Polysubstituted aryl derivative as well as preparation method and application thereof

Abstract

The invention relates to a polysubstituted aryl derivative, a preparation method of the polysubstituted aryl derivative and application of a pharmaceutical composition containing the polysubstituted aryl derivative in medicine. Specifically, the invention relates to a polysubstituted aryl derivative as shown in a general formula (I), a preparation method and a medicinal salt thereof, and application of the polysubstituted aryl derivative as a therapeutic agent, especially as a Kv1.3 potassium channel inhibitor, and definition of each substituent in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a polysubstituted aryl derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a therapeutic agent, in particular as a Kv1.3 inhibitor. Background Art

[0002] Ion channels are proteins located in the cell membrane that selectively control the flow of ions (such as potassium, sodium, calcium, etc.) across the membrane, thereby forming a concentration gradient between the intracellular components of the cell and the surrounding extracellular fluid. Since ion concentration is directly involved in the electrical activity of excitable cells, ion channels can significantly control the electrical characteristics and state of cells. If ion channels can be opened and closed, they are called "gated". Among them, voltage-gated channels are found in neurons, muscle cells, and non-excitable cells such as lymphocytes. They open and close in response to changes in charge across the plasma membrane, and play an important role in cell communication, signal transduction pathways, and the overall homeostasis of tissues and various organ functions.

[0003] Potassium ions are one of the main cations in the body. They play an important role in maintaining cell membrane potential and play an indispensable role in cell proliferation, activation and apoptosis. Kv1.3 channel is a member of the voltage-gated potassium channel (Kv) family. It is encoded by the KCNA3 gene and is located at position 1p13.3 of human chromosome. It is composed of four similar subunits. Each subunit contains a main part composed of 6 transmembrane structural elements (S1-S6), and the N-terminus and C-terminus connected to S1 and S6 respectively. Among them, the transmembrane structural elements (S1-S4) constitute the voltage-sensitive region of the channel, and the S5-S6 of the four subunits and the S5-S6 connecting fragment (P-loop) embedded in the membrane aggregate to form the pore of the channel. Each S4 in the voltage-sensitive region contains abundant positive charges, which are necessary for the channel to respond to the depolarization voltage of the cell membrane.

[0004] Kv1.3 channels were first discovered in human T lymphocytes and are also expressed in the immune system, central nervous system, and vascular smooth muscle cells. Kv1.3 plays an important role in regulating resting membrane potential, cell apoptosis, cell volume regulation, and immune cell activation and proliferation. In T cells, cell membrane depolarization leads to Ca 2+ Activates calcium channels by releasing calcium ions (Ca 2+ release-activated Ca 2+ channel, CRAC) enters the cell, leading to intracellular Ca 2+When the concentration increases, the cell membrane depolarizes, thereby mediating the activation of downstream signaling pathways such as calmodulin and calmodulin in the cell, and increasing the expression of Kv1.3 on the cell membrane. As a result, intracellular potassium ions flow out to maintain the osmotic pressure balance inside and outside the cell. This is a necessary condition for the transcription-dependent step in T cell activation. The Kv1.3 potassium ion channel is the key to the sustained activation of effector T cells. In microglial cells, Kv1.3 is involved in the process of killing neurons in sudden respiratory burst neuroinflammation. In dendritic cells, together with Kv1.5, it is involved in the secretion of inflammatory cytokines. Because Kv1.3 is involved in these key roles, it is associated with many autoimmune diseases, such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

[0005] Studies have shown that selective inhibition of Kv1.3 channels may achieve the goal of selectively inhibiting the activation process of effector T cells, which provides a new idea for the treatment of autoimmune diseases related to effector T cells. Kv1.3 has therefore become a new target protein for the treatment of autoimmune diseases. In addition, Kv1.3 is also involved in the body's neurotoxic effects and the occurrence and development of cancer. Abnormal expression of Kv1.3 has been detected in a variety of tumor cells such as breast cancer, prostate cancer, ovarian cancer, and microglia. Experiments have shown that inhibiting the activity of Kv1.3 can induce apoptosis of tumor cells. Therefore, drugs targeting Kv1.3 have important clinical value.

[0006] There are no new drugs targeting Kv1.3 targets on the market. Currently, only two small molecule compounds, DES-7114 and YR-001, have entered clinical phase I. There are also three peptide clinical compounds, of which the highest clinical stage is dalazatide, developed by Kv1.3 Therapeutics, which is in phase II. It is a peptide compound derived from sea anemone toxin. As a relatively cutting-edge research direction, there is still a huge space for exploration in the research of Kv1.3 targets. It is necessary to continue to study its mechanism of action and develop new inhibitors. Summary of the invention

[0007] In view of the above technical problems, the present invention provides a polysubstituted aryl derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0008]

[0009] in:

[0010] Ring A is selected from 6- to 14-membered spiro heterocyclic groups;

[0011] R 1 is selected from a hydrogen atom or an alkyl group;

[0012] R 4 is selected from a hydrogen atom, an alkyl group or a halogen;

[0013] X1, X2, X3 are each independently selected from hydrogen atom, halogen, cyano, alkyl, cycloalkyl, halocycloalkyl or haloalkyl;

[0014] Alternatively, X1 and X2, X2 and X3 independently form together with the carbon atoms to which they are attached a 5-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl or 4-10 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;

[0015] R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R A replaced by;

[0016] R A are the same or different and are each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR9 C(=O)R 10 or -NR 9 C(=O)OR 10 ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;

[0017] R 3 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

[0018] Or, two R 3 Together with the same carbon atom to which it is attached, it forms a -C(=O)-;

[0019] R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0020] R 6 and R 7 Each is independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0021] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group contains one or more N, O or S(O)r, and the 3-12 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0022] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0023] n is 0, 1, 2, 3 or 4; and

[0024] r is each independently 0, 1 or 2;

[0025] Provided that: when ring A is selected from When two R 3 It does not form -C(=O)- with the same carbon atom to which it is attached.

[0026] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1A hydrogen atom.

[0027] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 A hydrogen atom.

[0028] A preferred embodiment of the present invention is a compound of the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1, X2 and X3 are each independently selected from a hydrogen atom or a halogen.

[0029] A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0030]

[0031] Among them: Ring A, R 2 , R 3 and n are as defined in the general formula (I).

[0032] A preferred embodiment of the present invention is a compound of the general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 3-membered / 6-membered monospiro heterocyclic group, a 4-membered / 4-membered monospiro heterocyclic group, a 4-membered / 5-membered monospiro heterocyclic group, a 4-membered / 6-membered monospiro heterocyclic group, a 5-membered / 5-membered monospiro heterocyclic group, a 5-membered / 6-membered monospiro heterocyclic group, and a 6-membered / 6-membered monospiro heterocyclic group.

[0033] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is selected from the following groups:

[0034]

[0035] in "---" indicates the connection point between ring A and the benzene ring in the general formula (I) or (II); "---" indicates the connection point between ring A and R in the general formula (I) or (II) 2 connection site.

[0036] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, hydroxyl groups, C 1-6 alkyl, 3-6 membered heterocyclic group or 3-6 membered cycloalkyl group, wherein the C 1-6 The alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group may be further substituted with one or more R A replaced by;

[0037] R A are the same or different and are independently selected from hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 The alkoxy, 3-6 membered heterocyclic or 3-6 membered cycloalkyl groups are optionally further substituted with one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0038] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 2 Selected from the following groups: hydrogen atom, hydroxyl group,

[0039]

[0040] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 is a hydrogen atom; or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

[0041] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0042]

[0043]

[0044] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0045] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0046] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0047] The present invention provides a use of a compound described in general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a Kv1.3 inhibitor.

[0048] The present invention also provides a use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by Kv1.3, wherein the disease mediated by Kv1.3 is preferably an autoimmune disease; wherein the disease mediated by Kv1.3 is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

[0049] The present invention further provides use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0050] The present invention provides a use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, in the preparation of a medicament for treating rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

[0051] Detailed description of the invention

[0052] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0053] "Alkyl" as a group or a part of a group refers to a group consisting of C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0054] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring are carbon atoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably having a 3-7-membered monocyclic ring or a 4-18-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0055] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing 0, 1 or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

[0056] "Fused cycloalkyl" refers to a 4 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalinyl, tetradecahydrophenanthryl.

[0057] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

[0058] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a non-aromatic heterocyclic group in which one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably with 3 to 7 membered monocyclic or 4 to 18 membered bicyclic or tricyclic rings, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclic radicals" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine.

[0059] The heterocyclic group may be substituted or unsubstituted.

[0060] "Spiro heterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, and the rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group, more preferably 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0061]

[0062]

[0063] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatom, the remaining ring atoms are carbon, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin (dioxine).

[0064] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain 0, 1 or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0065] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, the aromatic group is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[0066] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridinyl, pyridin- 2(1H)-onyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyrimidin-2(1H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolyl, quinazolinyl, 2H-isoindolyl, furano[3,2-b]pyridinyl, furano[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl.

[0067] A heteroaryl group can be substituted or unsubstituted.

[0068] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated π-electron aromatic system, and at least one ring may contain 0, 1 or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, 1 or more selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl, preferably 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include, but are not limited to:

[0069]

[0070] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0071] "Nitro" refers to a -NO2 group.

[0072] "Hydroxy" refers to an -OH group.

[0073] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0074] "Amino" refers to -NH2.

[0075] "Cyano" refers to -CN.

[0076] "Benzyl" refers to -CH2-phenyl.

[0077] "Carboxy" refers to -C(=O)OH.

[0078] The "carboxylate group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein the alkyl group and the cycloalkyl group are as defined above.

[0079] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group wherein alkyl is as defined above.

[0080] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0081] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0082] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0083] "DMSO" refers to dimethyl sulfoxide.

[0084] "BOC" refers to tert-butoxycarbonyl.

[0085] "Bn" refers to benzyl.

[0086] "THP" refers to 2-tetrahydropyranyl.

[0087] "TFA" refers to trifluoroacetic acid.

[0088] “FA” stands for formic acid.

[0089] "Ts" refers to p-toluenesulfonyl.

[0090] "Bn" refers to benzyl.

[0091] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0092] "Cbz" refers to benzyloxycarbonyl.

[0093] "TBS" refers to tert-butyldimethylsilyl.

[0094] "Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

[0095] "Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. "Substituted" or "substituted" as described in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, halocycloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylate, =O, OR 5 、OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 substituted by a substituent;

[0096] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 Substituents; R 6 and R 7 Each is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0097] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group contains one or more N, O or S(O)r, and the 3-12 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0098] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0099] r is independently 0, 1 or 2.

[0100] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0101] Unless otherwise indicated, structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.

[0102] "Pharmaceutically acceptable salts" refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0103] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity. DETAILED DESCRIPTION

[0104] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0105] Example

[0106] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0107] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0108] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0109] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0110] In the following examples, unless otherwise indicated, all temperatures are degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0111] CD3OD: deuterated methanol.

[0112] CDCl3: deuterated chloroform.

[0113] DMSO-d6: deuterated dimethyl sulfoxide.

[0114] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0115] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0116] The compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.

[0117] Example 1

[0118] 2-(2,3-dichloro-6-hydroxyphenyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-6-one

[0119] 2-(2,3-Dichloro-6-hydroxyphenyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-6-one

[0120]

[0121]

[0122] first step

[0123] 7-benzyl 2-(tert-butyl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

[0124] 7-Benzyl 2-(tert-butyl) 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

[0125] 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 1a (10 g, 44.19 mmol, commercially available) and triethylamine (5.37 g, 53.02 mmol) were dissolved in tetrahydrofuran (100 mL), benzyl chloroformate (9.05 g, 53.02 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, water (100 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 7-benzyl 2-(tert-butyl) 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 1b (11 g), with a yield of 69.07%.

[0126] MS m / z(ESI):305.5[M-55]

[0127] Step 2

[0128] 7-benzyl 2-(tert-butyl)6-oxo-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

[0129] 7-Benzyl 2-tert-butyl 6-oxo-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

[0130] 7-Benzyl 2-(tert-butyl) 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 1b (11 g, 30.52 mmol), ruthenium trichloride (3.16 g, 15.26 mmol) and sodium periodate (13.05 g, 61.04 mmol) were dissolved in a mixed solvent of ethyl acetate (95 mL) and water (95 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was complete, it was washed with sodium thiosulfate solution (100 mL), extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: A system) to obtain 7-benzyl 2-tert-butyl 6-oxo-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 1c (3 g), with a yield of 26.25%. MS m / z(ESI):375.2[M+1]

[0131] Step 3

[0132] benzyl 6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0133] Benzyl 6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0134] 7-Benzyl 2-tert-butyl 6-oxo-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 1c (1 g, 2.67 mmol) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure to obtain 6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester 1d (730 mg), yield: 99.64%.

[0135] MS m / z(ESI):275.0[M+1]

[0136] Step 4

[0137] 2-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonan-6-one

[0138] 2-(2,3-Dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonan-6-one

[0139] Benzyl 6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate 1d (730 mg, 2.66 mmol) and (2-((3,4-dichloro-2-iodophenoxy)methoxy)ethyl)trimethylsilane 1e (372 mg, 887.50 μmol, prepared according to the patent publication "WO2021071802") were dissolved in 1,4-dioxane (10 mL), tri(dibenzylideneacetone)dipalladium (81.27 mg, 88.75 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (110.52 mg, 177.50 μmol) and cesium carbonate (867.49 mg, 2.66 mmol) were added to the reaction mixture, replaced with nitrogen 3 to 5 times, and the reaction mixture was stirred at 110 ° C overnight. After the reaction is complete, the product is filtered and the residue is separated and purified by reverse phase column chromatography (eluent: D system) to obtain 2-(2,3-dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-6-one 1f (252 mg) with a yield of 65.82%.

[0140] MS m / z(ESI):431.2[M+1]

[0141] Step 5

[0142] 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)p

[0143] henyl)-2,7-diazaspiro[3.5]nonan-6-one

[0144] 7-(2-(tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonan-6-one

[0145] 2-(2,3-Dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-6-one 1f (138 mg, 319.87 μmol) was added to tetrahydrofuran (5 mL), sodium hydride (27.74 mg, 639.74 μmol, purity 60%) was added, and the mixture was stirred at 0°C for 30 minutes, and then (2-bromoethoxy)(tert-butyl)dimethylsilane 1g (382.60 mg, 1.60 mmol, commercially available) was added and stirred at 60°C overnight. The solvent was removed under reduced pressure, water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 7-(2-(tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-6-one 1h (30 mg), yield: 15.90%.

[0146] MS m / z(ESI):589.2[M+1]

[0147] Step 6

[0148] 2-(2,3-dichloro-6-hydroxyphenyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-6-one

[0149] 2-(2,3-Dichloro-6-hydroxyphenyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-6-one

[0150] 7-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-(2,3-dichloro-6-(2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonan-6-one 1h (27 mg, 45.78 μmol) was dissolved in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% FA+H2O, mobile phase B: CH3CN) to obtain 2-(2,3-dichloro-6-hydroxyphenyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-6-one 1 (1.37 mg) with a yield of 8.67%.

[0151] MS m / z(ESI):345.1[M+1]

[0152] 1 H NMR (400MHz, MeOD) δ6.68(d,J=8.8Hz,1H),6.49(d,J=8.8Hz,1H),4.09(d,J=8.0Hz,2H),3.98(d,J= 8.0Hz,2H),3.60(t,J=5.4Hz,2H),3.41(dt,J=14.4,5.6Hz,4H),2.54(s,2H),1.99(t,J=6.0Hz,2H).

[0153] Example 2

[0154] 3,4-dichloro-2-(7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenol

[0155] 3,4-Dichloro-2-(7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenol

[0156] first step

[0157] 1-(benzyloxy)-3,4-dichloro-2-iodobenzene

[0158] 1-(Benzyloxy)-3,4-dichloro-2-iodobenzene

[0159] 3,4-dichloro-2-iodophenol 2a (200 mg, 692.29 μmol, commercially available), benzyl bromide (236.81 mg, 1.38 mmol), cesium carbonate (563.90 mg, 1.73 mmol) were added to acetonitrile (6 mL). The reaction was carried out at 40°C for 2 hours, and new spots were generated by thin layer chromatography. The reaction solution was concentrated under reduced pressure and then chromatographed on a silica gel column (eluent: A system) to obtain 1-benzyloxy-3,4-dichloro-2-iodobenzene 2b (132 mg), with a yield of 50.31%.

[0160] MS m / z(ESI):380.1[M+1]

[0161] Step 2

[0162] tert-butyl 2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0163] tert-Butyl 2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0164] 1-(Benzyloxy)-3,4-dichloro-2-iodobenzene 2b (200 mg, 527.68 μmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 2c (143.30 mg, 633.21 μmol, commercially available), palladium acetate (23.69 mg, 105.54 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (131.43 mg, 211.07 μmol), cesium carbonate (343.85 mg, 1.06 mmol) were added to toluene (5 mL) and reacted at 100 °C for 16 hours. After the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl 2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 2d (110 mg). The crude product was used directly in the next step.

[0165] MS m / z(ESI):421.2[M-55]

[0166] Step 3

[0167] 2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane

[0168] 2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane

[0169] 2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 2d (90 mg, 188.51 μmol) was added to trifluoroacetic acid (0.5 mL) and dichloromethane (2.5 mL). The mixture was reacted at 25°C for 2 hours. After the reaction was completed, the mixture was spin-dried to obtain 2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane 2e (160 mg), which was used directly in the next step.

[0170] MS m / z(ESI):377.1[M+1]

[0171] Step 4

[0172] 2-(2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-ol

[0173] 2-(2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-ol

[0174] 2-(6-(Benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonane 2e (140 mg, 371.05 μmol), 2-bromoethanol (92.74 mg, 742.10 μmol), potassium carbonate (102.56 mg, 742.10 μmol) were added to N,N-dimethylformamide (2 mL). The mixture was reacted at 80°C for 2 hours. After the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 2-(2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-ol 2f (34 mg) with a yield of 21.75%.

[0175] MS m / z(ESI):421.2[M+1]

[0176] Step 5

[0177] 3,4-dichloro-2-(7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenol

[0178] 3,4-Dichloro-2-(7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenol

[0179] 2-(2-(6-(benzyloxy)-2,3-dichlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-ol 2f (20 mg, 47.47 μmol) and palladium on carbon (10.10 mg, 9.49 μmol, 10%) were added to methanol (2 mL), hydrogen was replaced, and the reaction was carried out at 40° C. for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenol 2 (6.62 mg) with a yield of 42.11%.

[0180] MS m / z(ESI):331.0[M+1]

[0181] 1HNMR (400MHz, MeOD) δ6.78 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 4.15 (s, 4H), 3.89-3.82 (m, 2H), 3.27-3.08 (m, 6H), 2.30-2.00 (m, 4H).

[0182] Example 3

[0183] 3,4-dichloro-2-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0184] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0185] first step

[0186] tert-butyl7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carbo

[0187] Xylate

[0188] 7-(2,3-Dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-

[0189] Butyl Ester

[0190] Tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate 1a (809.89 mg, 3.58 mmol, commercially available) and (2-((3,4-dichloro-2-iodophenoxy)methoxy)ethyl)trimethylsilane 1e (500 mg, 1.19 mmol, prepared according to patent WO2021071802A1) were dissolved in 1,4-dioxane (10 mL), tri(dibenzylideneacetone)dipalladium (109.23 mg, 119.29 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (148.55 mg, 238.57 μmol) and cesium carbonate (1.17 g, 3.58 mmol) were added to the reaction mixture, replaced with nitrogen 3 to 5 times, and then the reaction mixture was stirred at 110 ° C for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate 3a (356 mg) with a yield of 57.66%.

[0191] MS m / z(ESI):517.3[M+1]

[0192] Step 2

[0193] 3,4-dichloro-2-(2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0194] 3,4-Dichloro-2-(2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0195] Tert-butyl 7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate 3a (306 mg, 591.24 μmol) was dissolved in dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure to obtain 3,4-dichloro-2-(2,7-diazaspiro[3.5]nonane-7-yl)phenol 3b (169 mg), and the crude product was directly used in the next step.

[0196] MS m / z(ESI):286.9[M+1]

[0197] Step 3

[0198] 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-3,4-dichlorophenol

[0199] 2-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-3,4-dichlorophenol

[0200] 2-((tert-Butyldimethylsilyl)oxy)acetaldehyde 3c (205.16 mg, 1.18 mmol, commercially available) and 3,4-dichloro-2-(2,7-diazaspiro[3.5]nonan-7-yl)phenol 3b (169 mg, 588.47 μmol) were dissolved in 1,2-dichloroethane (3 mL), sodium triacetoxyborohydride (137.19 mg, 647.32 μmol) was added to the reaction mixture and stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, water (20 mL) was added, and the crude product was extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate to obtain 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,7-diazaspiro[3.5]nonane-7-yl)-3,4-dichlorophenol 3d (260 mg). The crude product was directly used in the next step. MS m / z(ESI):445.3[M+1]

[0201] Step 4

[0202] 3,4-dichloro-2-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0203] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenol

[0204] 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-3,4-dichlorophenol 3d (260 mg, 583.62 μmol) was dissolved in dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenol 3 (2.39 mg) with a yield of 1.24%.

[0205] MS m / z(ESI):331.1[M+1]1H NMR(400MHz,MeOD)δ7.15(d,J=8.8Hz,1H),6.75(d,J=8.8Hz,1H),4.18-4.09(m,2H),4.04 -3.93(m,2H),3.86–3.67(m,2H),3.38–3.34(m,2H),3.24-2.96(m,4H),2.19-1.95(m,4H).

[0206] Example 4

[0207] 3,4-dichloro-2-(7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl)phenol

[0208] 3,4-Dichloro-2-(7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl)phenol

[0209] first step

[0210] tert-butyl

[0211] 2-(2,3-dichloro-6-methoxyphenyl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate

[0212] tert-Butyl 2-(2,3-dichloro-6-methoxyphenyl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate

[0213] 1,2-Dichloro-3-iodo-4-methoxybenzene 4a (1 g, 3.30 mmol, commercially available) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen 3 to 5 times and cooled to -78 °C, n-butyl lithium (2.5 M, 2.64 mL) was slowly added to the reaction mixture, and then the reaction mixture was stirred at -78 °C for 1 hour, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 4b (1.19 g, 4.95 mmol, commercially available) was dissolved in tetrahydrofuran (10 mL) and slowly added, and then the reaction mixture was gradually warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to give tert-butyl 2-(2,3-dichloro-6-methoxyphenyl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate 4c (0.88 g) with a yield of 64.03%.

[0214] MS m / z(ESI):360.0[M-55]

[0215] Step 2

[0216] 2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane

[0217] 2-(2,3-Dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane

[0218] Tert-butyl 2-(2,3-dichloro-6-methoxyphenyl)-2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate 4c (0.88 g, 2.11 mmol) was dissolved in dichloromethane (10 mL). Triethylsilane (1.84 g, 15.85 mmol) and trifluoroacetic acid (843.53 mg, 7.40 mmol) were then added, and the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated in vacuo and the residue was purified by reverse phase column chromatography (eluent: D system) to give 2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane 4d (190 mg) with a yield of 29.94%.

[0219] MS m / z(ESI):300.0[M+1]

[0220] Step 3

[0221] 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]

[0222] nonane

[0223] 7-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane

[0224] 2-(2,3-Dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane 4d (190 mg, 632.86 μmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (174.94 mg, 1.27 mmol) and 2-bromoethoxytert-butyldimethylsilane 4e (227.09 mg, 949.30 μmol) were added, and the reaction mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: System A) to give 7-(2-(tert-butyldimethylsilyloxy)ethyl)-2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane 4f (100 mg) with a yield of 34.46%.

[0225] MS m / z(ESI):458.0[M+1]

[0226] Step 4

[0227] 3,4-dichloro-2-(7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl)phenol

[0228] 3,4-Dichloro-2-(7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl)phenol

[0229] 7-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-(2,3-dichloro-6-methoxyphenyl)-7-azaspiro[3.5]nonane 4f (100 mg, 218.09 μmol) was dissolved in dichloromethane (2 mL), the reaction solution was cooled to -78 °C, boron tribromide (218.54 mg, 872.34 μmol, 1 mL) was slowly added to the reaction mixture, and then the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with methanol at -78 ° C, the pH was adjusted to 7-8 with aqueous ammonia, and the solution was removed by concentration under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl)phenol 4 (6.52 mg) with a yield of 9.05%.

[0230] MS m / z(ESI):330.1[M+1]

[0231] 1H NMR(400MHz,MeOD-d4)δ7.16(d,J=4.0Hz,1H),6.72(d,J=8.0Hz,1H),4.19-4.13(m,1H),3.89(s,2H),3.59-3.48(m,2H), 3.23(s,2H),3.06(dd,J=49.6,11.6Hz,2H),2.82–2.61(m,2H),2.33–2.16(m,2H),2.12-2.06(m,2H),1.99-1.87(m,2H).

[0232] Example 5

[0233] 3,4-dichloro-2-(2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-6-yl)phenol

[0234] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-2-azaspiro[3.3]hept-6-yl)phenol

[0235]

[0236]

[0237] first step

[0238] tert-butyl 6-(2,3-dichloro-6-methoxyphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

[0239] tert-Butyl 6-(2,3-dichloro-6-methoxyphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

[0240] 1,2-Dichloro-3-iodo-4-methoxybenzene 4a (700 mg, 2.81 mmol) was added to tetrahydrofuran (2 mL), cooled to -78 °C, and n-butyl lithium (2.5 M, 2.25 mL) was slowly added dropwise. After stirring for 30 minutes, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate 5a (713.20 mg, 3.38 mmol, commercially available) was added dropwise, and the mixture was slowly transferred to room temperature for reaction for 2 hours. After the reaction was completed, ammonium chloride solution (10 mL) was added to quench, and ethyl acetate was used for extraction (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 6-(2,3-dichloro-6-methoxyphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 5b (500 mg) with a yield of 45.77%. MS m / z (ESI): 388.2 [M+1]

[0241] Step 2

[0242] 6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane

[0243] 6-(2,3-Dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane

[0244] 6-(2,3-dichloro-6-methoxyphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 5b (500 mg, 1.29 mmol) was added to trifluoroacetic acid (2 mL), and triethylsilane (0.5 mL) was slowly added. The reaction was allowed to react at room temperature for 1.5 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to adjust the pH to a weak alkaline state, and ethyl acetate was added for extraction (10 mL×3). The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane 5c (250 mg) with a yield of 71.33%. MS m / z(ESI):272.0[M+1]

[0245] Step 3

[0246] 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]hepta

[0247] ne

[0248] 2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane

[0249] 6-(2,3-Dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane 5c (250 mg, 918.54 μmol) was added to N,N-dimethylformamide (2 mL), cooled to 0°C, sodium hydride (79.64 mg, 1.84 mmol, 60%) was slowly added, stirred for 30 minutes, and then 2-bromoethoxytert-butyldimethylsilane 4e (329.61 mg, 1.38 mmol) was added, and the mixture was slowly transferred to room temperature for reaction for 1.5 hours. The reaction was monitored by mass spectrometry. After the reaction was completed, the reaction solution was poured into ice water to quench, and ethyl acetate was added for extraction (10 mL×3). The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane 5d (213 mg) with a yield of 53.87%.

[0250] MS m / z(ESI):430.2[M+1]

[0251] Step 4

[0252] 3,4-dichloro-2-(2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-6-yl)phenol

[0253] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-2-azaspiro[3.3]hept-6-yl)phenol

[0254] 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2,3-dichloro-6-methoxyphenyl)-2-azaspiro[3.3]heptane 5d (200 mg, 464.60 μmol) was added to dichloromethane (1 mL), and boron tribromide (232.78 mg, 929.19 μmol) was added dropwise at 0°C, and the mixture was slowly heated to room temperature for 1.5 hours. After the reaction, the reaction solution was poured into ice water, saturated sodium bicarbonate solution was added to adjust the pH to weak alkalinity, and ethyl acetate was added for extraction (10 mL×3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)-2-azaspiro[3.3]hept-6-yl)phenol 5 (26 mg) with a yield of 12.39%.

[0255] MS m / z(ESI):302.2[M+1]

[0256] 1H NMR (400MHz, DMSO-d6) δ10.25(s,1H),7.28(d,J=8.7Hz,1H),6.83(d,J=8.8Hz,1H),5.18(t,J=4.8Hz,1H),4.21(s,2H),4.09( s,2H),3.97–3.83(m,1H),3.58(q,J=5.0Hz,2H),3.20(t,J=5.0Hz,2H),2.78(dd,J=12.2,8.8Hz,2H),2.62(t,J=10.7Hz,2H).

[0257] According to the synthesis method of Example 1, Examples 6-8, 11-16 were synthesized, and their specific structures and characterizations are shown in the following table:

[0258]

[0259]

[0260] Example 9

[0261] 3,4-dichloro-2-((7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenol

[0262] 3,4-Dichloro-2-((7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenol

[0263] first step

[0264] tert-butyl 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0265] tert-Butyl 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0266] Dissolve 2,3-dichloro-6-methoxybenzaldehyde 9a (800 mg, 3.90 mmol, prepared according to the patent publication "WO2007052123") and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 9b (1.32 g, 5.85 mmol, commercially available) in dichloromethane (35 mL), add anhydrous magnesium sulfate at room temperature, and stir to react for 4 hours. Cool the system to 0°C, add sodium triacetoxyborohydride (2.48 g, 11.71 mmol), slowly raise to room temperature and react for 12 hours. After the reaction is complete, filter, and wash the filter cake with dichloromethane / methanol (1:1) (3×5 mL). The filtrate was collected and concentrated. The residue was purified by preparative liquid separation (separation column: Waters 3767 Column: Sunfire C18, 19*250 mm, 10 μm, 40 mL / min; mobile phase A: 0.05% trifluoroacetic acid + water, mobile phase B: acetonitrile) to obtain tert-butyl 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 9c (820 mg) with a yield of 50.6%.

[0267] MS m / z(ESI):415.1[M+1]

[0268] Step 2

[0269] 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane

[0270] 2-(2,3-Dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane

[0271] 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 9c (410 mg, 987.11 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.69 g, 14.81 mmol, 1.13 mL) was added dropwise at 0°C, and the mixture was stirred and reacted for 4 hours after warming to room temperature. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and dichloromethane was added to dilute the mixture, and the mixture was washed with saturated sodium bicarbonate aqueous solution until the pH was ≥ 7. Dichloromethane was extracted (3×50 mL), and the combined organic phase was washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, 2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane 9d (420 mg) was obtained with a yield of 99.12%.

[0272] MS m / z(ESI):315.0[M+1].

[0273] Step 3

[0274] 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]n

[0275] onane

[0276] 7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane

[0277] 2-(2,3-Dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane 9d (420 mg, 978.43 μmol) and tert-butyldimethylsilyl acetaldehyde 3c (136.44 mg, 782.74 μmol) were dissolved in dichloromethane (10 mL), anhydrous magnesium sulfate (294.43 mg, 2.45 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The system was cooled to 0 °C, sodium triacetoxyborohydride (622.10 mg, 2.94 mmol) was added, and the temperature was slowly raised to room temperature for 4 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with dichloromethane / methanol (1:1, V / V) (3×10 mL). The filtrate was collected, concentrated, and the residue was purified by preparative liquid separation (Separation column: Waters 3767 Column: Sunfire C 18,19*250mm,10μm,40mL / min;mobile phase A:0.05% trifluoroacetic acid+water,mobile phase B:acetonitrile) to obtain 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane 9e (89 mg) with a yield of 19.21%.

[0278] MS m / z(ESI):473.1[M+1]

[0279] Step 4

[0280] 3,4-dichloro-2-((7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenol

[0281] 3,4-Dichloro-2-((7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenol

[0282] 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,3-dichloro-6-methoxybenzyl)-2,7-diazaspiro[3.5]nonane 9e (89 mg, 187.94 μmol) was dissolved in dichloromethane (1 mL), cooled to -78 °C, added with boron tribromide (1 M, 4.22 mL), and slowly warmed to room temperature for 2 hours. Methanol (2 mL) was added to the reaction solution to quench, and the reaction solution was concentrated. The residue was separated by preparative liquid phase separation (Separation column: Waters 3767 Column: Sunfire C 18 ,19*250mm,10μm,20mL / min;mobile phase A:0.1% formic acid+water,mobile phase B:acetonitrile) to obtain 3,4-dichloro-2-((7-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenol 9 (10 mg) with a yield of 19.20%.

[0283] MS m / z(ESI):345.0[M+1].

[0284] Example 10

[0285] 3,4-dichloro-2-(6-(2-hydroxyethyl)-6-azaspiro[2.5]octan-1-yl)phenol

[0286] 3,4-Dichloro-2-(6-(2-hydroxyethyl)-6-azaspiro[2.5]octan-1-yl)phenol

[0287]

[0288]

[0289] first step

[0290] (E)-N'-(2,3-dichloro-6-methoxybenzylidene)-4-methylbenzenesulfonohydrazide

[0291] (E)-N'-(2,3-Dichloro-6-methoxybenzylidene)-4-methylbenzenesulfonylhydrazide

[0292] 2,3-Dichloro-6-methoxybenzaldehyde 9a (100 mg, 487.71 μmol) and p-toluenesulfonyl hydrazide (90.83 mg, 487.71 μmol) were dissolved in methanol (0.5 mL) and stirred at room temperature for 4 hours. After the reaction was complete, the filter cake was collected and dried to obtain (E)-N'-(2,3-dichloro-6-methoxybenzylidene)-4-methylbenzenesulfonyl hydrazide 10a (180 mg) with a yield of 98.88%.

[0293] MS m / z(ESI):372.9[M+1].

[0294] Step 2

[0295] tert-butyl 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane-6-carboxylate

[0296] tert-Butyl 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane-6-carboxylate

[0297] (E)-N'-(2,3-dichloro-6-methoxybenzylidene)-4-methylbenzenesulfonylhydrazine 10a (1 g, 2.68 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (174.21 mg, 6.70 mmol) was added at 0°C, and the mixture was stirred for 1 hour. Then tert-butyl 4-methylenepiperidine-1-carboxylate 10b (634.23 mg, 3.21 mmol, 634.23 μL, commercially available) was slowly added to the above system and stirred for 30 minutes. After adding silver trifluoromethanesulfonate (275.35 mg, 1.07 mmol), the nitrogen was replaced, and the temperature was raised to 40°C and stirred for 18 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (3×50 mL), and the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane-6-carboxylate 10c (500 mg) in a yield of 48.31%.

[0298] MS m / z(ESI):330.0[M-55].

[0299] Step 3

[0300] 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane

[0301] 1-(2,3-Dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane

[0302] 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester 10c (500 mg, 1.29 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (442.73 mg, 3.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain 1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane 10d (300 mg) with a yield of 80.99%.

[0303] MS m / z(ESI):285.9[M+1].

[0304] Step 4

[0305] 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane

[0306] 6-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane

[0307] 1-(2,3-Dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane 10d (300 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (2.5 mL), potassium tert-butoxide (588.11 mg, 5.24 mmol) was added and stirred for half an hour, and then (2-bromoethoxy)(tert-butyl)dimethylsilane 1g (376.14 mg, 1.57 mmol) was added and stirred for reaction at room temperature. After the reaction was completed, the mixture was diluted with water (30 mL), extracted with ethyl acetate (3×50 mL), and the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane 10e (100 mg) with a yield of 21.46%.

[0308] MS m / z(ESI):444.0[M+1].

[0309] Step 5

[0310] 3,4-dichloro-2-(6-(2-hydroxyethyl)-6-azaspiro[2.5]octan-1-yl)phenol

[0311] 3,4-Dichloro-2-(6-(2-hydroxyethyl)-6-azaspiro[2.5]octan-1-yl)phenol

[0312] 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,3-dichloro-6-methoxyphenyl)-6-azaspiro[2.5]octane 10e (50 mg, 112.48 μmol) was dissolved in dichloromethane (0.2 mL), and boron tribromide (56.24 mg, 224.97 μmol) was added dropwise under ice bath, and the temperature was slowly raised to room temperature and stirred for 3 hours. Methanol was added to quench the reaction. After concentration, the residue was separated by preparative liquid phase separation (separation column: Waters 3767 Column: Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.1% formic acid + water, mobile phase B: acetonitrile) to obtain 3,4-dichloro-2-(6-(2-hydroxyethyl)-6-azaspiro[2.5]octan-1-yl)phenol 10 (12 mg) with a yield of 24.40%.

[0313] MS m / z(ESI):316.1[M+1].

[0314] Biological evaluation

[0315] Test Example 1: Manual patch clamp method to detect the effect of the compound of the present invention on hKv1.3 potassium ion channel

[0316] 1.1 Cells

[0317] The HEK293 cell line stably expressing hKv1.3 ion channel used in this experiment was constructed by Kanglong Chemical. The cell line was cultured in a medium containing 90% DMEM (source: Thermo Fisher Scientific), 10% fetal bovine serum, 100U / mL penicillin-streptomycin solution (source: Thermo Fisher Scientific) and 6μg / mL puromycin (source: Sigma). Before the experiment, the cells were digested and the cells were cultured at 5×10 5 The cells were seeded at a density of 1.50 μg / cm2 in a 3.5 cm culture dish containing a coverslip for subsequent manual patch clamp experiments.

[0318] 1.2 Experimental solution

[0319] 1) Extracellular solution: 132 mM sodium chloride, 4 mM potassium chloride, 3 mM calcium chloride, 0.5 mM magnesium chloride, 11.1 mM glucose and 10 mM HEPES (pH adjusted to 7.35 with sodium hydroxide).

[0320] 2) Intracellular solution: 10 mM EGTA, 10 mM HEPES, 10 mM potassium chloride, 10 mM sodium chloride, 110 mM potassium fluoride (pH adjusted to 7.2 with potassium hydroxide).

[0321] Note: The osmotic pressure of the solution is controlled between 280 and 300 mOsmol / kg. The solution needs to be filtered and stored at 4°C before use.

[0322] 1.3 Test compound solution

[0323] The compound to be tested was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM. The stock solution was then diluted in a gradient manner and further diluted into the extracellular fluid to obtain a total of five test solutions with the required final concentrations (μM): 30, 10, 3.33, 1.11 and 0.37. The content of DMSO in the test solution was 0.1-0.3% (volume ratio).

[0324] 1.4 Experimental procedures

[0325] 1) The hKv1.3 current test method is as follows: Apply a 2-second depolarization command voltage to depolarize the membrane potential from -80 mV to +50 mV, so that the hKv1.3 current can be observed. The peak value of the current is the magnitude of the hKv1.3 current.

[0326] 2) The hKv1.3 current used to detect the test compound was recorded for 120 seconds before administration to evaluate the stability of the hKv1.3 current generated by the test cells. Only stable cells within the acceptable range of the evaluation criteria can enter the subsequent compound testing.

[0327] 3) Test of the inhibitory effect of the test compound on hKv1.3 current: First, the hKv1.3 current measured in the extracellular fluid containing 0.1% DMSO is used as the detection baseline. After the hKv1.3 current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells from low concentration to high concentration. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cells and record the hKv1.3 current synchronously. After the recorded current becomes stable, record the last 5 hKv1.3 current values, and take the average value as the final current value at a specific concentration. After testing the compound, add 100 μM carvedilol to the same cell to completely inhibit its current as a positive control for the cell.

[0328] 1.5 Data Analysis

[0329] Note: Data is output by PatchMaster software.

[0330] 1) After perfusing the blank solvent or compound gradient solution, the average of the five consecutive current values ​​obtained was calculated and used as the "current magnitude" 空白 ” and “current magnitude 化合物 ”.

[0331] The current suppression percentage is calculated by the following formula.

[0332]

[0333] 2) The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.

[0334] 3) The standard deviation of the three sets of data is less than 15 (SD<15)

[0335] 1.6 Experimental Results

[0336] This experiment used manual patch clamp technique to evaluate whether the test compound has a potential inhibitory effect on the voltage-gated potassium channel hKv1.3. The results are shown in Table 1.

[0337] Table 1 IC inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel 50

[0338] Example No. <![CDATA[IC 50 (μM)]]> 2 0.96 4 0.79 5 0.10

[0339] The inhibitory activity of the compounds of the present invention on hKv1.3 potassium ion channel IC 50 <1μM, with good inhibitory effect.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: Ring A is selected from 6- to 14-membered spiro heterocyclic groups; R 1 is selected from a hydrogen atom or an alkyl group; R 4 is selected from a hydrogen atom, an alkyl group or a halogen; X1, X2, X3 are each independently selected from hydrogen atom, halogen, cyano, alkyl, cycloalkyl, halocycloalkyl or haloalkyl; Alternatively, X1 and X2, X2 and X3 independently form together with the carbon atoms to which they are attached a 5-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl or 4-10 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R A replaced by; R A are the same or different and are each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; R 3 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; Or, two R 3 Together with the same carbon atom to which it is attached, it forms a -C(=O)-; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; R 6 and R 7 Each is independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group contains one or more N, O or S(O)r, and the 3-12 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; n is 0, 1, 2, 3 or 4; and r is each independently 0, 1 or 2; Provided that: when ring A is selected from When two R 3 It does not form -C(=O)- with the same carbon atom to which it is attached.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 A hydrogen atom.

3. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom.

4. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X1, X2, and X3 are each independently selected from a hydrogen atom or a halogen.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to general formula (II): in: Ring A, R 2 , R 3 and n are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3-membered / 6-membered monospiro heterocyclyl, 4-membered / 4-membered monospiro heterocyclyl, 4-membered / 5-membered monospiro heterocyclyl, 4-membered / 6-membered monospiro heterocyclyl, 5-membered / 5-membered monospiro heterocyclyl, 5-membered / 6-membered monospiro heterocyclyl, and 6-membered / 6-membered monospiro heterocyclyl.

7. The compound according to claim 6, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: in "---" indicates the connection site between ring A and the benzene ring in the general formula (I) or (II); "---" indicates the connection site between ring A and R in the general formula (I) or (II) 2 connection site.

8. The compound according to any one of claims 1 to 7, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, hydroxyl groups, C 1-6 alkyl, 3-6 membered heterocyclic group or 3-6 membered cycloalkyl group, wherein the C 1-6 The alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group may be further substituted with one or more R A replaced by; R A are the same or different and are independently selected from hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 The alkoxy, 3-6 membered heterocyclic or 3-6 membered cycloalkyl groups are optionally further substituted with one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted with an alkoxy substituent.

9. The compound according to claim 8, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 Selected from the following groups: hydrogen atom, hydroxyl 10. The compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom; or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

11. The compound according to any one of claims 1 to 10, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

12. A compound represented by the following structure or its stereoisomer, tautomer or pharmaceutically acceptable salt:

13. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

14. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the preparation of a Kv1.3 potassium channel inhibitor.

15. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease mediated by Kv1.3 potassium channel; preferably, the disease mediated by Kv1.3 potassium channel is an autoimmune disease.

16. The use according to claim 15, wherein the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

17. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating an autoimmune disease.

18. The use according to claim 17, wherein the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

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