R a Selected from H and C 1-4 alkyl; and

[0160] x is an integer from 0 to 4.

[0161] In some embodiments, L in the above group C is selected from an oxygen atom. In some embodiments, L in the above group C is selected from a direct bond. In some embodiments, L in the above group C is selected from N(R a ).

[0162] In some embodiments, Cy1 in the above group C is selected from each optionally substituted by one or more independently selected from oxo, C 1-4 Alkyl, C 1-4 5-10 membered heterocycloalkyl or 5-10 membered heterocycloalkenyl substituted with alkoxy, halogen, -OH, -CN, or -NH2.

[0163] In some embodiments, Cy1 in the above group C is piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholine, 1,1-dioxothiomorpholinyl, 2-oxa-6-aza-spiro[3,3]heptyl, 8-azabicyclo[3.2.1]octanyl, pyrrolyl, azepanyl, hexahydropyrrolazinyl, piperazinyl, azetidinyl, octahydroquinolizinyl, each of which is optionally substituted by one or more groups independently selected from oxo, methyl, ethyl, methoxy, F, -OH, -CN, -NH2.

[0164] In some embodiments, x in the above group C is an integer from 0 to 3. In some embodiments, R in the above group C a In some embodiments, R in the above group C is selected from H and methyl. a For H.

[0165] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from: C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6The alkyl portion is substituted by a group selected from the group consisting of 5-10 membered heterocycloalkyl, amino(C1-6 alkyl), amino(C 1-6 alkyl) 2, and C optionally substituted by one or more groups independently selected from halogen, -NH 2 , -OH 6-10 Aryl.

[0166] In some embodiments, when When a double bond is represented, R2 is absent and R3 is independently selected from: C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6 The alkyl portion is substituted by a group selected from the group consisting of 5-10 membered heterocycloalkyl, amino (C 1- 6 alkyl), amino (C 1-6 alkyl)2, and C 6-10 Aryl.

[0167] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0168] when When represents a double bond, R2 is absent and R3 is independently selected from:

[0169] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0170] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0171] In some embodiments, when When represents a double bond, R2 is absent and R3 is independently selected from:

[0172] In some embodiments, R4 is Cl.

[0173] In some embodiments, m is 0.

[0174] In some embodiments, the compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof is selected from a compound of formula II, a compound of formula III, or a compound of formula IV, or a stereoisomer or pharmaceutically acceptable salt thereof,

[0175] wherein R1, R2, R3, R4, m and n are as defined in Formula I.

[0176] In some embodiments, the compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0177] wherein R1, R2, R3, and R4 are as defined in Formula I.

[0178] In some embodiments, the compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of formula III, or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0179] wherein R1, R3, R4, m and n are as defined in Formula I.

[0180] In some embodiments, the compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IV, or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0181] wherein R1, R2, R4, m and n are as defined in Formula I.

[0182] It should be understood that any embodiment of the compounds of the present disclosure as described above and any specific substituents described herein for specific R1, R2, R3, R4, m and n substituents in the compounds of the present disclosure as described above can be independently combined with other embodiments of the present application and / or substituents of the compounds to form embodiments of the present application not specifically described above. In addition, where a list of substituents is disclosed in a specific embodiment and / or claim for any specific R1, R2, R3, R4, m and n substituents, it should be understood that one or more substituents can be deleted from the list, and the remaining list of substituents will be considered to be an embodiment of the present application.

[0183] In a second aspect, the present application provides the following compound, or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0184] In a third aspect, the present application provides a pharmaceutical composition comprising the compound of formula I of the present application, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0186] In a fourth aspect, the present application provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of a drug for preventing or treating diseases or conditions such as cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema.

[0187] In a fifth aspect, the present application provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of a medicament for preventing or treating diseases or conditions associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema.

[0188] In a sixth aspect, the present application also provides the use of the compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs for cell protection in nervous system diseases.

[0189] In the seventh aspect, the present application also provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in preventing, treating or inhibiting cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, as well as diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema.

[0190] In an eighth aspect, the present application also provides a method for preventing or treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, as well as diseases or conditions associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0191] In a ninth aspect, the present application also provides a method for cell protection in a nervous system disease, comprising administering to a subject in need thereof a compound of formula I of the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the amount of the compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a therapeutically effective amount.

[0192] In the tenth aspect, the present application also provides the above-mentioned compound of formula I, or its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, as well as diseases or conditions associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema.

[0193] In the eleventh aspect, the present application also provides the compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for use in cell protection in nervous system diseases.

[0194] In some embodiments, the diseases associated with cerebral edema include cerebral ischemia, cerebral infarction, hydrocephalus, epilepsy, migraine, cerebral small vessel disease, and neurodegenerative diseases.

[0195] In some embodiments, the diseases associated with spinal cord edema include water imbalance disorders, hyponatremia, excessive fluid retention, and sepsis.

[0196] In some embodiments, the disease associated with retinal edema comprises retinal ischemia.

[0197] In some embodiments, the diseases associated with optic nerve edema include neuromyelitis optica, other eye diseases associated with abnormal intraocular pressure and / or tissue hydration.

[0198] In some embodiments, the diseases associated with cardiogenic edema include myocardial ischemia, myocardial ischemia-reperfusion injury, myocardial infarction, myocardial hypoxia, and congestive heart failure.

[0199] In some embodiments, the neurodegenerative disease includes Parkinson's disease and Alzheimer's disease.

[0200] In a twelfth aspect, the present application provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of a medicament for preventing or treating a disease or condition that benefits from the inhibition of aquaporin AQP4, or in the preparation of a medicament for inhibiting aquaporin AQP4.

[0201] In a thirteenth aspect, the present application provides the use of the above-mentioned compound of formula I, or its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in preventing or treating diseases or conditions that benefit from the inhibition of aquaporin AQP4, or in inhibiting aquaporin AQP4.

[0202] In the fourteenth aspect, the present application provides a method for preventing or treating a disease or condition that benefits from the inhibition of aquaporin AQP4 or a method for inhibiting aquaporin AQP4. It includes administering a compound of formula I of the present application, or a stereoisomer thereof, 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 of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a therapeutically effective amount.

[0203] In a fifteenth aspect, the present application provides the compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases or conditions that benefit from the inhibition of aquaporin AQP4 or for inhibiting aquaporin AQP4.

[0204] 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.

[0205] The compound of formula I of the present application, or its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition has excellent cytoprotective activity in nervous system diseases and can be used to prevent or treat brain edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema caused by various diseases, as well as diseases or conditions associated with brain edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema.

[0206] definition

[0207] 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.

[0208] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the compound after the substitution is stable. When the substituent is an oxo (i.e., =O), the oxo can be substituted on a carbon atom or a heteroatom (for example, substituted on an S atom to form S(=O) or S(=O)2). When the oxo is substituted on a carbon atom, it means that two hydrogen atoms are replaced. Oxo will not occur on an aromatic group.

[0209] The term "substituted by one or more groups" means that the number of substituents can be one or more (e.g., 1-6, 1-5, 1-4, 1-3 or 1-2), as long as the valence rules are met and the substituted compound is stable.

[0210] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] When the number of a substituent is 0, for example, -(R5)0, it means that the substituent R5 does not exist.

[0215] When one of the variables is selected from a direct bond, it means that the two groups it connects are directly connected. For example, in ALZ, when L represents a direct bond, it means that the structure is actually AZ.

[0216] In this article Indicates the attachment site.

[0217] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0218] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0219] The term "hydroxy" refers to an -OH group.

[0220] The term "cyano" refers to a -CN group.

[0221] The term "nitro" refers to a -NO2 group.

[0222] The term "amino" refers to a -NH2 group.

[0223] The term "alkylamino" or "amino(alkyl)" refers to -NH(alkyl) and the term "dialkylamino" refers to -N(alkyl)2.

[0224] 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 (e.g., 1, 2, 3, 4, 5, 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.

[0225] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 2-6 “Alkenyl” is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms. It is understood that in case the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl groups include, but are not limited to, ethenyl, propenyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, and the like. The above description of alkenyl may apply to alkenylene, but alkenylene is a divalent radical.

[0226] The term "alkoxy" refers to an -O-alkyl group.

[0227] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, condensed, 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.

[0228] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, fused, bridged, or spirocyclic ring. The heterocycle can be a 3-12 membered ring containing 1 to 5 heteroatoms (e.g., 1, 2, 3, 4, or 5 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen, such as a 3 to 10 membered, 3 to 8 membered, 3 to 7 membered, or 5-7 membered ring. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, and azetidinyl 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, thiepanyl, and 2-oxa-6-aza-spiro[3,3]heptanyl groups. Examples of 8-membered heterocycloalkyl groups include, but are not limited to, 8-azabicyclo[3.2.1]octanyl 3,8-diazabicyclo[3.2.1]octanyl Hexahydropyrrolizinyl Examples of other heterocycloalkyl groups include, but are not limited to, octahydroquinolizinyl and 1,1-dioxothiomorpholinyl wait.

[0229] The term "N-heterocycloalkyl" refers to a group having the following structure:

[0230] wherein Ring A is a heterocycloalkyl ring as defined above containing said nitrogen, i.e., a heterocycloalkyl ring containing N as the point of attachment to the rest of the molecule.

[0231] The term "heterocyclenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one double bond, wherein one or more of the ring atoms in the ring system is an element other than carbon, e.g., 1, 2, 3, 4, or 5 ring atoms are each independently a heteroatom selected from nitrogen, oxygen, and sulfur. No adjacent oxygen and / or sulfur atoms are present in the ring system. In some embodiments, the heterocyclenyl ring contains, for example, 5-12 ring atoms, 5-10 ring atoms, 5-8 ring atoms, 5-7 ring atoms, or 5-6 ring atoms. The prefix aza, oxa, or thia before the heterocyclenyl name indicates that at least one nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. Non-limiting examples of suitable monocyclic azaheterocycloalkenyls include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 2-pyrazolinyl, etc. Non-limiting examples of suitable oxacycloalkenyls include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, etc. Non-limiting examples of suitable polycyclic oxacycloalkenyls are 7-oxabicyclo[2.2.1]heptenyl.

[0232] 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.

[0233] 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 fusion of a heteroaromatic ring with an aromatic carbocycle, a heteroaromatic ring with a heteroaromatic ring, or a heteroaromatic ring with a non-aromatic carbocycle (e.g., cycloalkane, cycloalkene or cycloalkyne) or a heterocycle (e.g., heterocycloalkane, heterocycloalkene or heterocycloalkyne), and in the aforementioned fused heteroaryl group, the point of attachment of the heteroaryl group to the rest of the molecule can be on the heteroaromatic ring or on the other ring fused to the heteroaromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, wait.

[0234] 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:

[0235] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0236] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0237] 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:

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] As used herein, the term "subject" includes both 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.

[0244] 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.

[0245] 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".

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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).

[0251] 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.

[0252] 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 18 F 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.

[0253] 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.

[0254] 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.

[0255] Typical routes of administration of the compounds of the present invention, or their stereoisomers or pharmaceutically acceptable salts, 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.

[0256] 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.

[0257] 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.

[0258] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners and / or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose and / or starch paste; talc, starch, magnesium stearate, calcium stearate and / or stearic acid; lactose, sucrose, starch, mannitol, sorbitol and / or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pre-coated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose and / or cross-linked polyvinyl pyrrolidone, etc. Dragee cores may optionally be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

[0259] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] For the sake of clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0265] This application uses the following abbreviations:

[0266] DMSO: dimethyl sulfoxide; EA: ethyl acetate; THF: tetrahydrofuran; DIEA: N-ethyldiisopropylamine; DMF: N,N-dimethylformamide; DCM: dichloromethane; TBSCl: tert-butyldimethylsilyl chloride; TBS: tert-butyldimethylsilyl; ACN: acetonitrile; Pd2(dba)3: trisdibenzylideneacetone dipalladium; LCMS: liquid chromatography-mass spectrometry; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; RP-HPLC: reversed-phase high performance liquid chromatography; NaBH(AcO)3: sodium triacetoxyborohydride; AcOH: acetic acid; MeOH: methanol; EtOH: ethanol; PPh3: triphenylphosphine; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; TEA or Et3N: triethylamine; AcCl: acetyl chloride; Boc2O: di-tert-butyl dicarbonate; DMAP: 4-dimethylthiophene. Methylaminopyridine; m-CPBA: m-chloroperbenzoic acid; TBAB: tetrabutylammonium bromide; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; DIAD: diisopropyl azodicarboxylate; PE: petroleum ether; t-BuXphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; TBAF: tetrabutylammonium fluoride; NBS: N-bromosuccinimide; TMSCN: trimethylsilyl cyanide; STAB: sodium triacetoxyborohydride; DPPA: diphenylphosphoryl azide; 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.

[0267] Example

[0268] Example 1: 1-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)piperidin-4-ol

[0269] Synthesis route:

[0270] Step 1: 4-((tert-Butyldimethylsilyl)oxy)piperidine

[0271] Weigh 1g of piperidin-4-ol and 1.3g of imidazole and dissolve them in dichloromethane. Add 2.2g of tert-butyldimethylsilyl chloride at 0°C and stir at room temperature for two hours. Post-processing: After LCMS indicates completion of the reaction, add an appropriate amount of water to the reaction system. Extract the aqueous layer with dichloromethane, and combine the organic phases. Wash each with saturated NaCl solution. Dry and concentrate the organic phase to yield 1.6g of the crude target compound.

[0272] Step 2: 2-(4-((tert-Butyldimethylsilyl)oxy)piperidin-1-yl)ethan-1-ol

[0273] Dissolve 1.6 g of 4-((tert-butyldimethylsilyl)oxy)piperidine in 10 mL of water, then slowly add 1.48 mL of a 1 M ethylene oxide solution in tetrahydrofuran (TEF) dropwise. Stir at 50°C for two hours. Post-treatment: After TLC indicates completion of the reaction, extract the aqueous layer with dichloromethane and combine the organic phases. Wash each with saturated NaCl solution. Dry and concentrate the organic phase to yield 0.95 g of the crude title compound.

[0274] Step 3: 1-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)piperidin-4-ol

[0275] 950 mg of 2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethan-1-ol was dissolved in 5 mL of dimethyl sulfoxide. 820 mg of potassium tert-butoxide was added to the reaction system and stirred at room temperature for 30 minutes. 870 mg of 1,7-dichloroisoquinoline was added and stirred at room temperature for two hours. Post-treatment: After TLC indicated completion of the reaction, the product was purified by reverse medium pressure preparative purification (HCl.H2O / ACN = 0-100%) to afford the title compound as a white solid (42 mg). LCMS 307 [M+H]. 1 H NMR(400MHz,D2O)δ7.96(d,J=4.0Hz,1H),7.74–7.67(m,1H),7.66–7.52(m,2H),7 .29–7.23(m,1H),4.72(s,2H),4.14(s,1H),3.89(dq,J=11.4,6.2,5.4Hz,1H),3.7 0(d,J=8.7Hz,3H),3.51(dd,J=10.3,6.0Hz,1H),3.45–3.35(m,1H),3.19(t,J=11. 9Hz, 1H), 2.18 (d, J=12.9Hz, 1H), 1.96 (p, J=14.4, 13.2Hz, 2H), 1.81–1.68 (m, 1H).

[0276] Example 2: 4-(2-((6-chloroisoquinolin-1-yl)oxy)ethyl)morpholine

[0277] Synthesis route:

[0278] Weigh 199 mg of 2-morpholinylethanol-1-ol and 341 mg of potassium tert-butoxide and dissolve them in 5 mL of dimethyl sulfoxide. Stir at room temperature for 15 minutes. Add 200 mg of 1,6-dichloroisoquinoline and stir at room temperature for 30 minutes. After LCMS indicates the reaction is complete, add an appropriate amount of water to the reaction system. Extract the aqueous layer with ethyl acetate, combine the organic phases, and wash with saturated NaCl solution. Dry and concentrate the organic phases to obtain the crude product. The crude product is slurried with hydrochloric acid and ethyl acetate to obtain the hydrochloride salt of the title compound (100 mg) as a white solid. MS: 293 [M+H]. 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.41(d,J= 8.9Hz,1H),8.11–8.04(m,2H),7.66(dd,J=8.9,2.1Hz,1H),7.45(d,J=5.9Hz,1H),4.92–4.85(m,2H), 4.45(s,5H),4.02–3.84(m,5H),3.68(q,J=4.6Hz,2H),3.54(d,J=12.5Hz,2H),3.25(d,J=11.5Hz,2H).

[0279] Example 3: 4-(2-((4-chloroisoquinolin-1-yl)oxy)ethyl)morpholine

[0280] Synthesis route:

[0281] Weigh 199 mg of 2-morpholinylethanol-1-ol and 341 mg of potassium tert-butoxide and dissolve them in 5 mL of dimethyl sulfoxide. Stir at room temperature for 15 minutes. Add 1,4-dichloroisoquinoline and stir at room temperature for 30 minutes. After LCMS indicates the reaction is complete, add an appropriate amount of water to the reaction system. Extract the aqueous layer with ethyl acetate, and combine the organic phases. Wash with saturated NaCl solution. Dry and concentrate the organic phase to obtain the crude product. The crude product is slurried with hydrochloric acid and ethyl acetate to obtain the hydrochloride salt of the title compound (80 mg) as a white solid. MS: 293 [M+H]. 1H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 8.46 (d, J = 8.2Hz, 1H), 8.19 (s, 1H), 8. 14–8.07(m,1H),7.99(ddd,J=8.3,6.9,1.3Hz,1H),7.81(ddd,J=8.2,6.9,1.2 Hz,1H),4.88(t,J=4.8Hz,2H),4.03–3.94(m,2H),3.86(t,J=12.0Hz,2H),3. 74–3.65(m,2H),3.55(d,J=12.5Hz,2H),3.42(s,1H),3.26(q,J=10.7Hz,2H).

[0282] Example 4: 7-Chloro-N-(2-(piperidin-1-yl)ethyl)isoquinolin-1-amine

[0283] Synthesis route:

[0284] 50 mg of 1,7-dichloroisoquinoline, 38 mg of 2-(piperidin-1-yl)ethan-1-amine, 34 mg of Pd2(dba)3, 44 mg of Xantphos, and 206 mg of Cs2CO3 were dissolved in 5 ml of ultra-dry dioxane under nitrogen protection and stirred at 90°C for three hours.

[0285] Post-treatment: After LCMS showed the reaction was complete, the reaction system was filtered, the filter cake was rinsed with ethyl acetate, and the filtrate was concentrated and purified by reverse medium pressure preparative chromatography (HCl·H2O:ACN=30%) to afford the hydrochloride salt of the title compound, 21 mg, as a yellow solid. MS: 290 [M+H]. 1 H NMR(400MHz,D2O)δ8.36(s,1H),7.94–7.82(m,2H),7.55(d,J=7.0Hz,1H),7.26(d,J=7.0Hz,1H),4.03(t,J=6.2Hz, 2H),3.65–3.52(m,4H),3.04(t,J=12.1Hz,2H),1.94(d,J=13.6Hz,2H),1.83–1.69(m,3H),1.47(d,J=12.6Hz,1H).

[0286] Example 5: 7-Chloro-N-phenethylisoquinolin-1-amine

[0287] Obtained by a method similar to Example 4. MS: 283 [M+H] + . 1H NMR (400MHz, DMSO) δ9.95(s,1H),8.91(s,1H),8.00(s,2H),7.67(d,J=6.8Hz,1H),7.39(d,J=7.3Hz,2H ),7.32(t,J=7.4Hz,2H),7.24(dd,J=12.8,6.8Hz,2H),3.90(dd,J=14.2,6.2Hz,2H),3.13–3.04(m,2H).

[0288] Example 6: N1-(7-chloroisoquinolin-1-yl)-N2,N2-diethylethane-1,2-diamine

[0289] Synthesis route:

[0290] Dissolve 50 mg of 1,7-dichloroisoquinoline, 35 mg of N1,N1-diethylethane-1,2-diamine, 34 mg of Pd2(dba)3, 44 mg of Xantphos, and 206 mg of Cs2CO3 in 5 ml of ultra-dry dioxane under nitrogen atmosphere and stir at 90°C for three hours. Workup: After LCMS indicated completion of the reaction, filter the reaction mixture, rinse the filter cake with ethyl acetate, and concentrate the filtrate. Purify the mixture by reverse transpiration (HCl·H2O:ACN = 30%) to obtain the hydrochloride salt of the title compound (15 mg) as a yellow solid. MS: 278 [M+H]. 1 HNMR(400MHz,D2O)δ8.37(d,J=1.7Hz,1H),7.95–7.84(m,2H),7.57(d,J=7.0Hz,1H),7.28(d,J=7.0Hz,1H) ,4.03(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.51–3.37(m,1H),3.36–3.28(m,4H),1.29(t,J=7.3Hz,7H).

[0291] Example 7: 7-Chloro-N-(2-morpholinylethyl)isoquinolin-1-amine

[0292] Synthesis route:

[0293] Dissolve 50 mg of 1,7-dichloroisoquinoline, 39 mg of 2-morpholinylethane-1-amine, 34 mg of Pd(dba), 44 mg of Xantphos, and 206 mg of CsCO in 5 ml of ultra-dry dioxane under nitrogen atmosphere and stir at 90°C for three hours. Workup: After LCMS indicated completion of the reaction, filter the reaction mixture, rinse the filter cake with ethyl acetate, and concentrate the filtrate. Purify the mixture by reverse-phase purification (HCl·H2O:ACN = 30%) to obtain the hydrochloride salt of the title compound (21 mg) as a yellow solid. MS: 292 [M+H]. 1 H NMR(400MHz,D2O)δ8.38(d,J=1.7Hz,1H),7.95–7.83(m,2H),7.56(d,J=7.0Hz,1H),7.27(d,J=7 .0Hz,1H),4.07(t,J=6.1Hz,2H),3.98(s,4H),3.66(t,J=6.1Hz,2H),3.61(s,1H),3.46(s,4H).

[0294] Example 8: 7-Chloro-1-(2-(piperidin-1-yl)ethoxy)isoquinoline

[0295] Synthesis route:

[0296] Weigh 2-(piperidin-1-yl)ethan-1-ol (490 mg) into a 50 ml single-necked bottle, then add DMF (10 ml) and potassium tert-butoxide (853 mg), stir at 0°C for half an hour, then add 1,7-dichloroisoquinoline (5000 mg). The final system was stirred at 0°C for 10 minutes. Post-treatment and purification: LCMS showed that the target compound was generated and the raw material reaction was complete. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash the organic phase twice with saturated brine, dry, and concentrate. Purify on a medium-pressure preparative silica gel column (petroleum ether / ethyl acetate = 4:6 (volume ratio)). After concentration, add HCl / EA (4 M) dropwise to precipitate the solid. Filter, collect, and dry. 547 mg of the target compound as a white solid product (hydrochloride) was obtained. MS: 291 [M+H] + . 1H NMR(400MHz,D2O)δ8.02(s,1H),7.73(d,J=6.2Hz,1H),7.70–7.62(m,2H),7.33(d,J=6.2Hz,1H),4.75(d,J=4.6Hz, 2H),3.69–3.57(m,4H),3.11-3.04(m,2H),1.93(d,J=15.2Hz,2H),1.79-1.67(m,3H),1.47(tt,J=11.9,6.0Hz,1H).

[0297] Example 9: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)morpholine

[0298] Synthesis route:

[0299] Weigh 200 mg of 1,7-dichloroisoquinoline into a 100 mL single-necked flask and dissolve it in 15 mL of DMSO. Then, add 200 mg of 2-morpholinoethan-1-ol and 340 mg of t-BuOK to the reaction mixture. Stir at room temperature for 2 hours. Post-processing and purification: LC-MS indicated completion of the reaction. Add a large amount of water to the reaction mixture, extract with EA, concentrate the EA layer, and precipitate with HCl / EA. The precipitate was separated and purified by HPLC to yield 150 mg of the title compound as a white solid. 1 HNMR(400MHz,D2O)δ8.03(s,1H),7.73(d,J=6.16Hz,1H),7.66(d,J=8.76Hz,1H),7.62-7.60(dd,J=8.76,1.88Hz,1H),7.30(d ,J=6.16Hz,1H),4.76-4.73(m,2H),4.07(m,2H),3.85-3.82(m,2H),3.77-3.75(m,2H),3.60(m,2H),3.34(m,2H).MS:293[M+H] + .

[0300] Example 10: 4-(3-((7-chloroisoquinolin-1-yl)oxy)propyl)morpholine

[0301] Obtained in a manner similar to Example 9. 1HNMR(400MHz,D2O)δ8.08(s,1H),7.76(d,J=1.12Hz,2H),7.71(d,J=6.48Hz,1H),7.42(d,J=6.52Hz,1H),4.58-4.55(t,J=5.68Hz,2H),4.16-4.10 (m,2H),3.84-3.78(m,2H),3.61-3.58(m,2H),3.47-3.42(m,2H),3.27-3.20(m,2H),2.45-2.38(m,2H).MS:307[M+H] + .

[0302] Example 11: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)thiomorpholine

[0303] Obtained in a manner similar to Example 9. 1 HNMR(400MHz,D2O)δ8.03(d,J=1.92Hz,1H),7.75(d,J=6.12Hz,1H),7.68(d,J=8.76Hz,1H),7.63-7.61(dd,J=8.76,2.08Hz,1H) ,7.31(d,J=6.04Hz,1H),4.74-4.71(m,2H),3.87(m,2H),3.73-3.71(m,2H),3.38(m,2H),3.05(m,2H),2.87(m,2H).MS:309[M+H] + .

[0304] Example 12: 7-Chloro-1-((1-methylpyrrolidin-3-yl)oxy)isoquinoline

[0305] Obtained in a manner similar to Example 9. 1 HNMR(400MHz,D2O)δ7.92-7.86(m,1H),7.66-7.64(dd,J=6.12,1.84Hz,1H),7.60-7.54(m,2H),7.22(d,J=6.16 Hz,1H),5.60-5.53(m,1H),3.89-3.80(m,2H),3.50-3.23(m,2H),2.93(s,3H),2.47-2.28(m,2H).MS:263[M+H] + .

[0306] Example 13: 7-Chloro-1-((1-methylpiperidin-4-yl)oxy)isoquinoline

[0307] Obtained by a method similar to Example 9. MS: 277 [M+H] + .

[0308] Example 14: 2-((7-chloroisoquinolin-1-yl)oxy)-N,N-dimethylethane-1-amine

[0309] Obtained in a manner similar to Example 9. 1 HNMR(400MHz,D2O)δ8.01(s,1H),7.70(d,J=6.20Hz,1H),7.64(d,J=8.72Hz,1H),7.61-7.59(dd,J=8.7 6,2.00Hz,1H),7.29(d,J=6.12Hz,1H),4.72-4.69(m,2H),3.71-3.69(m,2H),2.97(s,6H).MS:251[M+H] + .

[0310] Example 15: 7-chloro-1-((1-methylpyrrolidin-2-yl)methoxy)isoquinoline

[0311] Obtained in a manner similar to Example 9. 1 HNMR(400MHz,D2O)δ7.92(d,J=2.20Hz,1H),7.75(d,J=6.12Hz,1H),7.68(d,J=8.72Hz,1H),7.64-7.61(dd,J=8.76,2.0 0Hz,1H),7.31(d,J=6.12Hz,1H),4.76-4.73(m,1H),4.73-4.72(m,1H),4.00-3.93(m,1H),3.78-3.72(m,1H),3.28-3.20 (m,1H),3.02(s,3H),2.49-2.42(m,1H),2.26-2..18(m,1H),2.15-2.04(m,2H).MS:277[M+H] + .

[0312] Example 16: 7-Chloro-1-((tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)isoquinoline

[0313] Obtained in a manner similar to Example 9. 1HNMR(400MHz,D2O)δ7.85(d,J=1.80Hz,1H),7.74(d,J=6.16Hz,1H),7.67(d,J=8.72Hz,1H),7.64-7.61(dd,J=8.76,1.76Hz,1H),7.32(d, J=6.12Hz,1H),4.55(s,2H),3.66-3.60(m,2H),3.30-3.24(m,2H),2.33-2.26(m,2H),2.24-2.20(m,2H),2.17-2.07(m,4H).MS:303[M+H] + .

[0314] Example 17: 3-((7-chloroisoquinolin-1-yl)oxy)-N,N-diethylpropane-1-amine

[0315] Obtained in a manner similar to Example 9. 1 HNMR (400MHz, DMSO-D6) δ10.80(s,1H),8.20(d,J=1.16Hz,1H),8.05(d,J=5.76Hz,1H),7.98(d,J=8.72Hz,1H),7.82-7.80(dd,J=8.68,1.68Hz,1H),7. 46(d,J=5.72Hz,1H),6.4(s,3H),4.55(t,J=5.80Hz,2H),3.30-3.25(m,2H) ,3.17-3.14(m,4H),2.31-2.27(m,2H),1.26(t,J=7.08Hz,6H).MS:293[M+H] + .

[0316] Example 18: 4-(2-(Isoquinolin-1-yloxy)ethyl)morpholine

[0317] Obtained in a manner similar to Example 9. 1 HNMR(400MHz,D2O)δ8.30(d,J=8.40Hz,1H),7.90(d,J=3.88Hz,1H),7.77(d,J=6.48Hz,1H),7.74-7.70(m,1H),7 .57(d,J=6.48Hz,1H),4.93-4.91(m,2H),4.07(m,2H),3.87-3.84(m,2H),3.64(m,2H),3.40(m,2H).MS:259[M+H] + .

[0318] Example 19: 7-Chloro-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)isoquinoline

[0319] Synthesis route:

[0320] Step 1: 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol

[0321] Weigh 4,4-difluoropiperidine (1.0 g) into a 100 mL single-necked flask and dissolve in 15 mL of water. Then, weigh 1.82 g of ethylene oxide and add it to the reaction mixture. Stir at 50°C for 3 h. Post-processing and purification: LCMS indicated completion of the reaction. Remove the THF and extract with EA. The organic phase was concentrated to dryness, and the crude product was used directly in the next step.

[0322] Step 2: 7-Chloro-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)isoquinoline

[0323] Weigh 200 mg of 1,7-dichloroisoquinoline into a 100 mL single-necked flask and dissolve it in 15 mL of DMSO. Then, add 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol (250 mg) and t-BuOK (340 mg) to the reaction mixture. Stir at room temperature for 2 hours. Post-processing and purification: LCMS indicated completion of the reaction. Add a large amount of water to the reaction mixture, extract with EA, concentrate the EA layer, and precipitate with HCl / EA. The precipitate was separated and purified by RP-HPLC to yield 30 mg of the title compound as a white solid. 1 HNMR(400MHz,D2O)δ8.10(s,1H),7.78(d,J=6.04Hz,1H),7.62(d,J=8.76Hz,1H),7.72(d,J=8.8Hz,1H),7.66-7.63(dd,J= 8.76,2.08Hz,1H),7.33(d,J=8.08Hz,1H),4.76-4.71(m,2H),3.78-3.76(m,4H),3.46(m,2H),2.38(m,4H).MS:327[M+H]+.

[0324] Example 20: 7-Chloro-1-(2-(pyrrolidin-1-yl)ethoxy)isoquinoline

[0325] Obtained in a manner similar to Example 19. 1HNMR(400MHz,D2O)δ8.04(s,1H),7.71(d,J=6.24Hz,1H),7.66(d,J=8.68Hz,1H),7.63-7.61(dd,J=6.84,1.92Hz,1H),7.31(d,J=6.16Hz ,1H),4.72-4.69(m,2H),3.77-3.75(m,2H),3.73-3.71(m,2H),3.27-3.18(m,2H),2.19-2.06(m,2H),2.04-1.93(m,2H).MS:277[M+H]+.

[0326] Example 21: 1-(2-(azepan-1-yl)ethoxy)-7-chloroisoquinoline

[0327] Obtained in a manner similar to Example 19. 1 HNMR(400MHz,D2O)δ8.12(s,1H),7.78-7.67(m,3H),7.38(d,J=6.16Hz,1H),4.77-4.74(m,2H),3.73-3 .71(m,2H),3.58-3.52(m,2H),3.34-3.28(m,2H),1.89-1.82(m,3H),1.66-1.63(m,4H).MS:305[M+H]+.

[0328] Example 22: 2-((7-chloroisoquinolin-1-yl)oxy)-N,N-bis(2-methoxyethyl)ethane-1-amine

[0329] Obtained in a manner similar to Example 19. 1 HNMR(400MHz,D2O)δ7.83(d,J=1.56Hz,1H),7.71(d,J=6.04Hz,1H),7.62(d,J=8.76Hz,1H),7.57-7.55(dd,J=8.76,2. 00Hz,1H),7.25(d,J=6.04Hz,1H),5.71-4.67(m,2H),3.78-3.76(m,2H),3.72-3.70(m,4H),3.54-3.51(m,4H),3.18(s, 6H).MS:339[M+H]+.

[0330] Example 23: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)thiomorpholine 1,1-dioxide

[0331] Obtained using a method similar to Example 19. MS: 341 [M+H] + .

[0332] Example 24: 1-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)piperidine-4-carbonitrile

[0333] Obtained in a manner similar to Example 19. 1 HNMR(400MHz,D2O)δ7.94(s,1H),7.66(d,J=6.24Hz,1H),7.56(m,2H),7.25(d,J=6.16Hz,1H),7.33(d,J=8.08 Hz,1H),3.70(m,4H),3.37-3.31(m,2H),3.19-3.02(m,2H),2.36-2.32(m,1H),2.21-2.05(m,4H).MS:316[M+H] + .

[0334] Example 25: 7-chloro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)isoquinoline

[0335] Obtained by a method similar to Example 19. MS: 321 [M+H] + .

[0336] Example 26: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2,2,2-trifluoroethane-1-amine

[0337] Synthesis route:

[0338] Step 1: 2-((2,2,2-trifluoroethyl)amino)ethan-1-ol

[0339] Weigh trifluoroethylamine (500 mg) into a 50 ml single-necked flask, then add water (10 ml) and ethylene oxide (1.2 ml, 3 min THF) and stir at 50°C for 1 hour. LCMS indicates the formation of the target compound and complete reaction of the starting materials. Add an appropriate amount of water to the system, extract the aqueous layer three times with ethyl acetate, and combine the organic phases. Wash the organic phase twice with saturated brine, dry, and add HCl / EA (4 M) dropwise to form a salt. Concentrate to obtain the crude target intermediate.

[0340] Step 2: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2,2,2-trifluoroethane-1-amine

[0341] 2-((2,2,2-trifluoroethyl)amino)ethan-1-ol (500 mg) was weighed into a 50 ml single-necked flask, DMSO (10 ml) and t-BuOK (387 ml) were added, and after stirring at room temperature for 1 hour, 1,7-dichloroisoquinoline (340 mg) was added. The final system was stirred at room temperature for 2 hours. LCMS showed that the target compound was produced and the starting material was completely reacted. An appropriate amount of water was added to the system, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined. The organic phase was washed twice with saturated brine, dried, and concentrated. Purification was performed by medium-pressure preparative column chromatography (petroleum ether / ethyl acetate = 10%). After concentration, HCl / EA (4 M) was added dropwise to precipitate the solid. Filter, collect, and dry. 90 mg of the target compound was obtained as a white solid product with a purity of 95.34%, MS: 305 [M+H] + . 1 H NMR(400MHz,D2O)δ8.14(d,J=1.5Hz,1H),7.75(d,J=6.2Hz,1H),7.66(dt,J=8.8,5.4Hz,2 H),7.33(d,J=6.2Hz,1H),4.74(d,J=4.9Hz,2H),4.11(q,J=8.8Hz,2H),3.81–3.74(m,2H).

[0342] Example 27: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-N-ethyl-2,2,2-trifluoroethane-1-amine

[0343] Synthesis route:

[0344] Steps:

[0345] N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2,2,2-trifluoroethane-1-amine (70 mg) was weighed into a 25 ml single-necked flask, and acetaldehyde (0.5 ml), THF (5 ml) and AcOH (5 drops) were added. After stirring at room temperature for 1 hour, NaBH(AcO)3 was added. The final system was stirred at room temperature overnight. Post-treatment and purification: LCMS showed that the target compound was produced and the raw materials were completely reacted. An appropriate amount of water was added to the system, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined. The organic phase was washed twice with saturated brine, dried and concentrated. The product was purified by medium-pressure preparative silica gel column (petroleum ether / ethyl acetate = 10%). After concentration, HCl / EA (4 M) was added dropwise to precipitate a solid. The solid was filtered and collected. Purified by preparative HPLC (ACN / H2O) and lyophilized to obtain 8.4 mg of the target compound as a white solid product, MS: 291 [M+H] + .

[0346] Example 28: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2,2,2-trifluoro-N-methylmethylethane-1-amine

[0347] Obtained using a method similar to Example 27. MS: 319 [M+H] + . 1 H NMR (400MHz, D2O) δ7.99 (s, 1H), 7.72–7.54 (m, 3H), 7.29 (d, J = 4.8Hz, 1H), 4.23–4.14 (m, 2H), 3.83 (s, 2H), 3.06 (s, 3H).

[0348] Example 29: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-N-ethyl-2,2-difluoroethane-1-amine

[0349] Synthesis route:

[0350] Step 1: N-ethyl-2,2-difluoroethane-1-amine

[0351] Weigh difluoroethylamine (1.0 g) into a 50 ml single-necked bottle, then add MeOH (15 ml) and 40% acetaldehyde aqueous solution (4.0 ml), DIEA (0.5 ml). Stir under ice bath for 3 hours, then slowly add NaBH4 (2.0 g) in batches under ice bath. Finally, stir the system at 0°C for 30 minutes. Post-treatment and purification: LCMS confirmed the formation of the target product and the complete reaction of the raw materials. NaOH solution was added dropwise to the system to quench NaBH4. The aqueous layer was extracted 3 times with dichloromethane, and the organic phases were combined. Wash with saturated brine twice and dry. Add an appropriate amount of HCl / EA (4M) solution to prepare the hydrochloride and concentrate. 1.5 g of the crude product of the target compound was obtained.

[0352] Step 2: 2-((2,2-difluoroethyl)(ethyl)amino)ethan-1-ol

[0353] Weigh N-ethyl-2,2-difluoroethane-1-amine (1.5 g) into a 50 ml single-necked bottle, then add H2O (10 ml) and ethylene oxide 3M THF solution (14.0 ml), and stir at 50°C for 3 hours. Post-treatment and purification: LCMS confirmed the formation of the target product and the complete reaction of the raw material compound. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash the organic phase twice with saturated brine and dry. Add appropriate amount of HCl / EA (4 M) solution to prepare the hydrochloride salt and concentrate. Obtain 0.7 g of the crude product of the target compound.

[0354] Step 3: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-N-ethyl-2,2-difluoroethane-1-amine

[0355] Weigh 2-((2,2-difluoroethyl)(ethyl)amino)ethan-1-ol (480 mg) into a 50 ml single-necked flask, then add DMF (8 ml) and t-BuOK (240 mg), stir under ice bath for half an hour, then add 1,7-dichloroisoquinoline (200 mg), and stir at this temperature for 20 minutes. Post-treatment and purification: LCMS showed the formation of the target compound and the reaction of the raw materials was complete. Add an appropriate amount of water to the system, extract the aqueous layer three times with ethyl acetate, and combine the organic phases. Wash the organic phase twice with saturated brine, dry, and concentrate. Purify by flash column chromatography, concentrate, and add HCl / EA (4 M) dropwise to precipitate a solid. Filter, collect, and dry. 200 mg of the target compound was obtained as a white solid product. MS: 315 [M+H] + . 1 H NMR(400MHz,D2O)δ7.93(d,J=1.2Hz,1H),7.74(d,J=6.1Hz,1H),7.63(dd,J=15.1,5.4Hz,2H),7.30(d,J=6.1H z,1H),6.62–6.25(m,1H),4.81–4.74(m,2H),3.97–3.80(m,4H),3.50(q,J=7.3Hz,2H),1.37(t,J=7.3Hz,3H).

[0356] Example 30: N-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2,2-difluoro-N-methylethan-1-amine

[0357] Obtained by a method similar to Example 29. MS: 301 [M+H] + .

[0358] Example 31: 2-((7-chloroisoquinolin-1-yl)oxy)-N-ethylethan-1-amine

[0359] Synthesis route:

[0360] Steps:

[0361] 1,7-Dichloroisoquinoline (200 mg) was weighed into a 100 mL single-necked flask and dissolved in 15 mL of DMSO. 2-((2,2-difluoroethyl)(ethyl)amino)ethan-1-ol (250 mg) and t-BuOK (340 mg) were added to the reaction system and stirred at room temperature for 2 hours. Post-processing and purification: LCMS indicated completion of the reaction. A large amount of water was added to the reaction solution, and the mixture was extracted with EA. The EA layer was concentrated and precipitated with HCl / EA. The precipitate was separated and purified by RP-HPLC to yield 5 mg of the title compound as a white solid. MS: 251 [M+H] + . 1 HNMR(400MHz,D2O)δ8.15(d,J=1.80Hz,1H),7.75-7.65(m,3H),7.34(d,J=6.16Hz,1H),4 .85-4.66(m,2H),3.59(t,J=4.76Hz,2H),3.20(q,J=7.32Hz,2H),1.29(t,J=7.28Hz,3H).

[0362] Example 32: 7-Chloro-1-(piperidin-3-yloxy)isoquinoline

[0363] Synthesis route:

[0364] Step 1: tert-Butyl 3-((7-chloroisoquinolin-1-yl)oxy)piperidine-1-carboxylate

[0365] 1,7-Dichloroisoquinoline (200 mg) was weighed into a 100 mL single-necked bottle and dissolved in 15 mL of DMSO. Then, tert-butyl 3-hydroxypiperidine-1-carboxylate (300 mg) was added. t-BuOK (340 mg) was added to the above reaction system and stirred at room temperature for 2 h.

[0366] Post-treatment and purification: LCMS showed that the reaction was complete. A large amount of water was added to the reaction solution, and the mixture was extracted with EA. The EA layer was concentrated and precipitated by adding HCl / EA. The precipitate was separated and purified by RP-HPLC to obtain 25 mg of the target compound hydrochloride as a white solid, MS: 363 [M+H] + .

[0367] Step 2: 7-Chloro-1-(piperidin-3-yloxy)isoquinoline

[0368] 250 mg of tert-butyl 3-((7-chloroisoquinolin-1-yl)oxy)piperidine-1-carboxylate (from the previous step) was weighed into a 100 mL single-necked vial. 10 mL of 4 M hydrogen chloride / ethyl acetate was added for dissolution. The mixture was stirred at room temperature for 2 h. Post-processing and purification: LC-MS indicated completion of the reaction. The precipitate was filtered and purified by RP-HPLC to yield 15 mg of the product as a white solid. 1 HNMR(400MHz,D2O)δ8.06(s,1H),7.65(d,J=6.08Hz,1H),7.57-7.51(m,2H),7.17(d,J=6.04Hz,1H),5.35(s,1H),3.61-3. 57(m,1H),3.44-3.34(m,2H),3.16-3.09(m,1H),2.13-2.06(m,1H),2.04-1.91(m,1H),1.87-1.81(m,1H).MS:263[M+H]+.

[0369] Example 33: (R)-7-Chloro-1-(pyrrolidin-3-yloxy)isoquinoline

[0370] Obtained by a method similar to Example 32. 1 H NMR(400MHz,D2O)δ8.00(d,J=1.8Hz,1H),7.73-7.62(m,3H),7.30(d,J=6.1Hz, 1H),5.64(d,J=2.1Hz,1H),3.80–3.45(m,4H),2.56–2.33(m,2H).MS:249[M+H] + .

[0371] Example 34: (S)-7-Chloro-1-(pyrrolidin-3-yloxy)isoquinoline

[0372] Obtained by a method similar to Example 32. 1 H NMR(400MHz,D2O)δ8.00(d,J=1.8Hz,1H),7.73-7.62(m,3H),7.30(d,J=6.1Hz, 1H),5.64(d,J=2.1Hz,1H),3.80–3.45(m,4H),2.56–2.33(m,2H).MS:249[M+H] + .

[0373] Example 35: 4-(2-((7-bromoisoquinolin-1-yl)oxy)ethyl)morpholine

[0374] Synthesis route:

[0375] Weigh 2-morpholinoethane-1-ol (400 mg) into a 50 ml single-necked flask, then add DMSO (10 ml) and t-BuOK (460 mg), stir at 0°C for half an hour, then add 7-bromo-1-chloroisoquinoline (500 mg). The final system is stirred at room temperature for 1 hour. Post-treatment and purification: LC-MS shows that the target compound is produced and the raw materials are completely reacted. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash the organic phase twice with saturated brine, dry and concentrate. Purify by flash column chromatography (methanol / dichloromethane = 1%), concentrate, and add HCl / EA (4 M) dropwise to prepare the hydrochloride salt, and a solid precipitates. Filter, collect and dry. 120 mg of the target compound hydrochloride salt white solid product is obtained with a purity of 93.69%, MS: 337 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.57(s,1H),8.08(d,J=5.8Hz,1H),7.98–7.87(m,2H),7.49(d,J=5.9Hz,1H),4. 94–4.82(m,2H),4.04–3.85(m,4H),3.69(d,J=4.1Hz,2H),3.53(d,J=12.2Hz,2H),3.33–3.18(m,2H).

[0376] Example 36: 4-(2-((8-chloroisoquinolin-1-yl)oxy)ethyl)morpholine

[0377] Synthesis route:

[0378] Weigh 2-morpholinylethane-1-ol (100 mg) into a 25 ml single-necked bottle, then add DMSO (5 ml) and t-BuOK (114 mg), stir at 0°C for half an hour, then add 1,8-dichloroisoquinoline (100 mg). The final system is stirred at room temperature for 1 hour. Post-treatment and purification: LC-MS shows that the target compound is generated and the raw material reaction is complete. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate 3 times, and combine the organic phases. Wash the organic phase twice with saturated brine, dry and concentrate. Purify by flash column chromatography {petroleum ether / ethyl acetate = 30%}, concentrate, add HCl / EA (4 M) dropwise to prepare the hydrochloride, and precipitate a solid. Filter, collect and dry. 110 mg of the target compound hydrochloride white solid product is obtained with a purity of 99.59%, MS: 293 [M+H] + . 1H NMR (400MHz, DMSO) δ8.07(d,J=5.7Hz,1H),7.90(dd,J=7.4,1.7Hz,1H),7.78–7.65(m,2H),7.52(d,J=5.7Hz,1H),4.98–4.85( m,2H),4.02–3.92(m,2H),3.86(t,J=11.8Hz,2H),3.68(d,J=3.8Hz,2H),3.53(d,J=12.3Hz,2H),3.28(dd,J=20.2,8.8Hz,2H).

[0379] Example 37: 4-(2-((5-chloroisoquinolin-1-yl)oxy)ethyl)morpholine

[0380] Synthesis route:

[0381] Weigh 2-morpholinylethane-1-ol (100 mg) into a 25 ml single-necked bottle, then add DMSO (5 ml) and t-BuOK (114 mg), stir at 0°C for half an hour, then add 1,5-dichloroisoquinoline (100 mg). The final system is stirred at room temperature for 1 hour. Post-treatment and purification: LCMS shows that the target compound is generated and the raw material reaction is complete. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate 3 times, and combine the organic phases. Wash the organic phase twice with saturated brine, dry and concentrate. Purify by flash column chromatography {petroleum ether / ethyl acetate = 35%}, concentrate, add HCl / EA (4 M) dropwise to prepare the hydrochloride, and precipitate a solid. Filter, collect and dry. 105 mg of the target compound hydrochloride white solid product is obtained with a purity of 98.79%, MS: 293 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.41(d,J=8.3Hz,1H),8.18(d,J=6.1Hz,1H),7.98(d,J=7.0Hz,1H),7.70–7.58(m,2H ),4.97–4.86(m,2H),3.99–3.88(m,4H),3.69(d,J=3.9Hz,2H),3.54(d,J=12.3Hz,2H),3.33–3.20(m,2H).

[0382] Example 38: 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0383] Synthesis route:

[0384] Step 1: tert-Butyl 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0385] Weigh 1.0 g of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate into a 100 ml single-necked flask, add 10 ml of water, then 8 ml of a 1 M ethylene oxide solution in tetrahydrofuran, and stir at 75°C for 2 hours. Post-processing and purification: LCMS confirms the formation of the target product and complete reaction of the starting materials. Add an appropriate amount of water to the system, extract three times with ethyl acetate, and combine the organic phases. Wash three times with saturated brine. Dry and concentrate. 1.0 g of crude product is obtained as an oil.

[0386] Step 2: tert-Butyl 8-(2-bromoethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0387] Weigh 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1.0 g) into a 100 ml single-necked flask and add DCM (20 ml). Then add CBr4 (2.5 g) and PPh3 (1.5 g) and stir at room temperature for 2 hours. Post-processing and purification: LCMS confirmed the formation of the target product and the complete reaction of the raw materials. Add appropriate amount of water to the system, extract with DCM three times, and combine the organic phases. Wash twice with saturated brine. Dry and concentrate. Purify by flash column chromatography to obtain 780 mg of an oil.

[0388] Step 3: 8-(2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl)-3,8-diazabicyclo[3.2.1]octane-3-tert-butyl ester

[0389] Weigh 8-(2-bromoethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (680 mg), 1,7-dichloroisoquinoline (457 mg), and TBAB (70 mg) into a 100 ml single-necked flask and add toluene (20 ml). Then add 50% NaOH aqueous solution and stir at 75°C for 2 hours. Post-treatment and purification: LCMS confirmed the formation of the target product and the complete reaction of the raw materials. Add an appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash twice with saturated brine. Dry and concentrate. Purify by flash column chromatography to obtain 780 mg of white solid product.

[0390] Step 4: 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0391] Add an appropriate amount of HCl / EA (4M) solution to the white solid product obtained in the above step and stir at room temperature for 2 hours. Post-processing and purification: LCMS confirmed the formation of the target product and complete reaction of the starting materials. Concentrate. Purify the product by preparative HPLC to obtain the target product. MS: 318 [M+H] + .

[0392] Example 39: 7-chloro-2-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl)isoquinolin-1(2H)-one

[0393] Synthesis route:

[0394] Weigh 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl)-7-chloroisoquinolin-1(2H)-one (400 mg) into a 50 ml single-necked flask and add THF / AcOH (10:1) (10 ml). Then add HCHO (2 ml), stir at room temperature for 30 minutes, and then add NaBH(AcO)3 (535 mg). The final system is stirred at room temperature for 2 hours. Post-processing and purification: LCMS confirms the formation of the target product and complete reaction of the raw materials. Add an appropriate amount of water to the system, extract with ethyl acetate three times, and combine the organic phases. Wash with sodium carbonate (1 M) three times. Dry and concentrate. 23.93 mg of white solid product is obtained. MS: 332 [M+H] + .

[0395] Example 40: 2-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0396] Obtained by a method similar to Example 38. MS: 318 [M+H] + . 1 H NMR (400MHz, D2O) δ8.16(d,J=1.9Hz,1H),7.68(dd,J=8.6,2.1Hz,1H),7.59(d,J=8.6Hz,1H),7.28(d,J=7.4Hz,1H),6.78(d,J=7 .4Hz,1H),4.45–4.29(m,4H),3.91(d,J=13.1Hz,2H),3.58(t,J=5.5Hz,2H),3.47(d,J=13.3Hz,2H),2.29(dd,J=7.0,2.7Hz,4H).

[0397] Example 41: 7-Chloro-2-(2-(8-methyl-3,8-azabicyclo[3.2.1]octan-3-yl)ethyl)isoquinolin-1(2H)-one

[0398] Obtained by a method similar to Example 39. MS: 332 [M+H] + . 1 H NMR(400MHz,D2O)δ8.18(d,J=9.4Hz,1H),7.72–7.56(m,2H),7.30(d,J=7.3Hz,1H),6.79(t,J=7.0Hz,1H),4.29(t,J=5.1Hz,2H),4.07 (s,2H),3.58(d,J=12.7Hz,2H),3.29(d,J=8.4Hz,2H),3.17(d,J=13.4Hz,2H),2.79(s,2H),2.47–2.13(m,2H),2.11(d,J=9.1Hz,2H).

[0399] Example 42: 7-Chloro-2-(2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)ethyl)isoquinolin-1(2H)-one

[0400] Synthesis route:

[0401] Step 1: 3-((tert-Butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane

[0402] Weigh 8-azabicyclo[3.2.1]octan-3-ol (2.0 g) into a 100 ml single-necked flask, then add DCM (25 ml), imidazole (3.2 g), and tert-butyldimethylsilyl chloride (4.76 g) and stir at room temperature. Post-processing and purification: LCMS indicated the formation of the target compound and complete reaction of the starting material SM1. Add an appropriate amount of dichloromethane to the system, and wash the organic phase three times with saturated sodium bicarbonate solution and twice with saturated brine. Dry the organic phase and concentrate. This yields 1.6 g of the crude target compound as a yellow solid.

[0403] Step 2: 2-(3-((tert-Butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol

[0404] Weigh 3-((tert-butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane (1.6 g) into a 100 ml single-necked flask, then add H2O (20 ml) and 1M ethylene oxide tetrahydrofuran solution (6.7 ml). Stir at 50°C for 2 hours. Post-treatment and purification: LCMS confirmed the formation of the target compound and the complete reaction of the raw materials. Add appropriate amount of water to the reaction system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash twice with saturated brine, dry, and concentrate. Obtain 1.5 g of the crude product of the target compound as a white solid.

[0405] Step 3: 8-(2-bromoethyl)-3-((tert-butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane

[0406] Weigh 2-(3-((tert-butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol (1.0 g) into a 100 ml single-necked flask and add DCM (15 ml). Then add CBr4 (1.7 g) and PPh3 (1.1 g) and stir at room temperature overnight. Post-treatment and purification: LCMS confirmed the formation of the target compound and the complete reaction of the raw materials. 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 600 mg of the target compound as a white solid.

[0407] Step 4: 2-(2-(3-(tert-Butyldimethylchlorosilyl)-8-azabicyclo[3.2.1]octan-8-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0408] Weigh 7-chloroisoquinolin-1(2H)-one (150 mg), 8-(2-bromoethyl)-3-((tert-butyldimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane (600 mg), TBAB (27 mg), and NaOH (168 mg) into a 100 ml single-necked flask, add toluene / H2O (10 ml), and stir at 75°C for 2 hours. Post-treatment and purification: LCMS confirmed the formation of the target compound and the complete reaction of the raw materials. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash the aqueous layer twice with saturated brine, dry the organic phase, and concentrate. Purify by flash column chromatography {petroleum ether / ethyl acetate} to obtain 300 mg of the target compound as a white solid.

[0409] Step 5: 7-chloro-2-(2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)ethyl)isoquinolin-1(2H)-one

[0410] To the compound obtained in the previous step, 10 volumes of tetrahydrofuran (1 M in THF) solution were added and stirred at room temperature overnight. Post-treatment and purification: LCMS confirmed the formation of the target compound and the complete reaction of the raw materials. Concentrate, dissolve with an appropriate amount of water, adjust the pH of the system to acidic with dilute HCl solution, and wash with dichloromethane. The aqueous phase was then adjusted to alkaline with saturated sodium carbonate solution, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined, dried, and concentrated. Purified by preparative HPLC, lyophilized to obtain 28 mg of a white solid product. MS: 334 [M+H] + . 1 H NMR (400MHz, D2O) δ7.95 (s, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.24 (d, J = 7.0Hz, 1H), 6.67 (d, J = 7.1Hz, 1H), 4.33 (s, 2H), 4.03 (t, J = 20.9Hz, 3H), 3.35 (s, 2H), 2.41 (d, J = 8.8Hz, 2H), 2.27 (d, J = 15.7Hz, 2H), 2.18 (s, 2H), 2.05 (d, J = 15.9Hz, 2H).

[0411] Example 43: N1-(7-chloroisoquinolin-1-yl)-N2-ethylethane-1,2-diamine

[0412] Synthesis route:

[0413] Step 1: tert-Butyl (2-((7-chloroisoquinolin-1-yl)amino)ethyl)(ethyl)formate

[0414] 1,7-Dichloroisoquinoline (200 mg), tert-butyl (2-aminoethyl)(ethyl)formate (287 mg), Pd2(dba)3 (100 mg), XantPhos (120 mg), and Cs2CO3 (1.0 g) were weighed into a 25 mL single-necked flask, followed by the addition of 1,4-dioxane (5 mL). The system was replaced with nitrogen three times, and stirred at 90°C for 2 hours under a nitrogen atmosphere. Workup and purification: LC-MS indicated the formation of the title compound and complete reaction of the starting material. The product was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 10%) to yield 100 mg of the title compound as a yellow oil.

[0415] Step 2: N1-(7-chloroisoquinolin-1-yl)-N2-ethylethane-1,2-diamine

[0416] Add an appropriate amount of HCl / EA to the compound obtained in the previous step and stir at room temperature. Post-processing and purification: LCMS confirmed the formation of the target product and complete reaction of the starting materials. The precipitated solid was filtered, collected, and dried. 62 mg of the target compound hydrochloride was obtained as a yellow solid. MS: 250 [M+H] + . 1 H NMR(400MHz,D2O)δ8.26(s,1H),7.82(dd,J=8.7,1.8Hz,2H),7.76(d,J=8.7Hz,1H),7.51(d,J=7.0Hz,1H) ,7.19(d,J=7.0Hz,1H),3.95(t,J=6.0Hz,2H),3.48(t,J=6.0Hz,2H),3.16(q,J=7.3Hz,2H),1.28(s,3H).

[0417] Example 44: 7-Chloro-2-phenethylisoquinolin-1(2H)-one

[0418] Synthesis route:

[0419] Weigh 7-chloroisoquinolin-1(2H)-one (0.5 g) and TBAB (0.09 g) into a 100 mL single-necked flask, add toluene (25.0 mL), then add (2-bromoethyl)benzene (0.67 g) and 50% NaOH solution (5.0 mL), and stir at 80°C for 2 hours. Post-treatment and purification: TLC shows the reaction is complete, and the toluene is removed by concentration. Add an appropriate amount of water to the system, extract the aqueous layer three times with ethyl acetate, combine the organic phases, wash three times with saturated brine, dry the organic phase, and concentrate. Pass the mixture through a normal phase silica gel column {petroleum ether / ethyl acetate} to obtain 420 mg of the product as a white solid. MS: 284 [M+H] + .

[0420] Example 45: 2-(2-(Benzo[d][1,3]dioxolan-5-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0421] Synthesis route:

[0422] Step 1: 5-(2-Bromoethyl)benzo[d][1,3]dioxolane

[0423] Weigh 2-(Benzo[d][1,3]dioxolan-5-yl)ethan-1-ol (1.0 g) into a 100 mL single-necked flask, add THF (20.0 ml), then CBr4 (2.4 g), and stir at room temperature. Then, slowly add PPh3 (1.9 g) in batches, stirring at room temperature. Workup and purification: TLC indicated completion of the reaction. Concentrate and pass the product through a normal phase silica gel column (petroleum ether / ethyl acetate) to yield 1.0 g of a colorless oil.

[0424] Step 2: 2-(2-(Benzo[d][1,3]dioxolan-5-yl)ethyl)-7-chloroisoquinolin-1(2H)-one

[0425] Weigh 5-(2-bromoethyl)benzo[d][1,3]dioxolane (500 mg), 7-chloroisoquinolin-1(2H)-one (510 mg), and TBAB (70.0 mg) into a 100 mL single-necked flask, then add toluene (10.0 mL). Then add 0.53 g of sodium hydroxide solution (50% aqueous solution) and stir at 85°C. Post-treatment: TLC shows the reaction is complete. 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. Pass through a normal phase silica gel column {petroleum ether / ethyl acetate} to obtain 500 mg of a white solid product. MS: 328 [M+H] + .

[0426] Example 46: 7-Chloro-2-(3,4-dihydroxyphenethyl)isoquinolin-1(2H)-one

[0427] Synthesis route:

[0428] Weigh BBr3 (1500 mg) into a 100 ml three-necked flask, then add DCM (10 ml). Cool to 0°C under nitrogen, then weigh 2-(2-(benzo[d][1,3]dioxolan-5-yl)ethyl)-7-chloroisoquinolin-1(2H)-one (dissolved in DCM) and slowly add it dropwise to the above system, stirring at room temperature. Post-treatment and purification: TLC shows the reaction is complete. Add an appropriate amount of water to the reaction system, extract the aqueous layer three times with DCM, combine the organic phases, wash three times with saturated brine, dry the organic phase, and concentrate. Purify on a normal silica gel column {petroleum ether / ethyl acetate} to obtain 140 mg of the crude target compound. Then purify by preparative HPLC to obtain 12.0 mg of the target compound as a white solid. MS: 316 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.35(d,J=1.9Hz,1H),7.58(d,J=2.1Hz,1H),7.44(d,J=8.5Hz,1H),6.89(t,J=9.5Hz,1H),6.81(d,J=8.0Hz,1H),6.74 (d,J=1.7Hz,1H),6.55(dd,J=8.0,1.6Hz,1H),6.46(d,J=7.3Hz,1H),5.52(d,J=137.5Hz,2H),4.16(t,J=7.3Hz,2H),2.93(t,J=7.3Hz,2H).

[0429] Example 47: 7-chloro-2-(2-(2-oxobenzo[d][1,3]dioxolan-5-yl)ethyl)isoquinolin-1(2H)-one

[0430] Synthesis route:

[0431] Weigh 7-chloro-2-(3,4-dihydroxyphenethyl)isoquinolin-1(2H)-one (100 mg) into a 100 ml single-necked flask, then add DCM (10 ml). Then add triethylamine (96 mg). Slowly add triphosgene (47 mg dissolved in DCM) while stirring at room temperature, and stir at room temperature for 2 hours. Post-treatment and purification: TLC shows the reaction is complete. Add an appropriate amount of water to the reaction system, extract the aqueous layer three times with DCM, combine the organic phases, wash three times with saturated brine, dry the organic phases, and concentrate. Purify on a normal silica gel column {dichloromethane / ethyl acetate = 20:1} to obtain 30 mg of the target compound as a white solid. MS: 341.7 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.16(d,J=1.5Hz,1H),7.73(dt,J=16.6,5.2Hz,2H),7.40(dd,J=17.9,10.5H z,3H),7.11(d,J=8.2Hz,1H),6.61(d,J=7.4Hz,1H),4.21(t,J=7.4Hz,2H),3.06(t,J=7.4Hz,2H).

[0432] Example 48: 7-Chloro-2-(2-(piperidin-1-yl)ethyl)isoquinolin-1(2H)-one

[0433] Synthesis route:

[0434] Weigh 7-chloroisoquinolin-1(2H)-one (0.5 g) into a 100 mL single-necked flask, add THF (10.0 mL) to dissolve, slowly add TBAB (0.1 g), add 1.5 ml of 50% NaOH solution, and then slowly add 1-(2-bromoethyl)piperidine (0.64 g). Stir and react at 70°C for 4 hours. Post-treatment and purification: TLC shows that the reaction is complete. Concentrate and remove toluene. Add appropriate amount of water to the reaction system, extract the aqueous layer with ethyl acetate three times, and combine the organic phases. Wash three times with saturated brine, dry, and concentrate. Pass through a normal phase silica gel column {petroleum ether / ethyl acetate} to obtain 180 mg of white solid product. MS: 291 [M+H] + .

[0435] Example 49: 7-Chloro-2-(2-cyclohexylethyl)isoquinolin-1(2H)-one

[0436] Obtained by a method similar to Example 48. MS: 290 [M+H] + .

[0437] Example 50: 2-((7-chloroisoquinolin-1-yl)oxy)-N,N-diethylethane-1-amine

[0438] Synthesis route:

[0439] Weigh 7-chloroisoquinolin-1(2H)-one (500 mg) and PPh3 (1.5 g) into a 50 ml single-necked flask, then add THF (10 ml) and 2-(diethylamino)ethan-1-ol (490 mg), stir at room temperature for half an hour, then add DIAD (1.1 g). The final system was stirred at room temperature for 2 hours. Post-treatment and purification: LCMS confirmed the formation of the target compound and the complete reaction of the raw material SM1. Concentrate. Purify by rapid silica gel column {petroleum ether / ethyl acetate = 50% (volume ratio)}. After concentration, add an appropriate amount of ethyl acetate to dissolve the sample, and add an appropriate amount of HCl / EA (4 M) dropwise to precipitate the solid. Filter, collect, and dry. 110 mg of the target compound hydrochloride white solid product was obtained. MS: 278.8 [M+H] + . 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.72(d,J=6.2Hz,1H),7.64(dt,J=8.8,5.4Hz,2H),7.31(d,J= 6.2Hz, 1H), 4.69 (d, J = 4.8Hz, 2H), 3.77–3.59 (m, 2H), 3.42–3.23 (m, 4H), 1.29 (t, J = 7.3Hz, 6H).

[0440] Example 51: 7-Chloro-1-(3-(piperidin-1-yl)propyl)isoquinoline

[0441] Synthesis route:

[0442] Step 1: 1-(Prop-2-yn-1-yl)piperidine

[0443] Weigh piperidine (1.0 g) into a 50 ml single-necked flask, then add EA (15 ml) and dropwise add 3-bromoprop-1-yne (2.1 g). Stir at room temperature for 1 hour. Post-processing and purification: LCMS confirmed the formation of the desired product and complete reaction of the starting materials. A solid precipitated and was filtered. The filtrate was concentrated to yield 500 mg of a yellow oil.

[0444] Step 2: 7-Chloro-1-(3-(piperidin-1-yl)prop-1-yn-1-yl)isoquinoline

[0445] Weigh 1,7-dichloroisoquinoline (500 mg), 1-(prop-2-yn-1-yl)piperidine (468 mg), and Pd(PPh3)4 (293 mg) into a 50 ml single-necked flask, then add TEA (10 ml). Displace the air in the system with nitrogen three times and stir at 60°C for 2 hours. Workup and purification: LCMS confirmed the formation of the desired product and complete reaction of the starting materials. Concentrate the product and perform column chromatography (petroleum ether / ethyl acetate = 80%) to yield 300 mg of a yellow oil.

[0446] Step 3: 7-Chloro-1-(3-(piperidin-1-yl)propyl)isoquinoline

[0447] The product obtained in the above step was dissolved in 20 volumes of methanol, and approximately 15 mg of Pd / C was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature for 2 hours. Post-processing and purification: LCMS showed the formation of the target compound and complete reaction of the starting materials. Filtration, concentration, and preparative purification (ACN / H2O) afforded 174 mg of the target compound as a white solid. MS: 289 [M+H] + . 1H NMR(400MHz,D2O)δ8.59(s,1H),8.37(d,J=6.6Hz,1H),8.29(d,J=6.6Hz,1H ),8.21(d,J=8.9Hz,1H),8.12(dd,J=8.9,1.7Hz,1H),3.66–3.56(m,2H),3. 51(d,J=12.3Hz,2H),3.39–3.23(m,2H),2.93(t,J=12.3Hz,2H),2.42–2.20 (m,2H),1.92(d,J=14.8Hz,2H),1.83–1.60(m,3H),1.44(q,J=12.6Hz,1H).

[0448] Example 53: 7-chloro-1-(2-(3,6-dihydropyridin-1(2H)-yl)ethoxy)isoquinoline

[0449] Synthesis route:

[0450] Step 1: 2-(4-Fluoropiperidin-1-yl)ethan-1-ol

[0451] Weigh 4-fluoropiperidine (1.0 g) into a 100 mL single-necked flask and dissolve in 15 mL of water. Then, weigh ethylene oxide (2.13 g) and add it to the reaction mixture. Stir at 50°C for 3 h. Post-processing and purification: LCMS indicated completion of the reaction. Extract with ethyl acetate, and concentrate the EA layer to dryness to obtain the crude target compound, which was used directly in the next step.

[0452] Step 2: 7-Chloro-1-(2-(3,6-dihydropyridin-1(2H)-yl)ethoxy)isoquinoline

[0453] 2-(4-Fluoropiperidin-1-yl)ethan-1-ol (200 mg) was weighed into a 100 mL single-necked flask and dissolved in 15 mL of DMSO. 1,7-Dichloroisoquinoline (220 mg) and t-BuOK (340 mg) were then added to the reaction system. The reaction was stirred at room temperature for 2 hours. Post-treatment and purification: LC-MS indicated completion of the reaction. A large amount of water was added to the reaction solution, and the mixture was extracted with EA. The EA layer was concentrated and precipitated with HCl / EA. The precipitate was separated and purified by RP-HPLC to yield 30 mg of the title compound as a white solid. MS: 289 [M+H] + . 1HNMR(400MHz,D2O)δ8.09(d,J=1.64Hz,1H),7.76(d,J=6.16Hz,1H),7.72(d,J=8. 76Hz,1H),7.67-7.64(dd,J=8.76,2.00Hz,1H),7.35(d,J=6.16Hz,1H),5.95-5.93 (m,1H),5.69-5.67(m,1H),4.77(t,J=4.52,2H),3.96-3.92(m,1H),3.79-3.74(m ,3H),3.70-3.67(m,1H),3.36-3.29(m,1H),2.53-3.47(m,1H),2.41-2.36(m,1H).

[0454] Example 54: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)benzene-1,2-diamine

[0455] Synthesis route:

[0456] Step 1: (4-Acetylaminophenethyl) acetate

[0457] 2-(4-Aminophenyl)ethan-1-ol (5.0 g) was weighed into a 250 mL single-necked flask and dissolved in 150 mL of DCM. Acetyl chloride (8.5 g) was then added dropwise to the reaction mixture, followed by triethylamine (10.8 g). The mixture was stirred at room temperature overnight. Post-processing and purification: LC-MS indicated completion of the reaction. The reaction mixture was washed with saturated NaCl. The DCM layer was concentrated and purified by column chromatography to yield 6.5 g of the title compound.

[0458] Step 2: (4-Acetylamino-3-nitrophenylethyl) acetate

[0459] Weigh 6.5 g of 4-acetamidophenethyl acetate into a 100 mL single-necked flask and cool in an ice bath. Then, mix 10 mL of concentrated sulfuric acid and 10 mL of concentrated nitric acid and cool in an ice bath. Add the cooled concentrated sulfuric acid and nitric acid dropwise to the single-necked flask and allow to react for 10 minutes in an ice bath and then for 30 minutes at room temperature. Post-processing and purification: LCMS indicated completion of the reaction. The reaction solution was added to a large amount of ice water, and the precipitate was extracted with EA. The EA layer was concentrated and purified by column chromatography to yield 4.0 g of the title compound.

[0460] Step 3: 2-(4-amino-3-nitrophenyl)ethan-1-ol

[0461] Weigh 4.0 g of 4-acetylamino-3-nitrophenylethyl acetate into a 100 mL single-necked flask and dissolve in an appropriate amount of methanol. Add 5 mL of 50% NaOH solution and react at room temperature for 30 min. Post-processing and purification: LCMS indicates completion of the reaction. Remove the methanol by vortexing, add a large amount of water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried, and filtered. The filtrate is concentrated and dissolved in a small amount of ethyl acetate. Add 2 mL of hydrochloric acid and ethyl acetate to precipitate a solid, which is filtered to yield 3.5 g of the target compound hydrochloride.

[0462] Step 4: 2-(3,4-Diaminophenyl)ethan-1-ol

[0463] 2-(4-Amino-3-nitrophenyl)ethan-1-ol (3.5 g) was weighed into a 100 mL single-necked flask and dissolved in 30 mL of methanol. 0.7 g of 10% palladium on carbon was added and the mixture was allowed to react under a stream of hydrogen at room temperature for 3 hours. Post-processing and purification: LCMS indicated the reaction was complete. The palladium on carbon was filtered and the methanol was removed by swirl to yield 3.0 g of the title compound.

[0464] Step 5: Di-tert-butyl (4-(2-hydroxyethyl)-1,2-phenyl)dicarboxylate

[0465] Weigh 3.0 g of 2-(3,4-diaminophenyl)ethan-1-ol into a 100 mL single-necked flask and dissolve it in 40 ml of water. Dissolve 17.2 g of Boc2O in an appropriate amount of dioxane and add the remaining solution to the flask. Adjust the pH to 8-9 with triethylamine and allow the mixture to react overnight at room temperature. Post-processing and purification: LCMS indicated completion of the reaction. Remove the dioxane and extract with EA. The EA layer was concentrated and purified by column chromatography to yield 3.2 g of the target compound.

[0466] Step 6: Di-tert-butyl (4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-1,2-phenyl)dicarboxylate

[0467] 1,7-Dichloroisoquinoline (200 mg) was weighed into a 100 mL single-necked flask and dissolved in 15 mL of DMSO. Then, di-tert-butyl (4-(2-hydroxyethyl)-1,2-phenyl)dicarboxylate (533 mg) was added. t-BuOK (340 mg) was added to the reaction system and stirred at room temperature for 2 hours. Post-processing and purification: LC-MS indicated the reaction was complete. A large amount of water was added to the reaction solution, and the mixture was extracted with EA. The EA layer was concentrated and precipitated with HCl / EA. The precipitate was collected and purified by RP-HPLC to obtain 125 mg of the title compound as a white solid. MS: 514 [M+H] + .

[0468] Step 7: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)benzene-1,2-diamine

[0469] Weigh 125 mg of di-tert-butyl (4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-1,2-phenyl)dicarboxylate into a 100 mL single-necked flask, dissolve in 10 mL of hydrochloric acid and ethyl acetate, and stir at room temperature for 2 hours. Post-processing and purification: LCMS indicated the reaction was complete. The precipitate was filtered and purified by RP-HPLC to yield the target compound hydrochloride as a white solid (85 mg). MS: 314 [M+H] + . 1 HNMR (400MHz, DMSO) δ8.11(s,1H),8.07(s,1H),8.04(d,J=5.76Hz,1H),7.96(d,J=8.68Hz,1H),7.80-7.70(m,6H),7.43(d, J=5.76Hz,1H),7.11(d,J=7.92Hz,1H),7.02(s,1H),6.89(d,J=7.92Hz,1H),4.62(t,J=6.60Hz,1H),3.07(t,J=6.52Hz,1H).

[0470] Example 55: 7-Chloro-2-(3,4-diaminophenethyl)isoquinolin-1(2H)-one

[0471] Synthesis route:

[0472] Step 1: Di-tert-butyl (4-(2-bromoethyl)-1,2-phenyl)dicarboxylate

[0473] Weigh CBr4 (9.0 g) into a 250 mL single-necked flask and dissolve in 150 mL of DCM. Then, add di-tert-butyl (4-(2-hydroxyethyl)-1,2-phenyl)dicarboxylate (3.2 g) and triphenylphosphine (7.8 g) to the reaction mixture. Stir at room temperature for 2 h. Post-processing and purification: LCMS indicated completion of the reaction. Water was added to the reaction mixture for extraction. The aqueous layer was washed with DCM and concentrated to dryness. Purification by column chromatography afforded 3.5 g of the title compound as a white solid, MS: 415 [M+H]. + .

[0474] Step 2: Di-tert-butyl (4-(2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl)-1,2-phenyl)dicarboxylate

[0475] 7-Chloroisoquinolin-1(2H)-one (200 mg) was weighed into a 100 mL single-necked flask and dissolved in 15 mL of toluene. Then, di-tert-butyl (4-(2-bromoethyl)-1,2-phenyl)dicarboxylate (278 mg) was added. TBAB (22 mg) was added to the reaction system, and 2.0 mL of NaOH solution was added. The reaction was stirred at room temperature for 3 hours. Post-processing and purification: LCMS indicated the reaction was complete. The toluene was removed by rotary evaporation, and the product was extracted with EA. The EA layer was concentrated and purified by RP-HPLC to obtain 250 mg of the title compound as a white solid. MS: 514 [M+H]. + .

[0476] Step 3: 7-chloro-2-(3,4-diaminophenethyl)isoquinolin-1(2H)-one

[0477] Weigh 250 mg of di-tert-butyl (4-(2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl)-1,2-phenyl)dicarboxylate into a 100 mL single-necked flask, dissolve in 10 mL of hydrochloric acid and ethyl acetate, and stir at room temperature for 2 hours. Post-processing and purification: LCMS indicated completion of the reaction. The precipitate was filtered and purified by RP-HPLC to yield the target compound hydrochloride as a white solid (200 mg). MS: 314 [M+H] +1 HNMR (400MHz, DMSO) δ8.17(d,J=1.72Hz,1H),7.93(m,6H),7.76-7.70(m,2H),7.42(d,J=7.36Hz,1H),7.06(d,J=8.04 Hz,1H),6.87(s,1H),6.74(d,J=7.24Hz,1H),6.62(d,J=7.32Hz,1H),4.15(t,J=7.36Hz,1H),2.89(t,J=7.28Hz,1H).

[0478] Example 56: 7-Chloro-1-(2-(4-fluoropiperidin-1-yl)ethoxy)isoquinoline

[0479] Synthesis route:

[0480] Procedure: Weigh 7-chloroisoquinolin-1(2H)-one into a 100 mL single-necked flask and dissolve in 15 mL of THF. Then, add 2-(4-fluoropiperidin-1-yl)ethan-1-ol (176 mg), triphenylphosphine (393 mg), and DIAD (303 mg) to the reaction mixture. Stir at room temperature for 3 hours. Post-processing and purification: LCMS indicated completion of the reaction. THF was removed by evaporation, and the mixture was extracted with EA. The EA layer was washed with water and concentrated. RP-HPLC separation and purification yielded 50 mg of the title compound as a white solid. MS: 309 [M+H] + . 1 HNMR(400MHz,D2O)δ8.02(s,1H),7.73(d,J=6.12Hz,1H),7.67(d,J=8.76Hz,1H),7.63-7.60(dd,J=8.76Hz,J=1.80Hz,1H),7.30 (d,J=6.12Hz,1H),4.74-4.71(m,2H),3.79(m,2H),3.59-3.57(m,1H),3,41-3.22(m,2H),2.32-2.20(m,2H),2.10-1.97(m,2H).

[0481] Example 57: 7-Chloro-1-(2-(piperazin-1-yl)ethoxy)isoquinoline

[0482] Synthesis route:

[0483] Step 1: tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate

[0484] Weigh tert-butyl piperazine-1-carboxylate (2.0 g) into a 50 ml single-necked flask, add H₂O (10 ml), and then add ethylene oxide / tetrahydrofuran solution (3 M, 11 ml). Stir at 50°C for 2 hours. Post-processing and purification: LCMS indicated the formation of the target compound and complete reaction of the starting materials. Cool to room temperature, extract the aqueous layer three times with an appropriate amount of ethyl acetate, combine the organic phases, wash twice with saturated brine, combine the organic phases, dry, and concentrate. This yields 2.0 g of the crude target compound, which is carried on to the next step without column chromatography purification.

[0485] Step 2: tert-Butyl 4-(2-((7-chloroisoquinolin-1-oxy)ethyl)piperazine-1-carboxylate

[0486] Weigh tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (500 mg) into a 100 ml single-necked flask, add DMF (10 ml) and t-BuOK (365 mg). After stirring at room temperature for 1 hour, add 1,7-dichloroisoquinoline (640 mg). The final system was stirred at room temperature for 2 hours. Post-treatment and purification: LCMS showed that the target compound was generated and the raw materials reacted completely. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate 3 times, and combine the organic phases. Wash the organic phase twice with saturated brine, dry the organic phase, and concentrate. Purify {PE / EA} by column chromatography to obtain 280 mg of a yellow oil.

[0487] Step 3: 7-Chloro-1-(2-(piperazin-1-yl)ethoxy)isoquinoline

[0488] To the compound obtained in the previous step, add an appropriate amount of ethyl acetate to dissolve the sample, then add HCl / EA (2.0 ml). Stir at room temperature for 2 hours. Post-processing and purification: LCMS confirmed the formation of the target compound and the complete reaction of the starting materials. The precipitated solid was filtered, collected, and dried. 29 mg of the target compound was obtained as a yellow solid. MS: 292 [M+H] + . 1 H NMR (400MHz, D2O) δ8.18(d,J=1.7Hz,1H),7.82(d,J=6.1Hz,1H),7.77(d,J=8.8Hz,1H),7.69(dd,J=8.8,2.0 Hz,1H),7.39(d,J=6.1Hz,1H),4.86–4.79(m,2H),3.91–3.86(m,2H),3.83–3.76(m,4H),3.67–3.61(m,4H).

[0489] Example 58: 7-Chloro-1-(2-(4-methylpiperazin-1-yl)ethoxy)isoquinoline

[0490] Synthesis route:

[0491] 7-Chloro-1-(2-(piperazin-1-yl)ethoxy)isoquinoline (100 mg) was weighed into a 50 mL single-necked flask and dissolved in THF. Acetic acid (0.2 ml) was then added, and formaldehyde solution (3 ml) was added dropwise to the reaction system. The reaction was stirred for 30 minutes. NaBH(AcO)3 was added, and the reaction was stirred at room temperature for 2 hours. Post-processing and purification: LCMS indicated the reaction was complete. The reaction solution was quenched with methanol, concentrated, and purified by column chromatography to yield 85 mg of the title compound with a purity of 95.49%. MS: 306 [M+H]+. 1HNMR(400MHz,D2O)δ8.11(s,1H),7.76(d,J=6.08Hz,1H),7.70(d,J=8.76Hz,1H),7.66-7.63(dd,J=8.72Hz,J=1.68 Hz,1H),7.34(d,J=6.08Hz,1H),4.79-4.77(m,2H),3.99(m,2H),3.88-3.85(m,4H),3.61-3.53(m,4H),2.97(s,3H).

[0492] Example 59: 5-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-3-fluorobenzene-1,2-diamine

[0493] Synthesis route:

[0494] Step 1: 4-Bromo-2-fluoro-6-nitroaniline

[0495] Weigh 2-fluoro-6-nitroaniline (2.0 g) into a 100 ml single-necked flask, then add DCM (250 ml) and NBS (2.7 g) in portions. Stir at room temperature for 2 hours. Post-processing and purification: LCMS indicated the formation of the title compound and complete reaction of the starting materials. Add an appropriate amount of dichloromethane to the system, wash the organic phase three times with saturated sodium bicarbonate solution and twice with saturated brine. Dry and concentrate the organic phase. This yields 2.9 g of the crude title compound as a yellow solid, which is used directly in the next step for further purification.

[0496] Step 2: tert-Butyl (4-bromo-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate

[0497] Weigh 4-bromo-2-fluoro-6-nitroaniline (2.5 g) into a 100 ml single-necked flask, then add Boc2O (6.9 g), DMAP (129 mg), and DCM (50 ml). Stir at room temperature for 2 hours. Post-treatment and purification: TLC confirms complete reaction of the starting materials. Add appropriate amounts of water and ammonia to the reaction system and stir. Extract the aqueous layer three times with ethyl acetate, and combine the organic phases. Wash twice with saturated brine, dry, and concentrate. Purify by column chromatography to obtain 4.2 g of the crude target compound as a yellow solid.

[0498] Step 3: tert-Butyl (E)-(tert-Butoxycarbonyl)(4-(2-ethoxyvinyl)-2-fluoro-6-nitrophenyl)carboxylate

[0499] Weigh tert-butyl (4-bromo-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate (1.5 g) into a 100 ml single-necked flask, then add (E)-2-(2-ethoxyethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (682 mg), tetrakis(triphenylphosphine)palladium (200 mg), potassium carbonate (950 mg), and dioxane (15 ml). Stir overnight at room temperature. Post-processing and purification: TLC confirmed complete reaction of the starting materials. Purification by concentrating column chromatography (petroleum ether / ethyl acetate) afforded 1.2 g of the desired product as a yellow solid.

[0500] Step 4: tert-Butyl (tert-Butoxycarbonyl)(2-fluoro-6-nitro-4-(2-oxoethyl)phenyl)carboxylate

[0501] Weigh tert-butyl (E)-(tert-butyloxycarbonyl)(4-(2-ethoxyvinyl)-2-fluoro-6-nitrophenyl)carboxylate (1.2 g) and HCOOH (20 mL) into a 100 mL single-necked flask and stir at 60°C for 2 hours. Post-processing and purification: TLC confirmed complete reaction of the starting material. Purification by concentrating column chromatography (petroleum ether / ethyl acetate) afforded 460 mg of the desired product as a yellow liquid.

[0502] Step 5: tert-Butyl (tert-Butoxycarbonyl)(2-fluoro-4-(2-hydroxyethyl)-6-nitrophenyl)carboxylate

[0503] tert-Butyl (tert-butoxycarbonyl)(2-fluoro-6-nitro-4-(2-oxoethyl)phenyl)carboxylate (460 mg) and MeOH (10 mL) were weighed into a 100 mL single-necked flask. NaBH₄ (439 mg) was added portionwise and stirred at room temperature for 1 hour. Post-treatment and purification: TLC confirmed complete reaction of the starting material. NH₄Cl solution was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to yield 430 mg of the desired product as a yellow liquid.

[0504] Step 6: tert-Butyl (4-(2-bromoethyl)-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate

[0505] Triphenylphosphine (84.5 mg) and DCM (10 mL) were weighed into a 50 mL single-necked flask. CBr (106 mg) was added portionwise at 0°C over 5 minutes. Then, tert-butyl (tert-butyloxycarbonyl)(2-fluoro-4-(2-hydroxyethyl)-6-nitrophenyl)carboxylate (430 mg) was added. The mixture was warmed to room temperature and stirred for 1 hour. Post-processing and purification: TLC confirmed complete reaction of the starting materials. Purification was performed by concentrating column chromatography (petroleum ether / ethyl acetate) to yield 97 mg of the desired product as a yellow oil.

[0506] Step 7: tert-Butyl (tert-butoxycarbonyl)(4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2-fluoro-6-nitrophenyl)carboxylate

[0507] To a 20 mL sealed tube, add tert-butyl (4-(2-bromoethyl)-2-fluoro-6-nitrophenyl)(tert-butoxycarbonyl)carboxylate (97 mg), 7-chloroisoquinolin-1-ol (69 mg), sodium hydroxide (77.3 mg), TBAB (12.4 mg), water (2 ml), and toluene (10 ml). Stir at 78°C for 3 hours. Post-treatment and purification: TLC monitoring confirmed the absence of 7-chloroisoquinolin-1-ol. The mixture was separated, concentrated, and purified by column chromatography (PE / EA) to afford 80 mg of the title compound as a yellow solid.

[0508] Step 8: 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2-fluoro-6-nitroaniline

[0509] 80 mg of tert-butyl (tert-butoxycarbonyl)(4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2-fluoro-6-nitrophenyl)carboxylate was weighed and added to a 25 ml single-necked flask containing 10 ml of HCl / EA. Stirring was performed at room temperature for 1 hour, during which a white solid precipitated. Post-processing and purification: LCMS confirmed complete reaction of the starting material and the yield of the desired product. The solvent was removed by filtration, and the filter cake was rinsed with 10 ml of EA to yield 53 mg of the desired product (hydrochloride) as a white solid.

[0510] Step 9: 5-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-3-fluorobenzene-1,2-diamine

[0511] 4-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2-fluoro-6-nitroaniline (53 mg), zinc powder (95 mg), saturated NH4Cl solution (5 ml), and ethanol (15 mL) were weighed into a 50 mL single-necked flask and stirred under reflux overnight. Post-processing and purification: LCMS confirmed the formation of the target compound and complete reaction of the starting materials. The mixture was concentrated, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined, dried, and concentrated. The product was purified by preparative HPLC and lyophilized to obtain 28 mg of the trifluoroacetate salt of the white solid product. MS: 332 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.42(s,1H),8.85(s,1H),8.17(d,J=1.9Hz,1H),7.73(dt,J=15.5,5.3Hz,2H),7.37(d,J=7.4Hz, 1H),6.60(d,J=7.3Hz,1H),6.51–6.44(m,2H),4.94(s,2H),4.82(s,2H),4.11(t,J=7.4Hz,2H),2.80(t,J=7.3Hz,2H).

[0512] Example 60: 4-(3-(7-chloroisoquinolin-1-yl)propyl)morpholine

[0513] Synthesis route:

[0514] Step 1: 1,7-Dichloroisoquinoline

[0515] Weigh 7-chloroisoquinolin-1(2H)one (10.0 g) into a 250 ml single-necked flask, add SOCl2 (50 ml) and DMF (5 ml), and stir at 80°C for 2 hours. Post-treatment and purification: LCMS showed the formation of the target compound and complete reaction of the raw materials. Cool to room temperature, concentrate, and remove SOCl2. Add an appropriate amount of ethyl acetate to dissolve the sample and adjust the system to alkalinity with saturated sodium bicarbonate solution. Extract the aqueous layer three times with ethyl acetate, combine the organic phases, and wash twice with saturated brine. Collect the organic phases, dry, and concentrate. 8.5 g of yellow solid product is obtained.

[0516] Step 2: 4-(3-(7-chloroisoquinolin-1-yl)propyl-2-yn-1-yl)morpholine

[0517] Weigh 1,7-dichloroisoquinoline (300 mg), 4-(propyl-2-ynyl-1-yl)morpholine (285 mg), and Pd(PPh3)4 (350 mg) into a 50 mL single-necked flask and add Et3N (10 mL). Heat to 60°C under nitrogen and stir overnight. Workup and purification: LCMS indicated formation of the desired product and complete reaction of the starting materials. Cool to room temperature, concentrate, and column chromatography (DCM / MeOH) afford 600 mg of the desired compound as a yellow oil.

[0518] Step 3: 4-(3-(7-chloroisoquinolin-1-yl)propyl)morpholine

[0519] Add an appropriate amount of MeOH to the product obtained in the previous step to dissolve the sample, and then add an appropriate amount of Pd / C. Replace the air in the system with hydrogen three times and stir at room temperature overnight. Post-processing and purification: LCMS confirms the formation of the target compound and complete reaction of the starting materials. Filter and collect the filtrate. After concentration, purify it by preparative HPLC. After concentration, replace it with HCl / EA (4M) to obtain the hydrochloride salt, yielding 139 mg of the target compound as a white solid. MS: 291 [M+H] + . 1 H NMR (400MHz, D2O) δ8.58(s,1H),8.36(d,J=6.6Hz,1H),8.27(d,J=6.6Hz,1H),8.19(d,J=8.9Hz,1H),8.10(dd,J=8.9,1. 7Hz,1H),4.07(s,2H),3.79(s,2H),3.64–3.58(m,2H),3.50(s,2H),3.43–3.37(m,2H),3.20(s,2H),2.40–2.26(m,2H).

[0520] Example 61: N-Benzyl-1-(7-chloroisoquinolin-1-yl)methanamine

[0521] Synthesis route:

[0522] Step 1: 7-Chloroisoquinoline 2-oxide

[0523] Weigh 7-chloroisoquinoline (2.0 g) into a 100 ml single-necked flask, then add DCM (30 ml) and m-CPBA (4.22 g) and stir at room temperature for 2 hours. Post-processing and purification: LCMS indicated the formation of the title compound and complete reaction of the starting materials. Add an appropriate amount of dichloromethane to dilute the reaction system, wash the system three times with saturated sodium sulfite solution and once with saturated brine. Dry the organic phase and concentrate. This yields 2.5 g of the crude title compound as a white solid.

[0524] Step 2: 7-Chloroisoquinoline-1-carbonitrile

[0525] 7-Chloroisoquinoline 2-oxide (2.5 g) was weighed into a 100 ml single-necked flask, followed by the addition of THF (30 ml) and TMSCN (2.07 g). The mixture was stirred at room temperature for 2 hours. Post-processing and purification: LCMS confirmed the formation of the target compound and complete reaction of the starting material. The reaction mixture was concentrated and purified on a silica gel column (PE / EA = 35%) to afford 1.6 g of the target compound as a white solid.

[0526] Step 3: (7-Chloroisoquinolin-1-yl)methanamine

[0527] Weigh 7-chloroisoquinoline-1-carbonitrile (1.6 g) into a 250 ml single-necked flask and add EtOH (50 ml). Then, add Raney nickel (160 mg) and stir at 80°C overnight. Post-processing and purification: LCMS confirmed the formation of the target compound and complete reaction of the starting material. Filter the reaction mixture, wash the filter cake three times with EtOH, and combine the filtrates and concentrate to obtain 1.7 g of the crude target compound as a white solid.

[0528] Step 4: N-Benzyl-1-(7-chloroisoquinolin-1-yl)methanamine

[0529] (7-Chloroisoquinolin-1-yl)methanamine (200 mg), DCM (5 ml), benzaldehyde (66 mg), and acetic acid (two drops) were weighed into a 50 ml single-necked flask and stirred at room temperature for 1 hour. STAB (659 mg) was added and stirred at room temperature for 1 hour. Post-processing and purification: LCMS confirmed the formation of the target compound and complete reaction of the starting material. The reaction system was concentrated, purified by preparative HPLC, and lyophilized to obtain 14 mg of the product as a white solid. MS: 283 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.65(s,2H),8.60(d,J=5.7Hz,1H),8.30(s,1H),8.14(d,J=8.8Hz,1H),7.96(d,J=5.7Hz,1H ),7.91(dd,J=8.8,1.5Hz,1H),7.60(d,J=6.3Hz,2H),7.46(q,J=5.6Hz,3H),4.97(s,2H),4.34(s,2H),1.23(s,1H).

[0530] Example 62: 6-(2-((7-chloroisoquinolin-1-yl)oxy)ethyl)-2-oxa-6-azaspiro[3.3]heptane

[0531] Synthesis route:

[0532] Step 1: 6-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-oxa-6-azaspiro[3.3]heptane

[0533] Weigh 2-oxa-6-azaspiro[3.3]heptane (500 mg) into a 100 ml single-necked flask, add DCM (10 ml), Et3N (1.0 g), and 2-(tert-butyldimethylsilyloxy)acetaldehyde (1.30 g). Stir at room temperature for 1 hour. Then add NaBH(AcO)3 (3.2 g). Stir at room temperature for 2 hours. Post-processing and purification: LCMS showed the target compound was generated and the raw materials reacted completely. Add appropriate amount of water to the system, extract the aqueous layer with DCM three times, combine the organic phases, wash twice with saturated brine, dry and concentrate the organic phases. Obtain 1.2 g of colorless liquid product.

[0534] Step 2: 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethan-1-ol

[0535] Weigh 6-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-oxa-6-azaspiro[3.3]heptane (500 mg) into a 50 mL single-necked flask and add TBAF / THF (10 mL). Stir at room temperature for 2 hours. Workup and purification: LCMS indicated the formation of the desired product and complete reaction of the starting material. Concentrate and purify by preparative HPLC to yield 400 mg of the crude product.

[0536] Step 3: 6-(2-(7-chloroisoquinolin-1-yl)oxy)ethyl)-2-oxa-6-azaspiro[3.3]heptane

[0537] Weigh 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethane-1-ol (400 mg) into a 50 ml single-necked flask, add DMF (10 ml) and t-BuOK (85 mg). Stir at room temperature for 30 minutes, then add 1,7-dichloroisoquinoline (100 mg). The final system is stirred at room temperature for 2 hours. Post-treatment and purification: LCMS shows that the target compound is generated and the raw material reaction is complete. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, combine the organic phases, wash twice with saturated brine, dry the organic phase, and concentrate. Purify by column chromatography {DCM / MeOH} to obtain 57 mg of white solid product. MS: 305 [M+H] + . 1H NMR (400MHz, DMSO) δ8.11(d,J=1.9Hz,1H),8.02(d,J=5.8Hz,1H),7.97(d,J=8.7Hz,1H),7.80(dd,J=8.7, 2.2Hz,1H),7.43(d,J=5.8Hz,1H),4.60(s,4H),4.41(t,J=5.5Hz,2H),3.42(s,4H),2.82(t,J=5.0Hz,2H).

[0538] Example 63: 1-(2-(8-azabicyclo[3.2.1]octan-8-yl)ethoxy)-7-chloroisoquinoline

[0539] Synthesis route:

[0540] Step 1: tert-Butyl 8-azabicyclo[3.2.1]octane-8-carboxylate

[0541] Weigh tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (3.0 g) into a 250 ml single-necked flask, add diethylene glycol (40 ml) and N2H4.H2O (1.6 g), raise the temperature to above 50°C, and then add KOH (5.1 g). Heat to above 100°C and stir for 4 hours. Post-processing and purification: LCMS shows the target compound is formed and the raw materials are completely reacted. Add an appropriate amount of water to the system, extract the aqueous layer three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry the organic phase, and concentrate to obtain the crude compound.

[0542] Step 2: 8-Azabicyclo[3.2.1]octane

[0543] Add an appropriate amount of ethyl acetate to the compound obtained in the previous step to dissolve the sample, then add HCl / EA (4M, 5 ml). Stir at room temperature for 2 hours. Post-processing and purification: LCMS indicates the formation of the target product and complete reaction of the starting materials. Add an appropriate amount of water to the system, wash the aqueous layer twice with ethyl acetate, collect the aqueous layer, and concentrate to obtain the crude target compound. Proceed directly to the next step without column chromatography purification.

[0544] Step 3: 2-(8-Azabicyclo[3.2.1]octan-8-yl)ethan-1-ol

[0545] Add an appropriate amount of water to the compound obtained in the previous step to dissolve the sample, then add ethylene oxide (10.0 ml), heat to 50 ° C and stir for 2 hours. Post-treatment and purification: LCMS shows that the target compound is generated and the raw material reaction is complete. Add an appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, combine the organic phases, wash twice with saturated brine, dry the organic phase, and concentrate. The crude target compound is obtained and directly proceed to the next step of synthesis.

[0546] Step 4: 1-(2-(8-azabicyclo[3.2.1]octan-8-yl)ethoxy)-7-chloroisoquinoline

[0547] Weigh 2-(8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol (470 mg) into a 25 ml single-necked flask, add DMF (5 ml) and t-BuOK (170 mg). Stir at room temperature for 30 minutes, then add 1,7-dichloroisoquinoline (200 mg). Stir the mixture at room temperature for 2 hours. LCMS showed the formation of the target compound and complete reaction of the starting materials. Add an appropriate amount of water to the system, extract the aqueous layer three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry the organic phases, and concentrate. After concentration, purify the product by preparative HPLC and lyophilize to obtain 110 mg of the target compound as a white solid. MS: 317 [M+H] + . 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.77(t,J=5.0Hz,1H),7.68(dd,J=8.8,3.3Hz,1H),7.63–7.58(m,1H),7.29(d,J=6.0Hz,1H),4.71–4.66(m,2H) ,4.09(s,2H),3.53–3.46(m,2H),2.33–2.24(m,2H),2.05(q,J=6.0Hz,2 H),1.97(dd,J=19.5,5.2Hz,2H),1.83–1.74(m,2H),1.74–1.56(m,2H).

[0548] Example 64: 1-(2-(Piperidin-1-yl)ethoxy)isoquinoline-6,7-diol

[0549] Synthesis route:

[0550] Step 1: 6,7-dimethoxyisoquinolin-1(2H)one

[0551] (E)-3-(3,4-Dimethoxyphenyl)acrylic acid (10.0 g) was weighed into a 250 ml single-necked flask, and toluene (100 ml), Et3N (24 g), and DPPA (26 g) were added. The mixture was heated to above 60°C and stirred overnight under nitrogen. Post-processing and purification: LCMS indicated the formation of the target compound and complete reaction of the starting materials. The product was concentrated and purified by column chromatography (PE / EA) to yield 9.1 g of a pale yellow solid.

[0552] Step 2: 1-chloro-6,7-dimethoxyisoquinoline

[0553] Weigh 6,7-dimethoxyisoquinolin-1(2H)one (1.0 g) into a 50 ml single-necked flask and add POCl3 (10 ml). Heat to 110°C and stir for 1 hour. Post-treatment and purification: LCMS showed the formation of the target compound and complete reaction of the starting materials. Concentrate and add the remaining material dropwise into ice water to quench the POCl3. Adjust the pH value of the system to alkaline with saturated sodium bicarbonate solution, extract the aqueous layer three times with ethyl acetate, and combine. Wash the organic phase twice with saturated brine, dry, and concentrate. Purify by column chromatography {PE / EA} to obtain 80 mg of white solid product.

[0554] Step 3: 6,7-Dimethoxy-1-(2-(piperidin-1-yl)ethoxy)isoquinoline

[0555] 1-Chloro-6,7-dimethoxyisoquinoline (80 mg) and t-BuOK (80 mg) were weighed into a 25 ml single-necked flask. DMF (5 ml) and 2-(piperidin-1-yl)ethan-1-ol (70 mg) were added and stirred at room temperature for 2 hours. Post-treatment and purification: LCMS showed the target compound was produced and the starting materials reacted completely. An appropriate amount of water was added to the system, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined. The organic phase was washed twice with saturated brine, dried, and concentrated. Column chromatography (DCM / MeOH) was used to purify the product to give 60 mg of an oil.

[0556] Step 4: 1-(2-(Piperidin-1-yl)ethoxy)isoquinoline-6,7-diol

[0557] 6,7-Dimethoxy-1-(2-(piperidin-1-yl)ethoxy)isoquinoline (60 mg) was weighed into a 25 mL single-necked vial and DCM (5 mL) and BBr3 (95 mg) were added. The mixture was stirred at room temperature overnight. Post-processing and purification: LCMS confirmed the formation of the target compound and the complete reaction of the starting material. The product was concentrated, purified by preparative HPLC, and lyophilized to yield 12.9 mg of the target compound as a white solid. MS: 317 [M+H] + . 1H NMR(400MHz,D2O)δ7.55(d,J=6.6Hz,1H),7.41(s,1H),7.29(d,J=6.6Hz,1H),7.08(s,1H),4.90–4.82(m,2H),3.80–3.73( m,2H),3.66(d,J=11.8Hz,2H),3.19–3.08(m,2H),1.95(d,J=15.1Hz,2H),1.84–1.69(m,3H),1.49(dd,J=16.0,7.9Hz,1H).

[0558] Example 65: 7-Bromo-1-(2-(piperidin-1-yl)ethoxy)isoquinoline

[0559] Synthesis route:

[0560] Weigh 2-(piperidin-1-yl)ethane-1-ol (380 mg) into a 50 ml single-necked flask, add DMF (10 ml) and cool to 0°C, then add t-BuOK (556 mg) and stir at this temperature for 30 minutes. Then add 7-bromo-1-chloroisoquinoline (600 mg) and stir at room temperature for 1 hour. Post-treatment and purification: LCMS shows that the target compound is generated and the raw material reaction is complete. Add appropriate amount of water to the system, extract the aqueous layer with ethyl acetate three times, combine the organic phases, wash twice with saturated brine, dry the organic phase, and concentrate. Purify by column chromatography {PE / EA}, add appropriate amount of ethyl acetate after concentration to dissolve, add HCl / EA solution dropwise to prepare the hydrochloride, filter the precipitated solid, collect, and dry. 380 mg of white solid product is obtained. MS: 335[M+H] + . 1 H NMR(400MHz,D2O)δ8.25(d,J=1.8Hz,1H),7.82–7.76(m,2H),7.64(d,J=8.8Hz,1H),7.34(d,J=6.1Hz,1H),4.77–4.73(m,2H ),3.71–3.59(m,4H),3.09(td,J=12.3,2.7Hz,2H),1.94(d,J=15.6Hz,2H),1.83–1.68(m,3H),1.48(qd,J=12.1,3.6Hz,1H).

[0561] Example 66: 1-(2-(Piperidin-1-yl)ethoxy)isoquinolin-7-ol

[0562] Synthesis route:

[0563] 7-Bromo-1-(2-(piperidin-1-yl)ethoxy)isoquinoline (500 mg), Pd2(dba)3 (140 mg), t-BuXphos (124 mg), and KOH (250 mg) were weighed into a 25 ml single-necked flask, 1,4-dioxane / H2O (5 ml / 1 ml) was added, and the mixture was heated to 120°C and stirred for 2 hours under nitrogen protection. Post-treatment and purification: LCMS showed that the target compound was generated and the raw materials reacted completely. Filter, dilute the filtrate with ethyl acetate, wash twice with saturated brine, and dry the organic phase and concentrate. After concentration, the mixture was purified by preparative HPLC. After concentration, HCl / EA (4 M) was used to replace the hydrochloride to obtain 45 mg of the target compound as a white solid. MS: 273 [M+H] + . 1 H NMR(400MHz,D2O)δ7.72(d,J=8.8Hz,1H),7.59(d,J=6.4Hz,1H),7.45–7.34(m,3H),4.86–4.79(m,2H),3.78–3.71(m ,2H),3.64(d,J=11.8Hz,2H),3.12(td,J=12.2,2.5Hz,2H),1.94(d,J=15.1Hz,2H),1.83–1.67(m,3H),1.48(s,1H).

[0564] Example 67: 1-(2-(Piperidin-1-yl)ethoxy)isoquinolin-7-amine

[0565] Synthesis route:

[0566] 7-Bromo-1-(2-(piperidin-1-yl)ethoxy)isoquinoline (500 mg), Pd2(dba)3 (137 mg), XantPhos (173 mg), and t-BuOK (500 mg) were weighed into a 50 ml single-necked flask. Toluene (10 ml) and diphenylmethane (405 mg) were added. The mixture was heated to 120°C and stirred for 2 hours under nitrogen. The mixture was then cooled to room temperature and HCl / EA (4 M, 5 ml) was added, followed by stirring at room temperature for 1 hour. Post-treatment and purification: LCMS indicated the formation of the target compound and complete reaction of the starting material. The filtrate was filtered, concentrated, and purified by preparative HPLC. After concentration, the hydrochloride salt was replaced with HCl / EA (4 M) to obtain 235 mg of the target compound as a white solid. MS: 272 [M+H] + . 1H NMR(400MHz,D2O)δ8.22(s,1H),7.99(d,J=8.8Hz,1H),7.89(d,J=6.2Hz,1H),7.74(dd,J=8.8,1.9Hz,1H),7.50(d,J=6.2Hz,1H),4.91–4.8 0(m,2H),3.77–3.62(m,4H),3.12(td,J=12.3,2.6Hz,2H),1.94(d,J=14.9Hz,2H),1.74(ddd,J=16.0,10.2,3.4Hz,3H),1.55–1.41(m,1H).

[0567] Synthesis methods of other compounds besides the compounds synthesized in Examples 1-66 can be easily recognized by those skilled in the art by referring to the above-mentioned synthesis routes and source materials and synthesizing other compounds.

[0568] Biological evaluation

[0569] Study on the anti-edema efficacy of the compounds disclosed herein

[0570] Experimental content

[0571] 1) Primary astrocytes naturally expressing AQP4 were used as experimental subjects, and 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.

[0572] 2) C57BL / 6J mice or ICR mice were used as experimental subjects, and the compound of the present disclosure was injected into the tail vein, followed by intraperitoneal injection of pure water. The mortality rate of the mice was observed for 4 hours to determine the protective effect of the drug in the animal model.

[0573] 3) The tMACO-1.5h 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 cerebral infarction and brain edema after TTC staining.

[0574] The results of experiments 1)-3) show that the compound of formula I disclosed herein has at least one of the following effects:

[0575] The compounds of formula I disclosed herein can inhibit cell death caused by hypotonicity and have a cytoprotective effect;

[0576] The compounds of formula I disclosed herein can effectively increase the survival rate of experimental animals and reduce neurobehavioral damage to animals. After administration of the compounds of formula I disclosed herein, the survival rate of animals can be increased by more than 5%, more than 10%, more than 20%, more than 25%, or even more than 28%; and

[0577] The compound of formula I disclosed in the present invention has a significant protective effect in a rat cerebral ischemia model.

[0578] Experimental Example 1

[0579] Relationship between drug activity and AQP4 structure

[0580] 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.

[0581] Experimental groups: DMSO control group, and experimental groups with different doses of the compounds of the present disclosure.

[0582] Cells were pretreated with different doses of the disclosed example compounds or DMSO (solvent control) under isotonic conditions for 30 minutes. The culture medium was then aspirated (as dry as possible), and hypotonic culture medium (diluted with water to 20-25% of the normal culture medium osmotic pressure) was added. The corresponding dose of DMSO or compound was added to each well, and the cells were cultured in an incubator overnight.

[0583] After approximately 18-22 hours of hypotonic treatment, cell viability was observed under a microscope. Cells were stained with Calcein AM and photographed (three random fields per well). The area of ​​surviving cells in each field was counted.

[0584] Experimental results

[0585] Because primary astrocytes 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 1 to 53.

[0586] The cell protection effects of the compounds disclosed herein are shown in Table 1 below:

[0587] The results showed that cells treated with DMSO solvent control died in large numbers, while the compounds of the present disclosure could inhibit cell death caused by hypotonicity.

[0588] Experimental Example 2

[0589] Mouse water intoxication model-survival curve

[0590] Male C57BL / 6J mice or ICR mice aged 8-12 weeks were randomly divided into two groups. A blank control group received a tail vein injection of normal saline followed by an intraperitoneal injection of 22.5-24% body weight of purified water containing 10 μg / kg vasopressin. A treatment group received a tail vein injection of various doses of a compound of Formula I, followed by an intraperitoneal injection of 22.5-24% body weight of purified water containing 10 μg / kg vasopressin. The animals' survival time was observed and recorded over a 4-hour period.

[0591] Experimental results

[0592] As shown in Figures 54 to 61, the results show that:

[0593] The compound of Example 8 at a dose of 5 mg / kg can effectively increase the survival rate of experimental animals and prolong the survival time of animals. After administration of the compound of Example 8, the survival rate of animals increased from 30% to 46%.

[0594] The compound of Example 9 significantly increased the survival rate of experimental animals at a dose of 5 mg / kg, increasing the survival rate from 47.5% to 69.05%. The 10 mg / kg dose group showed a tendency to prolong the survival time, with the survival rate increasing to 53.33%.

[0595] The compound of Example 19 had the effect of increasing the survival rate of experimental animals at doses of 2.5 mg / kg and 5 mg / kg. After administration of the compound, the survival rate increased from 15% to 22.5% (2.5 mg / kg group) and 25% (5 mg / kg group).

[0596] After administration of 5 mg / kg of the compound of Example 31, the survival rate increased from 30% to 37.5%.

[0597] After administration of 5 mg / kg of the compound of Example 35, the survival rate increased from 10% to 18.18%.

[0598] The compound of Example 44 has the effect of increasing the survival rate of experimental animals. After administration of the compound, the survival rate increased from 0% to 25% (0.88 mg / kg group) and 12.5% ​​(1.75 mg / kg group). Considering the survival time of the experimental animals, the 0.88 mg / kg dose had a better effect.

[0599] The compound of Example 47 had similar pharmacological effects at doses of 0.53 mg / kg and 1.05 mg / kg. After administration, the survival rate of experimental animals increased from 26.09% to 50% (0.53 mg / kg group) and 54.17% (1.05 mg / kg group).

[0600] The compound of Example 50 improved both the survival ratio and the death rate of experimental animals at a dose of 1.86 mg / kg. After administration, the survival rate of the animals increased from 30% to 50%.

[0601] Experimental Example 3

[0602] Rat tMACO-1.5h model——24h TTC staining

[0603] Male Sprague-Dawley rats weighing 280-320 g were randomly divided into groups and subjected to a tMACO-1.5h surgical model. Catheterization was performed via the external carotid artery, and the observation endpoint was 24 hours. Three tail vein injections were administered: 60 minutes after embolization, 30 minutes after embolization, and 90 minutes after embolization. A vehicle control group received a tail vein injection of normal saline, while a treatment group received 5 mg / kg of the disclosed compound of Formula I in normal saline. TTC staining was performed 24 hours after surgery to calculate brain edema volume.

[0604] Experimental results

[0605] As shown in Figures 62-64, the results showed that in the index of cerebral infarction and brain edema volume calculated by TTC staining, the compound administration group of Example 8 can significantly reduce the infarct volume, with a p value of 0.0207 (*), and significantly reduce the edema volume, with a p value of 0.0025 (**). The compound administration group of Example 19 showed a clear trend in reducing the edema volume index, with a p value of 0.0439 (*). The compound administration group of Example 50 showed an improvement trend in both cerebral infarction and brain edema indexes, with a p value of 0.1199 for reducing the edema volume. This shows that the compound of Formula I disclosed herein has a protective effect in the rat cerebral ischemia model.

[0606] Experimental Example 4

[0607] Determination of hERG inhibition

[0608] 1. Cell Culture

[0609] 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:

[0610] 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%.

[0611] Cell passaging: Remove old culture medium and wash once with PBS, then add 1 mL of TrypLE TMExpress 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).

[0612] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%. Before patch clamp testing, cells were treated with TrypLE TM Express separation, add culture medium to terminate digestion, centrifuge, resuspend cells and count, adjust the cell density to 2×10 6 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.

[0613] 2. Electrophysiological Recording

[0614] 2.1. Record the liquid used

[0615] Extracellular fluid: K-007-1

[0616] 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.

[0617] Intracellular fluid: K-002-2

[0618] 20mM KCl, 115mM K-Aspartic, 1mM MgCl2·6H2O, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, KOH adjust pH=7.2.

[0619] 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.

[0620] 2.2. Patch clamp assay

[0621] Electrophysiological measurements were performed using a fully automated patch clamp instrument, QPatch 48X (Sophion).

[0622] 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.

[0623] 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.

[0624] 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.

[0625] 3. Data Quality Standards

[0626] The following criteria are used to determine whether the data is acceptable:

[0627] (1) Sealing resistance>1GΩ

[0628] (2) The initial access resistance is less than 15MΩ

[0629] (3) Access resistance ends <15MΩ

[0630] (4) Initial tail current peak > 200pA

[0631] (5) The peak value of the initial tail current is greater than the peak value of the activation current

[0632] (6) There is no obvious spontaneous decay of tail current

[0633] (7) No significant leakage current at a membrane potential of -80 mV (absolute value ≤ 25% of the maximum current peak)

[0634] 4. Data Analysis

[0635] 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.

[0636] Experimental results

[0637] The hERG inhibition rate of the compound of formula I disclosed herein 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.

[0638] The above results indicate that the compound of formula I of the present disclosure has significantly lower toxicity than AER-270 in terms of toxicity associated with hERG inhibition.

[0639] While the present invention has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made to the present invention. Therefore, such modifications and improvements, without departing from the spirit of the present invention, are intended to be within the scope of the present invention.

Claims

1. A compound of formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof: in: represents a single bond or a double bond; Each R1 is independently selected from: halogen, -CN, amino, alkyl and -OH; R2 is absent or is R'2, wherein R'2 is selected from: Heterocycloalkyl optionally substituted with alkyl; and Alkyl substituted with a group selected from: heterocycloalkyl or cycloalkyl, each optionally substituted with oxo, alkyl, halogen, -OH; aryl or heteroaryl, each optionally substituted with one or more groups independently selected from -NH2, halogen, -OH and oxo; and dialkylamino; The conditions are: when When it represents a single bond, R2 is R'2 and R3 is oxo; when When a double bond is represented, R2 is absent and R3 is independently selected from: Alkoxy substituted with a group selected from: amino optionally substituted with one or two groups independently selected from alkyl, cycloalkyl, alkoxyalkyl, haloalkyl; heterocycloalkyl or heterocycloalkenyl each optionally substituted with one or more groups independently selected from oxo, alkyl, halogen, -OH, -CN, alkoxy, -NH2; and aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH; -OR c , where R c Selected from: heterocycloalkyl optionally substituted by alkyl; alkenyl substituted with heterocycloalkyl; Alkyl substituted with a group selected from the group consisting of heterocycloalkyl; aryl optionally substituted with one or more groups independently selected from halogen, -NH2, -OH; and amino optionally substituted with one or two groups independently selected from alkyl and arylalkyl, wherein the amino is substituted with at least one arylalkyl group, and wherein the aryl in the arylalkyl is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and Alkylamino, wherein the alkyl portion of the alkylamino is optionally substituted by a group selected from the group consisting of heterocycloalkyl, alkylamino, dialkylamino, and aryl optionally substituted by one or more groups independently selected from halogen, -NH2, -OH; Each R4 is independently selected from halogen; n is an integer selected from 0, 1, 2, 3 or 4; and m is an integer selected from 0, 1 and 2.

2. The compound of formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R1 is independently selected from: halogen, -CN, amino, C 1-6 Alkyl and -OH; or Each R1 is independently selected from: Cl, Br, -CN, -NH2, methyl and -OH; or each R1 is independently selected from halogen, -NH2 and -OH; or n is 1 or 2.

3. A compound of formula I as claimed in claim 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: when When it represents a single bond, R2 is R'2, and the R'2 is selected from: Optional C 1-4 Alkyl-substituted 5-12 membered heterocycloalkyl; and C substituted by a group selected from 1-4 Alkyl: each optionally substituted with oxo, C 1-4 alkyl, halogen, -OH substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; each optionally substituted by one or more groups independently selected from -NH2, halogen, -OH and oxo 6-12 Aryl or C 2-12 Heteroaryl; and amino (C 1-4 alkyl)2; or when When it represents a single bond, R2 is R'2, and the R'2 is selected from: Optional C 1-2 Alkyl-substituted 5-10 membered heterocycloalkyl; and C substituted by a group selected from 1-3 Alkyl: each optionally substituted with oxo, C 1-2 alkyl, halogen, -OH substituted 5-8 membered heterocycloalkyl or 3-8 membered cycloalkyl; each optionally substituted by two or three groups independently selected from -NH2, halogen, -OH 6-10 Aryl or C 2-10 Heteroaryl; C substituted by oxo 2-10 Heteroaryl; and amino (C 1-4 alkyl)2; or when When it represents a single bond, R2 is R'2, and the R'2 is selected from: C substituted by a group selected from 1-4 Alkyl: each optionally replaced by C 1-4 alkyl-substituted 5-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; each optionally substituted by one or more groups independently selected from -NH2, -OH and oxo 6-12 Aryl or C 2- 12 heteroaryl; or when When it represents a single bond, R2 is R'2, and the R'2 is selected from: C substituted by a group selected from 1-4 Alkyl: C 6-12 Aryl or C optionally substituted by oxo 2-12 heteroaryl; or when When it represents a single bond, R2 is R'2, and the R'2 is selected from: octahydroquinolizinyl, piperidinyl substituted with methyl, and pyrrolyl substituted with methyl; and C substituted by a group selected from 2-3 Alkyl: cyclohexyl; piperidinyl optionally substituted with methyl or F; morpholinyl; thiomorpholinyl; 1,1-dioxothiomorpholinyl; 3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl; 8-azabicyclo[3.2.1]octanyl optionally substituted with -OH; phenyl optionally substituted with two or three groups independently selected from -NH2, F, Cl, -OH; pyridinyl substituted with two -NH2; and -N(CH2CH3)2; or when When it represents a single bond, R2 is R'2, and the R'2 is selected from:

4. A compound of formula I as claimed in claim 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: when When a double bond is represented, R2 is absent and R3 is independently selected from: C substituted by a group selected from 1-6 Alkoxy: optionally substituted by one or two independently selected from C 1-6 Alkyl, 3-10 members Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 haloalkyl group substituted amino; each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 alkoxy, -NH2 substituted 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl; and C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6- 12 Aryl; -OR c , where R c Selected from: Optional C 1-6 Alkyl-substituted 3-10 membered heterocycloalkyl; C substituted by 3-10 membered heterocycloalkyl 2-6 alkenyl; C substituted by a group selected from 1-6 Alkyl: 3-10 membered heterocycloalkyl; C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl; and optionally one or two independently selected from C 1-6 Alkyl and C 6- 12 Aryl C 1-6 An amino group substituted with an alkyl group, wherein the amino group is replaced by at least one C 6-12 Aryl C 1-6 alkyl group, and wherein the C 6-12 Aryl C 1-6 C in the alkyl group 6-12 The aryl group is optionally substituted with one or more groups independently selected from -NH2, -OH and halogen; and C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6 The alkyl portion is optionally substituted by a group selected from the group consisting of 5-10 membered heterocycloalkyl, amino (C 1-6 Alkyl), amino (C 1-6 alkyl)2, and C optionally substituted by one or more groups independently selected from halogen, -NH2, -OH 6-10 Aryl; or when When a double bond is represented, R2 is absent and R3 is independently selected from: C substituted by a group selected from 1-6 Alkoxy: optionally substituted by one or two independently selected from C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 haloalkyl group substituted amino; each optionally substituted by one or more independently selected from oxo, C 1-6 Alkyl, halogen, -OH, -CN, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with an alkoxy group; and C 6-12 Aryl; -OR c , where R c Selected from: Optional C 1-6 Alkyl-substituted 3-10 membered heterocycloalkyl; C substituted by 3-10 membered heterocycloalkyl 1-6 Alkyl; and C 1-6 Alkylamino, wherein the C 1-6 C in alkylamino 1-6 The alkyl portion is optionally replaced by C 6-10 Aryl substitution; or when When a double bond is represented, R2 is absent and R3 is independently selected from: C substituted by a group selected from 1-6 Alkoxy: optionally with one or two C 1-6 Alkyl-substituted amino; 3-10 membered heterocycloalkyl optionally substituted by one or more halogens; or when When a double bond is represented, R2 is absent and R3 is independently selected from: C substituted by a group A selected from the following 1-3 alkyl: In the above group A, R a Selected from H and C 1-4 Alkyl, each R b is independently selected from -NH2, -OH and halogen, x is an integer from 1 to 4, and y is an integer from 0 to 4; or when When a double bond is represented, R2 is absent and R3 is independently selected from the following groups B: In the above group B: L is a direct bond, oxygen atom or N(R a ), where R a Selected from H and C 1-4 alkyl; Each R b independently selected from -NH2, -OH and halogen; x is an integer from 1 to 4; as well as y is an integer from 0 to 4; or when When a double bond is represented, R2 is absent and R3 is a group C as follows: In the above group C: L is selected from a direct bond, an oxygen atom, a C 2-6 Alkenylene and N(R a ); Cy1 is each optionally substituted with one or more independently selected from oxo, C 1-6 Alkyl, C 1-6 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl substituted with alkoxy, halogen, -OH, -CN, -NH2; R a Selected from H and C 1-4 Alkyl; and x is an integer from 0 to 4; or when When a double bond is represented, R2 is absent and R3 is independently selected from:

5. A compound of formula I according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R4 is Cl; or m is 0.

6. A compound of formula I according to any one of claims 1 to 5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, a compound of formula III or a compound of formula IV, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R1, R2, R3, R4, m and n are as defined in Formula I.

7. The following compounds, or their stereoisomers or pharmaceutically acceptable salts:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

9. The compound according to any one of claims 1 to 7, or its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 8 for use in the preparation of a medicament for preventing or treating cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema and diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and cardiogenic edema, or for use in the preparation of a medicament for cell protection in a nervous system disease.

10. The use according to claim 9, wherein: The diseases associated with cerebral edema include cerebral ischemia, cerebral infarction, hydrocephalus, epilepsy, migraine, cerebral small vessel disease and neurodegenerative diseases; Conditions associated with spinal cord edema include water imbalance disorders, hyponatremia, excess fluid retention, and sepsis; The diseases associated with retinal edema include retinal ischemia; The diseases associated with optic nerve edema include neuromyelitis optica, other eye diseases associated with abnormal intraocular pressure and / or tissue hydration; The diseases associated with cardiogenic edema include myocardial ischemia, myocardial ischemia-reperfusion injury, myocardial infarction, myocardial hypoxia and congestive heart failure; Preferably, the neurodegenerative diseases include Parkinson's disease and Alzheimer's disease.

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